ESSENTIALS OF DIAGNOSIS
Decline in the GFR over months to years.
Persistent proteinuria or abnormal renal morphology may be present.
Hypertension in most cases.
Symptoms and signs of uremia when nearing end-stage disease.
Bilateral small or echogenic kidneys on ultrasound in advanced disease.
CKD affects at least 10% of Americans. Most are 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 African Americans.
Table 22–4.Stages of chronic kidney disease: a clinical action plan.1,2 |Favorite Table|Download (.pdf) Table 22–4. Stages of chronic kidney disease: a clinical action plan.1,2
|Stage3 ||Description ||GFR (mL/min/1.73 m2) ||Action |
|1 ||Kidney damage with normal or ↑↑ GFR ||≥ 90 ||Diagnosis and treatment of underlying etiology if possible. Treatment of comorbid conditions. Estimate progression, work to slow progression. Cardiovascular disease risk reduction. |
|2 ||Kidney damage with mildly ↓ GFR ||60–89 |
|3a ||Mildly-moderately ↓ GFR ||45–59 ||As above, and evaluating and treating complications. |
|3b ||Moderately-severely ↓ GFR ||30–44 |
|4 ||Severely ↓ GFR ||15–29 ||Preparation for end-stage renal disease (ESRD). |
|5 ||End-stage renal disease (ESRD) ||< 15 (or dialysis) ||Dialysis, transplant, or palliative care. |
Table 22–5.Major causes of chronic kidney disease. |Favorite Table|Download (.pdf) Table 22–5. Major causes of chronic kidney disease.
|Glomerular Diseases |
Primary glomerular diseases
Focal segmental glomerulosclerosis
Alport syndrome (hereditary nephritis)
Secondary glomerular diseases
Collagen-vascular diseases (eg, SLE)
HCV-associated membranoproliferative glomerulonephritis
|Tubulointerstitial Nephritis |
Sickle cell nephropathy
|Cystic Diseases |
Polycystic kidney disease
Medullary cystic disease
|Obstructive Nephropathies |
|Vascular Diseases |
Renal artery stenosis
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, a relatively insensitive marker for 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 particularly 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.
In the early stages, CKD is 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 and weakness; anorexia, nausea, vomiting, and a metallic taste in the mouth are also common. Patients or family members may report irritability, memory impairment, insomnia, restless legs, paresthesias, and twitching. Generalized pruritus without rash may occur. Decreased libido and menstrual irregularities are common. Pericarditis, a rare complication of CKD, may present with pleuritic chest pain. Drug toxicity can develop as renal clearance worsens; in particular, since insulin is renally cleared, hypoglycemia may develop and can be life-threatening in patients with diabetes.
eTable 22–2.Symptoms and signs of uremia. |Favorite Table|Download (.pdf) eTable 22–2. Symptoms and signs of uremia.
|Organ System ||Symptoms ||Signs |
|General ||Fatigue, weakness ||Sallow-appearing, chronically ill |
|Skin ||Pruritus, easy bruisability ||Pallor, ecchymoses, excoriations, edema, xerosis |
|ENT ||Metallic taste in mouth, epistaxis ||Urinous breath |
|Eye || ||Pale conjunctiva |
|Pulmonary ||Shortness of breath ||Rales, pleural effusion |
|Cardiovascular ||Dyspnea on exertion, retrosternal pain on inspiration (pericarditis) ||Hypertension, cardiomegaly, friction rub |
|Gastrointestinal ||Anorexia, nausea, vomiting, hiccups || |
|Genitourinary ||Nocturia, erectile dysfunction ||Isosthenuria |
|Neuromuscular ||Restless legs, numbness and cramps in legs || |
|Neurologic ||Generalized irritability and inability to concentrate, decreased libido ||Stupor, asterixis, myoclonus, peripheral neuropathy |
The most common physical finding in CKD is hypertension—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 typical physical signs of 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 improves or resolves 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 tract infections, obstruction, hypovolemia, hypotension, nephrotoxins (such as NSAIDs, aminoglycosides, or proton pump inhibitors), severe or emergent hypertension, and heart failure should be excluded.
Table 22–6.Reversible causes of kidney injury. |Favorite Table|Download (.pdf) Table 22–6. Reversible causes of kidney injury.
|Reversible Factors ||Diagnostic Clues |
|Infection ||Urine culture and sensitivity tests |
|Obstruction ||Bladder catheterization, then renal ultrasound |
|Extracellular fluid volume depletion or significant hypotension relative to baseline ||Blood pressure and pulse, including orthostatic pulse |
|Hypokalemia, hypercalcemia, and hyperuricemia (usually >15 mg/dL) ||Serum electrolytes, calcium, phosphate, uric acid |
|Nephrotoxic agents ||Drug history |
|Severe/urgent hypertension ||Blood pressure, chest radiograph |
|Heart failure ||Physical examination, chest radiograph |
CKD is usually defined by an abnormal GFR persisting for at least 3 months. Persistent proteinuria or abnormalities on renal imaging (eg, polycystic kidneys) are also diagnostic of CKD, even when eGFR is normal. It is helpful to plot the inverse of serum creatinine (1/SCr) or eGFR (if reported by the laboratory) versus time. If three or more prior measurements are available, the time to ESRD can be roughly estimated (Figure 22–1). If the slope of the line acutely declines, new and 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.
Decline in kidney function (expressed as the reciprocal of serum creatinine as shown here, or as estimated glomerular filtration rate [eGFR]) plotted against time to end-stage renal disease (ESRD). The solid line indicates the linear decline in kidney function over time. The dotted line indicates the approximate time to ESRD.
The finding of small, echogenic kidneys bilaterally (less than 9–10 cm) by ultrasonography supports a diagnosis of CKD, although normal or even 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.
Complications of chronic kidney disease (CKD) by stage and glomerular filtration rate (GFR). Complications arising from CKD tend to occur at the stages depicted, although there is considerable variability noted in clinical practice. HTN, hypertension; PTH, parathyroid hormone. (Adapted, with permission, from William Bennett, MD.)
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 precise biologic mechanisms for this enhanced mortality are unclear but may have to do with the uremic milieu including abnormal phosphorus and calcium homeostasis, increased burden of oxidative stress, increased vascular reactivity, increased left ventricular hypertrophy, and underlying coexistent comorbidities such as hypertension and diabetes mellitus.
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 nonpharmacologic therapy (eg, diet, exercise, weight loss, treatment of obstructive sleep apnea) and pharmacologic therapy. 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 11–5); 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 11–7). When an ACE inhibitor or an ARB is initiated or uptitrated, patients must have serum creatinine and potassium checked within 7–14 days. Hyperkalemia or a rise in serum creatinine greater than 30% from baseline mandates reduction or cessation of the drug. An ACE inhibitor and ARB should not be used in combination. Hypertension in CKD can be difficult to control and additional agents from other classes are often needed. Current guidelines from the Joint National Commission suggest a blood pressure goal of less than 140/90 mm Hg for patients with CKD. The SPRINT trial showed a cardiovascular and mortality benefit for those without CKD who randomized to a systolic blood pressure goal of less than 120 mm Hg; in the roughly 2600 patients with CKD (without diabetes), there was a trend toward benefit of a lower blood pressure goal, but it was not significant. Experts agree that more studies are needed in this patient population, and that it is prudent to continue with an individualized approach.
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.
The complications of CKD result in increased cardiac workload via hypertensive disease, 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 are present in most patients starting dialysis. 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 close monitoring for hyperkalemia and worsening kidney function.
Pericarditis rarely develops in uremic patients; typical findings include pleuritic chest pain and a friction rub. Development of a significant 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.
Uremic pericardial effusion. (Used, with permission, from E Foster.)
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 cause vascular calcification, which may be partly responsible for the accelerated CVD and excess mortality seen in the CKD population. Epidemiologic studies in humans 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.
Mineral abnormalities of chronic kidney disease (CKD). Decline in glomerular filtration rate (GFR) and loss of renal mass lead directly to increased serum phosphorus and hypovitaminosis D. Both of these abnormalities result in hypocalcemia and hyperparathyroidism. Many CKD patients also have nutritional 25(OH) vitamin D deficiency. PTH, parathyroid hormone.
Pathogenesis of bone diseases in chronic kidney failure. (Reproduced, with permission, from Brenner BM, Lazarus JM. Chronic renal failure. In: Harrison's Principles of Internal Medicine, 12th ed. Wilson JD et al [editors]. McGraw-Hill, 1991.)
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 (defined as a serum phosphorus of less than or equal to 4.5 mg/dL in pre-ESRD CKD, or less than or equal to 5.5 mg/dL in ESRD patients). 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, such as calcium carbonate (650 mg/tablet) or calcium acetate (667 mg/capsule), block absorption of dietary phosphorus in the gut and are given thrice daily with meals. These should be titrated to a serum phosphorus of less than 4.6 mg/dL in stage 3–4 CKD and less than 4.6–5.5 mg/dL in ESRD. Maximal recommended elemental calcium doses are 1500 mg/day (eg, nine tablets of calcium acetate); doses should be decreased if serum calcium rises above 10 mg/dL. Phosphorus-binding agents that do not contain calcium are sevelamer and lanthanum. Sevelamer, 800–3200 mg, and lanthanum carbonate, 500–1000 mg, are given orally at the beginning of meals and may be combined with calcium-containing binders. 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 serum phosphorus greater than 7 mg/dL or for short periods (eg, 3 weeks) in CKD patients. Newer iron-based, non–calcium-containing phosphorus binders for long-term use include ferric citrate and sucroferric oxyhydroxide. Clinical experience with these agents is lacking, but certainly these agents should not be administered to patients with iron overload.
Once serum phosphorus levels are controlled, active vitamin D (1,25[OH] vitamin D, or calcitriol) or active vitamin D analogs are recommended to treat secondary hyperparathyroidism in stage 3–5 CKD. 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 generally 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
The anemia of CKD is primarily due to decreased erythropoietin production, which often becomes clinically significant during stage 3 CKD. Many patients are iron deficient as well due to impaired GI iron absorption.
Erythropoiesis-stimulating agents (ESAs, eg, recombinant erythropoietin [epoetin] 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 Hgb values are less than 9 g/dL. The starting dose of epoetin is 50 units/kg (3000–4000 units/dose) once or twice a week, and darbepoetin is started at 0.45 mcg/kg and can be administered 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 erythropoietin 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 complication of treatment with ESAs in about 20% of patients. The dosage may require adjustment, or antihypertensive drugs may need to be given.
Iron stores must be adequate to ensure response to ESAs. Hepcidin, a molecule that blocks GI iron absorption and mobilization of iron from body stores, tends to be high in CKD. Therefore, traditional measures of iron stores are measured in CKD patients but are targeted to higher goals; in CKD, a serum ferritin below 100–200 ng/mL or iron saturation less than 20% is suggestive of iron deficiency. Iron stores should be repleted with oral or parenteral iron prior to the initiation of an ESA. 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 to three times daily, is the initial therapy in pre-ESRD CKD. For those who do not respond due to poor GI absorption or lack of tolerance, intravenous iron may be necessary.
The preliminary investigation of anemia in any CKD patient should also include assessment of thyroid function tests, and serum vitamin B12 testing prior to initiating therapy with an ESA.
The bleeding diathesis that may occur in advanced stage 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. 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. Cryoprecipitate (10–15 bags) is rarely used and lasts less than 24 hours.
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 21–6). Cardiac monitoring is indicated for any ECG changes seen with hyperkalemia or a serum potassium level greater than 6.0–6.5 mEq/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 also be administered for their kaliuretic effect as long as the patient is not volume-depleted.
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 and to growth retardation in children with CKD. Chronic acidosis can also result in muscle protein catabolism, and may accelerate progression of CKD. The serum bicarbonate level should be normalized. Reduction in the intake of dietary animal protein and the administration of oral sodium bicarbonate (in doses of 0.5–1.0 mEq/kg/day divided twice daily and titrated as needed) may achieve this goal. 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, which 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.
There is risk of hypoglycemia in treated diabetic patients with advanced CKD due to decreased renal elimination of insulin. 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. Whether to discontinue metformin when the eGFR is between 30 mL/min and 60 mL/min is controversial.
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.
Treatment of the underlying cause of CKD is vital. Control of diabetes should be aggressive in early CKD; 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 disease (see section on hypertension regarding blood pressure goals). Several small studies suggest a possible benefit of oral bicarbonate therapy in slowing CKD progression when acidemia is present; there is also theoretic value in lowering uric acid levels in those with concomitant hyperuricemia, but clinical data are lacking. Obese patients should be encouraged to lose weight. Management of traditional cardiovascular risk factors should also be emphasized.
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.
Reduced intake of animal protein to 0.6-0.8 g/kg/day may retard CKD progression and is likely not harmful in the otherwise well-nourished patient; it 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.
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 gastrointestinal tract as GFR declines. Sodium polystyrene sulfate and newer potassium-binding agents (such as sodium zirconium cyclosilicate) can be used to increase gastrointestinal tract potassium removal by binding potassium in the gut.
4. Phosphorus restriction
The phosphorus level should be kept in the “normal” range (less than 4.5 mg/dL) predialysis, and between 3.5 and 5.5 mg/dL in ESRD, with a dietary restriction of 800–1000 mg/day. Foods rich in phosphorus such as cola beverages, eggs, dairy products, nuts, beans, and meat should be limited, although care must be taken to avoid protein malnutrition. Processed foods are often preserved with highly bioavailable phosphorus and should be avoided. 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 (see above).
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 End-Stage Renal Disease
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.
Dialysis initiation should be considered when GFR is 10 mL/min/1.73 m2. Studies suggest that the well-selected patient without overt uremic symptoms may wait to initiate dialysis until GFR is closer to 7 mL/min/1.73 m2. Other indications for dialysis, which may occur when GFR is 10–15 mL/min/1.73 m2 include (1) uremic symptoms, (2) fluid overload unresponsive to diuresis, and (3) refractory hyperkalemia.
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.
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 are also common.
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 2–6 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 dysrythmia. 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 fibroblast growth factor (FGF)-23 levels are a novel 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 patients with decompensation of problems related to CKD, such as worsening of acid-base status, electrolyte abnormalities, and volume status that cannot be appropriately treated in the outpatient setting.
Admission is appropriate when a patient needs to start dialysis and is not stable for outpatient initiation.
et al. Use of renin angiotensin system inhibitors in patients with chronic kidney disease. Intern Med J. 2016 May;46(5):626–30.
JM. Timing of initiation of RRT and modality selection. Clin J Am Soc Nephrol. 2015 Jun 5;10(6):1072–7.
NK. Diagnosis and management of cardiovascular disease in advanced and end-stage renal disease. J Am Heart Assoc. 2016 Aug 4;5(8). pii: e003648.
et al. SPRINT: The study nephrologists might take with a grain of salt. J Clin Hypertens (Greenwich). 2016 Nov;18(11):1185–8.
et al. Renal transplantation in advanced chronic kidney disease patients. Med Clin North Am. 2016 May;100(3):465–76.
et al. Dietary interventions to improve outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens. 2015 Nov;24(6):505–10.
et al; Chronic Kidney Disease Prognosis Consortium. Kidney-failure risk projection for the living kidney-donor candidate. N Engl J Med. 2016 Feb 4;374(5):411–21.
et al. Kidney disease and maternal and fetal outcomes in pregnancy. Am J Kidney Dis. 2015 Jul;66(1):55–9.
et al. Survival by dialysis modality—who cares? Clin J Am Soc Nephrol. 2016 Jun 6;11(6):1083–7.
et al. Dietary interventions for mineral and bone disorder in people with chronic kidney disease. Cochrane Database Syst Rev. 2015 Sep 16;9:CD010350.
et al. Phosphate binders, past—present—future. A critical appraisal. Expert Opin Pharmacother. 2016 Feb;17(3):297–300.
et al. Altered dietary salt intake for people with chronic kidney disease. Cochrane Database Syst Rev. 2015 Feb 18;2:CD010070.
et al. PPIs and kidney disease: from AIN to CKD. J Nephrol. 2016 Oct;29(5):611–6.
et al. Supportive care: comprehensive conservative care in end-stage kidney disease. Clin J Am Soc Nephrol. 2016 Aug 10. [Epub ahead of print]
et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015 Jan 15;372(3):222–31.
et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2014 Dec 8;12:CD010590.
et al. HMG CoA reductase inhibitors (statins) for persons with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2014 May 31;5:CD007784.
et al. Disorders of iron metabolism and anemia in chronic kidney disease. Semin Nephrol. 2016 Jul;36(4):252–61.
et al. APOL1 risk variants, race and progression of chronic kidney disease. N Engl J Med. 2013 Dec 5;369(23):2183–96.
et al. Established and emerging strategies in the treatment of chronic kidney disease. Semin Nephrol. 2016 Jul;36(4):331–42.
et al. Drug management in the elderly adult with chronic kidney disease: a review for the primary care physician. Mayo Clin Proc. 2015 May;90(5):633–45.
KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696–702.
AA. JAMA patient page. Chronic kidney disease. JAMA. 2016 May 24–31;315(20):2248.
MV. Chronic hemodialysis therapy in the west. Kidney Dis (Basel). 2015 Dec;1(3):178–86.
et al. Heart failure in patients with chronic kidney disease: a systematic integrative review. Biomed Res Int. 2014;2014:937398.
et al. Role of sodium restriction and diuretic therapy for "resistant" hypertension in chronic kidney disease. Semin Nephrol. 2014;34(5):514–9.
SPRINT Research Group, Wright
et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015 Nov 26;373(22):2103–16.
et al. Epidemiology and mechanisms of uremia-related cardiovascular disease. Circulation. 2016 Feb 2;133(5):518–36.
et al; National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Practical approach to detection and management of chronic kidney disease for the primary care clinician. Am J Med. 2016 Feb;129(2):153–62.e7.
et al. Optimal treatment strategies in patients with chronic kidney disease and coronary artery disease. Am J Med. 2016 Dec;129(12):1288–98.
et al. Chronic kidney disease. Lancet. 2017 Mar 25;389(10075):1238-52.
Atherosclerotic ischemic renal disease accounts for most cases of renal artery stenosis. Fibromuscular dysplasia is a less common cause of renal artery stenosis. Approximately 5% of Americans with hypertension suffer from renal artery stenosis. It occurs most commonly in those over 45 years of age with a history of atherosclerotic disease. Other risk factors include CKD, diabetes mellitus, tobacco use, and hypertension.
Patients with atherosclerotic ischemic renal disease may have refractory hypertension, new-onset hypertension (in an older patient), pulmonary edema with poorly controlled blood pressure, and AKI upon starting an ACE inhibitor. In addition to hypertension, physical examination may reveal an audible abdominal bruit on the affected side. Fibromuscular dysplasia primarily affects young women. Unexplained hypertension in a woman younger than 40 years is reason to screen for this disorder.
Laboratory values can show elevated BUN and serum creatinine levels in the setting of significant renal ischemia.
Abdominal ultrasound can reveal asymmetric kidney size when one renal artery is affected out of proportion to the other or small hyperechoic kidneys if both are affected.
Three prevailing methods used for screening are Doppler ultrasonography, CT angiography, and magnetic resonance angiography (MRA). According to the American College of Cardiology/American Heart Association guidelines, one of these should be undertaken if a corrective procedure would be performed when a positive test result is found. Doppler ultrasonography is highly sensitive and specific (85% and 92% respectively in a meta-analysis of 88 studies) and relatively inexpensive. However, this method is extremely operator and patient dependent. Measurements of blood flow must be made at the aorta and along each third of the renal artery in order to assess the disease. This test is a poor choice for patients who are obese, unable to lie supine, or have interfering bowel gas patterns.
CT angiography consists of intravenous digital subtraction angiography with arteriography and is a noninvasive procedure. The procedure uses a spiral (helical) CT scan with intravenous contrast injection. The sensitivities from various studies range from 77% to 98%, with less varying specificities in a range of 90–94%.
MRA is an excellent but expensive way to screen for renal artery stenosis, particularly in those with atherosclerotic disease. Sensitivity is 77–100%, although one study with particular flaws showed a sensitivity of only 62%. Specificity ranges from 71% to 96%. Turbulent blood flow can cause false-positive results. The imaging agent for MRA (gadolinium) has been associated with nephrogenic systemic fibrosis, which occurs primarily in patients with a GFR of less than 15 mL/min/1.73 m2, and rarely in patients with a GFR of 15–29 mL/min/1.73 m2. It has also been seen in those with AKI and kidney transplants.
Renal angiography is the gold standard for diagnosis but more invasive than the screening tests above. Thus, this is performed after a positive screening test. CO2 subtraction angiography can be used in place of dye when the risk of dye nephropathy exists—eg, in diabetic patients with kidney injury. Lesions are most commonly found in the proximal third or ostial region of the renal artery. The risk of atheroembolic phenomena after angiography ranges from 5% to 10%. Fibromuscular dysplasia has a characteristic “beads-on-a-string” appearance on angiography.
Treatment of atherosclerotic ischemic renal disease is controversial. Options include medical management, angioplasty with or without stenting, and surgical bypass. Two large randomized trials have shown that vascular intervention is no better than optimal medical management in typical patients with renal artery stenosis. Angioplasty might reduce the number of antihypertensive medications but does not significantly change the progression of kidney dysfunction in comparison to patients medically managed. Stenting produces significantly better angioplastic results. However, blood pressure and serum creatinine are similar at 6 months of observation compared with both angioplasty and stents. Angioplasty is equally as effective as, and safer than, surgical revision.
Treatment of fibromuscular dysplasia with percutaneous transluminal angioplasty is often curative, which is in stark contrast to treatment for atherosclerotic causes.
et al; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014 Jan 2;370(1):13–22.
et al. Management of atherosclerotic renovascular disease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL). Nephrol Dial Transplant. 2015 March;30(3):366–75.
et al. Recent developments in the understanding and management of fibromuscular dysplasia. J Am Heart Assoc. 2014 Dec;3(6):e001259.