22-11: Chronic Kidney Disease

CKD affects at least 10% of Americans. Many may be unaware of the condition because they remain asymptomatic until the disease is near end stage. The National Kidney Foundation’s staging system helps clinicians formulate practice plans (Table 22–4). Over 70% of cases of late-stage CKD (stage 5 CKD and ESRD) in the United States are due to diabetes mellitus or hypertension/vascular disease. Glomerulonephritis, cystic diseases, chronic tubulointerstitial diseases, and other urologic diseases account for the remainder (Table 22–5). Genetic polymorphisms of the APOL-1 gene have been shown to be associated with an increased risk of the development of CKD in persons of African descent.

CKD usually leads to a progressive decline in kidney function even if the inciting cause can be identified and treated or removed. Destruction of nephrons leads to compensatory hypertrophy and supranormal GFR of the remaining nephrons in order to maintain overall homeostasis. As a result, the serum creatinine may remain relatively normal even in the face of significant loss of renal mass and is, therefore, an insensitive marker for early renal damage and scarring. In addition, compensatory hyperfiltration leads to overwork injury in the remaining nephrons, which in turn causes progressive glomerular sclerosis and interstitial fibrosis. Angiotensin receptor blockers (ARBs) and ACE inhibitors can help reduce hyperfiltration injury and are helpful in slowing the progression of proteinuric CKD.

While CKD is an independent risk factor for cardiovascular disease (CVD), proteinuric CKD confers the highest risk. Most patients with stage 3 CKD die of underlying CVD prior to progression to ESRD.

A. Symptoms and Signs

Stages 1–4 CKD are asymptomatic. Symptoms develop slowly with the progressive decline in GFR, are nonspecific, and do not manifest until kidney disease is far advanced (GFR less than 5–10 mL/min/1.73 m²). At this point, the accumulation of metabolic waste products, or uremic toxins, results in the uremic syndrome (eTable 22–2). General symptoms of uremia may include fatigue, anorexia, nausea, and a metallic taste in the mouth. Neurologic symptoms such as irritability, memory impairment, insomnia, restless legs, paresthesias, and twitching may be due to uremia. Generalized pruritus (without rash) may occur, as may decreased libido and menstrual irregularities. Pericarditis, a rare complication of CKD, may present with pleuritic chest pain. Medications that are cleared by the kidneys will accumulate as kidney function worsens and toxicity may ensue; an important example is insulin and an increasing risk of significant hypoglycemia if doses are not appropriately reduced.

The most common physical finding in CKD is hypertension; this is due in part to impaired sodium excretion. It is often present in early stages of CKD and tends to worsen with CKD progression. In later stages of CKD, sodium retention may lead to clinically apparent volume overload. Uremic signs are seen with a profound decrease in GFR (less than 5–10 mL/min/1.73 m²) and may include a generally sallow and ill appearance, halitosis (uremic fetor), and the uremic encepholopathic signs of decreased mental status, asterixis, myoclonus, and possibly seizures.

Symptoms and signs of uremia warrant immediate hospital admission and nephrology consultation for initiation of dialysis. The uremic syndrome is ameliorated with dialytic therapy.

In any patient with kidney disease, it is important to identify and correct all possibly reversible insults or exacerbating factors (Table 22–6). Urinary obstruction, hypovolemia, hypotension, nephrotoxins (such as NSAIDs, aminoglycosides, or proton pump inhibitors), severe or emergent hypertension, and heart failure exacerbation should be excluded.

B. Laboratory Findings

CKD is usually defined by an abnormal GFR persisting for at least 3 months. Persistent proteinuria or abnormalities on renal imaging (eg, polycystic kidneys or a single kidney) are also diagnostic of CKD, even when eGFR is normal. It is helpful to plot the eGFR versus time; if multiple measurements are available, the rate of progression to ESRD can be roughly estimated (Figure 22–1). If the slope of the line acutely declines, potentially reversible renal insults should be excluded as outlined above. Anemia, hyperphosphatemia, hypocalcemia, hyperkalemia, and metabolic acidosis are common complications of advanced CKD. The urinary sediment may show broad waxy casts as a result of dilated, hypertrophic nephrons. Proteinuria may be present. If so, it should be quantified as described above. Quantification of urinary protein is important for several reasons. First, it helps narrow the differential diagnosis of the etiology of the CKD (Table 22–5); for example, glomerular diseases tend to present with protein excretion of more than 1 g/day. Second, the presence of proteinuria is associated with more rapid progression of CKD and with increased risk of cardiovascular mortality.

C. Imaging

The finding of small, echogenic kidneys bilaterally (less than 9–10 cm) by ultrasonography suggests the chronic scarring of advanced CKD. Large kidneys can be seen with adult polycystic kidney disease, diabetic nephropathy, HIV-associated nephropathy, plasma cell myeloma, amyloidosis, and obstructive uropathy.

The complications of CKD tend to occur at relatively predictable stages of disease as noted in Figure 22–2.

A. Cardiovascular Complications

Patients with CKD experience greater morbidity and mortality from CVD in comparison to the general population. Roughly 80% of patients with CKD die, primarily of CVD, before reaching the need for dialysis. Of those undergoing dialysis, 45% will die of a cardiovascular cause. The mechanisms for enhanced cardiovascular mortality in CKD are complex and include abnormal phosphorus and calcium homeostasis, increased burden of oxidative stress, increased vascular reactivity, left ventricular hypertrophy, and underlying coexistent comorbidities such as hypertension and diabetes mellitus.

1. Hypertension

Hypertension is the most common complication of CKD; it tends to be progressive and salt-sensitive. Hyperreninemic states and exogenous erythropoietin administration can also exacerbate hypertension.

As with other patient populations, control of hypertension should focus on both pharmacologic and nonpharmacologic therapy (eg, diet, exercise, weight loss, treatment of obstructive sleep apnea). CKD results in disturbed sodium homeostasis such that the ability of the kidney to adjust to variations in sodium and water intake becomes limited as GFR declines. A low salt diet (2 g/day) is often essential to control blood pressure and help avoid overt volume overload. Diuretics are nearly always needed to help control hypertension (see Table 11–8); thiazides work well in early CKD, but in those with a GFR less than 30 mL/min/1.73 m², loop diuretics are more effective. However, volume contraction as a result of very low sodium intake (especially with intercurrent illness) or over-diuresis in the presence of impaired sodium homeostasis can result in AKI. Initial drug therapy for proteinuric patients should include ACE inhibitors or ARBs (see Table 11–6); however, there is no evidence of superiority of these drugs over other drug classes for nonproteinuric CKD. When an ACE inhibitor or an ARB is initiated or uptitrated, patients must have serum creatinine and potassium checked within 7–14 days. A rise in serum creatinine greater than 30% from baseline mandates reduction or cessation of the drug. Hyperkalemia may also warrant drug cessation, except in the reliable patient who can follow a low-potassium diet and adhere to a newer potassium-binding resin; such patients should be monitored closely. An ACE inhibitor and ARB should not be used in combination. CKD is a common cause of refractory hypertension and agents from multiple classes are often needed. Current guidelines differ with respect to blood pressure goals in CKD; those from the Joint National Commission suggest a blood pressure goal of less than 140/90 mm Hg, while the American Heart Association advocates for less than 130/80 mm Hg. As patients with CKD are at risk for renal hypoperfusion and AKI with overtreatment of hypertension, many experts agree that it is prudent to continue with an individualized approach to blood pressure control.

2. Coronary artery disease

Patients with CKD are at higher risk for death from CVD than the general population. Traditional modifiable risk factors for CVD, such as hypertension, tobacco use, and hyperlipidemia, should be aggressively treated in patients with CKD. Uremic vascular calcification involving disordered phosphorus homeostasis and other mediators may also be a cardiovascular risk factor in these patients.

3. Heart failure

The complications of CKD result in increased cardiac workload due to hypertension, volume overload, and anemia. Patients with CKD may also have accelerated rates of atherosclerosis and vascular calcification resulting in vessel stiffness. All of these factors contribute to left ventricular hypertrophy and heart failure with preserved ejection fraction, which is common in CKD. Over time, heart failure with decreased ejection fraction may also develop. Diuretic therapy, in addition to prudent fluid and salt restriction, is usually necessary. Thiazides may be adequate therapy for most patients through CKD stage 3, but loop diuretics are usually needed when the GFR is less than 30 mL/min/1.73 m²; higher doses may be needed as kidney function declines. Digoxin is excreted by the kidney, and its toxicity is exacerbated in the presence of electrolyte disturbances, which are common in CKD. ACE inhibitors and ARBs can be used for patients with advanced CKD with close monitoring of blood pressure as well as for hyperkalemia and worsening kidney function.

4. Atrial fibrillation

Patients with advanced CKD and ESRD suffer disproportionate rates of atrial fibrillation; some estimations suggest a nearly 20% prevalence in patients receiving dialysis. Rate and rhythm management should be addressed. While those with up to CKD stage 4 should be treated as the general population, the question of anticoagulation for prevention of thromboembolic events becomes challenging in those nearing or receiving dialysis due to competing risks of bleeding and clotting, as well as a lack of data to support routine anticoagulation in this population.

5. Pericarditis

Pericarditis rarely develops in uremic patients; typical findings include pleuritic chest pain and a friction rub. Development of a significant pericardial effusion may result in pulsus paradoxus, an enlarged cardiac silhouette on chest radiograph, and low QRS voltage and electrical alternans on ECG. The effusion (VIDEO 22–1) is generally hemorrhagic, and anticoagulants should be avoided if this diagnosis is suspected. Cardiac tamponade can occur; therefore, uremic pericarditis is a mandatory indication for hospitalization and initiation of hemodialysis.

B. Disorders of Mineral Metabolism

The metabolic bone disease of CKD refers to the complex disturbances of calcium and phosphorus metabolism (eFigure 22–7), parathyroid hormone (PTH), active vitamin D, and fibroblast growth factor-23 (FGF-23) homeostasis (see Chapter 21 and Figure 22–3). A typical pattern seen as early as CKD stage 3 is hyperphosphatemia, hypocalcemia, and hypovitaminosis D, resulting in secondary hyperparathyroidism. These abnormalities can contribute to vascular calcification and may be responsible in part for the accelerated CVD and excess mortality seen in the CKD population. Epidemiologic studies show an association between elevated phosphorus levels and increased risk of cardiovascular mortality in early CKD through ESRD. As yet, there are no intervention trials suggesting the best course of treatment in these patients; control of mineral and PTH levels per current guidelines is discussed below.

Bone disease, or renal osteodystrophy, in advanced CKD is common and there are several types of lesions. Renal osteodystrophy can be diagnosed only by bone biopsy, which is rarely done. The most common bone disease, osteitis fibrosa cystica, is a result of secondary hyperparathyroidism and the osteoclast-stimulating effects of PTH. This is a high-turnover disease with bone resorption and subperiosteal lesions; it can result in bone pain and proximal muscle weakness. Adynamic bone disease, or low-bone turnover, is becoming more common; it may result iatrogenically from suppression of PTH or via spontaneously low PTH production. Osteomalacia is characterized by lack of bone mineralization. In the past, osteomalacia was associated with aluminum toxicity—either as a result of chronic ingestion of prescribed aluminum-containing phosphorus binders or from high levels of aluminum in impure dialysate water. Currently, osteomalacia is more likely to result from hypovitaminosis D; there is also theoretical risk of osteomalacia associated with use of bisphosphonates in advanced CKD.

All of the above entities increase the risk of fractures. Aluminum exposure should be avoided. In addition, treatment may involve correction of calcium, phosphorus, and 25-OH vitamin D levels toward normal values, and mitigation of hyperparathyroidism. Understanding the interplay between these abnormalities can help target therapy (Figure 22–3). Declining GFR leads to phosphorus retention. This results in hypocalcemia as phosphorus complexes with calcium, deposits in soft tissues, and stimulates PTH. Loss of renal mass and low 25-OH vitamin D levels often seen in CKD patients result in low 1,25(OH) vitamin D production by the kidney. Because 1,25(OH) vitamin D is a suppressor of PTH production, hypovitaminosis D also leads to secondary hyperparathyroidism.

The first step in treatment of metabolic bone disease is control of hyperphosphatemia. This involves dietary phosphorus restriction initially (see section on dietary management), followed by the administration of oral phosphorus binders if targets are not achieved. Oral phosphorus binders block absorption of dietary phosphorus in the gut and are given thrice daily with meals. These should be titrated to a near-normal serum phosphorus level. Calcium-containing binders (calcium carbonate, 650 mg/tablet, or calcium acetate, 667 mg/capsule, used at doses of one to three pills per meal) are relatively inexpensive but may contribute to positive calcium balance and vascular calcification; overt hypercalcemia may also occur. Thus, current guidelines suggest limiting their use in favor of the non-calcium–containing binders sevelamer carbonate (800–3200 mg/meal) and lanthanum carbonate (500–1000 mg/meal). Newer, iron-based phosphorus binders include ferric citrate and sucroferric oxyhydroxide may be considered when other binders are not tolerated either due to hypercalcemia or constipation. They should be avoided in patients with iron overload. Aluminum hydroxide is a highly effective phosphorus binder but can cause osteomalacia and neurologic complications when used long-term. It can be used in the acute setting for severe hyperphosphatemia or for short periods (eg, 3 weeks) in CKD patients.

Once serum phosphorus levels are controlled, active vitamin D (1,25[OH] vitamin D, or calcitriol) or other vitamin D analogs are used by nephrologists to treat secondary hyperparathyroidism in advanced CKD and ESRD. Serum 25-OH vitamin D levels should be measured and brought to normal (see Chapter 26) prior to considering administration of active vitamin D. Active vitamin D (calcitriol) increases serum calcium and phosphorus levels; both need to be monitored closely during calcitriol therapy, and its dose should be decreased if hypercalcemia or hyperphosphatemia occurs. Typical calcitriol dosing is 0.25 or 0.5 mcg orally daily or every other day. Cinacalcet targets the calcium-sensing receptors of the parathyroid gland and suppresses PTH production. Cinacalcet, 30–90 mg orally once a day, can be used if elevated serum phosphorus or calcium levels prohibit the use of vitamin D analogs; cinacalcet can cause serious hypocalcemia, and patients should be closely monitored for this complication. Optimal PTH levels in CKD are not known, but because skeletal resistance to PTH develops with uremia, relatively high levels are targeted in advanced CKD to avoid adynamic bone disease. Expert guidelines suggest goal PTH levels near or just above the upper limit of normal for moderate CKD, and at least twofold and up to ninefold the upper limit of normal for ESRD.

C. Hematologic Complications

1. Anemia

The anemia of CKD is primarily due to decreased erythropoietin production, which often becomes clinically significant during stage 3 CKD. CKD is also associated with high levels of hepcidin, which blocks GI iron absorption and mobilization of iron from body stores; this results in a functional iron deficiency—the so-called “anemia of chronic disease.” The approach to a patient with CKD and anemia begins with ensuring that the bone marrow can respond to erythropoietin. Thus, thyroid function tests, serum vitamin B₁₂ levels, and iron stores (ferritin and iron saturation) should be checked. Iron stores are targeted to higher goals due to a functional blockade of iron utilization in this population. In CKD, a serum ferritin below 100–200 ng/mL or iron saturation less than 20% is suggestive of iron deficiency. Iron stores may be repleted with oral or parenteral iron; iron therapy should probably be withheld if the serum ferritin is greater than 500–800 ng/mL, even if the iron saturation is less than 20%. Oral therapy with ferrous sulfate, gluconate, or fumarate, 325 mg once daily, is the initial therapy in pre-ESRD CKD; higher doses will result in increasing hepcidin levels. For those who do not respond due to poor GI absorption or lack of tolerance, intravenous iron (eg, iron sucrose or iron gluconate) may be necessary.

Erythropoiesis-stimulating agents (ESAs, eg, recombinant erythropoietin [epoetin alfa or beta] and darbepoetin) are used to treat the anemia of CKD if other treatable causes are excluded. There is likely no benefit of starting an ESA before hemoglobin (Hgb) values are less than 9 g/dL. The starting dose of epoetin alfa is 50 units/kg (3000–4000 units/dose) once or twice a week, and darbepoetin is started at 0.45 mcg/kg and administered every 2–4 weeks; epoetin beta is given every 2–4 weeks. These agents can be given intravenously (eg, to the hemodialysis patient) or subcutaneously (to both the predialysis or dialysis patient); subcutaneous dosing of epoetin alfa is roughly 30% more effective than intravenous dosing. ESAs should be titrated to an Hgb of 10–11 g/dL for optimal safety; studies show that targeting a higher Hgb increases the risk of stroke and possibly other cardiovascular events. When titrating doses, Hgb levels should rise no more than 1 g/dL every 3–4 weeks. Hypertension is a common complication of treatment with ESAs.

2. Coagulopathy

The bleeding diathesis that may occur in stage 4–5 CKD is mainly due to platelet dysfunction, but severe anemia may also contribute.

Treatment is required only in patients who are symptomatic. Raising the Hgb to 9–10 g/dL in anemic patients can reduce risk of bleeding via improved clot formation. Desmopressin (25 mcg intravenously every 8–12 hours for two doses) is a short-lived but effective treatment for platelet dysfunction and it is often used in preparation for surgery or kidney biopsy; hyponatremia is a potential adverse effect of this. Conjugated estrogens, 2.5–5 mg orally for 5–7 days, may have an effect for several weeks but are seldom used. Dialysis improves the bleeding time.

D. Hyperkalemia

Potassium balance generally remains intact in CKD until stages 4–5. However, hyperkalemia may occur at earlier stages when certain conditions are present, such as type 4 renal tubular acidosis (seen in patients with diabetes mellitus), high potassium diets, or medications that decrease renal potassium secretion (amiloride, triamterene, spironolactone, eplerenone, NSAIDs, ACE inhibitors, ARBs) or block cellular potassium uptake (beta-blockers). Other causes include acidemic states and any type of cellular destruction causing release of intracellular contents, such as hemolysis and rhabdomyolysis.

Treatment of acute hyperkalemia is discussed in Chapter 21 (see Table 21–4). Cardiac monitoring is indicated for any ECG changes seen with hyperkalemia or a serum potassium level greater than 6.0–6.5 mEq/L or mmol/L. Chronic hyperkalemia is best treated with dietary potassium restriction (2 g/day) and minimization or elimination of any medications that may impair renal potassium excretion, as noted above. Loop diuretics may be administered for their kaliuretic effect as long as the patient is not volume-depleted, and newer potassium-binding resins may be considered.

E. Acid-Base Disorders

Damaged kidneys are unable to excrete the 1 mEq/kg/day of acid generated by metabolism of dietary animal proteins in the typical Western diet. The resultant metabolic acidosis is primarily due to decreased GFR; proximal or distal tubular defects may contribute to or worsen the acidosis. Excess hydrogen ions are buffered by bone; the consequent leaching of calcium and phosphorus from the bone contributes to the metabolic bone disease described above. Chronic acidosis can also result in muscle protein catabolism as well as growth retardation in children with CKD and may accelerate progression of CKD. Reduction of dietary animal protein and increased fruit and vegetable intake, and the administration of oral sodium bicarbonate (in doses of 0.5–1.0 mEq/kg/day divided twice daily and titrated as needed) are strategies to bring serum bicarbonate levels toward normal. Citrate salts increase the absorption of dietary aluminum and should be avoided in CKD.

F. Neurologic Complications

Uremic encephalopathy, resulting from the aggregation of uremic toxins, does not occur until GFR falls below 5–10 mL/min/1.73 m². Symptoms begin with difficulty in concentrating and can progress to lethargy, confusion, seizure, and coma. Physical findings may include altered mental status, weakness, and asterixis. These findings improve with dialysis.

Other neurologic complications that can manifest with advanced CKD include peripheral neuropathies (stocking-glove or isolated mononeuropathies), erectile dysfunction, autonomic dysfunction, and restless leg syndrome. These may not improve with dialysis therapy.

G. Endocrine Disorders

Decreased renal elimination of insulin in advanced CKD confers risk for hypoglycemia in treated diabetic patients. Doses of oral hypoglycemics and insulin may need reduction. The risk of lactic acidosis with metformin is due to both dose and eGFR; it should be discontinued when eGFR is less than 30 mL/min/1.73 m².

Decreased libido and erectile dysfunction are common in advanced CKD. Men have decreased testosterone levels; women are often anovulatory. Women with serum creatinine less than 1.4 mg/dL are not at increased risk for poor outcomes in pregnancy; however, those with serum creatinine greater than 1.4 mg/dL may experience faster progression of CKD with pregnancy. Fetal survival is not compromised, however, unless CKD is advanced. Despite a high degree of infertility in patients with ESRD, pregnancy can occur in this setting; however, fetal mortality approaches 50%, and babies who survive are often premature. In female patients with ESRD, renal transplantation with a well-functioning allograft affords the best chances for a successful pregnancy.

A. Slowing Progression

Treatment of the underlying cause of CKD is vital. Control of diabetes should be aggressive in early CKD; however, risk of hypoglycemia increases in advanced CKD, and glycemic targets may need to be relaxed to avoid this dangerous complication. Blood pressure control is vital to slow progression of all forms of CKD; agents that block the renin-angiotensin-aldosterone system are particularly important in proteinuric patients. Obese patients should be encouraged to lose weight. Management of traditional cardiovascular risk factors is vital. Risks for AKI should be minimized or avoided. Other interventions that may slow progression, though strong data are lacking, include treatment of metabolic acidosis and of hyperuricemia.

B. Dietary Management

Patients with CKD should be evaluated by a renal nutritionist. Patient-specific recommendations should be made concerning protein, salt, water, potassium, and phosphorus intake to help manage CKD progression and complications.

1. Protein restriction

There is increasing interest in evaluating plant-based diets for the treatment of CKD. Reduced intake of animal protein to 0.6–0.8 g/kg/day may slow CKD progression and is likely not harmful in the otherwise well-nourished patient. However, significant protein restriction is not advisable in those with cachexia or low serum albumin in the absence of the nephrotic syndrome.

2. Salt and water restriction

In advanced CKD, the kidney is unable to adapt to large changes in sodium intake. Intake of greater than 3–4 g/day can lead to hypertension and hypervolemia, whereas intake of less than 1 g/day can lead to volume depletion and hypotension. A goal of 2 g/day of sodium is reasonable for most patients. Daily fluid restriction to 2 L may be needed if volume overload is present.

3. Potassium restriction

Restriction is needed once the GFR has fallen below 10–20 mL/min/1.73 m², or earlier if the patient is hyperkalemic. Patients should receive detailed lists describing potassium content of foods and should limit their intake to less than 50–60 mEq/day (2 g/day). An aggressive bowel regimen should be instituted for patients with hyperkalemia (more than two bowel movements daily), since a higher percentage of potassium is excreted through the GI tract as GFR declines. Newer potassium-binding agents (such as sodium zirconium cyclosilicate) can be used to increase GI tract potassium removal by binding potassium in the gut.

4. Phosphorus restriction

Guidelines suggest lowering elevated serum phosphorus levels toward normal in all stages of CKD. Dietary phosphate restriction to 800–1000 mg/day is the first step. Processed foods and cola beverages are often preserved with highly bioavailable phosphorus and should be avoided. Foods rich in phosphorus such as eggs, dairy products, nuts, beans, and meat may also need to be limited, although care must be taken to avoid protein malnutrition. When GFR is less than 20–30 mL/min/1.73 m², dietary restriction is rarely sufficient to reach target levels, and phosphorus binders are usually required.

C. Medication Management

Many drugs are excreted by the kidney; dosages should be adjusted for GFR. Insulin doses may need to be decreased as noted above. Magnesium-containing medications, such as laxatives or antacids, and phosphorus-containing medicines (eg, cathartics) should be avoided. Active morphine metabolites can accumulate in advanced CKD; this problem is not encountered with other opioid agents. Drugs with potential nephrotoxicity (NSAIDs, intravenous contrast, as well as others noted in the Acute Kidney Injury section) should be avoided.

D. Treatment of ESRD

When GFR declines to 5–10 mL/min/1.73 m², renal replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation) is required to sustain life. Patient education is important in understanding which mode of therapy is most suitable, as is timely preparation for treatment; therefore, referral to a nephrologist should take place in late stage 3 CKD, or when the GFR is declining rapidly. Such referral has been shown to improve mortality. Preparation for ESRD treatment requires a team approach with the involvement of dieticians, social workers, primary care clinicians, and nephrologists. For very elderly patients, or those with multiple debilitating or life-limiting comorbidities, dialysis therapy may not meaningfully prolong life, and the option of palliative care should be discussed with the patient and family. Conversely, for patients who are otherwise relatively healthy, evaluation for possible kidney transplantation should be considered prior to initiation of dialysis.

1. Dialysis

Dialysis initiation should be considered when GFR is near 10 mL/min/1.73 m² and uremic symptoms are present. Other indications for dialysis, which may occur when GFR is 10–15 mL/min/1.73 m², are fluid overload unresponsive to diuresis and refractory hyperkalemia.

A. HEMODIALYSIS

Hemodialysis requires a constant flow of blood along one side of a semipermeable membrane with a cleansing solution, or dialysate, along the other. Diffusion and convection allow the dialysate to remove unwanted substances from the blood while adding back needed components. Vascular access for hemodialysis can be accomplished by an arteriovenous fistula (the preferred method) or prosthetic graft; creation of dialysis access should be considered well before dialysis initiation. An indwelling catheter is used when there is no useable vascular access. Because catheters confer a high risk of bloodstream infection, they should be considered a temporary measure. Native fistulas typically last longer than prosthetic grafts but require a longer time after surgical construction for maturation (6–8 weeks for a fistula versus 2 weeks for a graft). Infection, thrombosis, and aneurysm formation are complications seen more often in grafts than fistulas. Staphylococcus species are the most common cause of soft tissue infections and bacteremia.

Treatment at a hemodialysis center occurs three times a week. Sessions last 3–5 hours depending on patient size and type of dialysis access. Other hemodialysis schedules can be considered depending on available resources and patient preferences. Home hemodialysis is often performed more frequently (3–6 days per week for shorter sessions) and requires a trained helper. Results of trials comparing quotidian modalities (nocturnal and frequent home hemodialysis) to conventional in-center dialysis have not thus far shown significant mortality differences, but there may be improvements in blood pressure control, mineral metabolism, and quality of life.

B. PERITONEAL DIALYSIS

With peritoneal dialysis, the peritoneal membrane is the “dialyzer.” Dialysate is instilled into the peritoneal cavity through an indwelling catheter; water and solutes move across the capillary bed that lies between the visceral and parietal layers of the membrane into the dialysate during a “dwell.” After equilibration, the dialysate is drained, and fresh dialysate is instilled—this is an “exchange.”

There are different kinds of peritoneal dialysis: continuous ambulatory peritoneal dialysis (CAPD), in which the patient exchanges the dialysate four to six times a day manually; continuous cyclic peritoneal dialysis (CCPD), which utilizes a cycler machine to automatically perform exchanges at night.

Peritoneal dialysis permits significant patient autonomy. Its continuous nature minimizes the symptomatic volume and electrolyte shifts observed in hemodialysis patients, and some uremic toxins (such as phosphorus) are better cleared. However, peritoneal dialysate removes large amounts of albumin; thus, nutritional status must be closely watched.

The most common complication of peritoneal dialysis is peritonitis. Peritonitis may present with nausea and vomiting, abdominal pain, diarrhea or constipation, and fever. The normally clear dialysate becomes cloudy; and a diagnostic peritoneal fluid cell count greater than 100 white blood cells/mcL with a differential of greater than 50% polymorphonuclear neutrophils is present. Staphylococcus aureus is the most common infecting organism, but streptococci and gram-negative species may also be causative. Empiric intraperitoneal administration of either vancomycin or a first-generation cephalosporin (cefazolin) plus a third-generation cephalosporin (ceftazidime) should be instituted with the first signs of peritonitis and subsequently tailored based on culture results.

2. Kidney transplantation

Many patients with ESRD are otherwise healthy enough to be suitable for transplantation, although standard criteria for recipient selection are lacking between transplant centers. Two-thirds of kidney allografts come from deceased donors, with the remainder from living related or unrelated donors. Over 100,000 patients are on the waiting list for a deceased donor transplant in the United States; the average wait is 3–7 years, depending on geographic location and recipient blood type.

The 1- and 5-year kidney graft survival rates are approximately 95% and 80%, respectively, for living donor transplants and 89% and 66%, respectively, for deceased donor transplants. Factors that determine outcome include antigenic disparity (ABO blood groups and major histocompatibility or HLA) between donor and recipient, the type of immunologic response mounted by the host, and the immunosuppressive regimen used to prevent graft rejection. Nonimmunologic factors that affect the risk of chronic rejection include age and race of recipient; donor age; length of time on dialysis; and coexisting hyperlipidemia, hypertension, or cytomegalovirus infection.

Immunosuppressive regimens to prevent allograft rejection generally include a combination of a corticosteroid, an antimetabolite (azathioprine or mycophenolate mofetil), and a calcineurin inhibitor (tacrolimus or cyclosporine) or mTor inhibitor (sirolimus). Maintenance doses must balance the risk of allograft rejection as well as the adverse effects of immunosuppressives, including the development of certain cancers, infections, new onset diabetes, and chronic allograft dysfunction (calcineurin inhibitor). Additionally, calcineurin inhibitors have a narrow therapeutic window, and their hepatic metabolism is affected by many drugs (especially azoles and calcium channel blockers). Any changes in the transplant recipient's medical regimen should, therefore, occur only after consultation with a trained pharmacist or transplant nephrologist. Transplant recipients are at higher risk for CVD than the general population. Patients who have undergone transplantation should be assessed for CVD risk factors, monitored for bone health (maintenance of normal vitamin D status, periodic bone densitometry, and evaluation and treatment of residual hyperparathyroidism), and screened for skin cancers routinely; in addition, the patients' medication list should be scrutinized for adverse drug-drug interactions, and their vaccination status should be reviewed regularly.

3. Medical management of ESRD

As noted above, some patients are not candidates for kidney transplantation and may not benefit from dialysis. Very elderly persons may die soon after dialysis initiation; those who do not may nonetheless rapidly lose functional status in the first year of treatment. The decision to initiate dialysis in patients with limited life expectancy should be weighed against possible deterioration in quality of life. For patients with ESRD who elect not to undergo dialysis or who withdraw from dialysis, progressive uremia with gradual suppression of sensorium results in a painless death within days to months. Hyperkalemia may intervene with a fatal cardiac dysrhythmia. Diuretics, volume restriction, and opioids, as described in Chapter 5, may help decrease the symptoms of volume overload. Involvement of a palliative care team is essential.

Compared with kidney transplant recipients and age-matched controls, mortality is higher for patients undergoing dialysis. There is likely little difference in survival for well-matched peritoneal versus hemodialysis patients.

Survival rates on dialysis depend on the underlying disease process. Five-year Kaplan-Meier survival rates vary from 37% for patients with diabetes to 54% for patients with glomerulonephritis. Overall 5-year survival is currently estimated at 40%. Patients undergoing dialysis have an average life expectancy of 3–5 years, but survival for as long as 25 years may be achieved depending on comorbidities. The most common cause of death is cardiac disease (more than 50%). Other causes include infection, cerebrovascular disease, and malignancy. Diabetes, advanced age, a low serum albumin, lower socioeconomic status, and inadequate dialysis are all significant predictors of mortality; high FGF-23 levels are a marker for mortality in ESRD.

• A patient with stage 3–5 CKD should be referred to a nephrologist for management in conjunction with the primary care provider.

• A patient with other forms of CKD such as those with proteinuria greater than 1 g/day or polycystic kidney disease should be referred to a nephrologist at earlier stages.

• Admission should be considered for decompensation of problems related to CKD, such as worsening of acid-base status, electrolyte abnormalities, and volume overload, that cannot be appropriately treated in the outpatient setting.

• Admission is appropriate when a patient needs to start dialysis and is not stable for its outpatient initiation.