Renal Diseases

Renal Diseases

Karo Parsegian, DMD, MDSc, PhD

Ruchir Trivedi, MD, MSc, MRCP (UK)

Effie Ioannidou, DDS, MDSc

Kidneys play a vital role in maintaining internal balance (homeostasis) and a pivotal role in a number of basic physiologic functions, including filtration and excretion of metabolic waste products and toxins, blood pressure control, salt and water homeostasis, blood cell production, acid–base balance, and calcium (Ca2+) homeostasis. Therefore, kidney diseases are one of the leading causes of morbidity, mortality, and healthcare expenditure. The traditional view of kidney function is limited and focuses on its regulation of excretory, endocrine, acid–base, and electrolytes domains. The more expanded view encompasses the role of kidneys in determining the composition of blood, contributing to immunologic balance, and engaging in constant cross‐talk with the heart, gut, brain, and other vital organs.

This chapter provides a comprehensive and evidence‐based overview of the renal structure, function, and diagnostic tools for impaired renal function, as well as oral symptoms and signs observed in patients with chronic kidney disease prior to and during in‐center hemodialysis, patients undergoing peritoneal dialysis, and those received a kidney transplant. Finally, we describe the most current understanding of these diseases’ etiology and pathogenesis, provide evidence‐based dental therapy approaches, and highlight the importance of the interprofessional interaction between dental practitioners and the nephrology team.


The human kidneys are bean‐shaped organs located in the retroperitoneum at the level of the waist. Each adult kidney weighs approximately 160 g and measures 10–15 cm in length. Coronal sectioning of the kidney reveals two distinct regions: an outer region called the cortex and an inner region known as the medulla (Figure 16‐1). Structures that are located at the corticomedullary junction extend into the kidney hilum and are called papillae. Each papilla is enclosed by a minor calyx, which collectively communicates with the major calyces to form the renal pelvis. The renal pelvis collects urine flowing from the papillae and passes it to the bladder via the ureters. Vascular flow to the kidneys is provided by the renal artery, which branches directly from the aorta. This artery subdivides into segmental branches to perfuse the upper, middle, and lower regions of the kidney. Further subdivisions account for the arteriole–capillary–venous network or vas recta. The venous drainage of the kidney is provided by a series of veins leading to the renal vein and ultimately to the inferior vena cava.

Schematic illustration of coronal sectioning of the kidney reveals two distinct regions: an outer region called the cortex and an inner region known as the medulla.

Figure 16‐1 Coronal sectioning of the kidney reveals two distinct regions: an outer region called the cortex and an inner region known as the medulla. Licensed under the Creative Commons Attribution 3.0 Unported license.

The kidney’s functional unit is the nephron (Figure 16‐2) and each kidney is made up of approximately 800,000–1,600,000 nephrons. For a given individual, nephron endowment depends on maternal health, mainly intrauterine environment; micronutrients and protein deficiencies; exposure to tobacco, alcohol, and certain nephrotoxic medications; genetics; and other environmental factors. Each nephron consists of Bowman’s capsule (surrounds the glomerular capillary bed), the proximal convoluted tubule, the loop of Henle, and the distal convoluted tubule (which empties into the collecting ducts). The glomerulus is a unique network of capillaries that is suspended between afferent and efferent arterioles enclosed within Bowman’s capsule and that serves as a filtering funnel for waste. The filtrate drains from the glomerulus into the tubule, which alters the concentration along its length by various processes to form urine. The glomerulus funnels ultra‐filtrate to the remaining portion of the nephron or renal tubule. Following filtration, the second step of urine formation is the selective reabsorption and secretion of filtered substances, which occur along the length of the tubule via active and passive transport processes.

Schematic illustration of the kidney’s functional unit is the nephron.

Figure 16‐2 The kidney’s functional unit is the nephron. Licensed under the Creative Commons Attribution 3.0 Unported license.

Each day, the kidneys excrete approximately 1.5–2.5 L of urine; although the removal of toxic and waste products from the blood remains their major role, the kidneys are also essential for the production of hormones (such as vitamin D and erythropoietin) and the modulation of salt and water excretion (Table 16‐1). Once destroyed, nephrons do not regenerate. However, the kidney compensates for the loss of nephrons by hypertrophy of the remaining functioning units. Low nephron endowment and/or destruction from diseases reduce the number of nephrons significantly enough to cause hypertrophy (nephromegaly) and hyperfiltration of remaining nephrons. Most kidney donors maintain near normal kidney function after kidney donation that results in 50% reduction in nephron mass, with excellent long‐term outcome and a very small risk of development of hypertension and albuminuria explaining a successful and orderly pattern of functional adaptation with nephron loss.1 Structural and functional adaptations of kidneys compel us to rethink our view that progressive kidney diseases are due to the disorderly and inefficient function of nephrons. In reality, progressive kidney diseases such as hypertensive and diabetic nephropathies likely represent an extremely efficient function of too few nephrons unable to carry out their required tasks in spite of maximum functional adaptation in the face of ongoing destructive disease processes. Unfortunately, in the United States, progressive kidney diseases disproportionately affect minorities such as patients of African American and Hispanic origins, hence a preventive focus and treatment of hypertension (HTN) and diabetes mellitus (DM) play a pivotal role in order to decrease their incidence and prevalence.

Table 16‐1 Major functions of the kidneys.

Nonexcretory functions
Degradation of polypeptide hormones
Growth hormone
Antidiuretic hormone
Vasoactive intestinal polypeptide
Synthesis and activation of hormones
Erythropoietin (stimulates erythrocyte production by bone marrow)
Prostaglandins (vasodilators that act locally to prevent renal ischemia)
Renin (important in regulation of blood pressure)
1,25‐Dihydroxyvitamin D3 (final hydroxylation of vitamin D to its most potent form)
Excretory functions
Excretion of nitrogenous end products of protein metabolism (e.g., creatinine, uric acid, urea)
Maintenance of ECF volume and blood pressure by altering Na+ excretion
Maintenance of plasma electrolyte concentration within normal range
Maintenance of plasma osmolality by altering water excretion
Maintenance of plasma pH by eliminating excess H+ and regenerating HCO3
Provision of route of excretion for most drugs

ECF, extracellular fluid; H+, hydrogen; HCO3, bicarbonate; Na+, sodium; pH, hydrogen ion concentration.


With advancing nephron destruction, water and electrolyte regulation becomes increasingly more difficult. Adaptations to sudden shifts in intake occur slowly, resulting in wide swings in water and solute concentrations. The first clinical sign of diminished renal function is a decreased ability to concentrate the urine (isosthenuria). As a result of this inability to conserve water, dehydration ensues. With early renal insufficiency, sodium is also lost in the urine. This loss is often independent of the amount of water lost. As the renal disease progresses, salt and water handling becomes progressively less efficient, resulting in volume overload and leading to hypertension and congestive heart failure. When glomerular filtration becomes markedly diminished, the distal tubule can no longer secrete sufficient potassium, leading to hyperkalemia.

In a healthy body, the acid–base balance is maintained via buffers, respiration, and the amounts of acid or alkaline wastes in the urine; this is because the daily load of endogenous acid is excreted into the urine with buffering compounds such as phosphates. As the glomerular filtration rate (GFR) progressively decreases, the tubular excretory capacity for positive hydrogen (H+) ions is overwhelmed because renal ammonia production becomes inadequate. In its early phases, the resultant acidosis usually has a normal anion gap. As the kidney deteriorates, metabolically derived acids accumulate, leading to an increase in the anion gap. Clinically, this metabolic acidosis is manifested as anorexia, nausea, fatigue, weakness, and Kussmaul’s respiration (a deep gasping respiration similar to that observed in patients with diabetic ketoacidosis).


Biochemical Profile

In the presence of kidney dysfunction, changes in homeostasis are reflected in serum chemistry. Sodium, chloride, blood urea nitrogen (BUN), glucose, creatinine, carbon dioxide, potassium, phosphate, and Ca2+ levels provide useful tools to evaluate the degree of renal impairment and disease progression. Serum creatinine and BUN are often important markers to the GFR. Both of these products are nitrogenous waste products of protein metabolism that are normally excreted in the urine, but they may increase to toxic levels in the presence of renal dysfunction. A characteristic profile of changes occurs with advancing renal dysfunction, including elevations in serum creatinine, BUN, and phosphate, compared with low levels of serum Ca2+. Laboratory findings commonly seen in renal disease are summarized in Table 16‐2.

Table 16‐2 Laboratory changes in progressive renal disease.

Laboratory Test Normal Range Level in Symptomatic Renal Failure
Glomerular filtration rate 90–120 mL/min/1.73 m2 < 15 mL/min
Creatinine clearance 85–125 mL/min (female) 10–60 mL/min (moderate failure)
97–140 mL/min (male) < 15 mL/min (severe failure)
Serum creatinine 0.6–1.20 mg/dL > 5 mg/dL
Blood urea nitrogen 8–18 mg/dL > 50 mg/dL
Serum calcium 8.5–10.5 mg/dL Depressed
Serum phosphate 2.5–4.5 mg/dL Elevated
Serum potassium 3.8–5.0 mEq/L Elevated

Creatinine originates from the nonenzymatic hydrolysis of creatine and phosphocreatine found almost exclusively in muscles. This hydrolysis occurs at a constant rate. Serum creatinine concentration not only depends on muscle mass but also on tubular secretions, dietary protein intake, hepatic synthesis (low in liver diseases), and intestinal exchange. BUN and cystatin C also share properties of acceptable markers for renal clearance (Table 16‐2). Combined GFR estimates based on creatinine and cystatin C have been presented, and their use will likely increase in future.2


The most important aspects of urine examination in patients with renal disease include the detection of protein or blood in the urine, determination of the specific gravity or osmolality, and microscopic examination. The hallmarks of renal dysfunction detected by urinalysis are hematuria (the presence of blood in the urine) and proteinuria (the presence of protein/albumin in the urine). Hematuria can result from bleeding anywhere in the urinary tract. Rarely, hematuria is a sign of clinically significant renal disease. Microscopic hematuria in patients younger than 40 years is almost always benign, and further workup is rarely indicated. Occasionally, significant underlying disease, such as a neoplasm or proliferative glomerulonephritis, can cause hematuria. However, the accompanying active sediment of proteins and red blood cell casts makes the diagnosis relatively straightforward. In older people, hematuria warrants further evaluation, including urologic studies to rule out prostatic hypertrophy and neoplasia, urine cultures to rule out infection, urine cytology, and advanced renal studies (such as renal ultrasound or noncontrast computed tomography [CT] scan of the abdomen and pelvis) to rule out intrinsic abnormalities.

Proteinuria (a urine dipstick will only detect albumin) is probably the most sensitive sign of renal dysfunction. The upper limit of normal urinary protein is 150 mg per day; anything greater should be considered pathologic and warrant further investigation. Patients who excrete >3 g of protein per day have, by definition, a glomerular pathology and carry a diagnosis of nephrotic syndrome (discussed below). However, many benign conditions (including exercise, stress, and fever) can produce transient elevated protein in the urine. Daily proteinuria estimation can be ascertained by measuring the total protein‐to‐creatinine ratio (expressed in grams of protein/grams of creatinine), which can be extrapolated to grams of proteinuria per day. Should any doubt still exist, or precise quantification is necessary, 24‐hour urine collection can be performed. This procedure has fallen out of favor, as it is cumbersome and somewhat difficult for the patient to complete accurately. The 24‐hour urine test remains a useful tool for determining daily salt intake, calculating creatinine and urea clearance, and while analyzing the urinary metabolic profile in recurrent nephrolithiasis. Urine specific gravity is measured to determine the concentration of urine. In chronic kidney disease (CKD), the kidney initially loses its ability to concentrate the urine and then loses its ability to dilute the urine, resulting in a relatively fixed osmolality near the specific gravity of plasma. This occurs when approximately 80% of the nephron mass has been destroyed.

Creatinine Clearance Test

The GFR assesses the amount of functioning renal tissue and can be calculated indirectly by the endogenous creatinine clearance test. Creatinine is a breakdown product of muscle, liberated from muscle tissue, and excreted from the urine at a constant rate. This results in a steady plasma concentration of 0.7–1.5 mg/dL (often slightly higher in men because of increased muscle mass). Creatinine is 100% filtered by the glomerulus and is not reabsorbed by the tubule. Although a very small portion is secreted by the tubule, this test is an effective way to estimate the GFR. GFR is estimated by incorporating the serum creatinine into a formula, along with the patient’s age, weight, and race, and is expressed in milliliters per minute (min) of clearance (mL/min/1.73 m2). The two most common equations used are the Cockcroft–Gault formula and the modified diet in renal disease formula (Figure 16‐3).

Schematic illustration of  Cockcroft–Gault equation and MDRD formula.

Figure 16‐3 Cockcroft–Gault equation and MDRD formula.

Source: Adapted from Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41; and Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–470.

In some instances, it is necessary to measure absolute GFR. To accomplish this, a 24‐hour urine specimen and a blood sample in the same 24‐hour period are required. This has fallen out of favor, however, as the test is cumbersome and inconvenient for the patient.

Renal Ultrasonography

Grayscale ultrasonography and Doppler ultrasonography are the most commonly used and relied‐upon techniques for radiologic examination of the kidneys. These diagnostic procedures use high‐frequency sound waves (ultrasound) directed at the kidneys to produce reflected waves or echoes from tissues of varying densities, thereby forming images (sonograms). Ultrasound is a noninvasive method to determine kidney size, presence of retained urine within the renal pelvis or calices (hydronephrosis), identification and limited evaluation of vascular structures, and presence of fluid‐filled cysts within the kidney parenchyma.14 Renal ultrasonography is also utilized to localize the kidney during a percutaneous biopsy. Because it is noninvasive, readily available in most imaging centers, does not use radiation or intravenous (IV) contrast, and is quick, renal ultrasonography is the imaging modality of choice for initial evaluation of the kidneys. It is also the modality of choice for pregnant patients because it does not use radiation to obtain clinical images. Doppler ultrasound is used to assess vascular function and flow. Grayscale ultrasound also helps identify kidney stones, cysts, and parenchymal disease processes, and in assessment of bladder function in more complex kidney diseases.

Computed Tomography

CT imaging is utilized when the entire genitourinary (GU) tract or retroperitoneum needs evaluation. It provides more information about the structures of the GU tract (ureters, bladder, urethra, and prostate) and retroperitoneum, as well as surrounding structures that could contribute to renal pathology (tumors, lymphadenopathy, masses). Furthermore, because of technologic advances over the years, CT scanners are far more cost‐effective, quicker, and more readily available in hospitals or imaging centers. Like other CT scans, the procedure can be performed with or without IV contrast for vascular enhancement; with CKD, caution must be used with IV contrast media, as this can incur further renal decline (see the Acute Kidney Injury section). Contrast‐induced nephropathy is likely secondary to a vasoconstrictive effect of contrast media in addition to oxidative kidney injury. A noncontrast CT scan of the abdomen and pelvis is the imaging modality of choice when investigating the presence of kidney stones. A newer modality of CT scan, dubbed CT‐urography, can be used for a detailed, three‐dimensional evaluation of the GU tract.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is not commonly utilized as the first imaging modality for the diagnosis of kidney disorders. This modality can give much of the same information as a CT scan, with far more detail and information about specific tissues and structures. The cost, time investment, and, to a lesser extent, patient comfort prohibit this modality from becoming mainstream in kidney disease evaluation. Furthermore, the contrast medium used for magnetic resonance angiography (MRA) is gadolinium based. Gadolinium has been linked as a cause of a progressive skin fibrosis called nephrogenic systemic fibrosis (NSF), which is seen exclusively in patients with advanced kidney disease (GFR <30 mL/min/1.73 m2) or who are on dialysis. This condition carries a high morbidity and mortality burden; therefore, the gadolinium‐based contrast medium is generally not administered when the patient’s GFR is <30 mL/min/1.73 m2. Recent data indicate that NSF is exceedingly uncommon when macrocyclic or newer linear gadolinium compounds are used in patients with GFR <30 mL/min/1.73 m2. This knowledge will improve access to gadolinium‐based enhanced MRI when medical benefits clearly outweigh a very small risk.

The primary kidney‐related indications for utilizing MRI/MRA is either the evaluation of the renal vasculature if significant renal artery stenosis is suspected, or evaluation of a mass, solid or cystic, when radiocontrast cannot be used with a CT scan.

Intravenous Pyelography

Prior to ultrasonography and CT, IV pyelography was the most commonly used and relied upon radiologic examination of the kidneys. Following the IV injection of a contrast medium, a plain‐film abdominal radiograph is taken. Further films are exposed every minute for the first 5 minutes, followed by a film exposed at 15 minutes and a final film exposed at 45 minutes. Since various diseases of the kidney alter its ability to concentrate and excrete the dye, the extent of renal damage can be assessed. The location and distribution of the dye itself give information regarding the position, size, and shape of the kidneys. This examination has limited application, particularly in patients with severe azotemia (the building up of nitrogenous waste products in the blood)—that is, those whose BUN >70 mg/dL); for them this test is deferred because there is sufficiently low glomerular filtration to prevent the excretion of the dye, rendering information about the kidney nondiagnostic.

Nuclear Medicine (Radionuclide Scintigraphy)

While the aforementioned imaging modalities can provide structural information, radionuclide scintigraphy can provide qualitative and quantitative functional information about the kidneys. Using radiolabeled tracers, information can be garnered about renal blood flow, glomerular filtration, or urinary excretion. Several compounds are available that incorporate technetium‐99 as the radioactive isotope; these include diethylenetriamine pentaacetic acid, mercaptoacetyl triglycine, and 131I‐o‐iodohippurate (131I‐OIH). Measurement of these radiolabeled substances can be used to calculate true GFR or the presence/absence of renal blood flow. They can also be combined with captopril to investigate possible renal artery stenosis or furosemide to uncover unilateral urinary obstruction. Radionuclide scintigraphy is the modality of choice to accurately measure GFR in patients who have undergone a spinal injury, as serum creatinine is linked to muscle mass, which may be disproportionately lower in this patient population. This modality is frequently used in kidney transplant (KT) evaluation, as IV radiocontrast may be contraindicated and renal ultrasound may be equivocal.

Kidney Biopsy

The development and growing use of renal biopsy have considerably advanced the knowledge of the natural history of kidney diseases. Percutaneous needle biopsy guided by ultrasonography or CT can usually be performed by nephrologists, with the patient lying in a prone position with one to two firm pillows. Approximately 25% of cardiac output flows to the kidney; hence, intrarenal and perirenal bleeding may be common sequelae, with serious postprocedural bleeding and hematuria occurring in 5% of cases. The incidence of postprocedural bleeding also depends on needle size. When a 16G or 18G needle is used, 0.5% of patients require blood transfusion, as opposed to 2% with the use of a 14G needle. Careful assessment of the risk–benefit ratio is required before performing a kidney biopsy. Patients are placed on bed rest for at least 6 hours following the procedure while vital signs and abdominal changes are monitored. Safe conditions for performing kidney biopsy include hemoglobin >9 g/dL, platelets >100,000 × 109/L, normal coagulation profile (prothrombin time or PT/partial thromboplastin time or PTT), blood pressure preferably <160/90 mm Hg, and no active urine infection. Single kidney, atrophic kidneys with thin cortex, difficult anatomy with multiple kidney cysts, uncontrolled hypertension, and active pyelonephritis (infection) are relative contraindications of kidney biopsy.


Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine, a decrease in urine output, or both. AKI occurs in approximately 10%–15% of patients admitted to hospital, while its incidence in intensive care has been reported in more than 50% of patients. Complete recovery following AKI may not occur predisposing patients with residual kidney damage resulting in CKD. AKI is not a single disease, but rather a loose collection of diverse syndromes such as sepsis, cardiorenal syndrome, and urinary tract obstruction. Serum creatinine and urine output can be used to stage AKI based on AKI Network (AKIN) criteria (Table 16‐3).

Sepsis, shock, medications, surgery, pregnancy‐related complications, and trauma are the most common causes of AKI (Table 16‐4). Unlike patients who develop CKD, patients with AKI usually have normal baseline renal function, yet mortality from AKI even with medical intervention, including dialysis, remains high. The causes of AKI are often divided into three diagnostic categories: prerenal failure, postrenal failure, and acute intrinsic renal failure. Such denominations are increasingly becoming arbitrary, as significant overlap exists between prerenal AKI and acute intrinsic AKI (acute tubular necrosis, or ATN).

Table 16‐3 Staging Acute Kidney Injury (AKI) based on AKI Network criteria.

Source: Modified from Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380(9843):756–766.

Stage Serum Creatinine Urine Output
1 1.5–1.9 times baseline
≥0.3 mg/dL (≥26.5 μM/L) increase
<0.5 mL/kg/hr for 6–12 hrs
2 2.0–2.9 times baseline <0.5 mL/kg/h for 12 hrs
3 3.0 times baseline
Increase in serum creatinine to ≥4.0 mg/dL (≥353.6 μM/L)
Initiation of renal replacement therapy
In patients <18 years, decrease in eGFR to <35 mL/min/1.73m2
<0.3 mL/kg/h for ≥24 hrs
Anuria for ≥12 hrs

eGRF, estimated glomerular filtration rate.

Prerenal Acute Kidney Injury or Prerenal Azotemia

Prerenal AKI is by definition caused by inadequate blood flow to the kidneys without significant structural damage, and therefore is rapidly reversible following volume expansion (volume‐responsive prerenal AKI) and treatment of the underlying cause that results in volume depletion. Septic shock due to decreased effective circulating volume from endotoxin‐mediated vasodilation and loss of extracellular volume from diarrhea, vomiting, blood loss from trauma, and so on are frequent causes of prerenal AKI. Prerenal AKI represents hypoperfusion of kidneys from events occurring “outside” the kidneys. Decreased effective circulating volume is sensed by protective mechanisms such as activation of the sympathetic nervous system (SNS) and renin‐angiotensin‐aldosterone system (RAAS), resulting in increased sodium reabsorption in the kidneys (Table 16‐4).

Prerenal AKI can be diagnosed with urine indices such as low fractional excretion of sodium (FeNa) or low fractional excretion of urea (FeUrea) in the presence of low urine output (oliguria; urine output <400 mL/24 hrs). Etiologies such as heart failure, cirrhosis of liver, radiocontrast exposure, and bilateral renal artery stenosis can result in low FeNa due to perceived decrease in effective circulating volume sensed by the kidneys. In theory, a detailed history, clinical examination of accurate volume status, and, in carefully selected cases, invasive monitoring of volume status may help establish the correct diagnosis. Medications such as diuretics, blockers of the RAAS system, and nonsteroidal anti‐inflammatory drugs (NSAIDs) are frequently implicated in prerenal AKI. Newer urinary biomarkers may help in the diagnosis of AKI before the elevation of serum creatinine.4 When prerenal AKI persists for a long time, continued hypoperfusion of kidneys will lead to ischemia and ATN or intrinsic AKI.

Table 16‐4 Pathophysiology and mechanism of injury in select clinical conditions resulting in acute kidney injury.

Source: Based on Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380(9843):756–766.

Mechanism of Injury Pathophysiology
Renal hypoperfusion
Renal hypoperfusion activates sympathetic nervous system (SNS) and renin‐angiotensin‐aldosterone system (RAAS). Failure of renal autoregulation and resultant renal hypoperfusion lead to ATP depletion that activates epithelial cellular injury and death via necrosis or apoptosis
  • Volume depletion (from diarrhea, vomiting, diuretic use, etc.)
  • Systemic vasodilatation
  • Increased vascular resistance (inotrope use in ICU, RAS, HTN, etc.)

Result: Endothelial injury and intrinsic AKI or ATN

Acute worsening of cardiac function
  • Reduced effective circulation fluid volume or an increase in central venous pressure

Result: Cardiorenal syndrome (kidney dysfunction from acute worsening of cardiac function)

Nephrotoxin exposure
Nephrotoxic drugs (e.g., antibiotics, contrast media, NSAIDs), and endogenous toxins (e.g., myoglobin, uric acid among others)
  • Direct cytotoxic effect on renal tubular epithelial or endothelial cells
  • Impaired intrarenal hemodynamics
  • Precipitation of metabolites or crystals, among others

Result: Acute tubular necrosis

Sepsis and septic shock
Capillary microthrombi generation, decreased tissue perfusion, and imbalance in nitric oxide production
  • Endothelial damage leading to increased vascular permeability
  • Suppression of cardiac function

Result: Increased interstitial edema, redistribution of intrarenal perfusion, inflammation and septic cardiomyopathy leading to ischemic ATN

Major surgery
Blood loss, third spacing of fluids, peripheral vasodilation, myocardial depression
  • Effect of anesthesia and medications
  • Increased level of circulating cytokines and reactive oxygen species
  • Endotoxin load from gut and tissue hypoperfusion

Result: Impaired renal perfusion and ischemia‐reperfusion injury leading to prerenal and intrinsic AKI

Intraabdominal hypertension
Sustained intraabdominal pressure >12 mm Hg
(volume overload, ascites or interstitial edema of bowel loops)
  • Reduced arterial inflow and venous outflow
  • Elevated hydrostatic pressure in Bowman’s space (area of the nephron where filtrate enters after passing through filtration slits, also known as capsular space or urinary space)

Result: Decreased renal hypoperfusion leading to prerenal AKI and if left uncorrected intrinsic ATN

AKI, acute kidney injury; ATN, acute tubular necrosis; HTN, hypertension; ICU, intensive care unit; NSAID, nonsteroidal anti‐inflammatory drug; RAS, renal artery stenosis.

Intrinsic Acute Kidney Injury

Intrinsic AKI or ATN is characterized by the presence of structural damage to the kidneys, which is not rapidly reversible by correcting underlying or causal conditions. The outer medullary parenchymal region of the kidney is metabolically very active with high energy demands, but due to the anatomic arrangement of the renal vasculature, oxygen supply in this area is limited, making it highly susceptible to cellular kidney injury with prolonged ischemia. Firmly establishing cellular damage clinically is difficult. Most clinicians consider prerenal AKI and intrinsic AKI as a continuum, as both often coexist with patchy areas of structural cellular damage (ATN, intrinsic AKI) interspersed with areas of hypoperfusion that may still be structurally intact and upon receiving reperfusion (volume expansion) can rapidly resume normal nephron filtration function (prerenal AKI).

Glomerular disease, vascular disease, and tubulointerstitial disease comprise the three additional causes of acute intrinsic renal failure and describe the sites of pathology. Glomerulonephritis is an uncommon cause of AKI and usually follows a more subacute or chronic course. However, when fulminant enough to cause AKI, it is associated with active urinary sediment (dysmorphic red blood cells [RBCs], acanthocyturia, RBC casts), oliguria, and rapid deterioration of renal function. Prominent clinical and laboratory findings include hypertension, proteinuria, microscopic hematuria, and RBC casts. Postinfectious, membranoproliferative, and rapidly progressive glomerulonephritis, as well as glomerulonephritis associated with endocarditis, are the most common glomerular diseases to cause a sudden renal deterioration. The pathogenesis of glomerulonephritis appears to be related to the immunocomplex and complement‐mediated damage to the kidney.4

Vascular diseases that induce AKI cover the spectrum of vessel size from large (renal artery and vein) to microscopic (afferent and efferent arterioles of the glomerulus). Large vessel occlusive processes such as renal arterial or venous thromboses present as a classic triad of severe and sudden lower back pain, severe oliguria, and macroscopic hematuria. Medium‐ to small‐vasculature AKI is often caused by autoimmune vasculitides, thrombotic microangiopathies, or cholesterol crystal embolization.

By far the most common causes of acute intrinsic failure are tubulointerstitial disorders (>75% of cases), including interstitial nephritis and ATN. Infiltrative diseases (such as lymphoma or sarcoidosis), infections (such as syphilis and toxoplasmosis), and medications are the leading causes of interstitial nephritis. With drug‐induced interstitial nephritis, there are accompanying systemic signs of a hypersensitivity reaction, and the presence of eosinophils is a common finding in the urine. Although renal function usually returns to normal with the discontinuation of the offending drug, recovery may be hastened with corticosteroid therapy. ATN is a renal lesion that forms in response to prolonged ischemia or exposure to nephrotoxin, among other causes. ATN remains more of a clinical diagnosis of exclusion than a pathologic diagnosis. The period of renal failure associated with ATN can range from weeks to months, and the major complications of this transient failure are imbalances in fluid and electrolytes, as well as uremia. Serum levels of BUN and creatinine peak, plateau, and slowly fall, accompanied by a return of renal function over 10–14 days in most cases.4

Sudden renal failure in hospitalized patients is often very apparent from either oliguria or an increase in BUN and creatinine levels. However, renal dysfunction in the outpatient population is frequently more subtle. A patient can present to the dental office with vague complaints of lethargy and fatigue or entirely without symptoms. These patients can go undiagnosed but for abnormal results on routine urinalysis, the most common test for screening for renal disease.

Postrenal Failure

Postrenal causes of failure are less common (<5% of patients) than prerenal causes. Postrenal failure refers to conditions that obstruct the flow of urine from the kidneys at any level of the urinary tract, and that subsequently decrease the GFR. Postrenal failure can cause almost total anuria, with complete obstruction or polyuria. Renal ultrasonography often shows a dilated collecting system (hydronephrosis). Obstructive uropathy is, most commonly, seen in older men as a result of the enlargement of the prostate gland. If present in females, a thorough pelvic examination is warranted to elicit the cause of the obstruction. Although postrenal failure is the least common cause of AKI, it remains the most treatable.4


Epidemiology and Progression

The prevalence of kidney diseases worldwide is estimated to be between 8% and 16%.5 In the United States, over 30 million people or approximately 15% of US adults are estimated to have CKD and are at risk for progression of their renal disease (Figure 16‐4).6 Based on Medicare data assessing patients older than 65 years, the prevalence of recognized CKD in the United States has steadily risen year after year across all stages of CKD. From 2016 to 2017, the proportion of Medicare patients with recognized CKD increased from 13.8% to 14.5%, and these patients used 7.2% of total Medicare expenditure for less than 2% of the eligible Medicare patient population. As a result, CKD remained the ninth leading cause of death in the United States in 2017.

CKD is classified according to the GFR (Table 16‐5).7

Diabetes and hypertension are major disease processes that lead to CKD and ESRD. The burden of CKD may be examined in several ways, including individual or societal costs, attributable or excess mortality, years of life lost (YLL), and disability‐adjusted life years (DALYs). DALYs include YLLs plus years of poor health or disability. Elevated fasting plasma glucose levels, overweight, obesity, diets high in sodium, sugar‐sweetened beverages, and elevated systolic BP account for significant healthcare cost burden in CKD progression.8 Globally, CKD incidence increased by 89% and CKD‐attributable deaths swelled by 98%, according to data from the Global Burden of Disease Study, which incorporated kidney disease data from 1990 to 2016.9 Strong disparities in race, sex, and socioeconomic status continue in the United States and worldwide in the ESRD population. The lifetime risk of ESRD is more than twofold higher among non‐Hispanic black and Hispanic men compared with Caucasian men. In recent years, studies have started to examine the role of recreational drug use in CKD progression.10 Past or present marijuana use is not proven to be associated with an increased risk of kidney disease; however, persistent smoking, heroin, cocaine, or methamphetamine use is associated with increased risk of CKD progression and increased mortality among adults with established CKD. Given the rising incidence of CKD, screening for kidney disease with urinary albumin excretion has been attempted at a population level. Unfortunately, widespread population‐based screening models have not proved to be cost‐effective except in targeted high‐risk individuals with hypertension and DM. Urinary albumin excretion above 300 mg/g of creatinine is associated with a high risk of progression to ESRD and increased cardiovascular mortality.4

Graph depicts prevalence of CKD Stages 1–4 by Year: Data from the National Health and Nutrition Examination Survey.

Figure 16‐4 Prevalence of CKD Stages 1–4 by Year: Data from the National Health and Nutrition Examination Survey.

Source: Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System website. Accessed May 1, 2019.

Table 16‐5 Classification of Chronic Kidney Disease (CKD) based on Glomerular Filtration Rate (GFR).

Source: Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. New England Journal of Medicine. 2014;371(1):58–66. © 2014, Massachusetts Medical Society.

Stage of CKD Definition GFR (mL/min/1.73 m 2 )
Stage 1 Kidney damage with normal GFR ≥90
Stage 2 Kidney damage with mild decrease in GFR 60–89
Stage 3A Mild to moderate decrease in GFR 45–59
Stage 3B Moderate to severe decrease in GFR 30–44
Stage 4 Severe decrease in GFR 15–29
Stage 5 End‐stage renal disease (ESRD) <15
Stage 6 ESRD on dialysis therapy <15 with symptoms requiring dialysis therapy

Some medications such as cimetidine, trimethoprim, corticosteroids, pyrimethamine, salicylates, and active vitamin D metabolites have been reported to increase plasma creatinine without influencing its glomerular filtration via inhibiting the distal secretion of creatinine. Patients may present with worsening serum creatinine but preserved renal function while taking the above‐listed medications. Low thyroid function is associated with decreased GFR by decreasing renal blood flow, but not increased rates of kidney disease progression and ESRD.11

Diet and Chronic Kidney Disease

High sodium intake may exacerbate HTN and CKD progression. Motivated patients frequently ask about advice with regard to their fluid intake and diet. A recent study showed that drinking at least two cups of coffee per day was associated with a significantly lower risk of progression to ESRD.12 The renal benefits of coffee consumption may, in part, be secondary to chlorogenic acids that replenish glutathione and prevent oxidative injury to proximal tubular cells.12 In contrast, in patients with polycystic kidney disease (autosomal dominant kidney diseases with progressive bilateral kidney cysts and progression to ESRD) a reduction in caffeine intake has been recommended, because caffeine induces cyclic adenosine monophosphate, which is involved with cyst growth and disease progression. Diets low in animal protein and red meat may help preserve kidney function, provided nutritional parameters are carefully monitored and malnutrition is avoided. Increasing water intake has not been shown to reduce the risk of kidney function decline.13 Patients with kidney stones are advised to drink a sufficient amount of water to maintain urine output in the vicinity of 2.5–3.0 L, in order to minimize recurrent stone formation. For the general population, benefits of prescribed water intake in slowing the progression of CKD have not been identified. Sugar‐sweetened and artificially sweetened beverage intake is associated with higher risks of non‐dialysis‐dependent CKD, and their intake should be minimized.14 Control of diabetes and HTN will certainly help in slowing the progression of CKD.

Uremic Toxins, the Microbiome, and Chronic Kidney Disease

The term “microbiota” refers to the ensemble of microorganisms (composed of bacteria, bacteriophage, fungi, protozoa, and viruses) that live in or on the human body. The microbiome is the collective genome of the microbes. The interplay between the oral and colonic microbiome and ESRD is an active area of research.

A significant adaptation of gut function can assist in the excretion of solutes and water when kidney function is impaired. The gut assumes a progressively larger role in nitrogen waste excretion and potassium homeostasis that compensates, to a certain extent, for the loss of renal excretory function. Diarrhea was induced to treat uremia when dialysis was unavailable to physicians. Gut dialysis has been successfully used in animal and human renal failure.15 In addition to its role in salt and water absorption, potassium excretion, and feces propulsion, the colon plays a vital role in protein and energy metabolism in close synergy with the resident colonic microbiome. The gut microbiome has been shown to play a pivotal role in the metabolic derangements seen in patients with CKD.16

Chronic Kidney Disease, End‐Stage Renal Disease, and Cardiovascular Mortality

Although it is often perceived that standard dialysis treatment has been mostly unchanged for years, the outcomes in patients with ESRD have steadily improved. Even with this improvement, the five‐year hemodialysis (HD) survival rate across different nations ranges from 39% in the United States to 60% in Japan.17 The percentage of deaths in patients undergoing dialysis that can be attributed to cardiac arrest approaches 40%. The rate of sudden cardiac death is nearly 20‐fold higher in the dialysis population than in the general population. In patients undergoing dialysis, longer interdialytic interval, coexisting electrolyte abnormalities, mainly hyperkalemia, and massive fluctuation of volume status between dialysis days are all associated risk factors, resulting in higher cardiovascular mortality. Atrial fibrillation may act as a precipitator of heart failure and other dysrhythmias.18 Patients with CKD and ESRD have a higher incidence of atrial fibrillation and stroke, requiring treatment with Coumadin or one of the newer direct thrombin inhibitors. These patients, on the other hand, also have higher bleeding risk from anticoagulation, requiring careful evaluation of the risk–benefit ratio.

The natural history, progression, and outcomes of associated complications of chronic kidney disease are outlined in Table 16‐6.

Renal Replacement Therapy in End‐Stage Renal Disease

The human kidney is responsible for the composition of plasma. In addition to its excretory and synthetic functions (production of erythropoietin, activation of vitamin D, and others), the kidney’s role as a regulator of immune function is also being recognized. There are well‐established communication networks between the heart, brain, liver, gut, endocrine system, and kidneys. With the progression of kidney disease, eventually renal replacement therapy (RRT) may be required. RRT does barely replenish 10%–15% of normal renal function. There are no uniform criteria based on the percentage of kidney function loss that absolutely necessitates the onset of dialysis therapy. Need for dialysis is frequently based on advanced uremic symptoms such as nausea, vomiting, metallic taste, loss of appetite or failure to thrive, intractable volume overload or metabolic acidosis, and life‐threatening electrolyte abnormalities such as hyperkalemia.23 Occasionally, anemia that fails to respond to a maximum allowable dose of erythropoietin (EPO) or uremic bleeding diathesis may require initiation of RRT. Uremic encephalopathy, uremic pericarditis, and pericardial effusion are also acceptable indications to start RRT. RRT includes hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT). For eligible patients, KT remains the best and most cost‐effective form of RRT. Unfortunately, over the last few decades the number of patients waiting for KT has steadily increased, but the number of cadaveric and live kidney donations has lagged behind, making transplant waitlist time progressively longer for all waitlisted patients. Human artificial kidney transplantation and xenotransplantation remain exciting future innovations, but are still far from day‐to‐day clinical application. While these advances are very promising, existing patients have to make a choice between various forms of dialysis therapy while waiting on a transplant list, or pursue symptoms‐guided conservative medical therapy. In elderly patients with significant medical comorbidities and frailty, dialysis seldom adds to a meaningful quality of life. Conservative medical therapy and hospice therapy are the most underdiscussed options of RRT. Home‐based dialysis therapy, mainly PD and home HD, remains a very attractive option for working and self‐caring patients. Despite these facts, acceptance of home therapy is lower in the United States compared to other industrialized countries.

Table 16‐6 Natural history, progression, and outcomes of associated complications of chronic kidney disease.

CKD‐ and ESRD‐Related Complications Natural History and Progression Treatments and Outcome
Salt and water retention and HTN
  • Progressively worsens HTN and results in concentric left ventricular hypertrophy
  • Contributes to higher incidences of atrial fibrillation and diastolic heart failure
  • With the progression of CKD, adherence to a low salt diet is pivotal in maintaining acceptable volume status
  • Systolic BP <120 mm Hg can be a target in patients with a high degree of protein loss in urine19
  • Loop diuretics are frequently required to control BP in patients with volume overload and edema; they have no effect on cardiovascular system outcomes
Anemia of CKD and ESRD20
  • EPO deficiency from progressive CKD
  • Iron deficiency frequently coexists and can make EPO response suboptimal
  • Normalization of hemoglobin with supplemental EPO does not improve disease progression and mortality
  • Optimal dose of EPO or IV iron not established
  • Oral iron poorly absorbed in advanced CKD and ESRD
  • Outcome limited to symptom improvement
CKD‐mineral bone disease21
  • Spectrum includes biochemical abnormalities, renal osteodystrophy, and soft tissue calcifications
  • Secondary and tertiary hyperparathyroidism ensues if phosphorous control remains suboptimal
  • High blood phosphate levels, deficiency in vitamin D, and secondary hyperparathyroidism should be monitored and treated with phosphate binders, nutritional vitamin D, and analogs of 1,25‐dihydroxyvitamin D
Metabolic acidosis and electrolyte abnormalities22
  • In the early stages of CKD, there is a positive acid balance without low plasma bicarbonate due to buffering and renal adaptation
  • In later stages of CKD and ESRD, chronic metabolic acidosis contributes to skeletal muscle catabolism, insensitivity to endocrine hormones, and bone disease
  • In advanced stages of CKD and ESRD, hyperkalemia becomes progressively worse
  • Alkali therapy with sodium bicarbonate may be required to correct acidosis
  • Stopping of angiotensin‐converting enzyme inhibitors and gut binding of potassium may be required
  • Intractable metabolic acidosis and hyperkalemia frequently require initiation of dialysis

BP, blood pressure; CKD, chronic kidney disease; EPO, erythropoietin; ESRD, end‐stage renal disease; HTN, hypertension; IV, intravenous.

In‐center HD sessions comprise 3–4‐hour dialysis treatment, three times a week. Almost 80% of all dialysis patients in the United States undergo in‐center hemodialysis as opposed to home‐based therapies like peritoneal dialysis or home hemodialysis. Patients undergoing in‐center HD frequently describe a feeling of being “wiped out,” and almost 40% of patients will take 2–6 hours post dialysis to recover to their usual state of health.24 Many of these patients have never been offered a formal CKD education program that helps them make an informed decision about dialysis modality choice. For‐profit dialysis providers and greater comorbidities of in‐center patients undergoing dialysis result in the lowest KT rate in in‐center HD patients as opposed to other dialysis modalities.25 Compared to in‐center dialysis, frequent home hemodialysis (HHD) therapy results in fewer episodes of low BP, intradialytic hypotension, and better control of salt and water balance, with fewer BP medications. Advances in HHD and the ability to remotely monitor HHD sessions have reassured many patients, and there appears to be a steady and slow uptake of the HHD modality among patients with ESRD. PD is easy to learn and does not involve contact with blood or self‐cannulation of vascular access, and hence remains the most acceptable form of home‐based RRT. In the PD modality, dialysis is performed repeatedly via a PD catheter using the osmotic force of sugar water solution. Here, the peritoneal membrane acts as a filter and performs the removal of uremic toxins. PD can be performed with the help of a cycler at night, giving some patients the ability and freedom to control their time during the day when they do not need to perform PD exchanges. PD patients preserve their residual renal function for a longer period of time compared to HD. Regulatory authorities have identified home‐based therapy as a preferred dialysis therapy and are putting in place financial and educational incentives to promote better uptake of home‐based dialysis therapy.


Patients with CKD, those undergoing in‐center HD and PD, and those receiving KT can be commonly seen and managed by various oral care professionals. These medical conditions are associated with a broad range of clinical manifestations and lesions affecting soft and hard tissues of the oral and maxillofacial area.26 These oral conditions can be directly associated with renal impairment or indirectly associated either with medications used in the treatment of renal conditions or various systemic comorbidities.5 We have categorized all oral clinical conditions into symptoms (subjective abnormalities perceived by a patient) and signs (objective abnormalities observed by a patient and examiner); see Table 16‐7.

Oral Symptoms


Up to 69% of patients with CKD,27,28 68% of patients undergoing in‐center HD,29 and 6% of patients received KT28 displayed oral manifestations, compared to up to 10% in control individuals without renal disease.30 The data on the prevalence of oral manifestations in patients undergoing PD are missing. These results demonstrate that patients with CKD and those undergoing HD have an increased prevalence of oral manifestations, whereas patients who received KT may have reduced or comparable prevalence compared to control individuals without renal disease.

Table 16‐7 Oral symptoms and signs in patients with renal disease.

Oral Symptoms Oral Signs
  • Xerostomia
  • Altered taste perception
  • Halitosis
  • Other oral manifestations
  1. Soft tissue lesions
    • 01 Oral mucosa lesions
      • Uremic stomatitis
      • Purpura
      • Fungal infections
      • Oral mucosal ulcers
      • Oral malignancies
      • Other oral mucosa conditions
    • 02 Tongue conditions
      • Saburral tongue
      • Dialysis‐related amyloidosis
      • Oral hairy leukoplakia
      • Other tongue conditions
    • 03 Periodontal conditions
      • Medication‐induced gingival enlargements
      • Periodontitis
      • Other periodontal conditions
  2. Hard tissue lesions
    • 01 Tooth conditions
      • Dental caries
      • Edentulism
      • Tooth periapical lesions
      • Other tooth conditions
    • 02 Bone conditions
      • Renal osteodystrophy
      • Primary hyperoxaluria
      • Other bone conditions

Xerostomia (ICD‐10‐CM Diagnosis Code K11.7)

This is a sensation of dry mouth with (objective) or without (subjective) a noticeable decrease in saliva production (Figure 16‐5).31

  • Patients with CKD (prior to undergoing in‐center HD). Smaller‐scale studies on patients with CKD prior to undergoing in‐center HD have shown that ~28%–69% of them presented with signs of xerostomia,27,28 which positively correlated with the increased age and stage of CKD.32
  • Patients undergoing in‐center HD. The large‐scale prospective multinational ORAL Diseases in Hemodialysis study has shown that 45% of dentate patients undergoing in‐center HD presented with signs of xerostomia.33 These findings also correlated with those in smaller‐scale studies reporting the prevalence of xerostomia to range from 33% to 56%, compared to 0%–29% in control individuals without renal disease.29,3436 However, compared to predialysis levels, the salivary flow rate (SFR) increased after the initiation of HD37 and PD.30 No studies reporting the prevalence of oral symptoms in patients undergoing PD have been identified.
    Photo depicts xerostomia (ICD-10-CM Diagnosis Code K11.7).

    Figure 16‐5 Xerostomia (ICD‐10‐CM Diagnosis Code K11.7).

  • Patients receiving KT. In these patients, the SFR improved compared to patients with CKD and those undergoing in‐center HD, but was still significantly lower compared to control individuals without renal disease.3840 A recent study has shown that the prevalence of xerostomia in KT patients was 35% 24 hours before the transplantation, and significantly decreased to 10.7% and 8.2% 15–20 and 45–60 days after the procedure, respectively.41

Etiology and Pathogenesis
  • Xerostomia‐inducing medications. Over 500 medications, including anticholinergic drugs, antihistamines, antihypertensive drugs, tranquilizers, and skeletal muscle relaxants, can affect SFR and induce xerostomia.31,4246
  • Decreased fluid intake and polyuria. Many patients with renal disease are elderly and naturally tend to drink less fluid. Combined with the reduced ability of the kidneys to reabsorb sodium and subsequent polyuria,28 this reduced intake of fluids can contribute to fluid loss and xerostomia.42
  • Stress and depression. Both stress and depression can reduce salivary gland activity in patients with CKD and those undergoing in‐center HD.47,48
  • Subjective xerostomia. A study that involved patients undergoing in‐center HD has shown that signs of xerostomia were reported by 68% of patients with decreased SFR and by 59% of those with normal SFR.35
  • Other mechanisms contributing to xerostomia/reduced SFR. Several other factors, including changes in salivary chemical composition,49 fibrosis and atrophy of minor salivary glands,35 and damage to salivary gland cells,50 have been proposed to contribute to xerostomia/reduced SFR. However, the large difference in the amounts of unstimulated and stimulated saliva (~3.4–3.6 times) suggests that the renal disease did not damage the structure of the salivary glands, but rather affected their functional activity.51

  • Functional impairment. Significantly more patients undergoing in‐center HD and displaying a reduced SFR experienced speech difficulty compared to control individuals without renal disease (22% vs. 15%).28,31,34,52 In patients undergoing in‐center HD, xerostomia was significantly associated with difficulty in chewing (odds ratio [OR] 2.7; 95% confidence interval [CI] 1.7–4.3; P < .001) and swallowing (OR 2.3; 95% CI 1.5–3.4; P < .001) and consequent avoidance of food intake (32% vs. 18% in nonxerostomic controls; OR 2.1; 95% CI 1.4–3.2; P < .001).53
  • Intraoral lesions. Xerostomia is associated with glossitis, fissured lips, and candidiasis.54
  • Systemic concerns. Xerostomia is significantly associated with hypertension (OR 5.24; 95% CI 1.11–24.89; P = .03);46 however, a wide confidence interval in this study should be noted.

Altered Taste Perception (ICD‐10‐CM Diagnosis Codes R43.8 and R43.9)

These conditions can be categorized into dysgeusia (altered taste perception), hypogeusia (reduced taste perception), and ageusia (absent taste perception).55

  • Patients with CKD (prior to undergoing in‐center HD). There seems to be a significantly higher prevalence of dysgeusia among patients prior to dialysis compared with individuals without renal disease.56 A questionnaire study of patients with CKD suggested that 31% of them perceived a metallic taste (vs. 0% in the control group without renal disease) and 53% of them felt a taste alteration (vs. 9% in the control group without CKD). These findings did not correlate with the disease duration, but were primarily encountered in elderly patients (88% of all cases).57
  • Patients undergoing in‐center HD. A large‐scale study has shown that 13.4% of patients undergoing in‐center HD had signs of dysgeusia,33 whereas smaller‐scale studies reported its prevalence to be 28%.28 No studies reporting the prevalence of oral lesions in patients undergoing PD have been identified.
  • Patients receiving KT. The prevalence of patients with KT and who experienced a metallic taste was lower compared to that in patients undergoing in‐center HD (6% vs. 28%), but higher than in control individuals without renal disease (0%).28

Etiology and pathogenesis

The proposed mechanisms include changes in salivary flow, pH, and chemical composition,58 thick tongue coating,36 and genetic ability to taste thiourea at low thresholds.59


Taste alterations in patients with renal disease can lead to impaired quality of life.

Halitosis (ICD‐10‐CM Diagnosis Code R19.6)

Halitosis is a perceived malodor with an intensity beyond a socially acceptable level.60 Six types of halitosis can be distinguished, depending on the mechanisms and origin of its development (physiologic, oral, airway, gastroesophageal, blood‐borne, and subjective halitosis).60 In patients undergoing in‐center HD, halitosis was one of the most common observations, with a prevalence of 30%–49% (vs. 0% in controls with normal renal function).30,36,61 No studies examining the prevalence of halitosis in patients with CKD (prior to undergoing in‐center HD), those undergoing PD, and those receiving KT have been identified.

Etiology and pathogenesis
  • Breakdown of organic compounds. In general, halitosis is attributed to the presence of various volatile organic compounds present in saliva and tongue coating, including volatile sulfur compounds (VSCs).62,63 These products are enzymatically generated by intraoral bacteria, including periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Prevotella intermedia),62,64,65 and a positive association between poor periodontal health and the levels of VSCs has been demonstrated.66
  • Reduced rinsing property of saliva. In patients with CKD who exhibit a reduced SFR, halitosis could be associated with the accumulated biofilm, bacteria, and desquamative epithelial cells from the tongue. However, no scientific evidence supporting this hypothesis has been shown.
  • Other reasons. Up to 42% of the general population have signs of subjective halitosis,67,68 which is a psychologic sensation, but not the objective presence, of halitosis.62 Since the presence of halitosis in several studies was determined using a questionnaire, its prevalence could be overestimated. Therefore, a series of questions for more objective differentiation between objective and subjective types of halitosis has been developed.60


Halitosis in patients with renal conditions can lead to impaired quality of life.

Other Oral Manifestations

Patients with CKD, especially those exhibiting oral candidiasis and anemia,69 could also display glossodynia, a chronic debilitating oral condition characterized by the presence of a burning sensation of the oral mucosa,29,7072 tongue,30 and gingiva.73

Oral Signs

(A) Soft Tissue Lesions: 01. Oral Mucosa Lesions


  • Patients with CKD (prior to undergoing in‐center HD). Sex‐ and age‐adjusted regression analysis has shown that predialysis patients with CKD had a significantly higher likelihood of developing clinically observable oral symptoms compared to controls with normal renal function (OR 153.3; 95% CI 40.1–584.8; P < .001)74; however, an extremely wide CI makes the interpretation of these results challenging. These patients were also reported to have a significantly higher prevalence of oral manifestations compared to control individuals without renal disease (66% vs. 37%; OR 3.3; 95% CI 1.9–5.6; P < .001).30
  • Patients undergoing in‐center HD. Smaller‐scale studies have shown that the prevalence of oral lesions in patients undergoing in‐center HD varied substantially, ranging from 9% to 94%.28,39,75 A large‐scale study has shown that the overall prevalence of oral lesions was 40%,76 with HD duration (<12 or >12 months) not affecting their prevalence.28 These patients also had a statistically higher risk of the development of various combinations of oral lesions with oral manifestations, with ORs ranging from 2.6 to 14.0.30 No studies reporting the prevalence of oral lesions in patients undergoing PD have been identified.
  • Patients receiving KT. These patients had a higher prevalence of oral lesions compared to control individuals without renal disease (32%–96 vs. 57%)28,39,7779 and patients undergoing in‐center HD (32% vs. 9%).39 A recent study has also shown that 24 hours prior to KT, oral lesions were observed in 3.7% of patients, and their prevalence increased substantially, reaching 23.7% and 25.7% 15–20 and 45–60 days after KT, respectively.41 Their prevalence was not related to post‐transplant period duration28 or patient age.41

Uremic Stomatitis (ICD‐10‐CM Diagnosis Code K12.1)

Inflammation of the oral mucosa (stomatitis) is associated with impaired renal function and urea accumulation. Due to a slow rate of disease progression over a period of years, its incidence is estimated as low, but this has not been confirmed in epidemiologic studies. There are four variants of uremic stomatitis:80,81

  • Ulcerative stomatitis is the most common presentation, characterized by extremely painful ulcerations on the tongue, cheeks, lips, and palate with indefinite margins, often covered by a thick, adherent, yellowish covering on the tongue. Other symptoms include xerostomia, metallic taste, mouth burning sensation, erythematous lingual and palatal mucosa, and fissuring and bleeding at the corner of the mouth. Tissue biopsy is needed to perform differential diagnosis with vesiculobullous diseases.81
  • Erythematosus membranous stomatitis is characterized by the formation of gray pseudomembranes that consist of a thick, sticky exudate on the erythematous mucosa and overlay painful erythema patches.
  • Hemorrhagic stomatitis is characterized by the presence of bleeding of the gingival or oral mucosa. In combination with immune deficiency, bacterial infection can cause extremely painful ulcerations and pseudomembranes, often on the ventral surface of the tongue.
  • Hyperparakeratotic stomatitis occurs rarely and is characterized by hyperkeratosis, sometimes in combination with ulcerations.82

Etiology and Pathogenesis

The precise mechanisms of the development and progression of uremic stomatitis remain unclear; however, it has long been associated with higher levels of caustic salivary ammonia, causing a slowly developing “chemical burn.”83 Indirect evidence of the association between salivary urea and stomatitis can be observed in patients with acute necrotic pseudomembranous gingivostomatitis, which develops within a short period of time as a response to rapidly elevated BUN levels.84 Predisposing factors could be local bleeding, infectious environment, and compromised immune condition.85 In addition, patients with ESRD may present with white patches intraorally (tongue, mucosa of the floor of the mouth),86,87 as well as on the skin of the face and lips.88 These patches represent crystals of urea deposited after the evaporation of saliva or sweat and occur when the blood urea concentration >200 mg/dL.89 However, direct evidence of the adverse effects of ammonia, causing the “chemical burn” of the oral mucosa, and the role of uremic patches in this process have not been demonstrated.


Due to painful intraoral lesions, patients with ulcerative stomatitis may have a loss of appetite, dehydration, and weight loss. They can also develop generalized gastrointestinal changes, suggesting that the oral manifestations are local manifestations of generalized mucosal breakdown.84 Hemorrhagic stomatitis can impair the intactness of the oral mucosa of these patients and contribute to bacterial infection.

Purpura (ICD‐10‐CM Diagnosis Code D69)

This is the development of extravascular red‐ or purple‐colored spots on the oral mucosa. Depending on the size of the spots, purpura can be classified into petechiae (pinpoint size) and ecchymoses (larger than pinpoint size).90

  • Patients with CKD (prior to undergoing in‐center HD). These patients had a significantly higher prevalence of mucosal petechiae compared to control individuals without renal disease (15.1% vs. 0.8%; OR 23.0; 95% CI 3–178; P < .001);30 however a very wide confidence interval should be noted.
  • Patients undergoing in‐center HD. A large‐scale study has shown that the prevalence of petechiae in these patients was 7.9%,76 and a smaller‐scale study reported the prevalence of petechiae and/or ecchymoses to be 12%.36 No studies reporting the prevalence of purpura in patients undergoing PD have been identified.
  • Patients receiving KT. No studies have been identified.

Etiology and Pathogenesis

The proposed mechanisms include trauma (e.g., physical impact, biting) and platelet dysfunction.90


The purpura might be suggestive of platelet dysfunction or the use of anticoagulants, which are commonly encountered in patients undergoing in‐center HD and will be discussed in the Dental Considerations and Multidisciplinary Management section of this chapter.

Fungal Infections (ICD‐10‐CM Diagnosis Codes B37.0 and B37.9)

These are opportunistic conditions, which can be signs of systemic conditions, side effects of medications (antibiotics, steroids), and local factors (poorly maintained dental dentures, the use of steroid inhalers, and reduced SFR).91

  • Patients with CKD (prior to undergoing in‐center HD). A single study reported that significantly more of these patients had oral yeast infections compared to control individuals without renal disease (32% vs. 11%).92
  • Patients undergoing in‐center HD. A large‐scale study has shown that the prevalence of oral candidiasis in these patients was 4.6%.76 Smaller‐scale studies have shown that the prevalence of yeast infection was markedly higher in these patients compared to control individuals without renal disease (40%–54% vs. 18%–31%),9396, especially in those >45 years of age,97 and with a majority of yeast lesions (23.3%) being chronic erythematous candidiasis.93 Dorsal tongue coating with yeasts was a common finding in HD patients (78%), with Candida albicans and C. parapsilosis being the most common yeast species.75 In PD patients, the prevalence of yeast infections was slightly higher compared to control individuals without renal disease (21% vs. 18%).96
  • Patients receiving KT. These patients have a significantly higher risk (adjusted OR 3.49; 95% CI 1.27–9.18; P < .05)98 and prevalence of yeast infections compared to control individuals without renal disease (10%–32% vs. 0%–2.5%).41,77,99,100 Erythematous candidiasis was the most prevalent form of yeast infection (3.8%–13.3%)77,99 and C. albicans was the most common yeast (61.9%). A case of Histoplasma capsulatum–associated histoplasmosis in a long‐term immunosuppressed patient with KT and a history of maxillary tooth extractions and development of oro‐antral communication with maxillary sinus has also been described.101

Etiology and Pathogenesis
  • Dental prostheses. Oral candidiasis in patients undergoing in‐center HD was significantly associated with wearing a dental prosthesis (OR 4.5; 95% CI 1.6–12.7; P = .004).94,96 No association between the signs of yeast infection and the number of missing teeth, smoking status, HD duration, KT duration, and antibiotic use was observed.96
  • Xerostomia. In patients with ESRD and those undergoing in‐center HD, the prevalence of oral fungal infections was significantly higher when xerostomia was self‐reported compared to nonxerostomic patients.92
  • Systemic factors. Aging, endocrine disorders, and broad‐spectrum antibiotic therapy have been associated with yeast infection.102 A recent study has also demonstrated the significant positive correlation between oral candidiasis and the immunosuppressant drug azathioprine.41

  • Oral cavity. Yeast infections can be associated with denture stomatitis103 and glossodynia.104 Although older studies have suggested the association between oral yeast infections and mouth burning, the recent evidence did not establish this association.105
  • Systemic health. While oral candidiasis did not seem to be associated with all‐cause mortality (adjusted hazard ratio [HR] 1.37; 95% CI 1.0–1.86), it was significantly associated with cardiovascular mortality (adjusted HR 1.64; 95% CI 1.09–2.46) after adjusting for several critical cofounders.76 Similarly, the increased prevalence of oral candidiasis (OR 3.1; 95% CI 1.0–9.4; P = .04) and wearing dental prostheses (OR 4.1; 95% CI 1.2–13.9; P = .03) were associated with a higher risk for advanced coronary artery disease.94 In both these studies, low lower limits of the CIs should be noted.

Oral Mucosal Ulcers (ICD‐10‐CM Diagnosis Codes K12 and K13.7)

These are painful lesions in the oral cavity, which can be chronic or acute depending on the underlying mechanisms of their development.106 In patients undergoing in‐center HD, the prevalence of intraoral mucosal ulcers was 1.2%–1.7%.36,76 However, no studies reporting the prevalence of intraoral ulcers in patients with CKD (prior to undergoing in‐center HD) and those receiving KT have been identified.

Etiology and Pathogenesis

Oral ulcers can be a sign of ulcerative uremic stomatitis (see the earlier section on Uremic Stomatitis).

  • Other renal conditions. Oral ulcers can be associated with the development of lupus nephritis in patients with systemic lupus erythematosus (SLE) affecting kidney functions (rapidly developing glomerulonephritis) and predict their activity.107,108 Also, oral ulcers can often be presented in patients with Behçet disease109 associated with rapidly progressive glomerulonephritis.108
  • Cytomegalovirus (CMV) treatment. Oral ulcers can develop secondary to CMV treatment, such as the use of everolimus.41,73 The presence of ulcers on the oral mucosa, hard and soft palate, and tongue were observed in KT patients who developed CMV infection within the first three years after transplantation.110
  • Medications. Limited evidence suggests that in patients with KT, oral ulcers could be associated with immunosuppressant medications, such as sirolimus or mycophenolate mofetil.111,112


Painful oral ulcers can result in discomfort during meal intake, leading to malnutrition.

Oral Malignancies

The prevalence of intraoral neoplasms in patients undergoing in‐center HD was 2%,76 whereas it was up to 5% in those receiving KT.78,113 The development of spindle cell carcinoma in the lower lip78 and squamous cell carcinoma of the tongue after KT114 have also been described. However, no studies examining the prevalence of intraoral malignancies in patients with CKD (prior to undergoing in‐center dialysis) have been identified.

Etiology and Pathogenesis

Longstanding postallograft immunosuppression may predispose patients receiving KT to human herpesvirus 8 (HHV‐8) and associated Kaposi’s sarcoma.115,116 Shedding of HHV‐8 into the oral cavity was observed after the transplantation of a seropositive HHV‐8 kidney.117 Therefore, intraoral malignancies are likely to be associated with the immunocompromised conditions of these patients.118120 During the past two decades, the use of various antiviral medications has reduced the incidence of viral infections substantially.119,121124 However, studies examining the association between the reduced viral load and the prevalence of intraoral malignancies in patients with CKD and those on in‐center HD are missing.

Other Oral Mucosa Conditions

Patients undergoing in‐center HD and those receiving KT might also present with rare cases of other oral mucosa lesions, such as pyogenic granuloma.28,99 In addition, various types of viruses, including intraoral herpes simplex (0.5%–7.8% of cases),33,41,7678,125 Epstein–Barr virus, cytomegalovirus, and varicella zoster virus, were observed in patients prior to and those undergoing in‐center HD, especially in patients with severe periodontal destruction.126 Studies have shown that patients with CKD might also display a higher prevalence of pale oral mucosa compared to control individuals without renal disease (40% vs. 12%).30 This could likely be due to the impaired absorption of dietary iron and functional iron deficiency,127,128 impaired EPO synthesis,30 and malnutrition.127,129 A recent large cohort study has shown that anemic conditions positively correlated with the stage of CKD (44%, 64%, and 73% for stages 3, 4, and 5, respectively).130 Cases of fibroma in patients undergoing in‐center HD can also be encountered (Figure 16‐6).

(2) Tongue Conditions

Saburral (Coated) Tongue (ICD‐10‐CM Diagnosis Code K14.9)

This is a yellowish‐white, thrush‐like coating on the back of the tongue, representing large amounts of normal desquamated epithelial cells and bacterial colonies (more commonly Staphylococci), without the presence of yeasts131 and coexisting with elongated (<3 mm) filiform papillae.77 Its development is commonly associated with poor oral hygiene;132 however, the precise mechanisms are still unclear. Initially, these lesions were described in patients during episodes of acute rejection following KT and after treatment with high doses of steroids,131 but later studies have described their development in other patients with CKD as well.

  • Patients with CKD (prior to undergoing in‐center HD). A series of studies have shown that these patients had a significantly higher prevalence (12%–37% vs. 3%)28,30,36 and risk for saburral tongue compared to control individuals without renal disease (OR 7.0; 95% CI 2.3–21.4; P < 0.001);30 however, a wide confidence interval makes the interpretation of these results challenging.
    Photo depicts other oral mucosa conditions.

    Figure 16‐6 Other oral mucosa conditions.

  • Patients undergoing in‐center HD. No studies have been identified.
  • Patients receiving KT. Studies have shown that 22%–42% of patients with KT developed saburral tongue, especially within the first year after the transplantation.28,77

Etiology and Pathogenesis

The precise mechanisms of the development of saburral tongue in patients with renal disease are unclear. Patients with renal disease prior to in‐center HD (especially those >50 years) displayed a thick tongue coating, which, however, had no significant association with changes in blood levels of urea, creatinine, and albumin.133 It is likely that similar to individuals without renal disease,132 the development of saburral tongue in patients with renal disease is associated with poor oral hygiene. However, systemic disturbances, especially those resulting from immunosuppressive medications, should also be considered.


Patients with saburral tongue may have a compromised taste perception and a risk for biting the tongue due to its enlargement.

Dialysis‐Related Amyloidosis (ICD‐10‐CM Diagnosis Code E85.4)

This is a rare and late complication of long‐term HD,134,135 characterized by multiple soft, painful, whitish‐to‐yellow nodules of various sizes >1 mm and with a cobblestone appearance on the dorsum and lateral borders of the tongue, causing macroglossia.136 However, cases of HD‐related amyloidosis with asymptomatic nodules have also been described.134,137 The nodules gradually enlarge over time, consistent with HD‐related amyloidosis,137139 which is not degraded in patients undergoing in‐center HD and cannot pass through a dialysis membrane.140 Depending on the intraoral location and extent, two types are described, lateral and diffuse, with no differences in the HD duration between them.135

  • Patients with CKD (prior to undergoing in‐center HD). An older large‐scale study that included 236 patients with CKD (prior to undergoing in‐center HD) with systemic amyloidosis showed that macroglossia was the most common intraoral sign, observed in 17% of these patients.141 A recent case report study described a case of lingual amyloidosis in an 82‐year‐old patient with CKD (prior to undergoing in‐center HD).142
  • Patients undergoing in‐center HD. Older studies have reported that some patients undergoing in‐center HD have a sensation of an enlarged tongue associated with amyloidosis.36,143,144 In patients undergoing long‐term (>10 years) in‐center HD, the prevalence of tongue amyloidosis was 1.7% compared to 0% in control individuals without renal disease.135 Rare cases of amyloid‐associated macroglossia in the HD patient with Fabry disease (inherited lysosomal storage disease due to α‐galactosidase A deficiency)145 and combined β2‐microglobulin and light chain deposits in a patient undergoing long‐term (18 years) HD have recently been reported.146
  • Patients receiving KT. A recent study has reported that 28% of patients with KT had macroglossia compared to 22% of patients undergoing in‐center HD; however, it is unknown whether or not this was associated with amyloidosis.147

Etiology and Pathogenesis

In patients undergoing in‐center HD, polyphosphate released from the activated platelets can induce precipitation of β2‐microglobulin, leading to the formation of amyloid.148


Dialysis‐related amyloidosis can lead to significant speech, taste, and swallowing difficulty.135,139,142,145 Macroglossia can be the first sign of amyloid‐associated renal dysfunction.149 Studies also suggest that the presence of macroglossia and progressive renal failure may be indicative of systemic amyloidosis with multiple myeloma.149

Oral Hairy Leukoplakia (ICD‐10‐CM Diagnosis Code K13.3)

This is a painless white patch with an irregular surface and prominent folds and projections, which cannot be scraped off. It can be unilateral or bilateral and typically involves the lateral and dorsolateral tongue.99

  • Patients with CKD (prior to undergoing in‐center HD). No studies have been identified.
  • Patients undergoing in‐center HD. No studies have been identified.
  • Patients receiving KT. In these patients, oral hairy leukoplakia (OHL) was the second most common oral lesion, with a prevalence of 6.8%–12.2% compared to a lack of cases in control individuals without renal disease.77,99,150
Etiology and Pathogenesis

OHL is probably caused by drug‐induced reactivation of the Epstein–Barr virus (EBV) in the basal layers of the oral epithelium.82 It is often observed in patients undergoing cyclosporine A (CsA) therapy, including patients receiving KT.99 A single OHL case on the lateral borders of the tongue in a patient with KT was associated with EBV.151


In some cases, OHL can be mimicked by uremic stomatitis with white tongue coating,82 and therefore can represent a diagnostic challenge.

Other Tongue Conditions

In patients undergoing in‐center HD, the prevalence of fissured tongue and geographic tongue was 10.7% and 4.9%, respectively.76 Patients receiving KT also presented with various tongue conditions (fissured tongue, geographic tongue, and black hairy tongue28,99); however, their prevalence has not been reported, except geographic tongue (11.1% vs. 5.6% compared to patients undergoing in‐center HD).147

(3) Periodontal Conditions

Medication‐Induced Gingival Enlargements (ICD‐10‐CM Diagnosis Code K06)

This is a subcategory of gingival diseases associated with medications that can induce overgrowth of gingival tissues.152 Clinically, medication‐induced gingival enlargement (MIGE) is characterized by enlarged gingiva with an irregular gingival margin, shorter clinical crowns, and periodontal pseudopockets (pockets with an increased probing depth [PPD] but without clinical attachment loss [CAL]).

  • Patients with CKD (prior to undergoing in‐center HD). No studies have been identified.
  • Patients undergoing in‐center HD. A recent study has shown that MIGE was observed in 17% of these patients.153 Another study has demonstrated that in these patients, MIGE was observed only after the failure of KT and not prior to the KT procedure.154
  • Patients receiving KT. The prevalence of MIGE in these patients ranged from 22% to 67.5%, thus making it their most common oral lesion, typically in the area of anterior teeth.77,78,99,125,153,155,156 The prevalence of gingival overgrowth is approximately similar between patients taking calcium‐channel blockers (e.g., nifedipine, amlodipine, felodipine; up to 34% of patients)157 and those receiving immunosuppressants (e.g., CsA, tacrolimus; up to 33% of patients).158 Some studies have reported that the intake of more than one medication has a cumulative effect;29,78 however, other studies could not establish that correlation.99

Etiology and Pathogenesis

In patients undergoing in‐center HD, MIGE was related to calcium‐channel blockers (e.g., amlodipine, nifedipine, verapamil) used as antihypertensive medications.154 In patients receiving KT, MIGE was associated with immunosuppressive therapy aimed to prevent allograft rejection following KT (e.g., using CsA, tacrolimus, azathioprine, cyclophosphamide, prednisone).154 Among patients who received KT, 55% took mycophenolate, 42% took glucocorticoids, 36% took CsA, and 34% took tacrolimus,159 thus predisposing a large cohort of them to MIGE. The severity and extent of gingival overgrowth in these patients were positively associated with the dosage of CsA, but not with the duration of its intake.160 In patients who received KT, there was a positive association of CsA‐induced MIGE with IL‐1α polymorphism161 and red complex microbiota.162

There are controversies surrounding the role of dental biofilm in MIGE. Some studies showed that the higher prevalence of gingival overgrowth significantly correlated with poor oral hygiene,77,163 whereas others observed gingival overgrowth even in the presence of meticulous oral hygiene.164 A double‐blinded randomized control study showed that 67.5% of CsA‐treated patients receiving KT developed MIGE, and a 7‐day course with metronidazole or azithromycin had no significant effects on gingival overgrowth,155 suggesting that overgrowth was primarily due to medications and not bacterial colonization of periodontal pockets.


MIGE conditions can impair the quality of a patient’s life by affecting their functional and esthetic demands.

Periodontitis (ICD‐10‐CM Diagnosis Code K05—Multiple Codes)

This is a polymicrobial multifactorial inflammatory disease of tooth‐supporting tissues (periodontium)165 and is one of the most common human infectious diseases, estimated at 42% in dentate US adults.166

  • Patients with CKD (prior to undergoing in‐center HD). A recent 10‐year large‐scale study showed that CKD was not associated with severe (interproximal CAL ≥5 mm) periodontal breakdown (adjusted OR 1.01; 95% CI 1.005–1.015).167 Similar findings were reported in smaller‐scale studies.168 Other studies, however, have shown that patients with CKD (prior to undergoing in‐center HD) had a significantly greater extent of CAL (a surrogate measure of periodontitis) and higher risk for tooth‐specific progression of total (slight, moderate, and severe) CAL, compared to control individuals without renal disease (OR 1.73; 95% CI 1.15–2.60; P < .05).169 A recent study has also shown that the risk of severe periodontitis was significantly associated with the advanced stages of CKD.170
  • Patients undergoing in‐center HD. Similar to studies on patients with CKD (prior to undergoing in‐center dialysis), studies on patients undergoing in‐center HD also report controversial findings on the prevalence of periodontitis. A recent study has shown that these patients had significantly greater mean CAL (1.8 mm vs. 1.2 mm), deeper mean PPD (2.3 mm vs. 1.8 mm), and prevalence of periodontitis (slight, moderate, and severe).34 Gingival index, plaque index, and PPD (but not CAL) were positively associated with the duration of HD (especially after 10 years).171 Other studies, however, have shown that the prevalence of periodontitis was similar between these patients and control individuals without renal disease. Periodontitis was observed in 41% of patients undergoing in‐center HD; however, average PPD of 1 mm questions the validity of the periodontal exam and periodontal status of these patients;33 in addition, the prevalence of periodontitis in this patient cohort was similar to that reported by a recent National Health and Nutrition Examination Survey (NHANES) III–based study (42%).166 Long‐term (11 years), large‐scale,172 and smaller‐scale173 studies have also shown no significant association between CKD and periodontitis.
  • Patients receiving KT. Studies on the prevalence of periodontitis in these patients were controversial and included both a positive association159 and the lack of it.40

Etiology and Pathogenesis
  • Poor oral hygiene. Periodontitis is developed as a result of dysbiosis of the commensal microflora (present in dental biofilm/plaque) in a susceptible host organism.174,175 Studies have shown that significantly more patients with CKD,92,168,176,177 those undergoing in‐center HD,178 and those receiving KT179 had poor oral hygiene compared to control individuals without renal disease. It has been shown that only 8.2% of HD patients use dental floss, 30% had a dental appointment within the past 6 months, 66% brush teeth twice a day, 21% were edentulous, and 42% had dental prostheses.33 Another study has shown that greater numbers of patients undergoing in‐center HD180 and those receiving KT179 wore dentures that could alleviate plaque retention and periodontal inflammation. Discrepancies between their compromised dental conditions and oral health–related quality of life might also suggest that patients undergoing in‐center HD did not realize their worse oral hygiene condition and therefore did not seek to see a dentist.181 Finally, due to their significantly lower income, these patients might not be able to afford dental treatment to the same extent as control individuals without renal disease.72,182,183 A recent review study has also summarized the current evidence for the kidney damage induced by oral microorganisms, primarily Streptococci; however, a majority of the included studies are extremely outdated.184
  • Increased salivary pH. Selected periodontal pathogens such as P. gingivalis, P. intermedia, and Fusobacterium nucleatum show optimal growth in alkaline pH.185 Urea can be hydrolyzed to alkaline ammonia by oral bacteria’s ureases, thus resulting in the increased pH levels.56,186189 Studies have shown that patients with CKD had significant and stage‐dependent increases in salivary pH compared to control individuals without renal disease.56,190 Similarly, patients undergoing in‐center HD also had significantly higher salivary pH compared to control individuals without renal disease,36,56,187 which positively correlated with the duration of HD.191 Interestingly, patients with severe periodontitis had significantly increased salivary urea concentrations,192 further supporting the role of urea in dysbiosis of periodontal microflora. Therefore, increased salivary pH in patients with CKD and those undergoing in‐center HD can lead to conditions providing more favorable growth of periodontal pathogens.
  • Systemic effects of urea. Uremia alters host response by several mechanisms, including functional abnormalities of neutrophils, monocytes/macrophages, and dendritic cells,193196 abnormal neutrophil activity,197 impaired maturation of T‐helper cells,198 and increased oxidative stress.199,200 Since periodontitis develops in a susceptible host environment, impaired immune responses will favor its development.


In patients with ESRD, periodontitis was associated with poorer quality of life, including physical and physiologic impairment.201

Other Periodontal Conditions

The limited and inconclusive evidence of the presence of gingival diseases other than MIGE (non‐dental biofilm‐induced gingival diseases30,40 and necrotizing gingivitis202) in patients with ESRD has been reported in the literature. Recent case series studies have reported that the prevalence of biofilm‐induced gingivitis was observed in 17%–61% of patients undergoing in‐center HD compared to 61%–75% of those who received KT.147,153

(B) Hard Tissue Lesions: 01. Tooth Conditions

Dental Caries (ICD‐10‐CM Diagnosis Code K02—Multiple Codes)

To quantify the prevalence of dental caries and characterize it further, DMF (missing teeth, and teeth with fillings), DMFS (dental caries, missing, and filled tooth surfaces), and DMFT (dental caries, missing teeth, teeth with fillings, and tooth loss) indices/scores are commonly used (Figure 16‐7.)203

  • Patients with CKD (prior to undergoing in‐center HD). The impact of CKD on the prevalence of dental caries remains controversial, as studies have shown that CKD was associated with a decreased, increased, or unchanged prevalence of dental caries. A recent systematic review with a meta‐analysis of 14 studies has shown no significant differences in the number of decayed (mean difference −0.18; 95% CI −1.52–1.17; P > .05) and filled (mean difference −0.47; 95% CI −2.84–3.78; P > .05) teeth or the DMFT score (mean difference −3.17; 95% CI −0.83–7.18; P > .05) between patients with CKD and those undergoing in‐center HD compared to control individuals without renal disease; however, the large heterogeneity in the studies makes interpretation of their results challenging.204
    Photo depicts dental caries (ICD-10-CM Diagnosis Code K02 – multiple codes).

    Figure 16‐7 Dental caries (ICD‐10‐CM Diagnosis Code K02 – multiple codes).

  • Patients undergoing in‐center HD. Although these patients displayed significantly greater amounts of dental biofilm and calculus173 and a prevalence of cariogenic bacteria (Streptococcus mutans, Lactobacillus salivarius, L. fermentum, L. vaginalis, Scardovia wiggsiae, and Actinomyces. naeslundii) in dental biofilm,205 the prevalence of dental caries was similar to that in control individuals without renal disease.173
  • Patients receiving KT. These patients had a higher but statistically nonsignificant prevalence of dental caries (DMFS or DMFT score) compared to control individuals without renal disease (5.3% vs. 1.4%).40,206 However, these patients had a significantly higher DMFT score compared to patients with other organ transplants (liver and lungs).159

Etiology and Pathogenesis

Caries resistance is associated with higher concentrations of ammonia due to the higher urease activity.207,208 Increases in salivary urea resulted in elevated pH and increased amounts of dental calculus (this will be discussed in more detail in the Periodontitis section of this chapter). At the same time, this environment neutralizes the acidic environment associated with tooth demineralization and caries development.209 In addition, the similarities in the prevalence of dental caries in renal patients and control individuals without renal disease due to the high degree of heterogeneity of various studies implies that the differences could be masked by various other factors (e.g., differences in patient selection and their renal disease status, the presence or absence of other systemic conditions).


A two‐year large multinational cohort study that included 4205 patients undergoing in‐center HD has shown that complete edentulism (adjusted HR 1.29; 95% CI 1.10–1.51; P < .001) and DMF score ≥14 (adjusted HR 1.70; 95% CI 1.33–2.17; P = .04) were associated with higher all‐cause mortality.210 These observations suggest that the low prevalence of dental caries can serve as a plausible preventive determinant of clinical outcomes in these patients.

Edentulism (ICD‐10‐CM Code K08—Multiple Codes)

This is a loss of one or several teeth (partial edentulism) or all teeth (complete edentulism) due to various reasons, most commonly periodontitis and dental caries.

  • Patients with CKD (prior to undergoing in‐center HD). A recent systematic review with a meta‐analysis showed that these patients lost significantly more teeth compared to control individuals without renal disease (mean difference 3.84; 95% CI 1.10–6.57; P ≤ .05).204 The increased tooth loss was significantly associated with the increased levels of cystatin C used as a surrogate estimate of decreased renal function (OR 7.70; 95% CI 1.24–47.84; P = .03), but not with age, CAL ≥4 mm, or body mass index (BMI);211 however, a large CI should be noted.
  • Patients undergoing in‐center HD. A systematic review of observational studies showed that 21% of patients with CKD undergoing in‐center HD were edentulous; however, no data on control individuals without renal disease were reported.212 A smaller‐scale study demonstrated that significantly more patients undergoing in‐center HD were completely edentulous compared to control individuals without renal disease (13.6% vs. 2.2%), and dentate ones lost more teeth compared to control individuals without renal disease (14 vs. 10 teeth).30
  • Patients receiving KT. No studies have been identified.

Etiology and Pathogenesis

Since several studies have shown that the prevalence of dental caries in patients with CKD (prior to undergoing in‐center HD) and control individuals without renal disease was similar, dental biofilm–associated periodontitis is the most feasible etiology of edentulism in these patients. In addition, a severe periodontal breakdown could lead to tooth loss in rare cases of primary hyperoxaluria.

  • Masticatory dysfunction. Tooth loss may result in compromised masticatory function of renal patients, which consequently leads to impaired quality of life. A large‐scale NHANES III–based study of patients with CKD (prior to undergoing in‐center HD) showed that the confounder‐adjusted tooth loss was significantly associated with malnutrition in these patients.213
  • Esthetic concerns. Tooth loss may result in esthetic concerns in renal patients.
  • Systemic dysfunction. A study that involved patients with CKD (prior to undergoing in‐center HD) and control individuals without renal disease (both cohorts presented with signs of carotid artery calcification) found that tooth loss was significantly more prevalent in patients with CKD. This study suggested that the combination of edentulism with calcification of the carotid artery might help in early diagnosis of renal diseases.214 Also, a recent study showed that the association between the number of lost teeth and the incidence of death was statistically (but likely not clinically) significant (HR 0.95; 95% CI 0.92–0.98; P = .002);215 which, however, could also be associated with the increased age of the participants.

Tooth Periapical Lesions (ICD‐10‐CM Diagnosis Code K04.90)

These are pathologic lesions associated with the apices of teeth and radiographically presented as radiolucencies. Periapical lesions can have odontogenic (periapical granulomas and radicular cysts) and, more rarely, nonodontogenic (periapical cemental osseous dysplasia) origin.

  • Patients with CKD (prior to undergoing in‐center HD). These patients had a significantly higher prevalence of apical periodontitis (OR 3.95; 95% CI 1.54–6.32; P < .004), but not the number of endodontically treated teeth (OR 2.54; 95% CI 0.9–5.32; P > .05), compared to control individuals without renal disease. The number of teeth with apical periodontitis significantly correlated with increased serum urea levels.216
  • Patients undergoing in‐center HD. Significantly more of these patients had periapical radiolucencies compared to patients with CKD (prior to undergoing in‐center HD).217
  • Patients receiving KT. A case of periapical radiolucency associated with odontogenic infection and no complications 7 years after its endodontic management was described in these patients.218

Etiology and Pathogenesis

A study that included patients with hypophosphatemic rickets due to the excessive loss of renal phosphate has shown that they have an increasing trend to develop endodontic infections, especially in the population >40 years.219 Dental manifestations in patients with hypophosphatemic rickets also include dental abscesses.220 In patients with CKD (prior to and undergoing in‐center HD), nonodontogenic periapical lesions could represent radiolucencies associated with brown tumor (see the section on Renal Osteodystrophy later in this chapter) and not odontogenic periapical lesions, especially if these teeth were vital and therefore did not require root canal therapy.221

Other Tooth Conditions

A large‐scale study has shown that 47% and 2.7% of patients undergoing in‐center HD presented with dental erosion and enamel hypoplasia, respectively.33 A smaller‐scale study has demonstrated that 3.7% of HD patients had enamel hypoplasia.36 A recent systematic review with a meta‐analysis of five studies found no significant differences in the prevalence of developmental enamel defects (mean difference 0.73; 95% CI 0.33–1.64; P > .05) in patients with CKD (prior to in‐center HD) and those undergoing in‐center HD compared to control individuals without renal disease;204 however, the large heterogeneity in this study makes interpretation of its results challenging. These conditions were primarily associated with extrinsic factors associated with decreased SFR and various electrolyte imbalances (P ≤ .05), including significantly decreased salivary (but not serum) Ca2+, increased salivary and serum phosphorus, and markedly increased parathyroid hormone (PTH) levels (P ≤ .01 for all comparisons).222 Tooth hypercementosis has also been reported.223

Several studies have also shown that patients with CKD had an increased prevalence of pulpal stones compared to control individuals without renal disease.224,225 A recent systematic review with a meta‐analysis of seven studies has demonstrated a significant association between pulpal and kidney stones (OR 1.97; 95% CI 1.21–3.18]; P < .05),226 which became even more pronounced in patients with ≥3 teeth with pulpal stones (OR 5.78; 95% CI 2.013–16.592; P < .05). Studies suggest that pulpal stones may predict undiagnosed kidney stones, and since kidney stones were significantly associated with the development of CKD (HR 1.46; 95% CI 1.2–1.77; P < .05), pulpal stones may have a diagnostic value for CKD as well.227

(2) Bone Conditions

Renal Osteodystrophy (ICD‐10‐CM Diagnosis Code N25.0)

CKD‐mineral and bone disorder (CKD‐MBD) is a systemic mineral and bone condition associated with CKD and presented with abnormalities in appendicular skeleton and craniofacial bones.228 Among these conditions, a spectrum of pathologic alterations of bone morphology in patients with renal disease is classified under the term “renal osteodystrophy” (RO). Studies have shown that 70% of patients undergoing in‐center HD for more than 3 years had signs of RO, evidenced by generalized calcification and bone resorption.229 A systematic review of 205 publications has demonstrated that the average age of RO patients was 30 years, with women being affected 1.7 times more often than men230 and with the highest prevalence in African Americans and lowest prevalence in those of Hispanic origin.231

Based on the rate of bone turnover and levels of circulating PTH, four types of RO can be distinguished: osteitis fibrosa (also called hyperparathyroidism bone disease, osteitis fibrosa cystica, leontiasis ossea, and von Recklinghausen’s disease), osteomalacia, adynamic bone disease, and mixed disease.232,233 In a cohort of patients with ESRD, 50% of them presented with osteitis fibrosa, 27% with adynamic bone disease, 7% with osteomalacia, and 15% with mixed disease; patients with adynamic bone disease were significantly older compared to those with osteitis fibrosa and mixed disease (56 vs. 41 vs. 39 years).233

Clinically, RO is characterized by painless or painful swelling masses of the jaw, causing facial deformity,234 which is observed in the mandible (41%), maxilla (29%), and both jaws (30%).230 This makes jaw hypertrophy the most common observation in RO, affecting up to 78% of patients.230 Up to 62% of patients diagnosed with CKD‐MBD had the severe form of RO called brown tumor;235 in these patients, jaws were affected in 62% of cases,236 with a higher prevalence in the mandible than maxilla (54 vs. 46%),235 thus making them the most frequent skeletal location. Despite its name, the brown tumor does not have any neoplastic characteristics, but rather reflects the expanding masses within the jaw.237 The higher prevalence of brown tumor in the mandible is thought to be due to circulating PTH stimulating osteoclastic activity in cortical bone, which makes brown tumor one of the earliest diagnostic signs of hyperparathyroidism.237 Due to early diagnosis and improved therapy, the incidence of brown tumors is low;229 however, it is three times more prevalent in women than in men and is more common in the third and fourth decades of life.237 Other forms of RO are also rare, with the continuously decreasing prevalence due to the improved early diagnosis using biochemical parameters and the withdrawal from aluminum‐containing dialysis fluids.238

Jaw hypertrophy can be accompanied by severe periodontitis,239 increased tooth mobility, pathologic tooth migration, diastemas (spaces between teeth),234 increased palatal size, and flattening of the nasal bridge due to the widening of the nares;240 however, the gingival covering of the expansive bone mass was normal.239 Clicking of the temporomandibular joint associated with pain around it and surrounding tissues has also been reported.241,242 Other clinical features may include delayed tooth eruption, hypoplastic enamel, and dental erosion.234 Various functional changes (e.g., masticatory dysfunction, nasal obstruction, epiphora, and diplopia) have also been reported.237,243 Whether RO‐associated periodontal breakdown is related to inflammation‐associated periodontitis is unclear, as the periodontal status of these patients was not described in detail. According to the 2017 classification of periodontal diseases and conditions by the American Academy of Periodontology and European Federation of Periodontology, periodontal changes secondary to hyperparathyroidism should be classified under the category of “systemic diseases or conditions affecting periodontal supporting tissues” and not under the general “periodontitis” category.244

Radiographic Features

Radiographic changes are among the earliest signs of RO, which become more pronounced with disease progression.234 In the most common type of RO, osteitis fibrosa, they have a diagnostic value in 47%231 and include the partial or complete loss of lamina dura of the tooth sockets (creating a characteristic “floating teeth” appearance245), loss of cortical bone in maxillary sinus walls and mandibular canal, generalized diffuse bone porosity, and widening of the periodontal ligament (PDL) space (suggesting an increased osteoclastic activity).234,237,246249 In contrast to control individuals without renal disease who presented with heterogeneous and dense trabecular bone, the bone pattern in patients with CKD had a “ground‐glass” appearance due to a finely meshed pattern of bone resorption237,250253 and a “salt and pepper” pattern of the skull bones on cone‐beam computed tomography (CBCT).254256 Well‐demarcated unifocal or multifocal bony lesions can be observed in patients with brown tumor.231,237,243 Multiple periapical lesions around the root apices (sometimes coalescent into a single multilocular radiolucent lesion) could also be seen, but contrary to periapical lesions of odontogenic origin, tooth vitality was not affected.241,246,248

Etiology and Pathogenesis

The development and progression of RO are associated with impaired hydroxylation of 1‐hydroxycholecalciferol to the active form of vitamin D (1,25‐dihydroxycholecalciferol, or calcitriol) and impaired Ca2+ balance (due to its decreased retention in renal tubules, reduced absorption in the gastrointestinal tract, and secondary hyperparathyroidism leading to increased Ca2+ release from bone to blood).229,257,258

  • Bone fracture. The decreased bone resistance in patients with RO may predispose them to a higher fracture risk;233,259,260 however, bone healing following tooth extraction appears to be unaffected.261
  • Functional impairment. Due to the expansive growth of the bone in patients with osteitis fibrosa, patients may have difficulty in swallowing and chewing and this may lead to airway obstruction, which can predictably be addressed by surgical therapy.223,262
  • Cardiovascular and anemia‐related conditions. Patients with RO can have compromised erythropoiesis and poorer response to EPO therapy, which have been associated with the mean serum PTH, the extent of the peritrabecular and marrow fibrosis, and the percentages of eroded bone surfaces.263 As mentioned in the section on renal replacement therapy in end‐stage renal disease, failure in production of EPO by the kidney is an underlying mechanism of anemia progression in renal disease patients.258 Also, PTH levels represent the main biochemical marker of RO and have been shown to be associated with the development of cardiovascular diseases.264

Primary Hyperoxaluria (ICD‐10‐CM Diagnosis Code R82.992)

This is a rare, inherited, autosomal recessive disorder of glyoxylate metabolism characterized by an accumulation of oxalate due to its excessive production and impaired excretion (systemic oxalosis).265268 It is commonly observed in patients with CKD stages 4 and 5,265 and although during CKD and early dialysis treatment the disease appears to be rather mild and not to affect the patient’s health substantially, it becomes much more severe after as short as 2 years of dialysis, likely due to the inefficiency of dialysis treatment to reduce oxalate load.265

Clinical Signs

The disease is characterized by the presence of needle‐ or star‐like crystals in virtually all tissues (systemic oxalosis), including alveolar bone, periodontium, dental pulp, and salivary glands. The degree to which the disease affects quality of life and life expectancy depends on the extent and rate of oxalate deposition in the tissues.266 The reported dental cases include patients in their 20–30s, suggesting a rapid progression of dental conditions.269271 Oral findings include poor oral hygiene, vital teeth,271 generalized gingival inflammation, external root resorption due to increased osteoclastic activity, increased tooth mobility due to severe periodontal breakdown and alveolar bone loss, and masticatory dysfunction.269271

Radiographic Findings

Radiographically, diffuse deposition of radiopaque oxalate crystals within various soft (oral mucosa, PDL, dental pulp) and hard tissues (dentin, alveolar bone, and cementum) was observed.269,270,272 Widened PDL273 and well‐demarcated bony lesions resembling cysts269 could also be observed.

Etiology and Pathogenesis

The oxalate crystal deposition can be alleviated by the increased permeability of blood vessels in periodontitis, thus leading to a greater extent of periodontal breakdown.274 However, it is unclear whether periodontal changes are associated with the deposit of crystals alone or aggravated by the inflammatory events of periodontitis. Since the 2017 classification of periodontal and peri‐implant conditions does not list primary hyperoxaluria among the systemic conditions affecting the periodontium,275,276 these conditions might be classified as periodontal abscesses associated with foreign bodies (oxalate crystals).

  • Local effects. Hyperoxaluria‐associated adverse effects could contribute to increased tooth mobility, tooth loss, and subsequent compromised chewing. However, the long‐term outcomes of dental management of oral lesions, especially in patients after KT and liver transplantation, have not been reported.274
  • Systemic effects. In addition to functional impairment of multiple tissues and organs, deposition of crystals in bone leads to an inflammatory reaction, activation of bone remodeling, and hyperparathyroidism.265 Progressive renal fibrosis induced by chronic inflammation leads to the deterioration of glomerular filtration, causing systemic oxalosis, primarily in the bones, causing pain, spontaneous fractures, and EPO‐resistant anemia, and radiographically presented with “bone‐within‐bone” and diffuse demineralization.277

Other Bone Conditions

A few cases of ossifying fibroma have been reported in patients undergoing in‐center HD with poorly controlled secondary hyperparathyroidism, radiographically presenting with osteolytic bone and displaced roots of the teeth.278,279 Also, aneurysmal bone cyst in a patient undergoing in‐center HD and presenting with hyperparathyroidism has been described.280 A more advanced stage of bisphosphonate‐related osteonecrosis of the jaw is significantly associated with eGFR281 and a poorer degree of response to therapy, especially in older individuals.282 Also, a case of extensive osteonecrosis of both maxilla and mandible (not related to bisphosphonate use) of a patient who received KT (15 years after transplantation) has been recently described.283


As already discussed, patients with renal disease present with various oral manifestations and pathologic lesions of soft and hard tissues and teeth. At the same time, the presence of oral lesions even in individuals without renal disease is associated with a statistically significant reduction in mean GFR compared to the respective controls without oral lesions (49.7 vs. 109.5 mL/min).74 These findings suggest that observation of oral lesions can serve as an early indicator of reduced GFR flow and a predictor of future renal diseases; however, long‐term follow‐up studies are needed to determine whether patients with oral signs and reduced GFR eventually develop renal disease. Due to the compromised systemic condition of patients with renal diseases, dental professionals must establish close multidisciplinary collaboration with the patient’s nephrologist team to ensure the patient’s safety, minimize the risk of complications, and provide the best possible care. At the same time, nephrologists need to understand the importance of dental care in the systemic health of their patients and ensure that all acute or chronic loci of dental infections are eliminated prior to renal treatment, which is especially relevant for patients receiving KT.284 Limited evidence suggests that the efficiency of this collaboration, however, appears to be inadequate. An older questionnaire study showed that 81% of dentists were aware of the kidney status of their patients with CKD and only 71% of patients had complete medical records;29 nevertheless, whether the use of modern electronic health records has improved this statistic remains unexplored. At the same time, only ~30% of Brazilian nephrologists referred their patients for dental consultations,285 although whether or not these data can be extrapolated to other countries is still uninvestigated. The importance of these gaps in patient management should not be overlooked.

Those who are not nephrologists frequently encounter issues with antibiotic dosing and electrolyte abnormalities in patients undergoing HD. Excellent volume control is necessary for certain tests or procedures so that patients can lie in the supine position for the duration of the test or procedure. Most dialysis units can accommodate longer or extra treatments before procedures that optimize acid–base and volume status prior to major procedures requiring general anesthesia.

Based on the available literature evidence, we have summarized the current knowledge on the dental management of patients with renal conditions.

Up to 70% of KT candidates require dental therapy prior to transplant surgery.286 The multidisciplinary dental management of patients receiving KT is similar to that for patients with CKD and those undergoing in‐center HD. However, patients receiving KT commonly present with more compromised immune conditions, which require special consideration. Ongoing dental infections (dental caries or periodontal breakdown) in these patients can contribute to fever, cough, and jaw pain, which are alleviated after addressing the respective dental conditions.287 Therefore, the United Network of Organ Sharing has published guidelines for patients anticipating organ transplants (including patients with renal diseases) that outline the process of preparation for transplantation and include a “dental exam clearance” communication form, which should be completed by a dentist and returned to the transplantation team before a patient can be “listed” for transplantation. Since most US kidney pre‐transplant patients have Medicare, their dental treatment preceding transplantation may not be covered (except for selective tooth extractions).288 This poses a higher risk of delaying KT procedures. Therefore, nephrologists should establish close communication with dentists regarding the schedule for KT and the patient’s dental needs.

Hematologic Conditions

The anemia and hypertension commonly seen in patients with renal disease as well as various anticoagulants used in HD therapy and vascular access maintenance258 pose a significant risk of increased bleeding. Up to 50% of patients with CKD and those undergoing in‐center HD had an increased tendency for systemic preoperative bleeding289 and a significantly higher perioperative risk of blood transfusion.290 A case report study of patients undergoing in‐center HD who displayed medication‐induced gingival overgrowth reported extensive (1650 mL) bleeding during gingivectomy and extensive tooth extraction (19 teeth), even despite normal blood tests (bleeding time and upper limits of PTT and PT).291

The mechanisms of the increased bleeding in patients with CKD prior to undergoing in‐center HD commonly include an impaired coagulation cascade and fibrinolytic system, platelet dysfunction, vasodilation with increased fragility of the blood vessel wall, impaired platelet–vessel wall interaction, and inflammation (see Table 16‐8).127,258,289 In select patients undergoing in‐center HD (typically three 3‐5‐hour courses of dialysis weekly), increased bleeding can be associated with the use of anticoagulants (commonly heparin, but danaparoid, lepirudin, and argatroban can also be used as alternatives292) prior to each procedure.258 Older studies have proposed performing dental procedures before dialysis, since any medications given by a dentist and their metabolites will be removed during subsequent dialysis.293 Currently, it is recommended that dental procedures be performed on alternate days to dialysis to avoid anticoagulant‐induced bleeding and the adverse effects of uremic metabolites, which may otherwise put the patient at hemorrhagic and/or cardiovascular risk, and to avoid conflicts in the dialysis and dental appointment schedule.258,294,295 Heparin dose in hemodialysis is very low and it is safe to treat patients after 6 hours from a coagulation point of view; however, logistically it may be better to do more invasive procedures after dialysis day. Caution needs to be exercised when doing invasive procedures in patients who are taking direct oral anticoagulants. These include antithrombotic agents such as acetylsalicylic acid and clopidogrel, anticoagulants (unfractionated heparin, low molecular weight heparin, fondaparinux), direct thrombin inhibitors (such as dabigatran), and direct factor Xa inhibitors (such as rivaroxaban or apixaban). Patients with advanced CKD (stages 4 and 5) and ESRD may experience higher bleeding risk than the general population, and this needs to be addressed when planning invasive dental procedures.

Table 16‐8 Mechanisms of increased bleeding in patients with renal disease.

Sources: Babitt JL, Lin HY. Mechanisms of anemia in CKD. JASN. 2012;23(10):1631–1634; Greenwood M, Meechan JG, Bryant DG. General medicine and surgery for dental practitioners. Part 7: renal disorders. Br Dent J. 2003;195(4):181–184; Lutz J, Menke J, Sollinger D, et al. Haemostasis in chronic kidney disease. Nephrol Dial Transplant. 2014;29(1):29–40.

  • Impaired coagulation cascade and fibrinolytic system
  • Platelet dysfunction (disturbance of the platelet α‐granules; impaired intracellular calcium flux; impaired synthesis and/or release of thromboxane A2 and a subsequent reduction in platelet adhesion and aggregation; deregulated metabolism of arachidonic acid and prostaglandins; intake of medications affecting platelet function)
  • Vasodilation with increased fragility of the blood vessel wall
  • Impaired platelet–vessel wall interaction (due to the decreased expression of platelet glycoprotein Ib, and impaired binding of von Willebrand factor and fibrinogen to activated platelets)
  • Inflammation (indirectly, due to increased tissue fragility)

Patients undergoing PD use their peritoneum as a filter, and routine use of anticoagulation is not required during PD; hence, clotting of blood in the extracorporeal system is not a potential complication.

Nevertheless, dentists who plan invasive dental procedures and expect greater than minor bleeding should still communicate with nephrologists to discuss the possible risk of excessive bleeding. In addition, they should be ready to use various local hemostatic agents (e.g., oxidized regenerated cellulose, Gelfoam with activated thrombin, tranexamic acid [Cyklokapron, 500 mg/5mL], and cellulose sponges),291,296 especially in patients with thrombocytopenia and platelet dysfunction (see Table 16‐9). Appropriate flap management and suturing techniques were required to minimize the risk of excessive bleeding297 and provide optimal healing of intraoral soft tissues.298

In an emergency, various systemic aids, including heparin antagonist protamine sulfate and desmopressin, antifibrinolytic drugs (tranexamic acid, epsilon aminocaproic acid), fresh frozen plasma, and platelet transfusion can also be performed in the appropriate settings (see Table 16‐10).291,296

If a patient receives warfarin to maintain shunt patency, International Normalized Ratio (INR) values prior to the procedure need to be obtained. Minor invasive procedures, such as isolated tooth extraction, can be safely performed with INR <3.5, whereas higher INR values require a nephrologist consultation.305 For a comprehensive review of bleeding disorders and their dental management, refer to the Bleeding and Clotting Disorders chapter of this textbook.

Table 16‐9 Local hemostatic agents used during invasive dental procedures.

Name Mode of Action Mode of Delivery
Oxidized regenerated cellulose Stimulates denaturation of blood proteins, activates platelet aggregation, and induces blood clot formation299,300 Local application to the wound area
Gelfoam with activated thrombin Gelfoam acts as a spongy carrier that can be soaked with thrombin that induces the formation of fibrin from fibrinogen301 Local application to the wound area
Cyklokapron (tranexamic acid) Antifibrinolytic; reduces the binding of plasminogen to fibrin302
  • Oral rinse (15 mL) 4×/day for 10 days
  • Soaking a piece of gauze and biting on it for 15–20 min
Sutures Mechanically approximate wound tissue margins Placed during the surgical invasion

Table 16‐10 Systemic hemostatic agents used during invasive dental procedures.

Sources: Nishide N, Nishikawa T, Kanamura N. Extensive bleeding during surgical treatment for gingival overgrowth in a patient on haemodialysis—a case report and review of the literature. Aust Dent J. 2005;50(4):276–281; Abed H, Burke M, Shaheen F. The integrated care pathway of nephrology and dental teams to manage complex renal and postkidney transplant patients in dentistry: a holistic approach. Saudi J Kidney Dis Transpl. 2018;29(4):766–774.

Name Mode of Action Effects
Protamine sulfate Heparin antagonist If emergency treatment has to be performed on a heparinized patient, protamine sulfate can be used to antagonize the anticoagulant effect of heparin294,295
Desmopressin Stimulates the release of von Willebrand factor from endothelial cells (effects last for up to 4 hours258,297,303) If prolonged bleeding time and low platelet aggregation tests are observed, 0.3 μg/kg of desmopressin can be administered subcutaneously or intravenously.304 Preferably perform the procedures in one visit to avoid the use of another dose of desmopressin


A non‐nephrologist frequently encounters issues with antibiotic dosing and electrolyte abnormalities in patients undergoing dialysis. Excellent volume control is necessary for certain tests or procedures so that patients can lie in a supine position for the duration of the test or procedure. Most dialysis units can accommodate longer or extra treatment before the procedure to optimize acid–base and volume status prior to major procedures requiring general anesthesia. Hyperkalemia, hyperphosphatemia, and hypocalcemia were the most commonly encountered electrolyte abnormalities in patients undergoing in‐center HD. Drugs that prolong the QT interval should be carefully prescribed in patients with ESRD (a noninclusive list is shown in Table 16‐11). Communication with dialysis units and nephrologists is key to delivering optimal care to medically complex patients undergoing in‐center HD.

Table 16‐11 The use of drugs prolonging QT interval in patients with renal disease.

Category Drugs
Antiarrhythmics Amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotolol
Antidepressants Amitryptyline, fluoxetine, sertraline, venlafaxine
Antimicrobials Azithromycin, clarithromycin, erythromycin, levofloxacin (fluoroquinolones), fluconazole (azole antifungals), pentamidine
Antipsychotics Chlorpromazine, clozapine, haloperidol, quetiapine, risperidone, ziprasidone
Miscellaneous Methadone, ranolazine, sumatriptan, zolmetriptan

As a general rule, clinicians should avoid prescribing any medications that are nephrotoxic or become nephrotoxic due to accumulation and prolonged plasma levels in patients with renal disease (see the detailed examples that follow).258,284 In these patients, other mechanisms of impaired pharmacokinetics of the drugs may include hypoalbuminemia (which limits the amount of proteins available to bind the drugs) and elevated urea levels (inhibiting the binding of proteins to plasma albumin), leading to the decreased availability of bound drugs and increased levels of free drugs. As a result, the doses and duration of various medications must be adjusted depending on the stage of renal disease. Therefore, it is essential to understand the pharmacokinetics of various drugs in patients with renal disease, taking into consideration their compromised health and increased risks for the development of infections.


Bacteremia is a common sequela of impaired renal function, often leading to the development of infective endocarditis (IE),306,307 Even while undergoing in‐center HD, patients have a significantly higher risk of IE (1.4% vs. 0.3% at 1 year, 2.2% vs. 0.6% at 3 years, and 3.9 vs. 0.9% at 5 years),308 which is a frequent cause of all‐cause mortality of these patients.309 Antibiotics were commonly used in the management of impaired renal function to prevent or minimize the risk of adverse complications associated with bacteremia.310 Since many of them were excreted by the kidneys,310 assessment of the functional activities of the kidneys is essential for choosing the optimal dose (see Table 16‐12). Several papers provide guidelines on the choice and dose of antibiotics depending on eGFR (see Table 16‐13).258,284,304,311313

To minimize the possible risk of IE after invasive dental procedures, US dentists use prophylaxis antibiotics according to the American Heart Association (AHA) and American College of Cardiology guidelines.314 Clinicians in Europe follow similar recommendations outlined by the European Society of Cardiology.315 However, since these guidelines do not address the need for prophylactic antibiotics prior to dental procedures in patients with renal disease and those who have received KT, some dentists have raised concern about this need. It has been argued that cessation of antibiotic prophylaxis, as recommended by the UK National Institute for Health and Care Excellence, has resulted in an increased incidence of IE.316 Although antibiotic prophylaxis appears to be safe and cost‐effective,298,316,317 81% of antibiotic prophylaxis prescriptions prior to dental procedures were made to patients not at high cardiac risk, thus not following the AHA guidelines.318 In patients receiving KT, antibiotic prophylaxis is recommended,284,319 and some authors suggest it for at least 2 years after KT.258 However, a retrospective study of patients receiving KT has shown that antibiotic prophylaxis prior to extraction procedures had no effect on the outcome of the procedure, and no difference in post‐healing events were found compared to patients receiving no antibiotic prophylaxis.261 Therefore, best practice remains discussion with the patient’s nephrologist to evaluate the indication for antibiotic prophylaxis in each individual case.294

Nonsteroidal Anti‐inflammatory Drugs

NSAIDs are commonly used to minimize inflammatory changes and reduce pain after invasive dental procedures. Extensive overviews of their use in dental patients with renal disease are available.311,320 In a healthy, well‐hydrated patient, the use of NSAIDs does not pose an increased nephrotoxic effect. However, in patients with impaired renal function, NSAIDs, especially those used for an extensive period of time or at high doses, can exert nephrotoxic effects, including the induction of hyperkalemia and hypertension, retention of sodium and fluids, and production of acidosis, and therefore they deteriorate already compromised renal function and contribute to the progression of CKD.312,321,322

Patients undergoing in‐center HD with reasonable residual renal function (urine output >200–300 mL/24 hrs) may want to avoid long‐term NSAIDs to preserve renal function. It is generally recommended to avoid NSAIDs, especially in patients with GFR <10 mL/min.296,311 In patients with eGFR 10–50 mL/min, aspirin can be used no more often than every 6 hours; however, it is recommended to avoid it due to increased platelet dysfunction, impaired renal blood flow, commonly observed gastrointestinal ulcers, increase in gastrointestinal bleeding, and deterioration in renal function.294,312 For postoperative pain management, acetaminophen is generally more recommended, since it does not cause bleeding and is tolerated better (every 6 hours if GFR 10–50 mL/min and every 8 hours if GFR <10 mL/min).294,311 However, chronic administration of acetaminophen should be avoided, since it can form phenacetin with nephrotoxic effects.312 NSAIDs with weaker effects on renal prostaglandins (e.g., nabumetone, etodolac, and sulindac)320 and nonacetylated salicylates (e.g., diflunisal, salsalate, magnesium choline salicylate, or salicyl salicylate)311 can also be considered in patients with ESRD.

Table 16‐12 Antibiotics.

Antibiotic Can It Be Used in Renal Patients? (Y/N) Recommended Dose
250–500 mg every 6 hrs
No dose adjustment necessary
Do not exceed 200 mg/day
Doxycycline and minocycline Y (excreted via bile)
Erythromycin (and other macrolides)
  • Y (in non‐renal‐transplant patients)
  • N (in patients receiving KT and taking CsA since it reduces CsA metabolism and leads to increased toxicity)
  • No dose adjustment necessary (stages 1–4)
  • 50%–75% of the normal dose (maximum 1.5 mg/day) for stage 5 and dialysis
  • N/A
Amoxicillin (and other penicillins, except potassium penicillins) Y
  • 500 mg (stages 1–4) every 12 hrs
  • 250 mg (stage 5) every 12 hrs
  • 250 mg every 24 hrs—dose after dialysis (HD)
  • Avoid high doses (>500 mg every 12 hrs) due to the possibility of seizures
Clindamycin Y No dose adjustment necessary (oral, 600–1800 mg/day in 2–4 divided doses)
Metronidazole Y
  • For CKD stages 1–4, no dose adjustment necessary (500 mg every 8–12 hrs)
  • For CKD stage 5 and dialysis, dose adjustment is necessary (500 mg every 12 hrs, dialyzable, dose after HD on dialysis days)
Aminoglycosides N
  • IV/IM
  • Nephrotoxic (AKI and AKI on CKD)
  • If no alternative, can use regular dose every 48–72 hrs with therapeutic drug level monitoring
Cephalosporins Y 0.5 mg IV 1 hr prior to procedure298

AKI, acute kidney injury; CKD, chronic kidney disease; CsA, cyclosporine A; HD, hemodialysis; IM, intramuscular; IV, intravenous; KT, kidney transplant; N, no; N/A, not applicable; Y, yes.

Table 16‐13 Antibiotic doses in patients with various estimated Glomerular Filtration Rates (eGFRs).

Sources: Greenwood M, Meechan JG, Bryant DG. General medicine and surgery for dental practitioners. Part 7: renal disorders. Br Dent J. 2003;195(4):181–184; Vasanthan A, Dallal N. Periodontal treatment considerations for cell transplant and organ transplant patients. Periodontol 2000. 2007;44:82–102; Saif I, Adkins A, Kewley V, et al. Routine and emergency management guidelines for the dental patient with renal disease and kidney transplant. Part 2. Dental update. 2011;38(4):245–248,250–251; Brockmann W, Badr M. Chronic kidney disease: pharmacological considerations for the dentist. J Am Dent Assoc. 2010;141(11):1330–1339; Svirsky JA, Nunley J, Dent CD, Yeatts D. Dental and medical considerations of patients with renal disease. J Calif Dent Assoc. 1998;26(10):761,763–770; Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487–1496.

eGFR Antibiotics
10–50 mL/min Regular dose of antibiotic of choice (e.g., amoxicillin, clindamycin, metronidazole, erythromycin)

  • Amoxicillin: 500 mg 21 tabs (3×/day for 7 days)
  • Metronidazole: regular dose every 12 hrs
<10 mL/min Reduced doses of antibiotics:

  • Amoxicillin: 250 mg 21 tabs (2–3×/day for 7 days)
  • Clindamycin: no dose adjustment
  • Erythromycin: 50–75% of a regular dose (maximum of 1500 mg/day)

Metronidazole: regular dose every 12 hrs

Dialysis (hemodialysis and peritoneal dialysis) Same as with eGFR <10 mL/min

Benzodiazepines and Opioid Drugs (Narcotics)

Many long‐lasting benzodiazepines (e.g., diazepam, clorazepate, and flurazepam) are excreted renally and produce toxic active metabolites with long half‐lives that accumulate in patients with renal impairment (see Table 16‐14).311,312

A recent review study has summarized various aspects of opioid use in older patients with CKD and suggested that opioids should only be used when absolutely necessary.323 Buprenorphine, fentanyl, ketamine, and hydromorphone form inactive metabolites and therefore are the safest opioids to use (Table 16‐15). In contrast, hydrocodone, oxycodone, and methadone form active metabolites, which may accumulate due to reduced renal function and induce toxicity (Table 16‐15). Due to greatly reduced clearance with renal impairment and possible enhancement of drug effects, codeine, morphine, and meperidine should also not be used in nondialysis renal patients (Table 16‐15).295,297,311,312,323 However, even safe and short‐lasting opioids delivered repeatedly can substantially prolong the elimination of the drug and its metabolites. Also, due to the anemia commonly seen in patients with renal disease, narcotics should be used with caution due to their respiratory depressant effects.61

Table 16‐14 Metabolites formed by benzodiazepines.

Sources: Brockmann W, Badr M. Chronic kidney disease: pharmacological considerations for the dentist. J Am Dent Assoc. 2010;141(11):1330–1339; Svirsky JA, Nunley J, Dent CD, Yeatts D. Dental and medical considerations of patients with renal disease. J Calif Dent Assoc. 1998;26(10):761,763–770.

Benzodiazepines Effects
Chloral hydrate Reduced excretion of its active metabolite 2,2,2‐trichloroethanol leads to its accumulation owing to a long half‐life (>10 hours) and excessive and prolonged sedation; avoid its use if GFR <50 mL/min
Meprobamate Eliminated via renal route almost entirely unchanged; unmetabolized meprobamate (10%–12% of total concentration) accumulates with repeated dosing due to long half‐life (>10 hours), resulting in excessive sedation; double the dosing interval when GFR is 10–50 mL/min and triple it when GFR <10 mL/min
Chlordiazepoxide, diazepam, clorazepate, flurazepam Active metabolites with long half‐lives; avoid multiple doses (as multiple dosing greatly increases the half‐life and prolongs sedation); reduce doses by 33%–50% if GFR >30 mL/min

Oral Sedatives

Patients with renal disease may require long‐term glucocorticoid therapy, which can result in an adrenal crisis during stressful events (such as dental treatment).258,294 Therefore, these patients should be treated in a quiet, stress‐free environment, as exogenous steroids can reduce the adrenal function to produce cortisol in response to stress, thus posing an increased risk for hypotension.324 When this is not possible, oral sedatives may provide an excellent level of sedation and patient comfort. Similar to various other medications, sedatives are affected by compromised renal function. A comprehensive review of the use of oral sedatives in renal patients has been published.311 Chlordiazepoxide, diazepam, clorazepate, and flurazepam produce active metabolites; therefore their dose should be reduced by 33%–50% if GFR >30 mL/min, and multiple doses should be avoided (as multiple dosing greatly increases the half‐life and prolongs sedation). Chloral hydrate can be accumulated in the form of its active metabolite, 2,2,2‐trichloroethanol, resulting in excessive sedation; therefore chloral hydrate should be avoided in GFR <50 mL/min. Meprobamate is eliminated via the renal route almost entirely unchanged; unmetabolized meprobamate accumulates with repeated dosing due to its long half‐life (>10 hours), resulting in excessive sedation; its dosing interval should be doubled in GFR 10–50 mL/min and tripled in GFR <10 mL/min.

Table 16‐15 Opioid drugs (Narcotics).

Sources: Alamo S, Esteve C, Pérez M. Dental considerations for the patient with renal disease. J Clin Experiment Dent. 2011;3(2):112–119; Ziccardi VB, Saini J, Demas PN, Braun TW. Management of the oral and maxillofacial surgery patient with end‐stage renal disease. J Oral Maxillofac Surg. 1992;50(11):1207–1212; Brockmann W, Badr M. Chronic kidney disease: pharmacological considerations for the dentist. J Am Dent Assoc. 2010;141(11):1330–1339; Svirsky JA, Nunley J, Dent CD, Yeatts D. Dental and medical considerations of patients with renal disease. J Calif Dent Assoc. 1998;26(10):761,763–770; Owsiany MT, Hawley CE, Triantafylidis LK, Paik JM. Opioid management in older adults with chronic kidney disease: a review. Am J Med. 2019;132(12):1386–1393.

Opioid Drug Effects
Buprenorphine, fentanyl,
ketamine, hydromorphone
Do not form active metabolites (relatively safe to use)
Hydrocodone, oxycodone,
Form active metabolites (should not be used in patients prior to undergoing in‐center HD; should be used judiciously in patients undergoing in‐center HD and those who have received KT)
Codeine Forms an active metabolite, morphine‐6‐glucuronide
Meperidine Forms an active metabolite, normeperidine (neurotoxic central nervous system stimulant and convulsant)
Propoxyphene Forms an active metabolite, norpropoxyphene, which accumulates due to its long half‐life (>36 hours) and causes cardiotoxic and seizure activity. Avoid its use in GFR <10 mL/min
Tramadol Forms an active metabolite, O‐desmethyltramadol, which accumulates and causes seizures and respiratory depression)

GFR, glomerular filtration rate; HD, hemodialysis; KT, kidney transplant.

Intravenous Sedation

A large cohort study that involved patients undergoing in‐center HD and conscious sedation by nephrologists has shown that midazolam alone was used in 95% of cases (mean dose of 3.4 mg); fentanyl alone in 1% of cases (mean dose 79 μg); and their combination in 4% of cases (mean doses 3.3 mg and 60 μg for midazolam and fentanyl, respectively). The study has concluded that both drugs were safe to use even in high‐risk patients, although in decreased doses.325 Another study has shown that compared to diazepam, midazolam was preferable because of the lower risk of thrombophlebitis.326

Local Anesthetics

Local anesthetics (administered during infiltration or nerve block anesthesia) have a hepatic route of elimination, and therefore they can be safely used in patients with renal disease at a regular dose (300–500 mg to 14 cartridges).258,284,297,311,312 Due to an increased prevalence of hypertension, epinephrine‐containing anesthetics should be used judiciously.312

Cardiovascular Considerations

Hypertension is a common etiologic factor, and at the same time a consequence of renal disease, which should be monitored pre‐ and postoperatively.258,295 In addition, some medications, such as NSAIDs, can produce hypertension.295 Due to the elevated blood potassium levels, renal patients may also present with increased neuromuscular excitability, potentially leading to life‐threatening ventricular arrhythmias and cardiac arrest.327 It is important to remember to protect dialysis access during dental procedures61,304,312 by avoiding the arm with vascular access for the measurement of blood pressure (as well as delivering IV medications or drawing blood),295,297,312 as its accidental damage can cause torrential hemorrhage.258 Patients should be kept in comfortable positions in the dental chair and allowed to take breaks as needed to minimize the risk of access obstruction.61 These patients should be treated sitting upright to minimize the risk of pulmonary edema and congestive heart failure.258 A recent study has shown that patients undergoing in‐center HD might have a higher prevalence of carotid artery calcifications identified in dental panoramic radiographs compared to patients with ESRD and CKD (26 vs. 22 vs. 16%).328 Therefore, a dentist may be the first healthcare specialist to observe these signs and refer the patient to a nephrologist or another medical specialist.

Nov 28, 2021 | Posted by in General Dentistry | Comments Off on Renal Diseases
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