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Chronic Kidney Disease CKD results from various etiologies that cause chronic damage to the glomeruli, tubulointerstitium, or vasculature. Glomerular damage is reflected by albuminuria. Tubulointerstitial damage may manifest as abnormalities in renal-concentrating abilities and low-grade tubular proteinuria. As the underlying structural abnormalities progress, GFR falls below normal levels. Most patients with CKD do not progress to ESKD. In healthy adults aged >30 years, the average rate of decline of eGFR is approximately 1 mL/min/1.73 m? per year; those with risk factors such as increased albuminuria/proteinuria and/or diabetic kidney disease are likely to have more rapid progres- sion. The most important predictors of progression to ESKD are baseline eGFR and severity of albuminuria/proteinuria. The eGER trajectory over time adds prognostic value for ESKD and cardiovascular outcomes. Renal risk variants in the apoli- poprotein L1 (APOL1) gene are prevalent in people with West African ancestry and are associated with higher rates of ESKD and progression of CKD, regardless of diabetes mellitus status (see Genetic Disorders and Kidney Disease). Screening FIGURE 22. Uremic frost presenting as powdery deposits of urea and uric acid salts on the skin in a patient with untreated chronic kidney disease. Uremic frost is Controversy exists regarding routine screening of asympto- a late and rarely seen manifestation of uremia. matic patients for CKD. Screening patients at risk for CKD, including those with diabetes, hypertension, or a family his- tory of kidney disease, is generally recommended. independent of GFR (such as extremes of muscle mass or diet), cystatin C should be measured to employ the CKD-EPI cystatin Cor creatinine-cystatin C equation. Initial assessment of albu- Clinical Manifestations minuria includes a spot urine albumin-creatinine ratio. If

Screening FIGURE 22. Uremic frost presenting as powdery deposits of urea and uric acid salts on the skin in a patient with untreated chronic kidney disease. Uremic frost is Controversy exists regarding routine screening of asympto- a late and rarely seen manifestation of uremia. matic patients for CKD. Screening patients at risk for CKD, including those with diabetes, hypertension, or a family his- tory of kidney disease, is generally recommended. independent of GFR (such as extremes of muscle mass or diet), cystatin C should be measured to employ the CKD-EPI cystatin Cor creatinine-cystatin C equation. Initial assessment of albu- Clinical Manifestations minuria includes a spot urine albumin-creatinine ratio. If CKD is typically asymptomatic except in advanced stages (G4, confirmation of albuminuria is required, the albumin excre- G5). As eGFR falls below 60 mL/min/1.73 m2, numerous alter- tion rate should be measured from a timed urine collection. ations in metabolic pathways, including 1,25-dihydroxyvita- See Clinical Evaluation of Kidney Function for more min D production and erythrocyte production, become altered information. due to the loss of nephron mass and hormone synthesis. Diagnosis of CKD requires an eGFR <60 mL/min/1.73 m? Moderate to severe CKD can also result in impaired ability to confirmed at least 3 months after initial assessment, or persis-

CKD is typically asymptomatic except in advanced stages (G4, confirmation of albuminuria is required, the albumin excre- G5). As eGFR falls below 60 mL/min/1.73 m2, numerous alter- tion rate should be measured from a timed urine collection. ations in metabolic pathways, including 1,25-dihydroxyvita- See Clinical Evaluation of Kidney Function for more min D production and erythrocyte production, become altered information. due to the loss of nephron mass and hormone synthesis. Diagnosis of CKD requires an eGFR <60 mL/min/1.73 m? Moderate to severe CKD can also result in impaired ability to confirmed at least 3 months after initial assessment, or persis- excrete salt and water, manifesting as edema. Patients with tent proteinuria or albuminuria regardless of eGFR. Kidney nephrotic-range proteinuria may also develop edema or biopsy is used to determine the etiology of CKD when a glo- anasarca. merular or tubulointerstitial disease is likely and when spe- When CKD progresses to ESKD, uremic symptoms, such cific therapy is available to delay or prevent further kidney as fatigue, nausea, loss of appetite, insomnia, irritability, dif- injury. Kidney biopsy is not routinely performed in the pres-

excrete salt and water, manifesting as edema. Patients with tent proteinuria or albuminuria regardless of eGFR. Kidney nephrotic-range proteinuria may also develop edema or biopsy is used to determine the etiology of CKD when a glo- anasarca. merular or tubulointerstitial disease is likely and when spe- When CKD progresses to ESKD, uremic symptoms, such cific therapy is available to delay or prevent further kidney as fatigue, nausea, loss of appetite, insomnia, irritability, dif- injury. Kidney biopsy is not routinely performed in the pres- ficulty concentrating, confusion, or pruritus can occur. Uremia ence of shrunken kidneys (<9 cm), which generally indicate can also induce pleuritis and pericarditis. Crystalized cutane- chronic irreversible disease. Ultrasound findings of hypere- ous urea and other nitrogenous waste deposits appear as choic kidneys may be noted consistent with medical kidney chalky skin deposits, termed uremic frost, and occur rarely as disease and usually reflect long-standing CKD. There is cur- a late manifestation of uremia (Figure 22). A large proportion rently a lack of evidence regarding the use of urinalysis as a of patients with CKD stage G5 manifest few or only intermit- routine screening test for CKD. tent uremic symptoms. Patients who experience acute kidney injury (AKI) can have slow recovery; studies have demonstrated that kidney function can continue to improve for up to 1 year after an ini- Diagnosis tial episode of AKI. Therefore, although diagnosis of CKD eGFR can be established using serum creatinine and the requires at least 3 months of persisting abnormalities in struc- Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration ture or function, a diagnosis of CKD made 3 months after AKI creatinine equation. If confirmation of GFR is required may be premature. AKI is a risk factor for subsequent CKD. because of conditions that affect serum creatinine Both the severity of AKI and the time required for recovery

ficulty concentrating, confusion, or pruritus can occur. Uremia ence of shrunken kidneys (<9 cm), which generally indicate can also induce pleuritis and pericarditis. Crystalized cutane- chronic irreversible disease. Ultrasound findings of hypere- ous urea and other nitrogenous waste deposits appear as choic kidneys may be noted consistent with medical kidney chalky skin deposits, termed uremic frost, and occur rarely as disease and usually reflect long-standing CKD. There is cur- a late manifestation of uremia (Figure 22). A large proportion rently a lack of evidence regarding the use of urinalysis as a of patients with CKD stage G5 manifest few or only intermit- routine screening test for CKD. tent uremic symptoms. Patients who experience acute kidney injury (AKI) can have slow recovery; studies have demonstrated that kidney function can continue to improve for up to 1 year after an ini- Diagnosis tial episode of AKI. Therefore, although diagnosis of CKD eGFR can be established using serum creatinine and the requires at least 3 months of persisting abnormalities in struc- Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration ture or function, a diagnosis of CKD made 3 months after AKI creatinine equation. If confirmation of GFR is required may be premature. AKI is a risk factor for subsequent CKD. because of conditions that affect serum creatinine Both the severity of AKI and the time required for recovery 76

Chronic Kidney Disease from AKI influence the likelihood of having CKD after 1 year. recommend a target blood pressure of <130/80 mm Hg Thirty percent to 47% of patients have CKD 1 year after an epi- in patients with hypertension and CKD. sode of AKI, and 1% to 3% of patients progress to stage G5 or An ACE inhibitor or an angiotensin receptor blocker is a ESKD. Therefore, patients with a history of AKI should have preferred drug for treatment of hypertension for patients with their kidney function monitored. stage G3 CKD or higher or for those with stage G1 or G2 CKD with albuminuria (albumin-creatinine ratio >300 mg/g). These medications may slow the progression of CKD in some e Chronic kidney disease is defined as abnormal kidney patients. Thiazide diuretics are a cornerstone of hypertension structure or function present for >3 months. treatment but lose efficacy with severe CKD. Therefore, loop ¢ Staging of chronic kidney disease is based on estimated diuretics serve an important role in managing salt and water glomerular filtration rate and albuminuria. retention associated with proteinuria and CKD. Dietary e Acute kidney injury is a substantial risk factor for sub- sodium chloride restriction is essential for blood pressure con- sequent chronic kidney disease. trol in most forms of CKD. KDIGO recommends restricting sodium intake to <2000 mg/d. See Hypertension for more information.

sequent chronic kidney disease. trol in most forms of CKD. KDIGO recommends restricting sodium intake to <2000 mg/d. See Hypertension for more information. Complications and Management Dyslipidemia According to KDIGO guidelines, referral to a nephrologist is Elevated LDL cholesterol and triglyceride levels with low HDL indicated for evaluation and management of CKD in the pres- cholesterol levels are common among patients with CKD. ence of the following: AKI or an abrupt, sustained fall in GFR; Conflicting data exist on the effect of treating dyslipidemia in GFR <30 mL/min/1.73 m?; persistent albuminuria (>300 mg/g); reducing proteinuria and in slowing the progression of CKD. progression of CKD; erythrocyte casts; >20 erythrocytes/hpf Statins have been shown to reduce cardiovascular and all- that is sustained and not readily explained; hypertension cause mortality in patients with CKD, although large trials refractory to treatment with four or more antihypertensive have failed to demonstrate a mortality benefit for statins in agents; persistent abnormalities of serum potassium; recur- patients with dialysis-dependent ESKD. KDIGO guidelines rent or extensive nephrolithiasis; or hereditary kidney recommend treatment with a statin in all patients aged disease. >50 years with non-dialysis-dependent CKD and in adults A kidney failure risk equation (KFRE) has been developed aged 18 to 49 years with non-dialysis-dependent CKD and any and validated (https://kidneyfailurerisk.com). The KFRE uses one of the following: coronary artery disease, diabetes, prior four variables (age, sex, eGFR, and albuminuria) to predict ischemic stroke, or a >10% estimated risk for coronary death or 2-year and 5-year risk for ESKD in patients with CKD stages nonfatal myocardial infarction. Statins are also recommended G3 to G5. The KFRE performs well across age, sex, and pres- for adult kidney transplant recipients. The 2018 AHA/ACC ence/absence of diabetes. The use of this equation is consistent Guideline on the Management of Blood Cholesterol indicates with KDIGO guidelines, which recommend integration of risk that it is reasonable to initiate a moderate-intensity statin with prediction in the evaluation and management of CKD. or without ezetimibe in adults 40 to 75 years of age with CKD, an LDL cholesterol measure of 70 to 189 mg/dL (1.8 to Cardiovascular Disease 4.9 mmol/L), and a 10-year atherosclerotic cardiovascular disease Cardiovascular disease is the leading cause of death among risk of 27.5%. The guideline recommends against initiating patients with CKD. The risk for cardiovascular-related death statin therapy in patients on dialysis, but it may be reasonable in patients with CKD stages G3 and G4 is four to five times to continue statins in patients beginning dialysis therapy. higher than the risk for progression to ESKD. Mortality risk Dyslipidemia associated with the nephrotic syndrome increases with decreasing eGFR and increasing albuminuria. helps maintain plasma oncotic pressure but, over time, may Unfortunately, many clinical trials guiding the prevention or hasten the progression of glomerular injury. Dyslipidemia in treatment of cardiovascular disease did not include patients the nephrotic syndrome requires aggressive treatment to pre- with advanced CKD. However, most post hoc analyses of rand- vent atherosclerotic disease. See Glomerular Diseases for more omized controlled trials that had participants with some degree information on the nephrotic syndrome. of CKD demonstrated efficacy regardless of baseline CKD sta- tus, including interventions such as percutaneous coronary Coronary Artery Disease interventions. Thus, experts recommend against withholding Coronary artery disease (CAD) prevalence is significantly otherwise efficacious therapies from those with CKD due to increased among patients with CKD compared with the gen- unsubstantiated concerns of lack of efficacy or harm. eral population. This is partly explained by the high prevalence of shared risk factors/comorbidities such as diabetes or hyper- Hypertension tension. However, CKD is independently associated with CAD. Both KDIGO and the 2017 American College of Cardiology (ACC)/ This association strengthens with declining eGFR and rising American Heart Association (AHA) blood pressure guideline albuminuria.

Complications and Management Dyslipidemia According to KDIGO guidelines, referral to a nephrologist is Elevated LDL cholesterol and triglyceride levels with low HDL indicated for evaluation and management of CKD in the pres- cholesterol levels are common among patients with CKD. ence of the following: AKI or an abrupt, sustained fall in GFR; Conflicting data exist on the effect of treating dyslipidemia in GFR <30 mL/min/1.73 m?; persistent albuminuria (>300 mg/g); reducing proteinuria and in slowing the progression of CKD. progression of CKD; erythrocyte casts; >20 erythrocytes/hpf Statins have been shown to reduce cardiovascular and all- that is sustained and not readily explained; hypertension cause mortality in patients with CKD, although large trials refractory to treatment with four or more antihypertensive have failed to demonstrate a mortality benefit for statins in agents; persistent abnormalities of serum potassium; recur- patients with dialysis-dependent ESKD. KDIGO guidelines rent or extensive nephrolithiasis; or hereditary kidney recommend treatment with a statin in all patients aged disease. >50 years with non-dialysis-dependent CKD and in adults A kidney failure risk equation (KFRE) has been developed aged 18 to 49 years with non-dialysis-dependent CKD and any and validated (https://kidneyfailurerisk.com). The KFRE uses one of the following: coronary artery disease, diabetes, prior four variables (age, sex, eGFR, and albuminuria) to predict ischemic stroke, or a >10% estimated risk for coronary death or 2-year and 5-year risk for ESKD in patients with CKD stages nonfatal myocardial infarction. Statins are also recommended G3 to G5. The KFRE performs well across age, sex, and pres- for adult kidney transplant recipients. The 2018 AHA/ACC ence/absence of diabetes. The use of this equation is consistent Guideline on the Management of Blood Cholesterol indicates with KDIGO guidelines, which recommend integration of risk that it is reasonable to initiate a moderate-intensity statin with prediction in the evaluation and management of CKD. or without ezetimibe in adults 40 to 75 years of age with CKD, an LDL cholesterol measure of 70 to 189 mg/dL (1.8 to Cardiovascular Disease 4.9 mmol/L), and a 10-year atherosclerotic cardiovascular disease Cardiovascular disease is the leading cause of death among risk of 27.5%. The guideline recommends against initiating patients with CKD. The risk for cardiovascular-related death statin therapy in patients on dialysis, but it may be reasonable in patients with CKD stages G3 and G4 is four to five times to continue statins in patients beginning dialysis therapy. higher than the risk for progression to ESKD. Mortality risk Dyslipidemia associated with the nephrotic syndrome increases with decreasing eGFR and increasing albuminuria. helps maintain plasma oncotic pressure but, over time, may Unfortunately, many clinical trials guiding the prevention or hasten the progression of glomerular injury. Dyslipidemia in treatment of cardiovascular disease did not include patients the nephrotic syndrome requires aggressive treatment to pre- with advanced CKD. However, most post hoc analyses of rand- vent atherosclerotic disease. See Glomerular Diseases for more omized controlled trials that had participants with some degree information on the nephrotic syndrome. of CKD demonstrated efficacy regardless of baseline CKD sta- tus, including interventions such as percutaneous coronary Coronary Artery Disease interventions. Thus, experts recommend against withholding Coronary artery disease (CAD) prevalence is significantly otherwise efficacious therapies from those with CKD due to increased among patients with CKD compared with the gen- unsubstantiated concerns of lack of efficacy or harm. eral population. This is partly explained by the high prevalence of shared risk factors/comorbidities such as diabetes or hyper- Hypertension tension. However, CKD is independently associated with CAD. Both KDIGO and the 2017 American College of Cardiology (ACC)/ This association strengthens with declining eGFR and rising American Heart Association (AHA) blood pressure guideline albuminuria. 77

Chronic Kidney Disease In patients with CKD, serum biomarkers for myocardial Parathyroids ischemia such as cardiac troponins may be chronically ele- vated due to decreased renal clearance. Serial troponin measurements and other markers such as creatine kinase- PTH €-10 MB can help distinguish acute ischemia from chronic | J elevations. 1,25(OH)2D Bone Kidney >| Gl Tract ¢ Guidelines recommenda target blood pressure of <130/80 mm Hg in patients with hypertension and ¥ 4 Increased osteoclast Increased tubular Increased intestinal chronic kidney disease. bone resorption calcium reabsorption calcium absorption e Treatment of hypertension in patients with stage G3 chronic kidney disease (CKD) or higher or for those with ) proteinuric CKD (albumin-creatinine ratio >300 mg/g) Decreased calcium

¢ Guidelines recommenda target blood pressure of <130/80 mm Hg in patients with hypertension and ¥ 4 Increased osteoclast Increased tubular Increased intestinal chronic kidney disease. bone resorption calcium reabsorption calcium absorption e Treatment of hypertension in patients with stage G3 chronic kidney disease (CKD) or higher or for those with ) proteinuric CKD (albumin-creatinine ratio >300 mg/g) Decreased calcium . excretion includes an ACE inhibitor or angiotensin receptor blocker, dietary sodium restriction to <2000 mg/d, and addition of a diuretic as needed to control vascular volume. Lael T Serum Cat* el e The Kidney Disease: Improving Global Outcomes guide- lines recommend treatment with a statin in all patients FIGURE 23. Overview of the metabolic systems that maintain calcium homeostasis. with non-dialysis-dependent chronic kidney disease Parathyroid hormone (PTH) stimulates increased 1,25-dihydroxyvitamin D [1,25(0H),D] (CKD) who are older than 50 years of age and in adults synthesis by the kidneys, and 1,25(OH),D causes feedback suppression of PTH production.

. excretion includes an ACE inhibitor or angiotensin receptor blocker, dietary sodium restriction to <2000 mg/d, and addition of a diuretic as needed to control vascular volume. Lael T Serum Cat* el e The Kidney Disease: Improving Global Outcomes guide- lines recommend treatment with a statin in all patients FIGURE 23. Overview of the metabolic systems that maintain calcium homeostasis. with non-dialysis-dependent chronic kidney disease Parathyroid hormone (PTH) stimulates increased 1,25-dihydroxyvitamin D [1,25(0H),D] (CKD) who are older than 50 years of age and in adults synthesis by the kidneys, and 1,25(OH),D causes feedback suppression of PTH production. 18 to 49 years of age with non-dialysis- dependent CKD Ca**= ionized calcium; Gl = gastrointestinal; 1,25(0H),D = 1,25-dihydroxyvitamin D (calcitriol); PTH = parathyroid hormone; T = increased. and any one of the following: coronary artery disease, diabetes mellitus, prior ischemic stroke, or a >10% esti- FGF-23 is a peptide secreted by osteocytes and likely by mated risk for coronary death or nonfatal myocardial other types of bone cells. It acts on the kidney to induce phos- infarction. phaturia and downregulates 1a-hydroxylase to inhibit synthe- e The 2018 American Heart Association/American College sis of 1,25-dihydroxyvitamin D. FGF-23 rises in stage G3a CKD, of Cardiology Guideline on the Management ofBlood preceding PTH elevation. As GFR falls and PTH rises, PTH Cholesterol indicates that it is reasonable to initiate a directly stimulates further FGF-23 production by osteocytes. moderate-intensity statin with or without ezetimibe in Initially, the high FGF-23 serves to increase renal phosphorus adults 40 to 75 years of age with chronic kidney disease, excretion and helps maintain normal phosphorus levels as an LDL cholesterol measure of 70 to 189 mg/dL (1.8 to GFR declines. 4.9 mmol/L), and a 10-year atherosclerotic cardiovascu- As CKD progresses, increased FGF-23 and decreased lar disease risk of 27.5%. nephron mass reduce the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by renal tubular cells. Reduction Chronic Kidney Disease-Mineral in 1,25-dihydroxyvitamin D levels results in lower intestinal and Bone Disorder absorption of calcium and phosphorus in the gut, mitigating As kidney function declines, homeostasis of calcium and increases in serum phosphorus but also contributing to hypoc- phosphorus becomes compromised, resulting in alterations of alcemia, especially late in CKD. Reduced 1,25-dihydroxyvita- blood levels of calcium, phosphorus, regulatory hormones, min D levels also increase PTH production by the parathyroid bone mineralization, and pathologic calcification. The term glands, and hypocalcemia is a potent stimulus for further chronic kidney disease-mineral and bone disorder (CKD- increases in PTH levels. MBD) encompasses these changes. Increased plasma PTH caused by CKD is referred to as secondary hyperparathyroidism. Increased PTH levels result Calcium and Phosphorus Homeostasis in reduced calcium excretion, increased calcium absorption Three hormones are largely responsible for regulating calcium from the gut, increased phosphorus excretion by the kidneys, and phosphorus homeostasis: parathyroid hormone (PTH), and activation of osteoclast bone resorption. Early in CKD, vitamin D, and fibroblast growth factor 23 (FGF-23). PTH is the the increase in renal phosphorus excretion induced by PTH most important regulator of calcium and phosphorus concen- and FGF-23 enables normal phosphorus levels despite trations. PTH has three separate mechanisms to increase reduced renal excretory capacity. However, as CKD pro- serum calcium: stimulation of osteoclasts to resorb bone, gresses, compensation for the increased release of phospho- hydroxylation of 25-hydroxyvitamin D in the kidneys, and rus from bone is lost, and phosphorus levels rise. This results tubular reabsorption of calcium (Figure 23). Concurrently, in a vicious cycle as hyperphosphatemia stimulates PTH PTH induces renal phosphorus excretion. production.

18 to 49 years of age with non-dialysis- dependent CKD Ca**= ionized calcium; Gl = gastrointestinal; 1,25(0H),D = 1,25-dihydroxyvitamin D (calcitriol); PTH = parathyroid hormone; T = increased. and any one of the following: coronary artery disease, diabetes mellitus, prior ischemic stroke, or a >10% esti- FGF-23 is a peptide secreted by osteocytes and likely by mated risk for coronary death or nonfatal myocardial other types of bone cells. It acts on the kidney to induce phos- infarction. phaturia and downregulates 1a-hydroxylase to inhibit synthe- e The 2018 American Heart Association/American College sis of 1,25-dihydroxyvitamin D. FGF-23 rises in stage G3a CKD, of Cardiology Guideline on the Management ofBlood preceding PTH elevation. As GFR falls and PTH rises, PTH Cholesterol indicates that it is reasonable to initiate a directly stimulates further FGF-23 production by osteocytes. moderate-intensity statin with or without ezetimibe in Initially, the high FGF-23 serves to increase renal phosphorus adults 40 to 75 years of age with chronic kidney disease, excretion and helps maintain normal phosphorus levels as an LDL cholesterol measure of 70 to 189 mg/dL (1.8 to GFR declines. 4.9 mmol/L), and a 10-year atherosclerotic cardiovascu- As CKD progresses, increased FGF-23 and decreased lar disease risk of 27.5%. nephron mass reduce the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by renal tubular cells. Reduction Chronic Kidney Disease-Mineral in 1,25-dihydroxyvitamin D levels results in lower intestinal and Bone Disorder absorption of calcium and phosphorus in the gut, mitigating As kidney function declines, homeostasis of calcium and increases in serum phosphorus but also contributing to hypoc- phosphorus becomes compromised, resulting in alterations of alcemia, especially late in CKD. Reduced 1,25-dihydroxyvita- blood levels of calcium, phosphorus, regulatory hormones, min D levels also increase PTH production by the parathyroid bone mineralization, and pathologic calcification. The term glands, and hypocalcemia is a potent stimulus for further chronic kidney disease-mineral and bone disorder (CKD- increases in PTH levels. MBD) encompasses these changes. Increased plasma PTH caused by CKD is referred to as secondary hyperparathyroidism. Increased PTH levels result Calcium and Phosphorus Homeostasis in reduced calcium excretion, increased calcium absorption Three hormones are largely responsible for regulating calcium from the gut, increased phosphorus excretion by the kidneys, and phosphorus homeostasis: parathyroid hormone (PTH), and activation of osteoclast bone resorption. Early in CKD, vitamin D, and fibroblast growth factor 23 (FGF-23). PTH is the the increase in renal phosphorus excretion induced by PTH most important regulator of calcium and phosphorus concen- and FGF-23 enables normal phosphorus levels despite trations. PTH has three separate mechanisms to increase reduced renal excretory capacity. However, as CKD pro- serum calcium: stimulation of osteoclasts to resorb bone, gresses, compensation for the increased release of phospho- hydroxylation of 25-hydroxyvitamin D in the kidneys, and rus from bone is lost, and phosphorus levels rise. This results tubular reabsorption of calcium (Figure 23). Concurrently, in a vicious cycle as hyperphosphatemia stimulates PTH PTH induces renal phosphorus excretion. production. 78

Chronic Kidney Disease If secondary hyperparathyroidism cannot be adequately controlled, tertiary hyperparathyroidism can ensue. Tertiary hyperparathyroidism is the result of prolonged PTH stimula- tion needed to maintain eucalcemia. This prolonged stimula- tion results in severe parathyroid hyperplasia with elevated PTH levels that are no longer suppressible by elevated plasma calcium concentration. Laboratory Abnormalities Serum calcium and phosphorus levels typically remain in the normal range until the eGFR drops below 30 mL/min/1.73 m?, at which point the ability of elevated FGF-23 and PTH levels to promote phosphorus excretion becomes overwhelmed, and hyperphosphatemia develops. Progressive decline in 1,25-dihydroxyvitamin D levels results in reduced intestinal FIGURE 24. Calcified vessels in a patient with chronic kidney disease. calcium absorption, and hyperphosphatemia promotes pre- cipitation of calcium and phosphorus in extraskeletal tissues, associated with cardiovascular and all-cause mortality; KDIGO leading to hypocalcemia. guidelines suggest treating patients with CKD and arterial In addition to reduced conversion of 25-hydroxyvitamin calcification as appropriate for patients in the highest category D (calcidiol) to 1,25-dihydroxyvitamin D (calcitriol), patients of cardiovascular risk, although treatments specifically tar- with CKD also have a higher prevalence of 25-hydroxyvitamin geted at reducing vascular calcification have not been shown D deficiency. KDIGO guidelines recommend that patients with to improve clinical outcomes.

D (calcidiol) to 1,25-dihydroxyvitamin D (calcitriol), patients of cardiovascular risk, although treatments specifically tar- with CKD also have a higher prevalence of 25-hydroxyvitamin geted at reducing vascular calcification have not been shown D deficiency. KDIGO guidelines recommend that patients with to improve clinical outcomes. an eGFR <60 mL/min/1.73 m? be evaluated for 25-hydroxyvi- tamin D deficiency and supplemented as per guidelines for the Renal Osteodystrophy general population. Renal osteodystrophy refers to alteration of bone morphology PTH levels are often elevated in patients with an eGFR with CKD, rendering affected patients at increased risk for bone <60 mL/min/1.73 m? and progressively increase with wors- pain, falls, and fractures. Five main types of histologic changes ening CKD. KDIGO guidelines recommend measuring in bone can occur (discussed below). Diagnosis of renal osteo- intact PTH levels to aid in the detection and management dystrophy can be supported by PTH levels followed over time, of secondary hyperparathyroidism and its complications but definitive diagnosis requires a bone biopsy. KDIGO guide- (Table 32). lines recommend a bone biopsy if knowledge of the type of renal osteodystrophy will affect treatment decisions. Vascular Calcification An increased prevalence of arterial calcification, including the Osteitis Fibrosa Cystica coronary arteries, has been noted in patients with CKD (Figure 24); Osteitis fibrosa cystica is due to abnormally high bone turno- the burden of calcification is highest in patients with ESKD. ver that occurs after prolonged exposure of bone to sustained Arterial calcification reduces vascular compliance and con- high levels of PTH in secondary hyperparathyroidism. It is tributes to the increased prevalence of left ventricular hyper- associated with increased number and activity of osteoblasts trophy observed in patients with CKD. Arterial calcification is and osteoclasts and expansion of osteoid surfaces. Classic skel- etal changes on radiograph include subperiosteal resorption of

an eGFR <60 mL/min/1.73 m? be evaluated for 25-hydroxyvi- tamin D deficiency and supplemented as per guidelines for the Renal Osteodystrophy general population. Renal osteodystrophy refers to alteration of bone morphology PTH levels are often elevated in patients with an eGFR with CKD, rendering affected patients at increased risk for bone <60 mL/min/1.73 m? and progressively increase with wors- pain, falls, and fractures. Five main types of histologic changes ening CKD. KDIGO guidelines recommend measuring in bone can occur (discussed below). Diagnosis of renal osteo- intact PTH levels to aid in the detection and management dystrophy can be supported by PTH levels followed over time, of secondary hyperparathyroidism and its complications but definitive diagnosis requires a bone biopsy. KDIGO guide- (Table 32). lines recommend a bone biopsy if knowledge of the type of renal osteodystrophy will affect treatment decisions. Vascular Calcification An increased prevalence of arterial calcification, including the Osteitis Fibrosa Cystica coronary arteries, has been noted in patients with CKD (Figure 24); Osteitis fibrosa cystica is due to abnormally high bone turno- the burden of calcification is highest in patients with ESKD. ver that occurs after prolonged exposure of bone to sustained Arterial calcification reduces vascular compliance and con- high levels of PTH in secondary hyperparathyroidism. It is tributes to the increased prevalence of left ventricular hyper- associated with increased number and activity of osteoblasts trophy observed in patients with CKD. Arterial calcification is and osteoclasts and expansion of osteoid surfaces. Classic skel- etal changes on radiograph include subperiosteal resorption of TABLE 32. Laboratory Abnormalities in Hyperparathyroidism bone, most prominently at the phalanges of the hands, and radiolucent bone cysts of the long bones (Figure 25). Types of Hyperparathyroidism | Primary Secondary Tertiary Adynamic Bone Disease | Calcium High Low High Adynamic bone disease occurs when there is a lack of bone | Phosphate Low to low High High | cell activity and a markedly reduced rate of bone turnover. normal | Histopathologic abnormalities include decreased osteoclast PTH High High Veryhigh activity with decreased osteoid. Patients have suppressed PTH Calcitriol High Low Low | levels (due to chronic illness or aggressive treatment with vita- FGF-23 Normal to High High min D analogues) or skeletal resistance to PTH from down- slightly regulation of the bone PTH receptor due to high circulating elevated PTH levels. Adynamic bone disease should be excluded before Calcitriol = 1,25-dihydroxyvitamin D; FGF-23 = fibroblast growth factor 23; PTH = | initiation of bisphosphonate therapy because these drugs can parathyroid hormone. | cause and/or worsen the disease by inhibiting osteoclast | *Data vary. activity.

TABLE 32. Laboratory Abnormalities in Hyperparathyroidism bone, most prominently at the phalanges of the hands, and radiolucent bone cysts of the long bones (Figure 25). Types of Hyperparathyroidism | Primary Secondary Tertiary Adynamic Bone Disease | Calcium High Low High Adynamic bone disease occurs when there is a lack of bone | Phosphate Low to low High High | cell activity and a markedly reduced rate of bone turnover. normal | Histopathologic abnormalities include decreased osteoclast PTH High High Veryhigh activity with decreased osteoid. Patients have suppressed PTH Calcitriol High Low Low | levels (due to chronic illness or aggressive treatment with vita- FGF-23 Normal to High High min D analogues) or skeletal resistance to PTH from down- slightly regulation of the bone PTH receptor due to high circulating elevated PTH levels. Adynamic bone disease should be excluded before Calcitriol = 1,25-dihydroxyvitamin D; FGF-23 = fibroblast growth factor 23; PTH = | initiation of bisphosphonate therapy because these drugs can parathyroid hormone. | cause and/or worsen the disease by inhibiting osteoclast | *Data vary. activity. 79

Chronic Kidney Disease among patients with CKD and ESKD. Observational studies suggest a mortality benefit of therapy with phosphate binders and vitamin D analogues to lower serum phosphorus and PTH. Unfortunately, prospective randomized trials are lacking in this field. Some trials comparing noncalcium-based to calcium-based binders suggest a mortality benefit of noncal- cium-based agents. A randomized trial of calcimimetics, which inhibit PTH secretion via activation of the calcium- sensing receptor, did not show benefit in the composite outcome of cardiovascular events and mortality. However, secondary analysis of available data suggests benefit for both the composite outcome and reduction in need for parathyroid- ectomy as well as fewer cases of calciphylaxis. Oral and intra- venous calcimimetics are available in the United States. There are currently no therapies aimed at lowering FGF-23 levels. KDIGO guidelines for treatment of CKD-MBD are based on the available data and expert opinion (Table 33). In patients with CKD stages G3a to G5, treatment is based on serial assessments of phosphorus, calcium, and PTH levels. KDIGO guidelines recommend that elevated phosphorus levels be lowered toward FIGURE 25. Humerus showing radiologic changes of osteitis fibrosa cystica, the normal range. Treatment options include dietary modifica- characterized by bone cysts and radiolucent lytic areas of the long bones caused by brown tumors. Brown tumors represent a collection of osteoclasts and fibrous tions and administration of phosphate binders. For patients material that appears brown secondary to hemosiderin deposition. with CKD stages G3a to G5 who are not on dialysis, optimal PTH levels are not known. Patients with rising or elevated levels should be evaluated for potentially modifiable contributors, Osteomalacia including elevated phosphorus levels or vitamin D deficiency. Osteomalacia is characterized by decreased mineralization of KDIGO guidelines recommend avoiding hypercalcemia osteoid at sites of bone turnover. Although patients with CKD and inappropriate calcium loading given concerns that expo- are at increased risk for osteomalacia, CKD does not cause sure to exogenous calcium contributes to harmful vascular cal- osteomalacia per se; vitamin D deficiency caused by coexisting cification in all stages of CKD. Use of calcitriol and vitamin D factors such as intestinal malabsorption or restricted access to analogues to lower PTH levels in patients with CKD stages G3a sunlight are often present. to G5 who are not on dialysis should be avoided. Instead, these agents should be reserved for patients with CKD stages G4 to G5 Mixed Uremic Osteodystrophy with severe and progressive hyperparathyroidism. The dose of Mixed uremic osteodystrophy is the term used to describe calcium-based phosphate binders should be minimized, or renal osteodystrophy containing elements of both high bone noncalcium-based binders can be used preferentially. turnover and decreased mineralization. In patients on dialysis, KDIGO guidelines recommend use of calcimimetics, calcitriol, or vitamin D analogues, or a com- Osteoporosis bination of calcimimetics and calcitriol or vitamin D ana- Patients with CKD may also develop osteoporosis. KDIGO logues, to lower PTH levels. guidelines indicate that in patients with CKD stages G3a to G5 Tertiary hyperparathyroidism does not respond to phos- with evidence of CKD-MBD and/or risk factors for osteoporo- phate binders or calcitriol therapy. Patients often require par- sis, bone mineral density testing is suggested to assess fracture athyroidectomy for definitive treatment. risk if results will affect treatment decisions. Patients with CKD who have osteoporosis and eGFR >30 mL/min/1.73 m? can be treated as per the non-CKD population. Bisphosphonates e Chronic kidney disease-mineral and bone disorder is are not recommended for use in patients with eGFR <30 to characterized by alterations of blood levels of the cal- 35 mL/min/1.73 m*. However, for patients with CKD stage G4 cium, phosphorus, and regulatory hormones; bone to G5 with fragility fractures and suspected osteoporosis, treat- mineralization; and pathologic calcification. ment may be considered, usually in conjunction with an expert in CKD-MBD. e Management of chronic kidney disease-mineral and bone disorder focuses upon normalizing serum phos-

among patients with CKD and ESKD. Observational studies suggest a mortality benefit of therapy with phosphate binders and vitamin D analogues to lower serum phosphorus and PTH. Unfortunately, prospective randomized trials are lacking in this field. Some trials comparing noncalcium-based to calcium-based binders suggest a mortality benefit of noncal- cium-based agents. A randomized trial of calcimimetics, which inhibit PTH secretion via activation of the calcium- sensing receptor, did not show benefit in the composite outcome of cardiovascular events and mortality. However, secondary analysis of available data suggests benefit for both the composite outcome and reduction in need for parathyroid- ectomy as well as fewer cases of calciphylaxis. Oral and intra- venous calcimimetics are available in the United States. There are currently no therapies aimed at lowering FGF-23 levels. KDIGO guidelines for treatment of CKD-MBD are based on the available data and expert opinion (Table 33). In patients with CKD stages G3a to G5, treatment is based on serial assessments of phosphorus, calcium, and PTH levels. KDIGO guidelines recommend that elevated phosphorus levels be lowered toward FIGURE 25. Humerus showing radiologic changes of osteitis fibrosa cystica, the normal range. Treatment options include dietary modifica- characterized by bone cysts and radiolucent lytic areas of the long bones caused by brown tumors. Brown tumors represent a collection of osteoclasts and fibrous tions and administration of phosphate binders. For patients material that appears brown secondary to hemosiderin deposition. with CKD stages G3a to G5 who are not on dialysis, optimal PTH levels are not known. Patients with rising or elevated levels should be evaluated for potentially modifiable contributors, Osteomalacia including elevated phosphorus levels or vitamin D deficiency. Osteomalacia is characterized by decreased mineralization of KDIGO guidelines recommend avoiding hypercalcemia osteoid at sites of bone turnover. Although patients with CKD and inappropriate calcium loading given concerns that expo- are at increased risk for osteomalacia, CKD does not cause sure to exogenous calcium contributes to harmful vascular cal- osteomalacia per se; vitamin D deficiency caused by coexisting cification in all stages of CKD. Use of calcitriol and vitamin D factors such as intestinal malabsorption or restricted access to analogues to lower PTH levels in patients with CKD stages G3a sunlight are often present. to G5 who are not on dialysis should be avoided. Instead, these agents should be reserved for patients with CKD stages G4 to G5 Mixed Uremic Osteodystrophy with severe and progressive hyperparathyroidism. The dose of Mixed uremic osteodystrophy is the term used to describe calcium-based phosphate binders should be minimized, or renal osteodystrophy containing elements of both high bone noncalcium-based binders can be used preferentially. turnover and decreased mineralization. In patients on dialysis, KDIGO guidelines recommend use of calcimimetics, calcitriol, or vitamin D analogues, or a com- Osteoporosis bination of calcimimetics and calcitriol or vitamin D ana- Patients with CKD may also develop osteoporosis. KDIGO logues, to lower PTH levels. guidelines indicate that in patients with CKD stages G3a to G5 Tertiary hyperparathyroidism does not respond to phos- with evidence of CKD-MBD and/or risk factors for osteoporo- phate binders or calcitriol therapy. Patients often require par- sis, bone mineral density testing is suggested to assess fracture athyroidectomy for definitive treatment. risk if results will affect treatment decisions. Patients with CKD who have osteoporosis and eGFR >30 mL/min/1.73 m? can be treated as per the non-CKD population. Bisphosphonates e Chronic kidney disease-mineral and bone disorder is are not recommended for use in patients with eGFR <30 to characterized by alterations of blood levels of the cal- 35 mL/min/1.73 m*. However, for patients with CKD stage G4 cium, phosphorus, and regulatory hormones; bone to G5 with fragility fractures and suspected osteoporosis, treat- mineralization; and pathologic calcification. ment may be considered, usually in conjunction with an expert in CKD-MBD. e Management of chronic kidney disease-mineral and bone disorder focuses upon normalizing serum phos- Management phorus, avoiding hypercalcemia, and addressing modi-

among patients with CKD and ESKD. Observational studies suggest a mortality benefit of therapy with phosphate binders and vitamin D analogues to lower serum phosphorus and PTH. Unfortunately, prospective randomized trials are lacking in this field. Some trials comparing noncalcium-based to calcium-based binders suggest a mortality benefit of noncal- cium-based agents. A randomized trial of calcimimetics, which inhibit PTH secretion via activation of the calcium- sensing receptor, did not show benefit in the composite outcome of cardiovascular events and mortality. However, secondary analysis of available data suggests benefit for both the composite outcome and reduction in need for parathyroid- ectomy as well as fewer cases of calciphylaxis. Oral and intra- venous calcimimetics are available in the United States. There are currently no therapies aimed at lowering FGF-23 levels. KDIGO guidelines for treatment of CKD-MBD are based on the available data and expert opinion (Table 33). In patients with CKD stages G3a to G5, treatment is based on serial assessments of phosphorus, calcium, and PTH levels. KDIGO guidelines recommend that elevated phosphorus levels be lowered toward FIGURE 25. Humerus showing radiologic changes of osteitis fibrosa cystica, the normal range. Treatment options include dietary modifica- characterized by bone cysts and radiolucent lytic areas of the long bones caused by brown tumors. Brown tumors represent a collection of osteoclasts and fibrous tions and administration of phosphate binders. For patients material that appears brown secondary to hemosiderin deposition. with CKD stages G3a to G5 who are not on dialysis, optimal PTH levels are not known. Patients with rising or elevated levels should be evaluated for potentially modifiable contributors, Osteomalacia including elevated phosphorus levels or vitamin D deficiency. Osteomalacia is characterized by decreased mineralization of KDIGO guidelines recommend avoiding hypercalcemia osteoid at sites of bone turnover. Although patients with CKD and inappropriate calcium loading given concerns that expo- are at increased risk for osteomalacia, CKD does not cause sure to exogenous calcium contributes to harmful vascular cal- osteomalacia per se; vitamin D deficiency caused by coexisting cification in all stages of CKD. Use of calcitriol and vitamin D factors such as intestinal malabsorption or restricted access to analogues to lower PTH levels in patients with CKD stages G3a sunlight are often present. to G5 who are not on dialysis should be avoided. Instead, these agents should be reserved for patients with CKD stages G4 to G5 Mixed Uremic Osteodystrophy with severe and progressive hyperparathyroidism. The dose of Mixed uremic osteodystrophy is the term used to describe calcium-based phosphate binders should be minimized, or renal osteodystrophy containing elements of both high bone noncalcium-based binders can be used preferentially. turnover and decreased mineralization. In patients on dialysis, KDIGO guidelines recommend use of calcimimetics, calcitriol, or vitamin D analogues, or a com- Osteoporosis bination of calcimimetics and calcitriol or vitamin D ana- Patients with CKD may also develop osteoporosis. KDIGO logues, to lower PTH levels. guidelines indicate that in patients with CKD stages G3a to G5 Tertiary hyperparathyroidism does not respond to phos- with evidence of CKD-MBD and/or risk factors for osteoporo- phate binders or calcitriol therapy. Patients often require par- sis, bone mineral density testing is suggested to assess fracture athyroidectomy for definitive treatment. risk if results will affect treatment decisions. Patients with CKD who have osteoporosis and eGFR >30 mL/min/1.73 m? can be treated as per the non-CKD population. Bisphosphonates e Chronic kidney disease-mineral and bone disorder is are not recommended for use in patients with eGFR <30 to characterized by alterations of blood levels of the cal- 35 mL/min/1.73 m*. However, for patients with CKD stage G4 cium, phosphorus, and regulatory hormones; bone to G5 with fragility fractures and suspected osteoporosis, treat- mineralization; and pathologic calcification. ment may be considered, usually in conjunction with an expert in CKD-MBD. e Management of chronic kidney disease-mineral and bone disorder focuses upon normalizing serum phos- Management phorus, avoiding hypercalcemia, and addressing modi- Elevated phosphorus, PTH, and FGF-23 levels are associated fiable factors. (Continued) with risk for adverse cardiovascular events and mortality

Management phorus, avoiding hypercalcemia, and addressing modi- Elevated phosphorus, PTH, and FGF-23 levels are associated fiable factors. (Continued) with risk for adverse cardiovascular events and mortality 80

Chronic Kidney Disease TABLE 33. Medications Used in the Treatment of Chronic Kidney Disease-Mineral and Bone Disorder Class/Agent Mechanism of Action Phosphate binders Binds phosphate in GI tract before it can be absorbed; the binder-phosphate complex is | Noncalcium-based binders (e.g., sevelamer hydrochloride, sevelamer excreted in the stool. carbonate, lanthanum carbonate)* lron-based (noncalcium) binders (e.g., sucroferric oxyhydroxide, ferric citrate)? Calcium-based binders (e.g., calcium carbonate, calcium acetate) Aluminum-based binders (e.g., aluminum hydroxide)? Activated vitamin D agents (e.g., calcitriol, paricalcitol, doxercalciferol) Inhibits PTH secretion via binding the vitamin D receptor on the parathyroid gland. Calcimimetic agents (e.g., cinacalcet, etelcalcetide) Inhibits PTH secretion via binding the calcium- sensing receptor, resulting in a morphology change and rendering the receptor more sensitive to the presence of calcium; for a given level of calcium, there is greater inhibition of PTH secretion. | Calcitriol = 1,25-dihydroxyvitamin D; GI = gastrointestinal; PTH = parathyroid hormone. @Preferred over calcium-based binders.

Calcimimetic agents (e.g., cinacalcet, etelcalcetide) Inhibits PTH secretion via binding the calcium- sensing receptor, resulting in a morphology change and rendering the receptor more sensitive to the presence of calcium; for a given level of calcium, there is greater inhibition of PTH secretion. | Calcitriol = 1,25-dihydroxyvitamin D; GI = gastrointestinal; PTH = parathyroid hormone. @Preferred over calcium-based binders. | 'Aluminum-based phosphate binders are associated with aluminum toxicity and should no longer be used in patients with chronic kidney disease.

Calcimimetic agents (e.g., cinacalcet, etelcalcetide) Inhibits PTH secretion via binding the calcium- sensing receptor, resulting in a morphology change and rendering the receptor more sensitive to the presence of calcium; for a given level of calcium, there is greater inhibition of PTH secretion. | Calcitriol = 1,25-dihydroxyvitamin D; GI = gastrointestinal; PTH = parathyroid hormone. @Preferred over calcium-based binders. | 'Aluminum-based phosphate binders are associated with aluminum toxicity and should no longer be used in patients with chronic kidney disease. An FDA boxed warning for use of ESAs includes an increased risk for thromboembolic events in postsurgical HVC ¢ Use of calcitriol and vitamin D analogues to lower para- patients not receiving anticoagulant therapy, and an increased thyroid hormone should be avoided in patients with risk for serious cardiovascular events when ESAs are adminis- chronic kidney disease who are not on dialysis unless tered to patients with hemoglobin levels >11 g/dL (110 g/L). they have progressive hyperparathyroidism. Prolyl hydroxylase inhibitors are a novel class of drugs ¢ Noncalcium-based phosphate binders should be used under investigation to treat anemia associated with CKD. preferentially over calcium based options in patients These oral medications can increase the endogenous produc- with chronic kidney disease-mineral and bone disorder. tion of erythropoietin and reduce hepcidin levels, improving iron availability and increasing hemoglobin levels. Anemia All patients with CKD and anemia should have iron pro- Anemia in the setting of CKD is common, and its prevalence files assessed, including total iron-binding capacity and increases as CKD progresses into stages G4 and G5. Most often ferritin levels. KDIGO suggests maintaining transferrin normocytic, anemia in CKD is multifactorial with contribut- saturation levels >30% and serum ferritin levels >500 ng/mL ing factors, including the relative lack of erythropoietin pro- (500 ug/L) using either oral or intravenous iron supplemen- duction due to decline in functional renal mass; erythropoie- tation. Inadequate iron stores contribute to ESA hyporespon- tin resistance; disordered iron handling with elevated hepcidin siveness. Blood transfusions can be used in patients with leading to functional iron deficiency as well as true iron defi- severe anemia or symptoms; however, erythrocyte transfu- ciency with blood loss; and neocytolysis in the uremic milieu. sions should be minimized because of concerns for iron Concern for the development of left ventricular hypertro- overload and sensitization to HLA antigens, which may lead phy and observational data linking higher hemoglobin levels to allosensitization and increased waiting times for kidney with better outcomes led to the belief that higher hemoglobin transplantation. values were beneficial in patients with CKD and ESKD. However, several large randomized controlled trials demon- Metabolic Acidosis strated either no benefit or an increased risk for cardiovascular Metabolic acidosis frequently occurs in patients with CKD events and strokes in groups randomly assigned to higher because of defective acid excretion. Untreated metabolic aci- hemoglobin targets via erythropoiesis-stimulating agents dosis can lead to muscle loss (due to increased muscle prote- (ESAs). Furthermore, these trials revealed only modest olysis) and bone loss (due to increased bone resorption and improvements in fatigue and no benefit in physical function- impaired bone formation). Patients with early CKD have a ing with higher hemoglobin targets. Thus, current KDIGO normal anion gap hyperchloremic metabolic acidosis due to recommendations as well as American Society of Nephrology impaired ammoniagenesis, resulting in reduced bicarbonate (ASN) high-value care tenets suggest considering ESAs only generation. As GFR declines, organic and inorganic anions are for patients with CKD who have hemoglobin concentrations retained, and an increased anion gap metabolic acidosis <10 g/dL (100 g/L). develops.

An FDA boxed warning for use of ESAs includes an increased risk for thromboembolic events in postsurgical HVC ¢ Use of calcitriol and vitamin D analogues to lower para- patients not receiving anticoagulant therapy, and an increased thyroid hormone should be avoided in patients with risk for serious cardiovascular events when ESAs are adminis- chronic kidney disease who are not on dialysis unless tered to patients with hemoglobin levels >11 g/dL (110 g/L). they have progressive hyperparathyroidism. Prolyl hydroxylase inhibitors are a novel class of drugs ¢ Noncalcium-based phosphate binders should be used under investigation to treat anemia associated with CKD. preferentially over calcium based options in patients These oral medications can increase the endogenous produc- with chronic kidney disease-mineral and bone disorder. tion of erythropoietin and reduce hepcidin levels, improving iron availability and increasing hemoglobin levels. Anemia All patients with CKD and anemia should have iron pro- Anemia in the setting of CKD is common, and its prevalence files assessed, including total iron-binding capacity and increases as CKD progresses into stages G4 and G5. Most often ferritin levels. KDIGO suggests maintaining transferrin normocytic, anemia in CKD is multifactorial with contribut- saturation levels >30% and serum ferritin levels >500 ng/mL ing factors, including the relative lack of erythropoietin pro- (500 ug/L) using either oral or intravenous iron supplemen- duction due to decline in functional renal mass; erythropoie- tation. Inadequate iron stores contribute to ESA hyporespon- tin resistance; disordered iron handling with elevated hepcidin siveness. Blood transfusions can be used in patients with leading to functional iron deficiency as well as true iron defi- severe anemia or symptoms; however, erythrocyte transfu- ciency with blood loss; and neocytolysis in the uremic milieu. sions should be minimized because of concerns for iron Concern for the development of left ventricular hypertro- overload and sensitization to HLA antigens, which may lead phy and observational data linking higher hemoglobin levels to allosensitization and increased waiting times for kidney with better outcomes led to the belief that higher hemoglobin transplantation. values were beneficial in patients with CKD and ESKD. However, several large randomized controlled trials demon- Metabolic Acidosis strated either no benefit or an increased risk for cardiovascular Metabolic acidosis frequently occurs in patients with CKD events and strokes in groups randomly assigned to higher because of defective acid excretion. Untreated metabolic aci- hemoglobin targets via erythropoiesis-stimulating agents dosis can lead to muscle loss (due to increased muscle prote- (ESAs). Furthermore, these trials revealed only modest olysis) and bone loss (due to increased bone resorption and improvements in fatigue and no benefit in physical function- impaired bone formation). Patients with early CKD have a ing with higher hemoglobin targets. Thus, current KDIGO normal anion gap hyperchloremic metabolic acidosis due to recommendations as well as American Society of Nephrology impaired ammoniagenesis, resulting in reduced bicarbonate (ASN) high-value care tenets suggest considering ESAs only generation. As GFR declines, organic and inorganic anions are for patients with CKD who have hemoglobin concentrations retained, and an increased anion gap metabolic acidosis <10 g/dL (100 g/L). develops. 81

Chronic Kidney Disease Large observational studies have showna strong associa- whether proteinuria is a marker of the underlying severity of tion between lower serum bicarbonate levels and increased kidney damage and disease, or if proteinuria itself activates progression of CKD and mortality. Meta-analysis of rand- inflammatory pathways and contributes to tubulointerstitial omized trials of alkali therapy, most commonly sodium fibrosis. Although renin-angiotensin system blockade will bicarbonate or sodium citrate, support delayed progression decrease proteinuria, the use of dual therapy combining ACE of CKD. KDIGO guidelines recommend initiating alkali inhibitors, angiotensin receptor blockers, or direct renin therapy when the serum bicarbonate level is chronically inhibitors results in more adverse events (hyperkalemia, <22 mEq/L (22 mmol/L). The alkali salt therapy dose should hypotension, AKI) without additional cardiovascular or be titrated to achieve a serum bicarbonate level within the renal benefits. normal range; excessive alkali therapy in the setting of a reduced GFR may induce a metabolic alkalosis, which is associated with increased mortality. An alternative approach Interventions to Slow is the provision of alkali through a diet rich in fruits and Renal Decline vegetables, which may have equal efficacy in improving Protein Restriction serum bicarbonate levels. In animal models, protein-restricted diets slow the progres- sion of kidney disease by reducing glomerular filtration pres- Nephrotoxins sure. However, in the Modification of Diet in Renal Disease

Large observational studies have showna strong associa- whether proteinuria is a marker of the underlying severity of tion between lower serum bicarbonate levels and increased kidney damage and disease, or if proteinuria itself activates progression of CKD and mortality. Meta-analysis of rand- inflammatory pathways and contributes to tubulointerstitial omized trials of alkali therapy, most commonly sodium fibrosis. Although renin-angiotensin system blockade will bicarbonate or sodium citrate, support delayed progression decrease proteinuria, the use of dual therapy combining ACE of CKD. KDIGO guidelines recommend initiating alkali inhibitors, angiotensin receptor blockers, or direct renin therapy when the serum bicarbonate level is chronically inhibitors results in more adverse events (hyperkalemia, <22 mEq/L (22 mmol/L). The alkali salt therapy dose should hypotension, AKI) without additional cardiovascular or be titrated to achieve a serum bicarbonate level within the renal benefits. normal range; excessive alkali therapy in the setting of a reduced GFR may induce a metabolic alkalosis, which is associated with increased mortality. An alternative approach Interventions to Slow is the provision of alkali through a diet rich in fruits and Renal Decline vegetables, which may have equal efficacy in improving Protein Restriction serum bicarbonate levels. In animal models, protein-restricted diets slow the progres- sion of kidney disease by reducing glomerular filtration pres- Nephrotoxins sure. However, in the Modification of Diet in Renal Disease Two major issues exist regarding drug administration in study, no definitive benefit was seen in renal outcomes in patients with CKD: 1) Renally excreted drugs require dose patients randomly assigned to the low-protein (0.6 g/kg/d) adjustment to avoid accumulation and potential side group. Although there is insufficient evidence to recommend effects; and 2) Reduced functional nephron mass increases routine use of low-protein diets to slow progression of CKD, the probability that a potentially nephrotoxic drug will high-protein diets may accelerate symptoms of uremia in cause nephrotoxicity. Nephrotoxins may cause AKI or patients with stage G5 CKD. Small studies suggest that low- CKD. protein diets might delay the onset of symptomatic uremia Conceptually, it is useful to compartmentalize nephro- and the need for renal replacement therapy in patients with toxic medications by their main site of action. Several medi- stage G5 CKD not yet on dialysis.

Two major issues exist regarding drug administration in study, no definitive benefit was seen in renal outcomes in patients with CKD: 1) Renally excreted drugs require dose patients randomly assigned to the low-protein (0.6 g/kg/d) adjustment to avoid accumulation and potential side group. Although there is insufficient evidence to recommend effects; and 2) Reduced functional nephron mass increases routine use of low-protein diets to slow progression of CKD, the probability that a potentially nephrotoxic drug will high-protein diets may accelerate symptoms of uremia in cause nephrotoxicity. Nephrotoxins may cause AKI or patients with stage G5 CKD. Small studies suggest that low- CKD. protein diets might delay the onset of symptomatic uremia Conceptually, it is useful to compartmentalize nephro- and the need for renal replacement therapy in patients with toxic medications by their main site of action. Several medi- stage G5 CKD not yet on dialysis. cations, including NSAIDs, calcineurin inhibitors, and ACE inhibitors/angiotensin receptor blockers, have effects on Smoking Cessation glomerular blood flow. Patients with AKI who are on NSAIDs Data strongly support the adverse impact of tobacco exposure should have the medications immediately discontinued. For on renal function. No prospective studies have been done to patients with CKD, the ASN recommends the avoidance of demonstrate improvement in CKD with tobacco cessation. NSAIDs, including cyclooxygenase-2 inhibitors, due to the However, given the well-documented harms of tobacco expo- risk of worsening kidney function. ACE inhibitors or angi- sure and the benefits gained with cessation in other organ otensin receptor blockers are a cornerstone of treatment systems, smoking cessation should be encouraged and sup- for patients with CKD; however, during episodes of acute ported for patients with CKD as well. illness and/or volume depletion, these drugs increase the risk for AKI due to their effects on intraglomerular pres- Diabetes Management sure. Drugs that cause glomerular injury, tubular injury, or In patients with type 2 diabetes and CKD, the American tubulointerstitial nephritis are reviewed in Acute Kidney Diabetes Association (ADA) and KDIGO recommend the Injury. addition of a sodium-glucose cotransporter 2 (SGLT2) Medications or toxin exposures associated with the devel- inhibitor to metformin to reduce the risk of CKD progres- opment and progression of CKD include proton pump inhibi- sion and cardiovascular events. The ADA recommends the tors, NSAIDs, combination ingredient analgesics, lithium, use of a glucagon-like peptide 1 (GLP-1) receptor agonist in exposure to lead, and environmental exposure to the carcino- patients with CKD who are at risk for cardiovascular genic plant toxin aristolochic acid. Care for patients with CKD events to reduce risk of progression of albuminuria and should include avoidance of medications such as NSAIDs and cardiovascular events. KDIGO recommends the adding a proton pump inhibitors as well as dose adjustment of fre- GLP-1 receptor agonist in patients who have not achieved quently used medications, including antibiotics and direct individualized glycemic targets despite use of metformin oral anticoagulants. and SGLT2 inhibitors, or who are unable to use those medications. Neither metformin nor SGLT2 inhibitors Proteinuria are recommended in patients with an eGFR <30 mL/min/ The severity of proteinuria is strongly associated with 1.73 m?. See Glomerular Diseases for more information on adverse clinical outcomes, including progression of CKD to diabetic kidney disease, diabetes mellitus, and SGLT2 ESKD, cardiovascular morbidity, and mortality. It is unclear inhibitors.

cations, including NSAIDs, calcineurin inhibitors, and ACE inhibitors/angiotensin receptor blockers, have effects on Smoking Cessation glomerular blood flow. Patients with AKI who are on NSAIDs Data strongly support the adverse impact of tobacco exposure should have the medications immediately discontinued. For on renal function. No prospective studies have been done to patients with CKD, the ASN recommends the avoidance of demonstrate improvement in CKD with tobacco cessation. NSAIDs, including cyclooxygenase-2 inhibitors, due to the However, given the well-documented harms of tobacco expo- risk of worsening kidney function. ACE inhibitors or angi- sure and the benefits gained with cessation in other organ otensin receptor blockers are a cornerstone of treatment systems, smoking cessation should be encouraged and sup- for patients with CKD; however, during episodes of acute ported for patients with CKD as well. illness and/or volume depletion, these drugs increase the risk for AKI due to their effects on intraglomerular pres- Diabetes Management sure. Drugs that cause glomerular injury, tubular injury, or In patients with type 2 diabetes and CKD, the American tubulointerstitial nephritis are reviewed in Acute Kidney Diabetes Association (ADA) and KDIGO recommend the Injury. addition of a sodium-glucose cotransporter 2 (SGLT2) Medications or toxin exposures associated with the devel- inhibitor to metformin to reduce the risk of CKD progres- opment and progression of CKD include proton pump inhibi- sion and cardiovascular events. The ADA recommends the tors, NSAIDs, combination ingredient analgesics, lithium, use of a glucagon-like peptide 1 (GLP-1) receptor agonist in exposure to lead, and environmental exposure to the carcino- patients with CKD who are at risk for cardiovascular genic plant toxin aristolochic acid. Care for patients with CKD events to reduce risk of progression of albuminuria and should include avoidance of medications such as NSAIDs and cardiovascular events. KDIGO recommends the adding a proton pump inhibitors as well as dose adjustment of fre- GLP-1 receptor agonist in patients who have not achieved quently used medications, including antibiotics and direct individualized glycemic targets despite use of metformin oral anticoagulants. and SGLT2 inhibitors, or who are unable to use those medications. Neither metformin nor SGLT2 inhibitors Proteinuria are recommended in patients with an eGFR <30 mL/min/ The severity of proteinuria is strongly associated with 1.73 m?. See Glomerular Diseases for more information on adverse clinical outcomes, including progression of CKD to diabetic kidney disease, diabetes mellitus, and SGLT2 ESKD, cardiovascular morbidity, and mortality. It is unclear inhibitors. 82

Chronic Kidney Disease HVC e Erythropoiesis-stimulating agents should not be used for most patients with chronic kidney disease and hemoglobin >11 g/dL (110 g/L) because of an increased risk for serious cardiovascular events and strokes. e The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend treatment of metabolic acidosis with alkali therapy in patients with chronic kidney disease when the serum bicarbonate is chroni- cally <22 mEq/L (22 mmol/L). FIGURE 26. Indurated papules and plaques are characteristic of early e Routine care for patients with chronic kidney disease nephrogenic systemic fibrosis. These will eventually coalesce into large plaques. should include avoidance of medications such as NSAIDs and proton pump inhibitors as well as dose adjustment of frequently used medications, including National Kidney Foundation consider group II GBCM to pre-

e The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend treatment of metabolic acidosis with alkali therapy in patients with chronic kidney disease when the serum bicarbonate is chroni- cally <22 mEq/L (22 mmol/L). FIGURE 26. Indurated papules and plaques are characteristic of early e Routine care for patients with chronic kidney disease nephrogenic systemic fibrosis. These will eventually coalesce into large plaques. should include avoidance of medications such as NSAIDs and proton pump inhibitors as well as dose adjustment of frequently used medications, including National Kidney Foundation consider group II GBCM to pre- antibiotics and direct oral anticoagulants. sent a very low to nonexistent risk of NSF and should be the GBCM type used for patients at risk for NSF who must receive HVC e ACE inhibitors and angiotensin receptor blockers MRI with contrast. There is insufficient data to quantify risk in decrease proteinuria and slow progression of proteinu- patients receiving group III GBCM. Additional recommenda- ric kidney diseases, but use of both drug classes in com- tions include using the lowest volume of contrast adequate for bination results in more adverse events without addi- the study and scheduling the study temporally close to the tional cardiovascular or renal benefits. next hemodialysis session for those receiving hemodialysis. e Sodium-glucose cotransporter 2 inhibitors and glucagon- like peptide 1 receptor agonists should be considered for Vaccination patients with type 2 diabetes mellitus and chronic kidney Patients with CKD are at increased risk for infections that can disease independent of hemoglobin A,,. be prevented by vaccination; however, these patients also have impaired immune responses to vaccines. Patients with CKD should receive vaccinations according to CDC guidelines, Special Considerations including COVID-19, which state that vaccinations in patients Imaging Contrast Agents with CKD may be more effective when performed before the Intravenous iodinated contrast has long been associated need for chronic dialysis or kidney transplantation. Special with AKI (termed contrast-associated nephropathy [CAN)]). considerations for patients with CKD include the following: Contrast-induced nephropathy (CIN), a subset of CAN, is e Patients with advanced CKD near dialysis dependence or directly mediated by the contrast agent. Recent data suggest those with ESKD on hemodialysis not already immune to that the frequency of CIN is less than originally believed, as hepatitis B virus (HBV) should be vaccinated against HBV. hospitalized patients who require noncontrast imaging e Patients with CKD or the nephrotic syndrome should receive develop AKI at the same frequency. However, the risk for CAN the 13- and 23-valent pneumococcal vaccines, with revacci- and CIN increases with increasing severity of CKD. The 2018 nation with the 23-valent vaccine after a minimum of5 years. American College of Radiology (ACR) Manual on Contrast Media suggests avoidance of iodinated contrast for patients e Influenza vaccine should be administered annually to

antibiotics and direct oral anticoagulants. sent a very low to nonexistent risk of NSF and should be the GBCM type used for patients at risk for NSF who must receive HVC e ACE inhibitors and angiotensin receptor blockers MRI with contrast. There is insufficient data to quantify risk in decrease proteinuria and slow progression of proteinu- patients receiving group III GBCM. Additional recommenda- ric kidney diseases, but use of both drug classes in com- tions include using the lowest volume of contrast adequate for bination results in more adverse events without addi- the study and scheduling the study temporally close to the tional cardiovascular or renal benefits. next hemodialysis session for those receiving hemodialysis. e Sodium-glucose cotransporter 2 inhibitors and glucagon- like peptide 1 receptor agonists should be considered for Vaccination patients with type 2 diabetes mellitus and chronic kidney Patients with CKD are at increased risk for infections that can disease independent of hemoglobin A,,. be prevented by vaccination; however, these patients also have impaired immune responses to vaccines. Patients with CKD should receive vaccinations according to CDC guidelines, Special Considerations including COVID-19, which state that vaccinations in patients Imaging Contrast Agents with CKD may be more effective when performed before the Intravenous iodinated contrast has long been associated need for chronic dialysis or kidney transplantation. Special with AKI (termed contrast-associated nephropathy [CAN)]). considerations for patients with CKD include the following: Contrast-induced nephropathy (CIN), a subset of CAN, is e Patients with advanced CKD near dialysis dependence or directly mediated by the contrast agent. Recent data suggest those with ESKD on hemodialysis not already immune to that the frequency of CIN is less than originally believed, as hepatitis B virus (HBV) should be vaccinated against HBV. hospitalized patients who require noncontrast imaging e Patients with CKD or the nephrotic syndrome should receive develop AKI at the same frequency. However, the risk for CAN the 13- and 23-valent pneumococcal vaccines, with revacci- and CIN increases with increasing severity of CKD. The 2018 nation with the 23-valent vaccine after a minimum of5 years. American College of Radiology (ACR) Manual on Contrast Media suggests avoidance of iodinated contrast for patients e Influenza vaccine should be administered annually to with an eGFR <30 mL/min/1.73 m?. Patients with CKD and an patients with CKD; patients with ESKD should preferen-

antibiotics and direct oral anticoagulants. sent a very low to nonexistent risk of NSF and should be the GBCM type used for patients at risk for NSF who must receive HVC e ACE inhibitors and angiotensin receptor blockers MRI with contrast. There is insufficient data to quantify risk in decrease proteinuria and slow progression of proteinu- patients receiving group III GBCM. Additional recommenda- ric kidney diseases, but use of both drug classes in com- tions include using the lowest volume of contrast adequate for bination results in more adverse events without addi- the study and scheduling the study temporally close to the tional cardiovascular or renal benefits. next hemodialysis session for those receiving hemodialysis. e Sodium-glucose cotransporter 2 inhibitors and glucagon- like peptide 1 receptor agonists should be considered for Vaccination patients with type 2 diabetes mellitus and chronic kidney Patients with CKD are at increased risk for infections that can disease independent of hemoglobin A,,. be prevented by vaccination; however, these patients also have impaired immune responses to vaccines. Patients with CKD should receive vaccinations according to CDC guidelines, Special Considerations including COVID-19, which state that vaccinations in patients Imaging Contrast Agents with CKD may be more effective when performed before the Intravenous iodinated contrast has long been associated need for chronic dialysis or kidney transplantation. Special with AKI (termed contrast-associated nephropathy [CAN)]). considerations for patients with CKD include the following: Contrast-induced nephropathy (CIN), a subset of CAN, is e Patients with advanced CKD near dialysis dependence or directly mediated by the contrast agent. Recent data suggest those with ESKD on hemodialysis not already immune to that the frequency of CIN is less than originally believed, as hepatitis B virus (HBV) should be vaccinated against HBV. hospitalized patients who require noncontrast imaging e Patients with CKD or the nephrotic syndrome should receive develop AKI at the same frequency. However, the risk for CAN the 13- and 23-valent pneumococcal vaccines, with revacci- and CIN increases with increasing severity of CKD. The 2018 nation with the 23-valent vaccine after a minimum of5 years. American College of Radiology (ACR) Manual on Contrast Media suggests avoidance of iodinated contrast for patients e Influenza vaccine should be administered annually to with an eGFR <30 mL/min/1.73 m?. Patients with CKD and an patients with CKD; patients with ESKD should preferen- eGFR <30 mL/min/1.73 m? who require iodinated contrast tially receive the inactivated influenza vaccine.

antibiotics and direct oral anticoagulants. sent a very low to nonexistent risk of NSF and should be the GBCM type used for patients at risk for NSF who must receive HVC e ACE inhibitors and angiotensin receptor blockers MRI with contrast. There is insufficient data to quantify risk in decrease proteinuria and slow progression of proteinu- patients receiving group III GBCM. Additional recommenda- ric kidney diseases, but use of both drug classes in com- tions include using the lowest volume of contrast adequate for bination results in more adverse events without addi- the study and scheduling the study temporally close to the tional cardiovascular or renal benefits. next hemodialysis session for those receiving hemodialysis. e Sodium-glucose cotransporter 2 inhibitors and glucagon- like peptide 1 receptor agonists should be considered for Vaccination patients with type 2 diabetes mellitus and chronic kidney Patients with CKD are at increased risk for infections that can disease independent of hemoglobin A,,. be prevented by vaccination; however, these patients also have impaired immune responses to vaccines. Patients with CKD should receive vaccinations according to CDC guidelines, Special Considerations including COVID-19, which state that vaccinations in patients Imaging Contrast Agents with CKD may be more effective when performed before the Intravenous iodinated contrast has long been associated need for chronic dialysis or kidney transplantation. Special with AKI (termed contrast-associated nephropathy [CAN)]). considerations for patients with CKD include the following: Contrast-induced nephropathy (CIN), a subset of CAN, is e Patients with advanced CKD near dialysis dependence or directly mediated by the contrast agent. Recent data suggest those with ESKD on hemodialysis not already immune to that the frequency of CIN is less than originally believed, as hepatitis B virus (HBV) should be vaccinated against HBV. hospitalized patients who require noncontrast imaging e Patients with CKD or the nephrotic syndrome should receive develop AKI at the same frequency. However, the risk for CAN the 13- and 23-valent pneumococcal vaccines, with revacci- and CIN increases with increasing severity of CKD. The 2018 nation with the 23-valent vaccine after a minimum of5 years. American College of Radiology (ACR) Manual on Contrast Media suggests avoidance of iodinated contrast for patients e Influenza vaccine should be administered annually to with an eGFR <30 mL/min/1.73 m?. Patients with CKD and an patients with CKD; patients with ESKD should preferen- eGFR <30 mL/min/1.73 m? who require iodinated contrast tially receive the inactivated influenza vaccine. should receive intravenous hydration with isotonic saline before and after receiving contrast unless there is evidence of Vascular Access frank pulmonary edema. Prophylactic saline infusion should Patients with advanced CKD may ultimately require renal also be considered in patients with an eGFR of 30 to 44 mL/ replacement therapy (RRT). For patients who choose hemodi- min/1.73 m? who have other risk factors for AKI. See Acute alysis, timely vascular access creation is essential. Referral to Kidney Injury for more information on CIN. an experienced surgeon many months before dialysis is critical Group I gadolinium-based contrast media (GBCM) used because arteriovenous fistula placement, the safest and most in MRI have been associated with nephrogenic systemic fibro- enduring option for vascular access, can be technically chal- sis (NSF) in patients with ESKD on dialysis and advanced CKD lenging and may require several months for full maturation. or AKI with eGFR <30 mL/min/1.73 m2. These patients present Arteriovenous fistulas have superior clinical outcomes com- with symmetrical, fibrotic indurated papules, plaques, or sub- pared with arteriovenous grafts. Tunneled catheters may be cutaneous nodules most commonly located on the legs, the used for dialysis promptly after placement, but they are associ- mid-thighs, and upper arms (Figure 26). The ACR and the ated with increased risk for bloodstream infection and death.

should receive intravenous hydration with isotonic saline before and after receiving contrast unless there is evidence of Vascular Access frank pulmonary edema. Prophylactic saline infusion should Patients with advanced CKD may ultimately require renal also be considered in patients with an eGFR of 30 to 44 mL/ replacement therapy (RRT). For patients who choose hemodi- min/1.73 m? who have other risk factors for AKI. See Acute alysis, timely vascular access creation is essential. Referral to Kidney Injury for more information on CIN. an experienced surgeon many months before dialysis is critical Group I gadolinium-based contrast media (GBCM) used because arteriovenous fistula placement, the safest and most in MRI have been associated with nephrogenic systemic fibro- enduring option for vascular access, can be technically chal- sis (NSF) in patients with ESKD on dialysis and advanced CKD lenging and may require several months for full maturation. or AKI with eGFR <30 mL/min/1.73 m2. These patients present Arteriovenous fistulas have superior clinical outcomes com- with symmetrical, fibrotic indurated papules, plaques, or sub- pared with arteriovenous grafts. Tunneled catheters may be cutaneous nodules most commonly located on the legs, the used for dialysis promptly after placement, but they are associ- mid-thighs, and upper arms (Figure 26). The ACR and the ated with increased risk for bloodstream infection and death. 83

Chronic Kidney Disease Protecting the nondominant arm veins is paramount and stage G3 progress to ESKD, but most die from cardiovascular involves limiting phlebotomy and intravenous catheters in that disease or infection before they progress to advanced CKD. arm. Data demonstrate that peripherally inserted central cath- Patients with an eGFR <30 mL/min/1.73 m? should be edu- eters (PICC lines) placed before or after initiation of hemodi- cated about RRT treatment options, including hemodialysis, alysis are independently associated with a 15% to 20% lower peritoneal dialysis, and kidney transplantation. Studies demon- likelihood of transition to any working fistula or graft. The strate no benefit in starting RRT in asymptomatic patients or at a ASN recommends that PICC line catheters should be avoided specific eGFR cutoff compared with watchful waiting and initi- in patients with an eGFR <60 mL/min/1.73 m?. Avoidance of ating RRT for symptoms or metabolic abnormalities that are subclavian venous catheters helps limit subclavian stenosis, refractory to medical treatment. Patients with advanced age or which can impair the proper functioning of an arteriovenous multiple comorbidities may not want any of these life-sustaining access used for dialysis. options. There has been increasing use of “kidney supportive care,” which involves services aimed at improving the quality of Older Patients life for patients with advanced CKD. Treatment is aligned with CKD stages G1 through G3a in older patients without albumi- the patient’s goals through culturally sensitive shared decision- nuria is of minimal clinical importance. For older patients making and advance care planning, along with treating symp- with progressing or severe CKD necessitating discussions toms resulting from uremia, hypervolemia, hyperkalemia, and/ about RRT and/or referral for evaluation for kidney transplan- or acidosis. Care should align with patient preferences and max- tation, a patient-centered approach is preferred. Comorbid imize the patient’s quality of life (Table 34). Shared decision- medical conditions, functional status, expected outcomes, and making regarding goals of care for patients with advanced CKD

Protecting the nondominant arm veins is paramount and stage G3 progress to ESKD, but most die from cardiovascular involves limiting phlebotomy and intravenous catheters in that disease or infection before they progress to advanced CKD. arm. Data demonstrate that peripherally inserted central cath- Patients with an eGFR <30 mL/min/1.73 m? should be edu- eters (PICC lines) placed before or after initiation of hemodi- cated about RRT treatment options, including hemodialysis, alysis are independently associated with a 15% to 20% lower peritoneal dialysis, and kidney transplantation. Studies demon- likelihood of transition to any working fistula or graft. The strate no benefit in starting RRT in asymptomatic patients or at a ASN recommends that PICC line catheters should be avoided specific eGFR cutoff compared with watchful waiting and initi- in patients with an eGFR <60 mL/min/1.73 m?. Avoidance of ating RRT for symptoms or metabolic abnormalities that are subclavian venous catheters helps limit subclavian stenosis, refractory to medical treatment. Patients with advanced age or which can impair the proper functioning of an arteriovenous multiple comorbidities may not want any of these life-sustaining access used for dialysis. options. There has been increasing use of “kidney supportive care,” which involves services aimed at improving the quality of Older Patients life for patients with advanced CKD. Treatment is aligned with CKD stages G1 through G3a in older patients without albumi- the patient’s goals through culturally sensitive shared decision- nuria is of minimal clinical importance. For older patients making and advance care planning, along with treating symp- with progressing or severe CKD necessitating discussions toms resulting from uremia, hypervolemia, hyperkalemia, and/ about RRT and/or referral for evaluation for kidney transplan- or acidosis. Care should align with patient preferences and max- tation, a patient-centered approach is preferred. Comorbid imize the patient’s quality of life (Table 34). Shared decision- medical conditions, functional status, expected outcomes, and making regarding goals of care for patients with advanced CKD patient preferences regarding goals of care should be consid- is an important high-value care tenet of the ASN.

Protecting the nondominant arm veins is paramount and stage G3 progress to ESKD, but most die from cardiovascular involves limiting phlebotomy and intravenous catheters in that disease or infection before they progress to advanced CKD. arm. Data demonstrate that peripherally inserted central cath- Patients with an eGFR <30 mL/min/1.73 m? should be edu- eters (PICC lines) placed before or after initiation of hemodi- cated about RRT treatment options, including hemodialysis, alysis are independently associated with a 15% to 20% lower peritoneal dialysis, and kidney transplantation. Studies demon- likelihood of transition to any working fistula or graft. The strate no benefit in starting RRT in asymptomatic patients or at a ASN recommends that PICC line catheters should be avoided specific eGFR cutoff compared with watchful waiting and initi- in patients with an eGFR <60 mL/min/1.73 m?. Avoidance of ating RRT for symptoms or metabolic abnormalities that are subclavian venous catheters helps limit subclavian stenosis, refractory to medical treatment. Patients with advanced age or which can impair the proper functioning of an arteriovenous multiple comorbidities may not want any of these life-sustaining access used for dialysis. options. There has been increasing use of “kidney supportive care,” which involves services aimed at improving the quality of Older Patients life for patients with advanced CKD. Treatment is aligned with CKD stages G1 through G3a in older patients without albumi- the patient’s goals through culturally sensitive shared decision- nuria is of minimal clinical importance. For older patients making and advance care planning, along with treating symp- with progressing or severe CKD necessitating discussions toms resulting from uremia, hypervolemia, hyperkalemia, and/ about RRT and/or referral for evaluation for kidney transplan- or acidosis. Care should align with patient preferences and max- tation, a patient-centered approach is preferred. Comorbid imize the patient’s quality of life (Table 34). Shared decision- medical conditions, functional status, expected outcomes, and making regarding goals of care for patients with advanced CKD patient preferences regarding goals of care should be consid- is an important high-value care tenet of the ASN. ered. For patients aged 280 years at the start of hemodialysis treatment, data demonstrate better survival among those who Dialysis received pre-hemodialysis nephrology care that followed a Hemodialysis planned management pathway, had good nutritional status, Hemodialysis achieves clearance of blood solutes by convec- and had an arteriovenous fistula as vascular access for hemo- tion and diffusion against a concentration gradient with dialysis at the time of hemodialysis initiation. dialysate flowing countercurrent to blood separated by a semi- permeable dialyzer membrane. Hemodialysis is commonly

ered. For patients aged 280 years at the start of hemodialysis treatment, data demonstrate better survival among those who Dialysis received pre-hemodialysis nephrology care that followed a Hemodialysis planned management pathway, had good nutritional status, Hemodialysis achieves clearance of blood solutes by convec- and had an arteriovenous fistula as vascular access for hemo- tion and diffusion against a concentration gradient with dialysis at the time of hemodialysis initiation. dialysate flowing countercurrent to blood separated by a semi- permeable dialyzer membrane. Hemodialysis is commonly e Patients with an estimated glomerular filtration rate performed three times per week for 3.5- to 4.5-hour treatment <30 mL/min/1.73 m?, who require iodinated contrast sessions at an outpatient dialysis unit. Frequent and/or longer should receive intravenous hydration with isotonic treatments provide better control of volume status and serum saline before and after receiving contrast unless there is electrolytes. In addition to the inconvenience of time spent in

<30 mL/min/1.73 m?, who require iodinated contrast sessions at an outpatient dialysis unit. Frequent and/or longer should receive intravenous hydration with isotonic treatments provide better control of volume status and serum saline before and after receiving contrast unless there is electrolytes. In addition to the inconvenience of time spent in evidence of frank pulmonary edema. the dialysis unit, patients may have symptomatic hypotension during or following dialysis. Some patients also describe e For patients with advanced chronic kidney disease who excessive fatigue following dialysis sessions. Some patients require MRI with a gadolinium-based contrast media perform hemodialysis at home four to five times per week but (GBCM), risk for nephrogenic systemic fibrosis is with shorter treatment sessions. reduced by using a group II GBCM at the lowest volume of contrast possible and timing proximate to the next scheduled hemodialysis for dialysis-dependent patients. Peritoneal Dialysis Peritoneal dialysis utilizes an indwelling catheter to perform e In patients with chronic kidney disease, peripherally exchanges of dialysate into the peritoneum, which serves as a inserted central venous catheters and subclavian venous semipermeable membrane allowing for diffusion of solutes catheters should be avoided to maintain central vein and osmosis of water. Dialysate is exchanged about three to patency for future dialysis vascular access. five times per day to maintain a high concentration gradient e Patients with advanced chronic kidney disease who and adequate solute clearance. Patients can perform exchanges choose hemodialysis for renal replacement therapy during the day, or a cycler can be used to exchange the fluid should be referred to an experienced surgeon for arterio- overnight while the patient sleeps. Peritoneal dialysis allows venous fistula placement months before the anticipated greater autonomy. Patients can work or perform activities dur- need for dialysis. ing the day. Clinical outcomes are similar for patients on peri- toneal dialysis compared with hemodialysis, although patients starting RRT who have residual renal function may have better End-Stage Kidney Disease outcomes with peritoneal dialysis. CKD stage G5 is defined as an eGFR <15 mL/min/1.73 m?, and Peritonitis is a complication associated with increased ESKD is defined as CKD stage G5 treated with chronic dialysis morbidity and even mortality. Repeated infections can cause or kidney transplantation. About 10% of patients with CKD peritoneal damage, reducing the efficacy of the dialysis

evidence of frank pulmonary edema. the dialysis unit, patients may have symptomatic hypotension during or following dialysis. Some patients also describe e For patients with advanced chronic kidney disease who excessive fatigue following dialysis sessions. Some patients require MRI with a gadolinium-based contrast media perform hemodialysis at home four to five times per week but (GBCM), risk for nephrogenic systemic fibrosis is with shorter treatment sessions. reduced by using a group II GBCM at the lowest volume of contrast possible and timing proximate to the next scheduled hemodialysis for dialysis-dependent patients. Peritoneal Dialysis Peritoneal dialysis utilizes an indwelling catheter to perform e In patients with chronic kidney disease, peripherally exchanges of dialysate into the peritoneum, which serves as a inserted central venous catheters and subclavian venous semipermeable membrane allowing for diffusion of solutes catheters should be avoided to maintain central vein and osmosis of water. Dialysate is exchanged about three to patency for future dialysis vascular access. five times per day to maintain a high concentration gradient e Patients with advanced chronic kidney disease who and adequate solute clearance. Patients can perform exchanges choose hemodialysis for renal replacement therapy during the day, or a cycler can be used to exchange the fluid should be referred to an experienced surgeon for arterio- overnight while the patient sleeps. Peritoneal dialysis allows venous fistula placement months before the anticipated greater autonomy. Patients can work or perform activities dur- need for dialysis. ing the day. Clinical outcomes are similar for patients on peri- toneal dialysis compared with hemodialysis, although patients starting RRT who have residual renal function may have better End-Stage Kidney Disease outcomes with peritoneal dialysis. CKD stage G5 is defined as an eGFR <15 mL/min/1.73 m?, and Peritonitis is a complication associated with increased ESKD is defined as CKD stage G5 treated with chronic dialysis morbidity and even mortality. Repeated infections can cause or kidney transplantation. About 10% of patients with CKD peritoneal damage, reducing the efficacy of the dialysis 84

Chronic Kidney Disease TABLE 34. Goals of Care for Patients with End-Stage Kidney Disease Treated with Dialysis Versus Kidney Supportive Care Issue Current Disease-Focused Metrics for Kidney Supportive Care Conventional Delivery of Dialysis Care Vascular access Creation and maintenance of an AVF; avoid Central venous catheter acceptable if patient central venous dialysis catheters as much as chooses hemodialysis. possible. Dialysis adequacy Target small solute clearance based on current Lower clearance acceptable if changes in dialysis | standards, intensifying the dialysis prescription prescription increase demands inconsistent with as needed to achieve targets. patient preference; may involve fewer hemodialysis sessions or more frequent but shorter sessions. Cardiovascular disease Treat cardiovascular risk factors, including BP Tolerate hypertension to avoid symptoms; no and dyslipidemia if indicated. indication for dyslipidemia treatment. Mineral and bone disorder Dietary counseling; binders to control Limited restrictions; more permissive hyperphosphatemia; vitamin D analogues with hyperphosphatemia and hyperparathyroidism. or without calcimimetics for secondary hyperparathyroidism. Nutrition Encourage dietary protein intake while limiting Reduce dietary restrictions. potassium, sodium, and phosphorus intake. Laboratory monitoring Routine monthly laboratory tests. Minimal necessary. AVF = arteriovenous fistula; BP = blood pressure.

Nutrition Encourage dietary protein intake while limiting Reduce dietary restrictions. potassium, sodium, and phosphorus intake. Laboratory monitoring Routine monthly laboratory tests. Minimal necessary. AVF = arteriovenous fistula; BP = blood pressure. treatments. Peritoneal dialysis—associated peritonitis is infre- for deceased-donor kidneys are several years long in most quent, with an average of one episode every 2 to 3 years. It is regions of the United States. usually caused by gram-positive skin flora and less commonly by gram-negative intestinal flora. Proper skin hygiene and Referral aseptic technique when handling the peritoneal dialysis cath- Patients should be referred to a kidney transplant center for eter are critical in preventing peritonitis. evaluation when the eGFR is 15 to 29 mL/min/1.73 m2. Early referral is important because preemptive kidney transplants Non-Dialytic Palliative Therapy (transplants before needing dialysis) are associated with Some patients with CKD stage G5 or ESKD may choose not to improved clinical outcomes compared with receiving a trans- initiate RRT, or patients already on RRT may decide to discon- plant after starting dialysis. Early referral also allows adequate tinue treatment. Palliative care and hospice services play an time to identify suitable living donors. important role in caring for these patients. Non-dialytic ther- Patients and donors undergo extensive health screening to apy is a reasonable treatment option for older patients with identify issues that may affect the safety and/or outcome of the ESKD and multiple comorbidities. Treatment focuses on symp- transplant. In the potential recipient, these include active malig- tom management and results in less hospitalization with simi- nancy, coronary artery disease, or infections. Adequate social lar or better quality of life compared with patients on RRT. For support and financial resources are important to ensure medi- patients who withdraw from RRT, death usually occurs within cation adherence and long-term survival of the transplanted 2 weeks. Nineteen percent to 23% of patients withdraw from allograft. Donors are screened for intrinsic kidney disease, RRT before death. Patients who are older, White, or have mul- hypertension, and diabetes to ensure there is minimal risk tiple comorbid conditions are more likely to elect withdrawal. related to reduced renal mass resulting from donation nephrec- tomy. Donors are at risk for future development of hypertension and proteinuria, with a small number of donors progressing to ¢ Clinical outcomes are similar for patients on peritoneal CKD. Blood pressure and kidney function of donors should be dialysis compared with hemodialysis. monitored as part of routine medical follow-up. HVC e Non-dialytic palliative therapy is a reasonable option for Patients are generally managed by a transplant nephrolo- older patients with end-stage kidney disease and multi- gist for at least the first 6 months posttransplant and are then ple comorbidities, with treatment focusing on symptom co-managed with a general nephrologist and/or internist. management and quality of life.

treatments. Peritoneal dialysis—associated peritonitis is infre- for deceased-donor kidneys are several years long in most quent, with an average of one episode every 2 to 3 years. It is regions of the United States. usually caused by gram-positive skin flora and less commonly by gram-negative intestinal flora. Proper skin hygiene and Referral aseptic technique when handling the peritoneal dialysis cath- Patients should be referred to a kidney transplant center for eter are critical in preventing peritonitis. evaluation when the eGFR is 15 to 29 mL/min/1.73 m2. Early referral is important because preemptive kidney transplants Non-Dialytic Palliative Therapy (transplants before needing dialysis) are associated with Some patients with CKD stage G5 or ESKD may choose not to improved clinical outcomes compared with receiving a trans- initiate RRT, or patients already on RRT may decide to discon- plant after starting dialysis. Early referral also allows adequate tinue treatment. Palliative care and hospice services play an time to identify suitable living donors. important role in caring for these patients. Non-dialytic ther- Patients and donors undergo extensive health screening to apy is a reasonable treatment option for older patients with identify issues that may affect the safety and/or outcome of the ESKD and multiple comorbidities. Treatment focuses on symp- transplant. In the potential recipient, these include active malig- tom management and results in less hospitalization with simi- nancy, coronary artery disease, or infections. Adequate social lar or better quality of life compared with patients on RRT. For support and financial resources are important to ensure medi- patients who withdraw from RRT, death usually occurs within cation adherence and long-term survival of the transplanted 2 weeks. Nineteen percent to 23% of patients withdraw from allograft. Donors are screened for intrinsic kidney disease, RRT before death. Patients who are older, White, or have mul- hypertension, and diabetes to ensure there is minimal risk tiple comorbid conditions are more likely to elect withdrawal. related to reduced renal mass resulting from donation nephrec- tomy. Donors are at risk for future development of hypertension and proteinuria, with a small number of donors progressing to ¢ Clinical outcomes are similar for patients on peritoneal CKD. Blood pressure and kidney function of donors should be dialysis compared with hemodialysis. monitored as part of routine medical follow-up. HVC e Non-dialytic palliative therapy is a reasonable option for Patients are generally managed by a transplant nephrolo- older patients with end-stage kidney disease and multi- gist for at least the first 6 months posttransplant and are then ple comorbidities, with treatment focusing on symptom co-managed with a general nephrologist and/or internist. management and quality of life. e For eligible patients, kidney transplantation is the pre- HVC Kidney Transplantation ferred treatment for end-stage kidney disease because Kidney transplantation is the preferred treatment for ESKD. It of improved mortality and quality of life and decreased improves life expectancy and quality of life, and provides sig- health care cost. nificant cost savings to the health care system compared with (Continued) dialysis. However, demand far exceeds supply, and waiting lists

e For eligible patients, kidney transplantation is the pre- HVC Kidney Transplantation ferred treatment for end-stage kidney disease because Kidney transplantation is the preferred treatment for ESKD. It of improved mortality and quality of life and decreased improves life expectancy and quality of life, and provides sig- health care cost. nificant cost savings to the health care system compared with (Continued) dialysis. However, demand far exceeds supply, and waiting lists 85

Chronic Kidney Disease Risks of Transplantation Immediately posttransplant, patients need to be monitored for e Patients should be referred to a kidney transplant center acute rejection and postoperative complications. Thereafter, for evaluation when the estimated glomerular filtration minimizing risk for infection and medication side effects rate is 15 to 29 mL/min/1.73 m2. becomes the focus while maintaining adequate immunosup- e Preemptive kidney transplants are associated with pression to prevent acute and chronic rejection. improved clinical outcomes compared with transplan- tation after dialysis. Infection Immunosuppression significantly increases the risk for infection. Within the first month after surgery, the most Immunosuppressive Therapy common infectious complications are similar to other sur- Immunosuppressive medications are required to prevent allo- geries and include urinary tract infections and wound infec- graft rejection. Induction therapy is started perioperatively tions. Afterward, opportunistic infections become more with polyclonal anti-T-cell antibodies (thymoglobulin) or prevalent. monoclonal anti-interleukin-2 receptor antibody (basilixi- Cytomegalovirus (CMV) is an important pathogen. Risk mab) in most patients. Calcineurin inhibitors with pulse glu- for infection depends on the serologic status of the donor and cocorticoids are also started. recipient at the time of transplant. The highest risk occurs Long-term maintenance therapy for most patients when a seropositive donor kidney is transplanted into a includes a combination of calcineurin inhibitors (tacrolimus seronegative recipient. Most patients receive prophylaxis or cyclosporine), antimetabolites (mycophenolate mofetil or against CMV with valganciclovir during the first 6 to azathioprine), and glucocorticoids. However, some patients 12 months; however, CMV infections can occur after the with well-matched allografts can discontinue glucocorti- medication is discontinued. Signs and symptoms include coids. Doses of these medications are highest immediately fever, leukopenia, pneumonitis, hepatitis, and gastroenteritis/ posttransplant and are decreased over the next several colitis. months to minimize side effects (Table 35), including Prophylaxis against Pneumocystis jirovecii pneumonia long-term nephrotoxicity, while maintaining adequate with trimethoprim-sulfamethoxazole is commonly used. immunosuppression. Atovaquone can be used for sulfa-allergic or hyperkalemic Calcineurin inhibitors are metabolized by the cytochrome patients. P450 system. Drug-drug interactions may occur, leading to Polyoma BK virus uniquely affects kidney transplant high or low levels of the calcineurin inhibitor and placing patients, only rarely occurring with other organ transplants or patients at risk for calcineurin toxicity or rejection. Care in immunosuppressed states. The most common clinical man- should be taken to check for potential interactions before add- ifestation is an acute or indolent rise in serum creatinine due ing new medications. to tubulointerstitial nephritis or ureteral stenosis. Treatment requires reduction in the immunosuppression dose, but this must be balanced against the risk of allograft rejection. e Potential drug-drug interactions with calcineurin Patients with latent tuberculosis infection found on rou- inhibitors should be checked before adding new medi- tine screening receive prophylactic therapy before transplant cations to avoid potential nontherapeutic or toxic drug to minimize risk of reactivation in the immune-suppressed levels. state.

Risks of Transplantation Immediately posttransplant, patients need to be monitored for e Patients should be referred to a kidney transplant center acute rejection and postoperative complications. Thereafter, for evaluation when the estimated glomerular filtration minimizing risk for infection and medication side effects rate is 15 to 29 mL/min/1.73 m2. becomes the focus while maintaining adequate immunosup- e Preemptive kidney transplants are associated with pression to prevent acute and chronic rejection. improved clinical outcomes compared with transplan- tation after dialysis. Infection Immunosuppression significantly increases the risk for infection. Within the first month after surgery, the most Immunosuppressive Therapy common infectious complications are similar to other sur- Immunosuppressive medications are required to prevent allo- geries and include urinary tract infections and wound infec- graft rejection. Induction therapy is started perioperatively tions. Afterward, opportunistic infections become more with polyclonal anti-T-cell antibodies (thymoglobulin) or prevalent. monoclonal anti-interleukin-2 receptor antibody (basilixi- Cytomegalovirus (CMV) is an important pathogen. Risk mab) in most patients. Calcineurin inhibitors with pulse glu- for infection depends on the serologic status of the donor and cocorticoids are also started. recipient at the time of transplant. The highest risk occurs Long-term maintenance therapy for most patients when a seropositive donor kidney is transplanted into a includes a combination of calcineurin inhibitors (tacrolimus seronegative recipient. Most patients receive prophylaxis or cyclosporine), antimetabolites (mycophenolate mofetil or against CMV with valganciclovir during the first 6 to azathioprine), and glucocorticoids. However, some patients 12 months; however, CMV infections can occur after the with well-matched allografts can discontinue glucocorti- medication is discontinued. Signs and symptoms include coids. Doses of these medications are highest immediately fever, leukopenia, pneumonitis, hepatitis, and gastroenteritis/ posttransplant and are decreased over the next several colitis. months to minimize side effects (Table 35), including Prophylaxis against Pneumocystis jirovecii pneumonia long-term nephrotoxicity, while maintaining adequate with trimethoprim-sulfamethoxazole is commonly used. immunosuppression. Atovaquone can be used for sulfa-allergic or hyperkalemic Calcineurin inhibitors are metabolized by the cytochrome patients. P450 system. Drug-drug interactions may occur, leading to Polyoma BK virus uniquely affects kidney transplant high or low levels of the calcineurin inhibitor and placing patients, only rarely occurring with other organ transplants or patients at risk for calcineurin toxicity or rejection. Care in immunosuppressed states. The most common clinical man- should be taken to check for potential interactions before add- ifestation is an acute or indolent rise in serum creatinine due ing new medications. to tubulointerstitial nephritis or ureteral stenosis. Treatment requires reduction in the immunosuppression dose, but this must be balanced against the risk of allograft rejection. e Potential drug-drug interactions with calcineurin Patients with latent tuberculosis infection found on rou- inhibitors should be checked before adding new medi- tine screening receive prophylactic therapy before transplant cations to avoid potential nontherapeutic or toxic drug to minimize risk of reactivation in the immune-suppressed levels. state. TABLE 35. Common Side Effects of Medications Used for Chronic Maintenance Immunosuppression After Kidney Transplantation

Risks of Transplantation Immediately posttransplant, patients need to be monitored for e Patients should be referred to a kidney transplant center acute rejection and postoperative complications. Thereafter, for evaluation when the estimated glomerular filtration minimizing risk for infection and medication side effects rate is 15 to 29 mL/min/1.73 m2. becomes the focus while maintaining adequate immunosup- e Preemptive kidney transplants are associated with pression to prevent acute and chronic rejection. improved clinical outcomes compared with transplan- tation after dialysis. Infection Immunosuppression significantly increases the risk for infection. Within the first month after surgery, the most Immunosuppressive Therapy common infectious complications are similar to other sur- Immunosuppressive medications are required to prevent allo- geries and include urinary tract infections and wound infec- graft rejection. Induction therapy is started perioperatively tions. Afterward, opportunistic infections become more with polyclonal anti-T-cell antibodies (thymoglobulin) or prevalent. monoclonal anti-interleukin-2 receptor antibody (basilixi- Cytomegalovirus (CMV) is an important pathogen. Risk mab) in most patients. Calcineurin inhibitors with pulse glu- for infection depends on the serologic status of the donor and cocorticoids are also started. recipient at the time of transplant. The highest risk occurs Long-term maintenance therapy for most patients when a seropositive donor kidney is transplanted into a includes a combination of calcineurin inhibitors (tacrolimus seronegative recipient. Most patients receive prophylaxis or cyclosporine), antimetabolites (mycophenolate mofetil or against CMV with valganciclovir during the first 6 to azathioprine), and glucocorticoids. However, some patients 12 months; however, CMV infections can occur after the with well-matched allografts can discontinue glucocorti- medication is discontinued. Signs and symptoms include coids. Doses of these medications are highest immediately fever, leukopenia, pneumonitis, hepatitis, and gastroenteritis/ posttransplant and are decreased over the next several colitis. months to minimize side effects (Table 35), including Prophylaxis against Pneumocystis jirovecii pneumonia long-term nephrotoxicity, while maintaining adequate with trimethoprim-sulfamethoxazole is commonly used. immunosuppression. Atovaquone can be used for sulfa-allergic or hyperkalemic Calcineurin inhibitors are metabolized by the cytochrome patients. P450 system. Drug-drug interactions may occur, leading to Polyoma BK virus uniquely affects kidney transplant high or low levels of the calcineurin inhibitor and placing patients, only rarely occurring with other organ transplants or patients at risk for calcineurin toxicity or rejection. Care in immunosuppressed states. The most common clinical man- should be taken to check for potential interactions before add- ifestation is an acute or indolent rise in serum creatinine due ing new medications. to tubulointerstitial nephritis or ureteral stenosis. Treatment requires reduction in the immunosuppression dose, but this must be balanced against the risk of allograft rejection. e Potential drug-drug interactions with calcineurin Patients with latent tuberculosis infection found on rou- inhibitors should be checked before adding new medi- tine screening receive prophylactic therapy before transplant cations to avoid potential nontherapeutic or toxic drug to minimize risk of reactivation in the immune-suppressed levels. state. TABLE 35. Common Side Effects of Medications Used for Chronic Maintenance Immunosuppression After Kidney Transplantation Class Medication Common Side Effects

Risks of Transplantation Immediately posttransplant, patients need to be monitored for e Patients should be referred to a kidney transplant center acute rejection and postoperative complications. Thereafter, for evaluation when the estimated glomerular filtration minimizing risk for infection and medication side effects rate is 15 to 29 mL/min/1.73 m2. becomes the focus while maintaining adequate immunosup- e Preemptive kidney transplants are associated with pression to prevent acute and chronic rejection. improved clinical outcomes compared with transplan- tation after dialysis. Infection Immunosuppression significantly increases the risk for infection. Within the first month after surgery, the most Immunosuppressive Therapy common infectious complications are similar to other sur- Immunosuppressive medications are required to prevent allo- geries and include urinary tract infections and wound infec- graft rejection. Induction therapy is started perioperatively tions. Afterward, opportunistic infections become more with polyclonal anti-T-cell antibodies (thymoglobulin) or prevalent. monoclonal anti-interleukin-2 receptor antibody (basilixi- Cytomegalovirus (CMV) is an important pathogen. Risk mab) in most patients. Calcineurin inhibitors with pulse glu- for infection depends on the serologic status of the donor and cocorticoids are also started. recipient at the time of transplant. The highest risk occurs Long-term maintenance therapy for most patients when a seropositive donor kidney is transplanted into a includes a combination of calcineurin inhibitors (tacrolimus seronegative recipient. Most patients receive prophylaxis or cyclosporine), antimetabolites (mycophenolate mofetil or against CMV with valganciclovir during the first 6 to azathioprine), and glucocorticoids. However, some patients 12 months; however, CMV infections can occur after the with well-matched allografts can discontinue glucocorti- medication is discontinued. Signs and symptoms include coids. Doses of these medications are highest immediately fever, leukopenia, pneumonitis, hepatitis, and gastroenteritis/ posttransplant and are decreased over the next several colitis. months to minimize side effects (Table 35), including Prophylaxis against Pneumocystis jirovecii pneumonia long-term nephrotoxicity, while maintaining adequate with trimethoprim-sulfamethoxazole is commonly used. immunosuppression. Atovaquone can be used for sulfa-allergic or hyperkalemic Calcineurin inhibitors are metabolized by the cytochrome patients. P450 system. Drug-drug interactions may occur, leading to Polyoma BK virus uniquely affects kidney transplant high or low levels of the calcineurin inhibitor and placing patients, only rarely occurring with other organ transplants or patients at risk for calcineurin toxicity or rejection. Care in immunosuppressed states. The most common clinical man- should be taken to check for potential interactions before add- ifestation is an acute or indolent rise in serum creatinine due ing new medications. to tubulointerstitial nephritis or ureteral stenosis. Treatment requires reduction in the immunosuppression dose, but this must be balanced against the risk of allograft rejection. e Potential drug-drug interactions with calcineurin Patients with latent tuberculosis infection found on rou- inhibitors should be checked before adding new medi- tine screening receive prophylactic therapy before transplant cations to avoid potential nontherapeutic or toxic drug to minimize risk of reactivation in the immune-suppressed levels. state. TABLE 35. Common Side Effects of Medications Used for Chronic Maintenance Immunosuppression After Kidney Transplantation Class Medication Common Side Effects Calcineurin inhibitor | Cyclosporine Hypertension; decreased GFR; dyslipidemia; hirsutism; gingival hyperplasia; tremor

TABLE 35. Common Side Effects of Medications Used for Chronic Maintenance Immunosuppression After Kidney Transplantation Class Medication Common Side Effects Calcineurin inhibitor | Cyclosporine Hypertension; decreased GFR; dyslipidemia; hirsutism; gingival hyperplasia; tremor Tacrolimus New-onset diabetes mellitus; decreased GFR; hypertension; gastrointestinal symptoms; tremor Antimetabolite Mycophenolate mofetil Diarrhea; nausea/vomiting; leukopenia; anemia Azathioprine Leukopenia; hepatitis; pancreatitis mTOR inhibitor Sirolimus Proteinuria; dyslipidemia; new-onset diabetes mellitus; anemia; leukopenia; Everolimus Rogungnids Glucocorticoid Prednisone Osteopenia, osteoporosis, osteonecrosis; hypertension; edema; new-onset | diabetes mellitus; glaucoma; cataracts | GFR = glomerular filtration rate. — sa — 86