Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and include anorexia, nausea, vomiting, stomatitis, dysgeusia, nocturia, lassitude, fatigue, pruritus, decreased mental acuity, muscle twitches and cramps, water retention, undernutrition, GI ulceration and bleeding, peripheral neuropathies, and seizures. Diagnosis is based on laboratory testing of renal function, sometimes followed by renal biopsy. Treatment is primarily directed at the underlying condition but includes fluid and electrolyte management, erythropoietin for anemia, and often dialysis or transplantation.

Etiology

CKD may result from any cause of renal dysfunction of sufficient magnitude (see Table 4: Renal Failure: Major Causes of Chronic Kidney Disease). The most common cause in the US is diabetic nephropathy (see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic nephropathy), followed by hypertensive nephroangiosclerosis and various primary and secondary glomerulopathies. Metabolic syndrome (see Obesity and the Metabolic Syndrome: Metabolic Syndrome), in which hypertension and type 2 diabetes are present, is a large and growing cause of renal damage.

Table 4
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Major Causes of Chronic Kidney Disease Cause Examples Chronic tubulointerstitial nephropathies see Table 3: Tubulointerstitial Diseases: Causes of Chronic Tubulointerstitial Nephritis Glomerulopathies (primary) Focal glomerulosclerosis Idiopathic crescentic glomerulonephritis IgA nephropathy Membranoproliferative glomerulonephritis Membranous nephropathy Glomerulopathies associated with systemic disease Amyloidosis Diabetes mellitus Hemolytic-uremic syndrome Postinfectious glomerulonephritis SLE Wegener's granulomatosis Hereditary nephropathies Hereditary nephritis (Alport's syndrome) Medullary cystic disease Nail-patella syndrome Polycystic kidney disease Hypertension Malignant glomerulosclerosis Nephroangiosclerosis Obstructive uropathy Benign prostatic hyperplasia Posterior urethral valves Retroperitoneal fibrosis Ureteral obstruction (congenital, calculi, cancer) Vesicoureteral reflux Renal macrovascular disease (vasculopathy of renal arteries and veins) Renal artery stenosis caused by atherosclerosis or fibromuscular dysplasia

Pathophysiology

CKD can be roughly categorized as diminished renal reserve, renal insufficiency, or renal failure (end-stage renal disease). Initially, as renal tissue loses function, there are few abnormalities because the remaining tissue increases its performance (renal functional adaptation); a loss of 75% of renal tissue causes a fall in GFR to only 50% of normal.

Decreased renal function interferes with the kidneys' ability to maintain fluid and electrolyte homeostasis. Changes proceed predictably, but considerable overlap and individual variation exist. The ability to concentrate urine declines early and is followed by decreases in ability to excrete phosphate, acid, and K. When renal failure is advanced (GFR ≤ 10 mL/min/1.73 m²), the ability to dilute urine is lost; thus urine osmolality is usually fixed close to that of plasma (300 to 320 mOsm/kg), and urinary volume does not respond readily to variations in water intake.

Plasma concentrations of creatinine and urea (which are highly dependent on glomerular filtration) begin a nonlinear rise as GFR diminishes. These changes are minimal early on. When the GFR falls below 10 mL/min/1.73 m² (normal = 100 mL/min/1.73 m²), their levels increase rapidly and are usually associated with systemic manifestations (uremia). Urea and creatinine are not major contributors to the uremic symptoms; they are markers for many other substances (some not yet well defined) that cause the symptoms.

Despite a diminishing GFR, Na and water balance is well maintained by increased fractional excretion of Na and a normal response to thirst. Thus, the plasma Na concentration is typically normal, and hypervolemia is infrequent unless dietary intake of Na or water is very restricted or excessive. Heart failure can occur from Na and water overload, particularly in patients with decreased cardiac reserve.

For substances whose secretion is controlled mainly through distal nephron secretion (eg, K), adaptation usually maintains plasma levels at normal until renal failure is advanced. K-sparing diuretics, ACE inhibitors, β-blockers, NSAIDs, cyclosporine, tacrolimus, or angiotensin II receptor blockers may raise plasma K levels in patients with less advanced renal failure.

Abnormalities of Ca, phosphate, parathyroid hormone (PTH), vitamin D metabolism, and renal osteodystrophy can occur. Decreased renal production of calcitriol contributes to hypocalcemia. Decreased renal excretion of phosphate results in hyperphosphatemia. Secondary hyperparathyroidism is common and can develop in renal failure before abnormalities in Ca or phosphate concentrations occur. For this reason, monitoring PTH in patients with moderate CKD, even before hyperphosphatemia occurs, has been recommended.

Renal osteodystrophy (abnormal bone mineralization resulting from hyperparathyroidism, calcitriol deficiency, elevated serum phosphate, or low or normal serum Ca) usually takes the form of increased bone turnover due to hyperparathyroid bone disease (osteitis fibrosa) but can also involve decreased bone turnover due to adynamic bone disease (with increased parathyroid suppression) or osteomalacia. Calcitriol deficiency may cause osteopenia or osteomalacia.

Moderate acidosis (plasma HCO₃ content 15 to 20 mmol/L) and anemia are characteristic. The anemia of CKD is normochromic-normocytic, with an Hct of 20 to 30% (35 to 50% in patients with polycystic kidney disease). It is usually caused by deficient erythropoietin production due to a reduction of functional renal mass (see Anemias Caused by Deficient Erythropoiesis). Other causes include deficiencies of iron, folate, and vitamin B₁₂.

Symptoms and Signs

Patients with mildly diminished renal reserve are asymptomatic. Even patients with mild to moderate renal insufficiency may have no symptoms despite elevated BUN and creatinine. Nocturia is often noted, principally due to a failure to concentrate the urine. Lassitude, fatigue, anorexia, and decreased mental acuity often are the earliest manifestations of uremia.

With more severe renal insufficiency (eg, creatinine clearance < 10 mL/min for patients without diabetes and < 15 mL/min for those with diabetes), neuromuscular symptoms may be present, including coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps, hyperreflexia, and seizures (usually the result of hypertensive or metabolic encephalopathy). Anorexia, nausea, vomiting, weight loss, stomatitis, and an unpleasant taste in the mouth are almost uniformly present. The skin may be yellow-brown. Occasionally, urea from sweat crystallizes on the skin (uremic frost). Pruritus may be especially uncomfortable. Undernutrition leading to generalized tissue wasting is a prominent feature of chronic uremia.

Clinical Calculator

In advanced CKD, pericarditis and GI ulceration and bleeding are common. Hypertension is present in > 80% of patients with advanced CKD, is usually related to hypervolemia, and is occasionally the result of activation of the renin-angiotensin-aldosterone system. Heart failure caused by hypertension or coronary artery disease and renal retention of Na and water may lead to dependent edema.

Diagnosis

• Electrolytes, BUN, creatinine, phosphate, Ca, CBC, urinalysis (including urinary sediment examination)
• Ultrasonography
• Sometimes renal biopsy

CKD is usually first suspected when serum creatinine rises. The initial step is to determine whether the renal failure is acute, chronic, or acute superimposed on chronic (ie, an acute disease that further compromises renal function in a patient with CKD—see Table 5: Renal Failure: Distinguishing Acute Kidney Failure From Chronic Kidney Disease). The cause of renal failure is also determined. Sometimes determining the duration of renal failure helps determine the cause; sometimes it is easier to determine the cause than the duration, and determining the cause helps determine the duration.

Table 5
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Distinguishing Acute Kidney Failure From Chronic Kidney Disease Finding Comment Prior known increase in serum creatinine Most reliable evidence of CKD Renal sonogram showing small kidneys Usually CKD Renal sonogram showing normal or enlarged kidneys May be ARF or some forms of CKD (diabetic nephropathy, PCKD, myeloma, malignant nephroangiosclerosis, rapidly progressive glomerulonephritis, infiltrative diseases [eg, lymphoma, leukemia, amyloidosis]) Oliguria, daily increases in serum creatinine and BUN Probably ARF or ARF superimposed on CKD Eye-band keratopathy Probably CKD No anemia Probably ARF or CKD due to PCKD Severe anemia, hyperphosphatemia, and hypocalcemia Possibly CKD but may be ARF Subperiosteal erosions on radiography Probably CKD Chronic symptoms or signs (eg, fatigue, nausea, pruritus, nocturia, hypertension) Usually CKD ARF = acute renal failure; CKD = chronic kidney disease; PCKD = polycystic kidney disease.

Testing includes urinalysis with examination of the urinary sediment, electrolytes, urea nitrogen, and creatinine, phosphate, Ca, and CBC. Sometimes specific serologic tests are needed to determine the cause. Distinguishing acute from chronic renal failure is most helped by a history of an elevated creatinine level or abnormal urinalysis. Urinalysis findings depend on the nature of the underlying disorder, but broad (> 3 WBC diameters wide) or especially waxy (highly refractile) casts often are prominent in advanced renal failure of any cause.

An ultrasound examination of the kidneys is usually helpful in evaluating for obstructive uropathy and in distinguishing acute from chronic renal failure based on kidney size. Except in certain conditions (see Table 4: Renal Failure: Major Causes of Chronic Kidney Disease), patients with chronic renal failure have small shrunken kidneys (usually < 10 cm in length) with thinned, hyperechoic cortex. Obtaining a precise diagnosis becomes increasingly difficult as renal function reaches values close to those of end-stage renal disease. The definitive diagnostic tool is renal biopsy, but it is not recommended when ultrasonography indicates small, fibrotic kidneys.

Classification

Staging CKD is a way of quantifying its severity. CKD has been classified into 5 stages.

• Stage 1: Normal GFR (≥ 90 mL/min/1.73 m²) plus either persistent albuminuria or known structural or hereditary renal disease
• Stage 2: GFR 60 to 89 mL/min/1.73 m²
• Stage 3: GFR 30 to 59 mL/min/1.73 m²
• Stage 4: GFR 15 to 29 mL/min/1.73 m²
• Stage 5: GFR < 15 mL/min/1.73 m²

GFR (in mL/min/1.73 m²) in CKD can be estimated by: 186.3 × (serum creatinine)−^1.154 × (age)− ^0.203. The result is multiplied by 0.742 if the patient is female and by 1.21 if African American. For female African Americans, the result is multiplied by 0.742 × 1.21 (0.898).

Prognosis

Progression of CKD is predicted in most cases by the degree of proteinuria. Patients with nephrotic-range proteinuria (> 3 g/24 h or urine protein/creatinine > 3) usually have a poorer prognosis and progress to renal failure more rapidly. Progression may occur even if the underlying disorder is not active. In patients with urine protein < 1.5 g/24 h, progression usually occurs more slowly if at all. Hypertension is associated with more rapid progression as well.

Treatment

• Control of underlying disorders
• Possible restriction of dietary protein, phosphate, and K
• Vitamin D supplements
• Treatment of anemia and heart failure
• Doses of all drugs adjusted as needed
• Dialysis for severely decreased GFR, uremic symptoms, or sometimes hyperkalemia or heart failure

Underlying disorders and contributory factors must be controlled. In particular, controlling hyperglycemia in patients with diabetic nephropathy and controlling hypertension in all patients substantially slows deterioration of GFR. Target BP should be about 110 to 130/ < 80 mm Hg. ACE inhibitors and angiotensin II receptor blockers decrease the rate of decline in GFR in patients with most causes of CKD, particularly those with proteinuria.

Activity need not be restricted, although fatigue and lassitude usually limit a patient's capacity for exercise. Pruritus may respond to phosphate binders if serum phosphate is elevated. If patients do not respond, ultraviolet phototherapy may help.

Nutrition

Severe protein restriction in renal disease is controversial. However, moderate restriction (0.8 g/kg/day) is safe and easy for most patients to tolerate. Some experts recommend 0.6 g/kg/day for patients with diabetes and, for patients without diabetes, > 0.8 g/kg/day if GFR is 25 to 55 mL/min/1.73 m² or 0.6 g/kg/day if GFR is 13 to 24 mL/min/1.73 m². Many uremic symptoms markedly lessen when protein catabolism and urea generation are reduced. Sufficient carbohydrate and fat are given to meet energy requirements and prevent ketosis. Patients for whom < 0.8 g/kg/day has been prescribed should be closely followed by a dietician.

Because dietary restrictions may reduce necessary vitamin intake, patients should take a multivitamin containing water-soluble vitamins. Administration of vitamin A and E is unnecessary. Vitamin D in the form of 1,25-dihydroxyvitamin D (calcitriol) or its analogs should be given as indicated by PTH concentrations. Dose is determined by stage of CKD, PTH concentration, and phosphate concentrations (see Table 6: Renal Failure: Target Levels for PTH and Phosphate in Chronic Kidney Disease). Target levels for Ca are 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L); for the Ca-phosphate product, < 55 mg²/dL².

Table 6
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Target Levels for PTH and Phosphate in Chronic Kidney Disease Disease Stage PTH (pg/mL) Phosphate (mg/dL [mmol/L]) 3 35–70 2.7–4.6 (0.87–1.49) 4 70–110 2.7–4.6 (0.87–1.49) 5 150–300 3.5–5.5 (1.13–1.78) PTH = parathyroid hormone.

A typical starting dose is calcitriol (or a calcitriol analog) 0.25 μg po once/day or 1 to 4 μg 2 times/wk. PTH levels are not corrected to normal because doing so risks precipitating adynamic bone disease.

Dietary modification may be helpful for hypertriglyceridemia. In patients with hypercholesterolemia, a statin is effective. Fibric acid derivatives (clofibrate, gemfibrozil) may increase risk of rhabdomyolysis in patients with CKD, especially if taken with statin drugs, whereas ezetimibe (which reduces cholesterol absorption) appears relatively safe. Correction of hypercholesterolemia may slow progression of the underlying renal disease and reduce coronary risk.

Fluid and electrolytes

Water intake is restricted only when serum Na concentration is < 135 mmol/L.

Na restriction of 2 g/day benefits patients, especially those with edema, heart failure, or hypertension.

K intake is closely related to meat, vegetable, and fruit ingestion and usually does not require adjustment. However, foods (especially salt substitutes) rich in K should generally be avoided. Hyperkalemia is infrequent (unless there is hyporeninemic hypoaldosteronism or K-sparing diuretic therapy) until end-stage renal failure, when intake may need to be restricted to ≤ 50 mmol/day. Mild hyperkalemia (< 6 mmol/L) can be treated by reducing K intake and correcting metabolic acidosis. More severe hyperkalemia (> 6 mmol/L) warrants urgent treatment (see Electrolyte Disorders: Moderate to severe hyperkalemia; see Renal Failure: Emergency treatment).

Phosphate restriction to < 1 g/day is often sufficient to maintain phosphate level in the target range during the early phase of stages 3 and 4 CKD. However, in the later phases, phosphate binders, such as Ca salts (acetate or carbonate but avoid citrate) or non–Ca-containing phosphate binders (sevelamer) are often necessary. No more than 1500 mg/day of elemental Ca should be given as binders (2000 mg/day of total Ca; binders plus dietary Ca).

Mild acidosis (pH 7.30 to 7.35) requires no therapy. However, most patients with chronic metabolic acidosis who have a pH < 7.3 have a plasma HCO₃ content < 15 mmol/L and symptoms of anorexia, lassitude, dyspnea, and exaggerated protein catabolism and renal osteodystrophy. NaHCO₃ 1 to 2 g po bid is given and amount is increased gradually until HCO₃ concentration is about 20 mEq/L or until evidence of Na overloading prevents further therapy.

Anemia and coagulation disorders

Anemia is treated to keep the Hb between 11 and 12 g/dL. Anemia slowly responds to recombinant human erythropoietin (eg, epoetin alfa 50 to 150 units/kg sc 1 to 3 times/wk). Because of increased iron utilization with stimulated erythropoiesis, iron stores must be replaced, usually with parenteral iron. Iron concentrations, iron-binding capacity, and ferritin concentrations should be followed closely. Transfusion should not be undertaken unless anemia is severe (Hb < 8 g/dL) or causes symptoms.

The bleeding tendency in CKD rarely needs treatment. Cryoprecipitate, RBC transfusions, desmopressin 0.3 to 0.4 μg/kg (20 μg maximum) in 20 mL of isotonic saline IV over 20 to 30 min, or conjugated estrogens 2.5 to 5 mg po once/day help when needed. The effects of these treatments last 12 to 48 h, except for conjugated estrogens, which may last for several days.

Heart failure

Symptomatic heart failure is treated with Na restriction and diuretics (see Heart Failure: Drugs). If left ventricular function is depressed, ACE inhibitors and β-blockers (carvedilol or metoprolol) should be used. Digoxin may be added, but the dosage must be reduced. Diuretics such as furosemide usually are effective even when renal function is markedly reduced, although large doses may be needed. Moderate or severe hypertension should be treated to avoid its deleterious effects on cardiac and renal function. Patients who do not respond to moderate reduction in Na intake (4 g/day) need further dietary Na restriction (2 g/day) and diuretic therapy (furosemide 80 to 240 mg po bid). Hydrochlorothiazide 50 mg po bid or metolazone 5 to 10 mg po once/day may be added to high-dose furosemide therapy if hypertension or edema is not controlled. Even in renal failure, the combination of a thiazide with a loop diuretic is quite potent and must be used with caution to avoid overdiuresis. Occasionally, dialysis may be required to control heart failure. If reduction of the ECF volume does not control BP, conventional antihypertensives are added. Azotemia may increase with such treatment but is acceptable short-term, even if temporary dialysis is required.

Drugs

Renal excretion of drugs is often impaired in patients with renal failure. Common drugs that require revised dosing include penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin, and digoxin. Hemodialysis reduces the serum concentrations of some drugs, which should be supplemented after hemodialysis. It is strongly recommended that physicians consult a reference on drug dosing in renal failure before prescribing drugs to these very vulnerable patients.

Certain drugs should be avoided entirely in patients undergoing dialysis. They include nitrofurantoin, metformin, and phenazopyridine.

Dialysis

Dialysis is initiated when GFR reaches ≤ 10 mL/min in a patient without diabetes or ≤ 15 mL/min in a patient with diabetes. Patients with uremic symptoms (eg, anorexia, vomiting, weight loss, pericarditis, pleuritis) or fluid overload who have no other conditions that would explain these symptoms should be started on dialysis even if GFR has not reached these levels. Other indications for dialysis in chronic kidney disease include hyperkalemia that causes ECG changes or that is persistent (K > 6 mmol/L) despite dietary restriction, heart failure poorly controlled with drugs, and metabolic acidosis that is difficult to control. (For dialysis preparation, see Renal Replacement Therapy: Hemodialysis.)

Transplantation

If a living kidney donor is available, better long-term outcomes occur when a patient receives the transplanted kidney early, even before beginning dialysis. Patients who are transplant candidates but have no living donor should receive a cadaveric renal transplant as early after initiating dialysis as possible (see Transplantation: Kidney Transplantation).

Last full review/revision December 2007 by James I. McMillan, MD