Evaluation of the Patient with Proteinuria

Hasan Bazari

Proteinuria may be an asymptomatic finding in an apparently healthy patient or a key diagnostic or prognostic finding in a patient who presents with an ongoing illness. Causes range from relatively uncommon immune-mediated conditions and serious dysproteinemias to the consequences of poorly controlled everyday illnesses such as diabetes and hypertension. With such a wideranging differential diagnosis, the diagnostic challenges posed by the onset of proteinuria can be substantial. For the primary care physician, the task is to initiate an efficient workup that begins to elucidate the most likely etiologies and their possible significance, working in consultation with the nephrologist to ensure timely referral when kidney biopsy is required. Applying a pathophysiologic approach to the workup can help focus the evaluation.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12)

The normal kidney filters about 180 L of ultrafiltrate per day. The concentration of albumin in the Bowman space is 1 mg/dL. The proximal convoluted tubule reabsorbs most of the albumin and low molecular weight proteins that are in the ultrafiltrate. About 150 mg or less is excreted in the urine in humans daily. The excretion of higher amounts of protein warrants evaluation. The approach is guided by an understanding of underlying mechanisms. These include the following.

Overflow Proteinuria

Overflow proteinuria occurs when there is overproduction of low molecular weight protein that is then filtered and excreted. The classic and most prevalent example is Bence Jones proteinuria, when excessive amounts of monoclonal light chains can be found in the urine of a patient with myeloma, amyloidosis, or, rarely, monoclonal gammopathy of uncertain significance. Light chains are less well detected by the urine dipstick compared with albumin. Hence, the urine dipstick may underestimate the amount of Bence Jones protein in the urine. Quantifying the proteinuria by 24-hour urine collection or by the use of a spot urine protein/creatinine ratio allows for measurement of the degree of proteinuria. The spot urine protein/creatinine ratio is a reliable surrogate for the severity of proteinuria compared with the 24-hour urine collection.

Tubular Proteinuria

Proteinuria may occur in conditions in which there is predominantly tubular injury. In such cases, the proteinuria is usually less than 1 g/d, reflecting the failure to reabsorb small, filtered proteins, as well as proteins that originate in the tubules. These are low molecular weight proteins when evaluated by electrophoresis.

Increased Glomerular Permeability

Most of the significant cases of proteinuria are related to loss of the permeability barrier in the glomerular basement membrane. The proteinuria can be divided into nephrotic-range proteinuria and a subnephrotic range of proteinuria. Nephrotic syndrome is a syndrome associated with greater than 3.5 g of proteinuria in 24 hours, hypertension, hyperlipidemia, and edema. Subnephrotic-range proteinuria is usually between 1 and 3.5 g per 24 hours. Although the underlying disease may be the same, the prognosis and management are significantly better for any given entity when there is subnephrotic-range proteinuria.

The earliest clinically detectable evidence of renal involvement in some diseases may be microalbuminuria. Microalbuminuria, which is classically associated with diabetes, is defined as the excretion of small but abnormal amounts of albumin below the level of detection by the standard screening dipstick. Transient proteinuria can be seen in patients in an acute illness such as fever, pneumonia, seizures, and congestive heart failure. It is presumed that there is a transient loss of the permeability barrier in these settings. It usually resolves with treatment of the underlying condition. Orthostatic proteinuria occurs predominantly in the upright position. The amount of protein is usually less than 1 g per 24-hour period. Understanding of the pathophysiology is
incomplete; the prognosis is good in long-term follow-up studies of patients with orthostatic proteinuria.

Clinical Presentations

Proteinuria often presents as a finding on routine urinalysis. Alternatively, it may be one of several manifestations of renal disease, including significant hypertension, anasarca, or renal failure. In these cases, the accompanying history and clinical features often provide clues to the etiology of the renal disease.

Isolated Proteinuria

Isolated proteinuria is a condition in which there is usually less than 1 g of protein excreted in a 24-hour period. By definition, the renal function is normal and unaccompanied by hematuria, hypertension, or a systemic disease known to have renal manifestations. When biopsied, most of these patients have either normal renal histology or minor abnormalities on the renal biopsy. Occasionally, thin basement membrane disease and immunoglobulin A nephropathy may be found on the biopsy of such patients. Patients with isolated proteinuria can be further characterized into several groups as follows.

Transient Proteinuria.

This is seen as a transient increase in glomerular proteinuria that can be brought about by exercise, fever, infection, and congestive heart failure. The proteinuria resolves completely after the acute event, and patients are normal when the urine test is repeated. It is postulated that adaptive hemodynamics induces the proteinuria and that it is mediated by increased levels of angiotensin II. This usually resolves in follow-up and warrants no further evaluation.

Orthostatic Proteinuria.

There is a group of patients who seem to have long-term reproducible proteinuria that occurs in the upright position. The long-term follow-up of these patients shows an excellent prognosis over a 25-year period with no evidence of the development of significant intrinsic renal disease or progression to persistent proteinuria.

Microalbuminuria.

This is the earliest detectable clinical evidence of renal disease involving the changes in glomerular permeability. In a disease such as diabetes mellitus, the onset of microalbuminuria often heralds the onset of clinically important diabetic nephropathy and creates a clinically detectable point of intervention for the prevention of progression to overt diabetic nephropathy. Studies have shown that blood pressure control, the use of angiotensin-converting enzyme inhibitors (ACEIs), and the use of angiotensin receptor blockers (ARBs) slow the progression to overt diabetic nephropathy.

Persistent Isolated Proteinuria.

This refers to proteinuria of less than 1 g/d and may include patients with earlier or milder forms of diseases that cause nephrotic syndrome. The prognosis for this group is mixed, and these patients need to be evaluated and followed for the development of overt more renal disease.

Proteinuria with Intrinsic Renal Disease.

Tubular proteinuria is often less than 1 g/d, and the composition of the proteinuria is low molecular weight proteins. It is often accompanied by significant decrements in glomerular filtration rate (GFR).

Other Presentations

Proteinuria of greater than 1 g/d, if not from overflow proteinuria, often reflects intrinsic glomerular disease. Proteinuria of greater than 3.5 g/d, if not from overflow proteinuria, is due to glomerular disease and often is associated with the nephrotic syndrome.

Nephrotic Syndrome.

Nephrotic syndrome can either be associated with primary renal disease or be part of a systemic disease. Hypoalbuminemia, hypertension, hyperlipidemia, and edema often but not always accompany the syndrome. The etiology of the edema may be either low oncotic pressure from severe hypoalbuminemia or primary salt and water retention by the kidneys. The classic teaching that low oncotic pressure is the mechanism for the development of edema in nephrotic syndrome is pertinent to many but not all cases of nephritic syndrome; in some, the kidneys mediate salt and water retention with suppressed aldosterone and renin. Hypertension associated with renal disease can be severe but is less prominent in minimal-change disease and HIV-associated nephropathy. The hyperlipidemia of nephrotic syndrome is due the increased synthesis of low density lipoprotein and very low density lipoprotein by the liver. Lipid-laden tubular cells form “oval fat bodies” and may be found in the urinary sediment as individual cells or as components of casts. “Maltese crosses” may be seen under polarizing light when the droplets contain large amounts of cholesterol. Other complications of the nephrotic syndrome include the hypercoagulable state as a result of loss of anticoagulants and clotting factors. The main anticoagulant that is lost in the urine is antithrombin III; the consequences of the prothrombotic state include deep venous thrombosis, pulmonary emboli, and renal vein thrombosis. The most common renal disease associated with renal vein thrombosis is membranous nephropathy, in which about 20% to 30% of patients may have overt or silent renal vein thrombosis. Loss of immunoglobulins can predispose to bacterial infections, and this is a particular problem in children, in whom ascites from nephrotic syndrome can predispose to spontaneous bacterial peritonitis. Loss of vitamin D attached to its binding protein can lead to deficiency of vitamin D and hypocalcemia. In patients with hypothyroidism, the onset of nephrotic syndrome can lead to changes in dosing requirement as a result of renal losses of vitamin D-binding protein.

DIFFERENTIAL DIAGNOSIS (13, 14, 15 and 16)

The approach to proteinuria is detailed in Figure 130-1. The evaluation should be tailored to the type, severity, and persistence of the proteinuria.

Isolated proteinuria has a limited differential diagnosis, as discussed previously. It may be transient proteinuria, orthostatic
proteinuria, or persistent with early stages of diseases that could eventually cause the nephrotic syndrome.

Figure 130-1 Approach to proteinuria. ARF, acute renal failure; CHF, congestive heart failure.

TABLE 130-1 Causes of Rapidly Progressive Glomerulonephritis

Anti-glomerular basement membrane disease or Goodpasture syndrome

ANCA-positive vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with angiitis (Churg-Strauss syndrome), pauciimmune necrotizing glomerulonephritis

Hypocomplementemic immune complex glomerulonephritis, systemic lupus, cryoglobulinemia, endocarditis, poststreptococcal glomerulonephritis, membranoproliferative glomerulonephritis

Normocomplementemic glomerulonephritis, immunoglobulin A nephropathy, Henoch-Schonlein purpura

Proteinuria with hematuria, especially if the hematuria includes the presence of dysmorphic red blood cells under phase contrast microscopy, indicates a glomerulonephritis with a wide differential diagnosis. These findings mandate expeditious and thorough evaluation. Among the conditions that can be associated with proteinuria and hematuria are those that cause rapidly progressive glomerulonephritis, listed in Table 130-1.

Nephrotic syndrome can be caused by idiopathic intrinsic renal disease or glomerular injury associated with systemic disease. The idiopathic nephrotic syndromes are summarized in Table 130-2. Although idiopathic membranous nephropathy has been the leading cause of idiopathic nephrotic syndrome in adults, recent series show that focal and segmental glomerulosclerosis may now be more common. Minimal-change disease remains a significant cause of nephrotic syndrome in adults but is less common than in children, among whom it is by far the leading cause. Minimal-change disease often has an abrupt and dramatic onset and is less likely to be associated with severe hypertension. Progressive renal insufficiency is rare with minimal-change disease; when it is seen, it is often due to acute tubular necrosis or misclassification of focal and segmental glomerulosclerosis, which has overlapping clinical and pathologic features early in the disease.

Secondary causes of nephrotic syndrome are summarized in Table 130-3. Among these, the most common cause of significant proteinuria and nephrotic syndrome is diabetes mellitus, which is the leading cause of end-stage renal disease in the United States. Diabetic nephropathy is inevitably associated with the presence of diabetic retinopathy in type I diabetes. Overt diabetic nephropathy is defined by the presence of greater than 500 mg of protein excretion in a 24-hour period, although the use of ACEIs and ARBs may ameliorate the severity of proteinuria. Among systemic diseases that cause nephrotic-range proteinuria, systemic lupus is one of the more common ones. Renal involvement in lupus can be minimally symptomatic or a cause of rapidly progressive glomerulonephritis.

Only gold members can continue reading. Log In or Register to continue