Chapter 23. Nephrotic Syndrome versus Nephritic Syndrome

Glomerulonephropathies are disorders that primarily affect the structure and function of the renal glomerular apparatus. Frequently encountered in clinical practice, glomerulopathies are usually suspected from the history and the urinary findings of hematuria, red cell casts, or proteinuria. The many different causes of glomerular disease can be generally classified into one of three major syndromes: Nephrotic syndrome, nephritic syndrome, and asymptomatic renal disease. However, there may be considerable overlap in their clinical presentation with some diseases presenting with components of both syndromes.

Essentials of Diagnosis

• Proteinuria >3.5 g/1.73 m2/24 hours (40–50 mg/kg/day).
• Hypoalbuminemia.
• Edema.
• Hyperlipidemia.
• Lipiduria.

General Considerations

Nephrotic syndrome may appear as a primary (idiopathic) renal disease or occur in association with any of a number of systemic conditions and hereditary diseases. The most common primary glomerular diseases include membranous nephropathy, focal segmental glomerular sclerosis, minimal change, and membranoproliferative glomerulonephritis (MPGN). In the United States, diabetes mellitus is the most common cause of nephrotic syndrome. Approximately one-third of patients with both type 1 and type 2 diabetes mellitus of at least a 25-year duration will develop nephrotic syndrome, predictably leading to renal failure. Other systemic diseases that may lead to the nephrotic syndrome include systemic lupus erythematous (SLE), amyloidosis, and leukemia.

Pathogenesis

Nephrotic syndrome generally reflects noninflammatory damage to the glomerular capillary wall. The underlying glomerular disease results in proteinuria, which occurs from alterations in the charge or size selectivity of the glomerular capillary wall. This increases glomerular permeability to plasma proteins. Albumin is the principal urinary protein lost, but other plasma proteins lost in the urine include hormone-carrying proteins such as vitamin D-binding protein, transferrin, and clotting inhibitors.

Prevention

We do not know how to prevent primary nephrotic syndrome. Secondary nephrotic syndromes can often be improved and sometimes completely reversed by treating and controlling the underlying disease.

Clinical Findings

Symptoms and Signs

Nephrotic syndrome can present with a spectrum of findings ranging from asymptomatic proteinuria to the most common presentation of edema. Edema occurs initially in areas of high intravascular hydrostatic pressure such as in the feet and ankles as well as in areas in which tissue hydrostatic pressure is lowest such as the periorbital and scrotal areas. If the edema is severe and generalized it can present as anasarca.

Laboratory Findings

Urinalysis

Urine dipstick often demonstrates 3+ to 4+ protein and 24-hour urine collection with >3.5 g protein/1.73 m2. Proteinuria can also be estimated from a single urine specimen by calculating the ratio of total urine protein in mg/dL to urine creatinine in mg/dL. This ratio approximates the actual 24-hour protein excretion in grams per day per 1.73 m2 body surface area. Typically the urine sediment has few cells or casts. Urinary lipid may be present in the sediment. It may be entrapped in casts, free in the urine, or enclosed in the plasma membrane of degenerated epithelial cells known as oval fat bodies. Under polarized light, the lipid in oval fat bodies appears as “Maltese crosses” (Figure 23–1).

Blood Chemistries

Fundamental laboratory abnormalities in nephrotic syndrome include decreased serum albumin (<3 g/dL), decreased total serum protein (<6 g/dL), and hyperlipidemia. Patients may have elevations in their blood urea nitrogen (BUN) and creatinine, but the glomerular filtration rate (GFR) can be normal. Some patients may also manifest anemia, elevated erythrocyte sedimentation rate (ESR), hypocalcemia, and vitamin D deficiency. Other less common laboratory tests may be indicated depending on the patient's clinical presentation. These may include serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) to evaluate for myeloma or amyloidosis, and antinuclear antibody (ANA) to evaluate for SLE. Other tests might include hepatitis serologies, syphilis serology, HIV, complements, cryoglobulins, and thyroid function tests.

Special Tests

Indications for and benefits of a renal biopsy remain controversial. Nevertheless, it is the standard procedure for determining the cause of proteinuria in adults. Biopsy is often recommended when the etiology of nephrotic-range proteinuria is in doubt, prior to beginning cytotoxic drugs, when the presence of multiple diseases contributing to the clinical picture confounds the diagnosis, or if the patient's clinical course differs from the expected. In general, renal biopsy may be used to aid in management decisions, for example, whether to discontinue therapy because of lack of salvageable renal parenchyma.

Differential Diagnosis

The differential diagnosis in nephrotic syndrome can be narrowed significantly based on the patient's age, race, and urine evaluation. For example, minimal change accounts for the majority of cases in children. In adults worldwide, membranous nephropathy and focal glomerulosclerosis are among the commonest causes of primary nephrotic syndrome. In adults over the age of 50 years, membranous nephropathy is the most common cause of idiopathic nephrotic syndrome while focal glomerulosclerosis is the most common cause in African-Americans. Overall, about 50% of patients with nephrotic syndrome have a secondary cause, with the majority of these being secondary to diabetic nephropathy.

Complications

Hyperlipidemia

Numerous alterations in lipid profiles occur in the nephrotic syndrome as a result of increased synthesis and decreased catabolism of individual lipid fractions. These include hypercholesterolemia, hypertriglyceridemia, and increased low-density protein (LDL) and very low-density protein (VLDL). These abnormalities may possibly contribute to accelerated atherosclerosis.

Thrombosis

Several abnormalities of the coagulation system occur in nephrotic syndrome. These abnormalities include urinary losses of antithrombin III, proteins C and S, and factors IX, XI, and XII. In addition, plasma fibrinogen, tissue plasminogen activator, and platelet aggregability are all increased. These aberrations lead to an increased incidence of venous and arterial thromboemboli, especially deep venous thrombosis, pulmonary embolism, and renal vein thrombosis. Renal vein thrombosis is most common in membranous nephropathy, with as many as 20–40% of patients affected.

Vitamin D Deficiency and Hypocalcemia

Vitamin D-binding protein is a relatively small protein (59 kDa) that is readily filtered and hence lost in the urine. 25-Hydroxyvitamin D, which is bound to vitamin D-binding protein, is also lost in the urine in nephrotic syndrome.

Infection

Patients with nephrotic syndrome have urinary losses of immunoglobulins and defects in the complement cascade. This results in a higher susceptibility to infection, especially with encapsulated organisms such as Streptococcus pneumoniae. In addition, the immunosuppressive medications often used to treat the underlying glomerulopathy contribute to the increased risk of infection in these patients.

Hypoalbuminemia

Serum levels of albumin are low in hypoalbuminemia secondary to both losses in the urine and increased albumin catabolism.

Malnutrition

Prolonged and massive proteinuria may culminate in malnutrition as a result of negative nitrogen balance with loss of lean body mass.

Anemia

Urinary losses of erythropoietin (30 kDa) and transferrin may lead to an iron-resistant microcytic hypochromic anemia. If renal function deteriorates to the point of chronic kidney disease decreased erythropoietin production may play a role as well.

Treatment

Underlying Systemic or Renal Disease Immunosuppressive Medications

Medications such as corticosteroids may be used for diseases such as minimal change disease and focal glomerular sclerosis. Other treatments may consist of antimicrobial agents such as those for the treatment of secondary syphilis, chemotherapy or tumor resection for nephrotic syndrome associated with malignancy, or simply discontinuing an offending medication such as nonsteroidal anti-inflamatory drugs (NSAIDs) or phenytoin.

Complications of the Nephrotic Syndrome

Hyperlipidemia

Premature atherosclerosis and anincreased incidence of myocardial infarction have been reported in patients with the nephrotic syndrome. In addition, hyperlipidemia is likely a separate risk factor for both atherosclerotic cardiovascular disease as well as for the progression of renal disease. Hyperlipidemia typically improves after the resolution of the nephrotic syndrome. All lipid-lowering medications have been used in nephrotic syndrome to help reduce the rate of adverse coronary events. The most potent agents are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors alone or in combination with bile acid sequestrants such as cholestyramine.

Edema

Nephrotic syndrome results in primary renal sodium retention. This may result in peripheral and periorbital edema and, if severe and generalized enough, may result in anasarca with serous effusions. Goals of treatment include salt restriction and use of loop diuretics to achieve slow resolution of edema; rapid diuresis can result in hypovolemia and hypotension. Occasionally, thiazide diuretics must be added to the loop diuretics in order to block sodium reabsorption at multiple sites in the nephron.

Thrombosis

Anticoagulation is indicated in patients with nephrotic syndrome and documented thrombotic events. Anticoagulation is usually continued until the patient experiences resolution of the nephrotic syndrome. Prophylactic anticoagulation and antiplatelet therapy in patients with nephrotic syndrome remain controversial. However, in patients with idiopathic membranous nephropathy the benefits of anticoagulation may outweigh the risks.

Treatment of Proteinuria

Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin II Receptor Blockers (ARB)

These agents work by lowering intraglomerular capillary hydrostatic pressure and preventing the development of hemodynamically mediated focal segmental glomerulosclerosis. ARBs also decrease the formation of tumor growth factor (TGF)-β 1, which has been shown to play a role in progressive renal fibrosis.

NSAIDs

NSAIDs probably work by altering glomerular hemodynamics or glomerular basement membrane permeability, but their benefits must be balanced against the risk of inducing acute renal failure, salt and water retention, and hyperkalemia.

Low Protein Diet

A low-fat soy-protein diet that provides 0.7 g protein/kg/day has been demonstrated to be beneficial in decreasing urinary protein excretion and lipid profiles. However, protein-restricted diets in general may lead to malnutrition, which is a known potent predictor for death in end-stage renal disease (ESRD) patients.

Prognosis

The prognosis in nephrotic syndrome is typically worse in patients with heavy proteinuria, renal insufficiency, and severe hypertension. The overall prognosis depends on etiology and is related to histology. For example, minimal change disease can have spontaneous remissions and is highly steroid responsive with an excellent prognosis. In contrast, spontaneous remission of primary focal segmental glomerulosclerosis (FSGS) is rare and the renal prognosis is relatively poor.

Essentials of Diagnosis

• Hematuria.
• Red blood cell (RBC) casts.
• Variable proteinuria.
• Renal insufficiency.
• Salt retention [hypertensive nephropathy (HTN) and edema].

General Considerations

Glomerulonephritis is characterized by an intraglomerular inflammatory process and renal dysfunction. It can be acute, subacute, or chronic and may or may not progress to ESRD. The nephritic syndrome may be caused by an intrinsic renal disease or may be part of a systemic disease process. Classic causes of the nephritic syndrome include postinfectious glomerulonephritis, immunoglobulin A (IgA) nephropathy, and lupus nephritis. IgA is the most common cause of glomerulonephritis worldwide. A subset of acute glomerulonephritis, known as rapidly progressive glomerulonephritis (RPGN), can present with severe and progressive renal failure. Examples of RPGNs include Goodpasture's disease, polyarteritis nodosum, and Wegener's granulomatosis.

Pathogenesis

The nephritic syndrome is characterized by an inflammatory process. The degree of glomerular inflammation in part determines the severity of renal dysfunction and associated clinical manifestations. Immunologic perturbations underlie many of the glomerulopathies. Two basic mechanisms of antibody-mediated glomerular injury exist. The first involves antibodies that bind to a structural component or other material implanted in the glomeruli. For example, circulating antibodies may form and be directed against the glomerular basement membrane (GBM) as in Goodpasture's disease. The second mechanism involves formation of circulating antigen–antibody complexes that escape the reticuloendothelial system and are then deposited in the glomerulus. Examples include DNA-nucleosome complexes in SLE and cryoglobulins in hepatitis C-related MPGN.

Other diseases, such as poststreptococcal glomerulonephritis, involve deposition of an antigen in the glomeruli with subsequent activation of complement. This can result in direct tissue injury or result in an inflammatory reaction, with proliferation of the intrinsic glomerular cells such as the mesangial, endothelial, and epithelial cells. In severe cases, obliteration of the glomerular capillary lumens can occur in addition to rupture of the glomerulus into Bowman's space resulting in crescent formation.

Prevention

It is not yet known how to guard against intrinsic renal diseases or systemic diseases that cause the nephritic syndrome such as IgA nephropathy or SLE. Hence, the focus in this area is aimed at early recognition with prompt diagnosis and therapy so as to prevent irreversible loss of renal function.

Clinical Findings

Symptoms and Signs

Nephritic syndrome can present with edema, oliguria, or uremic symptoms. Many patients have hypertension, which may even be malignant in some cases. Other physical examination findings depend on the underlying disorder. For example, a malar rash and oral ulcers may be found in SLE, whereas palpable purpura is found in Henoch–Schönlein purpura and cryoglobulinemia.

Laboratory Findings

Urinalysis

Patients may present with macroscopic hematuria often described as tea- or cola-colored urine. Microscopic urine examination often reveals RBCs. These are classically dysmorphic or misshapen as a result of the osmotic and chemical stress they incur as they pass through the nephron. Urinary RBCs with membrane blebs or “bubble-like” projections (acanthocytes) are strong evidence of a glomerular cause of hematuria. RBC casts may also be found. Urinary protein excretion varies widely in nephritic syndromes, but is generally less than 3 g of protein per day. Proteinuria can be quantified by either a 24-hour urine collection or can be estimated based on a single urine specimen.

Serum Chemistries

A chemistry profile should be obtained to assess electrolyte status and to estimate the GFR in order to document the degree of renal dysfunction. A complete blood count (CBC) will often demonstrate anemia as well as possibly thrombocytopenia or leukopenia as seen in SLE. Additional useful tests depend on the patient's history and physical examination. These may include blood cultures if a fever or heart murmur is heard, streptozyme and antistreptolysin O (ASO) titers if a sore throat is present, or a hepatitis panel and cryoglobulins if a history of intravenous drug abuse (IVDA) is obtained or hepatomegaly palpated. Other helpful tests might include complement levels, antineutrophilic cytoplasmic antibodies (ANCAs), anti-GBM, and immune complex disease markers such as ANA and anti-DNA. It is important to note that up to 10% of patients with heavy proteinuria may have negative serologic findings at presentation due to loss of antibody in the urine or tissue deposition.

Imaging Studies

Chest x-ray may demonstrate pulmonary edema or findings suggestive of Wegener's granulomatosis or Goodpasture's disease. An echocardiogram may identify a pericardial effusion or endocarditis. Renal ultrasound is frequently obtained when a decreased GFR is present in order to evaluate for kidney size. A kidney size of <9 cm may suggest extensive renal scarring with a low likelihood of reversibility.

Special Tests

Renal biopsy is often used for definitive diagnosis and is helpful in distinguishing between primary and secondary causes of renal disease as well as subtypes in SLE. It can allow rapid diagnosis in cases of RPGNs where prompt diagnosis and treatment are essential in preserving renal function. Renal biopsy can also yield information regarding the level of inflammation, extent of fibrosis, and overall prognosis.

Differential Diagnosis

The differential diagnosis of nephritic syndromes requires distinguishing between a primary renal disease and one that occurs as a result of a systemic disease process. A useful clinical approach can be based on the results of serum complement levels, serologies, and immunofluorescence findings on renal biopsy.

Complications

Nephritic syndrome can lead to fluid retention with resulting edema and HTN. Renal insufficiency also occurs and can require both short- and long-term renal replacement therapy. Anemia may occur as a result of resistance to erythropoietin or decreased production.

Treatment

Underlying Renal or Systemic Disease

Immunosuppressive Agents

For primary renal diseases such as IgA nephropathy treatment often involves corticosteroids. Fish oil in doses of 6–12 g/day has been employed to possibly prevent or slow the rate of loss of renal function.

Cytotoxic Agents

Diseases such as Gooodpastures's disease, Wegener's granulomatosis, and certain subtypes of SLE may require treatment with cytotoxic agents such as cyclophosphamide, mycophenolate mofetil, and azathioprine.

Plasmapheresis

Plasmapheresis is used to remove circulating pathogenic autoantibodies seen in diseases such as Goodpasture's disease and occasionally in pauci-immune crescentic glomerulonephritis and cryoglobulin-related MPGN.

Others

Successful treatment of infections such as hepatitis B with lamivudine, hepatitis C with interferon-α and ribavirin, or HIV with HAART may lead to substantial improvement in renal dysfunction. On the other hand, treatment of poststreptococcal glomerulonephritis is only supportive, as the use of antimicrobial agents does not prevent or attenuate its course. However, they should be given to prevent the spread of organisms to other susceptible hosts.

Complications of Nephritic Syndrome

Edema

Salt and water restriction in conjunction with diuretics may occur.

Htn

Antihypertensive treatment is usually achieved with ACEI and ARBS as these have the added antiproteinuric benefits via reduction in the intraglomerular capillary hydrostatic pressure.

Renal Insufficiency

If renal failure is severe or progressive renal replacement therapy will often be necessary.

Prognosis

Prognosis of the nephritic syndrome depends on the underlying etiology of the disease. In cases of poststreptococcal glomerulonephritis the prognosis is excellent with spontaneous recovery of renal function occurring in 70–85% of adults. However, in diseases such as MPGN the prognosis is generally unfavorable. Spontaneous remissions are infrequent, and at least 50% of patients with >10 g of proteinuria per day develop ESRD within 7 years after diagnosis. Other diseases such as Wegener's granulomatosis and Goodpasture's disease may be fatal if left untreated. However, with treatment with steroids and cytotoxic agents a dramatic recovery may be achieved.