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Chronic Kidney Disease
(Chronic Renal Failure; CKD)
Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia, nocturia, lassitude, fatigue, pruritus, decreased mental acuity, muscle twitches and cramps, water retention, undernutrition, 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, blood pressure control, treatment of anemia, various types of dialysis, and kidney transplantation.
Prevalence of CKD (stages 1 through 5) in the US adult general population is estimated at 14.8% (NHANES 2011–2014 database).
CKD may result from any cause of renal dysfunction of sufficient magnitude (see Table: Major Causes of Chronic Kidney Disease).
The most common causes in the US in order of prevalence are
Metabolic syndrome, in which hypertension and type 2 diabetes are present, is a large and growing cause of renal damage.
Major Causes of Chronic Kidney Disease
Chronic tubulointerstitial nephropathies
Idiopathic crescentic glomerulonephritis
Glomerulopathies associated with systemic disease
Anti-GBM antibody disease (also known as Goodpasture syndrome)
Hereditary nephritis (Alport syndrome)
Ureteral obstruction (congenital, calculi, cancer)
Renal macrovascular disease (vasculopathy of renal arteries and veins)
CKD is initially described as diminished renal reserve or renal insufficiency, which may progress to renal failure (end-stage renal disease). Initially, as renal tissue loses function, there are few noticeable abnormalities because the remaining tissue increases its performance (renal functional adaptation).
Decreased renal function interferes with the kidneys’ ability to maintain fluid and electrolyte homeostasis. The ability to concentrate urine declines early and is followed by decreases in ability to excrete excess phosphate, acid, and potassium. When renal failure is advanced (GFR ≤ 15 mL/min/1.73 m2), the ability to effectively dilute or concentrate urine is lost; thus, urine osmolality is usually fixed at about 300 to 320 mOsm/kg, close to that of plasma (275 to 295 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 hyperbolic rise as GFR diminishes. These changes are minimal early on. When the GFR falls below 15 mL/min/1.73 m2 (normal > 90 mL/min/1.73 m2), creatinine and urea levels are high 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, sodium and water balance is well maintained by increased fractional excretion of sodium in urine and a normal response to thirst. Thus, the plasma sodium concentration is typically normal, and hypervolemia is infrequent unless dietary intake of sodium or water is very restricted or excessive. Heart failure can occur due to sodium and water overload, particularly in patients with decreased cardiac reserve.
For substances whose secretion is controlled mainly through distal nephron secretion (eg, potassium), renal adaptation usually maintains plasma levels at normal until renal failure is advanced or dietary potassium intake is excessive. Potassium-sparing diuretics, ACE inhibitors, beta-blockers, NSAIDs, cyclosporine, tacrolimus, trimethoprim/sulfamethoxazole, pentamidine, or angiotensin II receptor blockers may raise plasma potassium levels in patients with less advanced renal failure.
Abnormalities of calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism can occur, as can renal osteodystrophy. 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 calcium 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 calcium) 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.
Anemia is characteristic of moderate to advanced CKD (≥ stage 3). The anemia of CKD is normochromic-normocytic, with an Hct of 20 to 30% (35 to 40% in patients with polycystic kidney disease). It is usually caused by deficient erythropoietin production due to a reduction of functional renal mass (see Overview of Decreased Erythropoiesis). Other causes include deficiencies of iron, folate, and vitamin B12.
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 failure to concentrate the urine. Lassitude, fatigue, anorexia, and decreased mental acuity often are the earliest manifestations of uremia.
With more severe renal disease (eg, estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73 m2), neuromuscular symptoms may be present, including coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps, hyperreflexia, restless legs syndrome, 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.
In advanced CKD, pericarditis and GI ulceration and bleeding may occur. Hypertension is present in > 80% of patients with advanced CKD and is usually related to hypervolemia. Heart failure caused by hypertension or coronary artery disease and renal retention of sodium and water may lead to dependent edema and/or dyspnea.
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: Distinguishing Acute Kidney Injury 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.
Distinguishing Acute Kidney Injury From Chronic Kidney Disease
Testing includes urinalysis with examination of the urinary sediment, electrolytes, urea nitrogen, creatinine, phosphate, calcium, and CBC. Sometimes specific serologic tests are needed to determine the cause. Distinguishing acute kidney injury from CKD 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 kidney injury from CKD based on kidney size. Except in certain conditions (see Table: Major Causes of Chronic Kidney Disease), patients with CKD 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; high procedural risk outweighs low diagnostic yield.
Staging CKD is a way of quantifying its severity. CKD has been classified into 5 stages.
GFR (in mL/min/1.73 m2) in CKD can be estimated by the MDRD equation: 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 the patient is African American. For female African Americans, the result is multiplied by 0.742 × 1.21 (0.898). This calculation is not very accurate for patients who are older and sedentary, very obese, or very thin. Alternatively, GFR can be estimated using the Cockcroft-Gault equation to approximate creatinine clearance; this equation tends to overestimate GFR by 10 to 40%.
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula is more accurate than the MDRD and Cockcroft and Gault formulas, particularly for patients with a GFR near normal values. The CKD-EPI equation yields fewer falsely positive results indicating chronic kidney disease and predicts outcome better than the other formulas.
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 ratio > 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, acidosis, and hyperparathyroidism are associated with more rapid progression as well.
Control of underlying disorders
Possible restriction of dietary protein, phosphate, and potassium
Vitamin D supplements
Treatment of anemia
Treatment of contributing comorbidities (eg, heart failure, diabetes mellitus, nephrolithiasis, prostatic hypertrophy)
Doses of all drugs adjusted as needed
Dialysis for severely decreased GFR if symptoms and signs not adequately managed by medical interventions
Maintaining sodium bicarbonate level at 23 mmol/L
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.
For hypertension, recent guidelines suggest a target BP of < 140/90 mm Hg, but some authors continue to recommend 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. Increasing evidence suggests that, compared with either drug alone, combined use of ACE inhibitors and angiotensin II receptor blockers increases incidence of complications and does not slow decline in renal function, even though combined use does reduce proteinuria more.
Activity need not be restricted, although fatigue and lassitude usually limit a patient’s capacity for exercise. Pruritus may respond to dietary phosphate restriction and phosphate binders if serum phosphate is elevated.
Severe protein restriction in renal disease is controversial. However, moderate restriction (0.8 g/kg/day) among patients with eGFR < 60 mL/min/1.73 m2 without nephrotic syndrome 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 if GFR is < 25 mL/min/1.73 m2. Many uremic symptoms markedly lessen when protein catabolism and urea generation are reduced. Also, rate of progression of CKD may slow down. 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: Target Levels for PTH and Phosphate in Chronic Kidney Disease). Target levels for calcium are 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L); for the calcium-phosphate product, < 55 mg2/dL2.
A typical starting dose is calcitriol (or a calcitriol analog) 0.25 mcg po once/day or 1 to 4 mcg 2 times/wk. PTH levels are not corrected to normal because doing so risks precipitating adynamic bone disease.
Dyslipidemia should be addressed. 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 is intended to reduce risk of cardiovascular disease, which is increased in patients with CKD.
Water intake is restricted only when serum sodium concentration is < 135 mmol/L or there is heart failure or severe edema.
Sodium restriction of < 2 g/day is recommended for CKD patients with eGFR < 60 mL/m/1.73 m2 who have hypertension, volume overload, or proteinuria.
Potassium restriction is individualized based on serum level, eGFR, dietary customs, and use of drugs that increase potassium levels (eg, ACE, ARBs, or potassium-sparing diuretics). Typically, potassium restriction is not needed with eGFR > 30 mL/min/1.73 m2. Treatment of mild to moderate hyperkalemia (5.1 to 6 mmol/L) entails dietary restriction (including avoiding salt substitutes), correction of metabolic acidosis, and use of potassium-lowering diuretics and gastrointestinal cation exchangers. Severe hyperkalemia (> 6 mmol/L) warrants urgent treatment.
Phosphate restriction of 0.8 to 1 g/day of dietary intake is typically sufficient to normalize serum phosphate level in patients with eGFR < 60 mL/min/1.73 m2. Additional intestinal phosphate binders (calcium-containing or noncalcium-containing) may be necessary for adequate control of hyperphosphatemia, which has been associated with increased cardiovascular risk. Noncalcium-containing binders are preferred in patients with hypercalcemia, suspected adynamic bone disease, or evidence of vascular calcification on imaging. If calcium-containing binders are prescribed, then the total dietary and medication sources of calcium should not exceed 2000 mg/day in patients with eGFR < 60 mL/min/1.73 m2.
Metabolic acidosis should be treated to bring serum bicarbonate to normal (> 23 mmol/L) to help reverse or slow muscle wasting, bone loss, and progression of CKD. Acidosis can be corrected with oral alkali sources such as sodium bicarbonate or an alkaline-ash diet (primarily fruits and vegetables). Sodium bicarbonate 1 to 2 g po bid is given and amount is increased gradually until bicarbonate concentration is about 23 mmol/L or until evidence of sodium overloading prevents further therapy. If the alkaline-ash diet is used, serum potassium is monitored because fruits and vegetables contain potassium.
Anemia is a common complication of moderate to advanced CKD (≥ stage 3), and, when severe, is treated with erythropoiesis-stimulating agents (ESA), such as recombinant human erythropoietin (eg, epoetin alfa). Due to risk of cardiovascular complications, including stroke, thrombosis, and death, the lowest dose of these agents needed to keep the Hb between 10 and 11 g/dL is used. Because of increased iron utilization with stimulated erythropoiesis, iron stores must be replaced, often requiring parenteral iron. Iron concentrations, iron-binding capacity, and ferritin concentrations should be followed closely. Target transferrin saturation (TSAT), calculated by dividing serum iron by total iron binding capacity and multiplying by 100%, should be > 20%. Target ferritin in patients not on dialysis is >100 ng/mL. Transfusion should not be done 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 mcg/kg (20 mcg 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.
Symptomatic heart failure is treated with sodium restriction and diuretics. Loop diuretics such as furosemide usually are effective even when renal function is markedly reduced, although large doses may be needed. If left ventricular function is depressed, ACE inhibitors (or ARBs) and beta-blockers (carvedilol or metoprolol) should be used. Aldosterone receptor antagonists are recommended in patients with advanced stages of heart failure. Digoxin may be added, but the dosage must be reduced based on degree of renal function.
Moderate or severe hypertension should be treated to avoid its deleterious effects on cardiac and renal function. Patients who do not respond to sodium restriction (1.5 g/day), should receive diuretics. Loop diuretics (eg, furosemide 80 to 240 mg po bid) may be combined with thiazide diuretics (eg, chlorthalidone 12.5 to 100 mg po once/day, hydrochlorothiazide 25 to 100 mg po in one to two divided doses/day, metolazone 2.5 to 20 mg po once/day) if hypertension or edema is not controlled. Even in renal failure, the combination of a thiazide diuretic 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 and may be necessary for adequate control of heart failure and/or hypertension.
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. Some appropriate references include
Most experts recommend avoiding NSAIDs in patients with CKD because they may worsen renal function, exacerbate hypertension, and precipitate electrolyte disturbances.
Certain drugs should be avoided entirely in patients with chronic kidney disease with eGFR < 60 mL/min/1.73m2. They include nitrofurantoin and phenazopyridine. The MRI contrast agent gadolinium has been associated with the development of nephrogenic systemic fibrosis in some patients; because risk is particularly high if patients have estimated GFR < 30 mL/min/1.73m2, gadolinium should be avoided whenever possible in these patients.
Dialysis is usually initiated at the onset of either of the following:
These problems typically occur when the estimated GFR reaches ≤ 10 mL/min in a patient without diabetes or ≤ 15 mL/min in a patient with diabetes; patients whose estimated GFR values are near these values should be closely monitored so that these signs and symptoms are recognized early. Dialysis is best anticipated so that preparations can be made and urgent insertion of a hemodialysis catheter can be avoided. Such preparations usually begin when the patient is in early to mid stage 4 CKD; preparation allows time for patient education, selection of the type of dialysis, and timely creation of an arteriovenous fistula or placement of a peritoneal dialysis catheter. (For dialysis preparation, see Hemodialysis.)
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 be placed on the waiting list of their regional transplant center early, because wait times may exceed several years in many regions of the US.
Common causes of chronic kidney disease (CKD) in the US are diabetic nephropathy (the most common), hypertensive nephrosclerosis, glomerulopathies, and metabolic syndrome.
Effects of CKD can include hypocalcemia, hyperphosphatemia, metabolic acidosis, anemia, secondary hyperparathyroidism, and renal osteodystrophy.
Distinguish CKD from acute kidney injury based on history, clinical findings, routine laboratory tests, and ultrasonography.
Control underlying disorders (eg, diabetes) and BP levels (usually with an ACE inhibitor or angiotensin II receptor blocker).
Give supplemental vitamin D and/or sodium bicarbonate and restrict potassium and phosphate as needed.
Treat heart failure, anemia, and other complications.
Educate patients with advanced CKD on treatment options (dialysis, kidney transplantation, or palliative care) early, to allow adequate time for planning.
Initiate dialysis for patients with severely decreased eGFR when signs and symptoms are inadequately controlled with drugs and lifestyle interventions.