Harrison’s Manual of Medicine



Differential Diagnosis
The Uremic Syndrome

The prevalence of CRF, defined as a long-standing, irreversible impairment of renal function, is thought to be substantially greater than the number of pts with end-stage renal disease (ESRD), now ³300,000 in the U.S. There is a spectrum of disease related to decrements in renal function; clinical and therapeutic issues differ greatly depending on whether the GFR reduction is moderate (e.g., 20– 60 mL/min) or severe (<20 mL/min). Dialysis is usually required to control symptoms of uremia with GFR < 5–10 mL/min. Common causes of CRF are outlined in Table 139-1.

Table 139-1 Common Causes of Chronic Renal Failure

Differential Diagnosis
The first step in the differential diagnosis of CRF is establishing its chronicity, i.e., disproving a major acute component. The two most common means of determining disease chronicity are the history (if available) and the renal ultrasound, which is used to measure kidney size. In general, kidneys that have shrunk (<10–11.5 cm, depending on body size) are more likely affected by chronic disease. While reasonably specific (few false positives), reduced kidney size is only a moderately sensitive marker for CRF, i.e., there are several relatively common conditions in which kidney disease may be chronic, without any reduction in renal size. Diabetic nephropathy, HIV-associated nephropathy, and infiltrative diseases such as multiple myeloma may be associated with relatively large kidneys despite chronicity. Renal biopsy is a more reliable means of proving chronicity; a predominance of glomerulosclerosis or interstitial fibrosis argues strongly for chronic disease. Hyperphosphatemia and other metabolic derangements are not reliable indicators in distinguishing acute from chronic disease.
Once chronicity has been established, clues from the physical exam, laboratory panel, and urine sediment evaluation can be used to determine etiology. A detailed Hx will identify important comorbid conditions, such as diabetes, HIV seropositivity, or peripheral vascular disease. The family Hx is paramount in the workup of autosomal dominant polycystic kidney disease or hereditary nephritis (Alport’s syndrome). An occupational Hx may reveal exposure to environmental toxins or culprit drugs (including over-the-counter agents, such as analgesics or Chinese herbs).
Physical exam may demonstrate abdominal masses (i.e., polycystic kidneys), diminished pulses (i.e., atherosclerotic peripheral vascular disease), or an abdominal bruit (i.e., renovascular disease). The Hx and exam may also yield important data regarding severity of disease. The presence of foreshortened fingers (due to resorption of the distal phalangeal tufts) and/or subcutaneous nodules may be seen with advanced renal failure and secondary hyperparathyroidism. Excoriations (uremic pruritus), pallor (anemia), muscle wasting, and a nitrogenous fetor are all signs of advanced chronic renal disease, as are pericarditis, pleuritis, and asterixis, complications of particular concern that usually prompt the initiation of dialysis.
LABORATORY FINDINGS   Serum and urine laboratory findings typically provide additional information useful in determining the etiology and severity of CRF. Heavy proteinuria (>3.5 g/d), hypoalbuminemia, hypercholesterolemia, and edema suggest nephrotic syndrome (see Chap. 142). Diabetic nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, amyloid, and HIV-associated nephropathy are principal causes. Proteinuria may decrease slightly with decreasing GFR but rarely to normal levels. Hyperkalemia and metabolic acidosis may complicate all forms of CRF eventually but are more prominent in pts with interstitial renal diseases.
The Uremic Syndrome
The culprit toxin(s) responsible for the uremic syndrome remain elusive. The serum creatinine (Cr) is the most common laboratory surrogate of renal function. The creatinine clearance (CrCl) is calculated as the urine concentration divided by serum concentration multiplied by the urine flow rate; it approximates the GFR and is a more reliable indicator of renal function than the serum Cr alone. Uremic symptoms tend to develop with serum Cr > 530–710 µmol/L (> 6– 8 mg/dL) or CrCl < 10 mL/min, although these values vary widely.
Symptoms of advanced uremia include anorexia, weight loss, dyspnea, fatigue, pruritus, sleep and taste disturbance, and confusion and other forms of encephalopathy. Key findings on physical exam include hypertension, jugular venous distention, pericardial and/or pleural friction rub, muscle wasting, asterixis, excoriations, and ecchymoses. Laboratory abnormalities may include: hyperkalemia, hyperphosphatemia, metabolic acidosis, hypocalcemia, hyperuricemia, anemia, and hypoalbuminemia. Most of these abnormalities eventually resolve with initiation of dialysis or renal transplantation (Chaps. 140, 141).

Hypertension complicates most forms of CRF and warrants aggressive treatment to reduce the risk of stroke and potentially to slow the progression of renal disease (see below). Volume overload contributes to hypertension in many cases, and potent diuretic agents are frequently required. Anemia can be reversed with recombinant human erythropoetin (rHuEPO); 2000–6000 units subcutaneously once or twice weekly can increase Hb concentrations toward the normal range in most pts.
Hyperphosphatemia can be controlled with judicious restriction of dietary potassium and the use of postprandial phosphate binders, usually calcium- based salts (calcium carbonate or acetate). Newer non-calcium-, non-aluminum-containing resins (e.g., sevelamer) are also used. Hyperkalemia should be controlled with dietary potassium restriction. Sodium polystyrene sulfonate (Kayexalate) can be used in refractory cases, although dialysis should be considered if the potassium >6 mmol/L on repeated occasions. If these conditions cannot be conservatively controlled, dialysis should be instituted (Chap. 140). It is also advisable to begin dialysis if severe anorexia, weight loss, and/or hypoalbuminemia develop, as it has been definitively shown that outcomes for dialysis pts with malnutrition are particularly poor.
Slowing Progression of Renal Disease Prospective clinical trials have explored the roles of blood pressure control and dietary protein restriction on the rate of progression of renal failure. Control of hypertension is of some benefit, although ACE inhibitors may exert unique beneficial effects, most likely due to their effects on intrarenal hemodynamics. Angiotensin receptor antagonists have similar effects; the effects of other drugs (e.g., calcium channel blockers) on intrarenal hemodynamics are relatively minor. The effects of ACE inhibitors and related drugs are most pronounced in pts with diabetic nephropathy and in those without diabetes but with significant proteinuria (>1 g/d). Dietary protein restriction may offer an additional benefit, particularly in these same subgroups.


For a more detailed discussion, see Skorecki K, Green J, Brenner BM: Chronic Renal Failure, Chap. 270, p. 1551, in HPIM-15.



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