Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder. It is more common among children and has both primary and secondary causes. Diagnosis is by determination of urine protein/creatinine ratio in a random urine sample or measurement of urinary protein in a 24-h urine collection; cause is diagnosed based on history, physical examination, serologic testing, and renal biopsy. Prognosis and treatment vary by cause.
Nephrotic syndrome occurs at any age but is more prevalent in children, mostly between ages 1½ and 4 yr. At younger ages, boys are affected more often than girls, but both are affected equally at older ages. Causes differ by age (see Table 1: Glomerular Disorders: Glomerular Disorders by Age and Presentation) and may be primary or secondary (see Table 4: Glomerular Disorders: Causes of Nephrotic Syndrome).
The most common primary causes are the following:
Secondary causes account for < 10% of childhood cases but > 50% of adult cases, most commonly the following:
Amyloidosis, an underrecognized cause, is responsible for 4% of cases.
Proteinuria occurs because of changes to capillary endothelial cells, the glomerular basement membrane (GBM), or podocytes, which normally filter serum protein selectively by size and charge.
The mechanism of damage to these structures is unknown in primary and secondary glomerular diseases, but evidence suggests that T cells may up-regulate a circulating permeability factor or down-regulate an inhibitor of permeability factor in response to unidentified immunogens and cytokines. Other possible factors include hereditary defects in proteins that are integral to the slit diaphragms of the glomeruli, activation of complement leading to damage of the glomerular epithelial cells and loss of the negatively charged groups attached to proteins of the GBM and glomerular epithelial cells.
The disorder results in urinary loss of macromolecular proteins, primarily albumin but also opsonins, immunoglobulins, erythropoietin, transferrin, hormone-binding proteins (including thyroid-binding globulin and vitamin D-binding protein), and antithrombin III. Deficiency of these and other proteins contribute to a number of complications (see Table 5: Glomerular Disorders: Complications of Nephrotic Syndrome); other physiologic factors also play a role.
Symptoms and Signs
Primary symptoms include anorexia, malaise, and frothy urine (caused by high concentrations of protein). Fluid retention may cause dyspnea (pleural effusion or laryngeal edema), arthralgia (hydrarthrosis), or abdominal pain (ascites or, in children, mesenteric edema).
Corresponding signs may develop, including peripheral edema and ascites. Edema may obscure signs of muscle wasting and cause parallel white lines in fingernail beds (Muehrcke's lines).
Other symptoms and signs are attributable to the many complications of nephrotic syndrome (see Table 5: Glomerular Disorders: Complications of Nephrotic Syndrome).
Diagnosis is suspected in patients with edema and proteinuria on urinalysis and confirmed by random (spot) urine protein and creatinine levels or 24-h measurement of urinary protein. The cause may be suggested by clinical findings (eg, SLE, preeclampsia, cancer); when the cause is unclear, additional (eg, serologic) testing and renal biopsy are indicated.
A finding of significant proteinuria (3 g protein in a 24-h urine collection) is diagnostic (normal excretion is < 150 mg/day). Alternatively, the protein/creatinine ratio in a random urine specimen usually reliably estimates grams of protein/1.73 m2 BSA in a 24-h collection (eg, values of 40 mg/dL protein and 10 mg/dL creatinine in a random urine sample are equivalent to the finding of 4 g/1.73 m2 in a 24-h specimen). Calculations based on random specimens may be less reliable when creatinine excretion is high (eg, during athletic training) or low (eg, in cachexia). However, calculations based on random specimens are usually preferred to 24-h collection because random collection is more convenient and less prone to error (eg, due to lack of adherence); more convenient testing facilitates monitoring changes that occur during treatment.
Besides proteinuria, urinalysis may demonstrate RBCs and casts (hyaline, granular, fatty, waxy, RBC, or epithelial cell). Lipiduria, the presence of free lipid or lipid within tubular cells (oval fat bodies), within casts (fatty casts), or as free globules, suggests a glomerular disorder causing nephrotic syndrome. Urinary cholesterol can be detected with plain microscopy and demonstrates a Maltese cross pattern under crossed polarized light; Sudan staining must be used to show triglycerides.
Adjunctive testing helps characterize severity and complications.
It is not routinely necessary to measure levels of α- and γ-globulins, immunoglobulins, hormone-binding proteins, ceruloplasmin, transferrin, and complement components, but these levels may also be low.
The role of testing for secondary causes (see Table 4: Glomerular Disorders: Causes of Nephrotic Syndrome) is controversial because yield may be low. Tests are best done as indicated by clinical context. Tests may include the following:
Test results may alter management and preclude the need for biopsy. For example, demonstration of cryoglobulins suggests mixed cryoglobulinemia (eg, from chronic inflammatory disorders such as SLE, Sjögren's syndrome, or hepatitis C virus infection), and demonstration of a monoclonal protein on serum or urine protein electrophoresis suggests a monoclonal gammopathy (eg, multiple myeloma), especially in patients > 50 yr.
Renal biopsy is indicated in adults to diagnose the disorder causing idiopathic nephrotic syndrome. Idiopathic nephrotic syndrome in children is most likely minimal change disease and is usually presumed without biopsy unless the patient fails to improve during a trial of corticosteroids. Specific biopsy findings are discussed under the individual disorders.
Prognosis varies by cause. Complete remissions may occur spontaneously or with treatment. The prognosis generally is favorable in corticosteroid-responsive disorders.
In all cases, prognosis may be worsened by the following:
The recurrence rate is high in kidney transplantation patients with focal segmental glomerulosclerosis, SLE, IgA nephropathy, and membranoproliferative glomerulonephritis (especially type II).
Treatment of underlying disorders may include prompt treatment of infections (eg, staphylococcal endocarditis, malaria, syphilis, schistosomiasis), allergic desensitization (eg, for poison oak or ivy and insect antigen exposures), and stopping drugs (eg, gold, penicillamine, NSAIDs); these measures may cure nephrotic syndrome in specific instances.
Angiotensin inhibition (ACE inhibitors or angiotensin II receptor blockers) is indicated to reduce systemic and intraglomerular BP and proteinuria. These drugs may cause or exacerbate hyperkalemia in patients with moderate to severe renal insufficiency.
Protein restriction is no longer recommended because of lack of demonstrated effect on progression.
Na restriction (< 2 g Na, or about 100 mmol/day) is recommended for patients with symptomatic edema.
Loop diuretics are usually required to control edema but may worsen preexisting renal insufficiency and hypovolemia, hyperviscosity, and hypercoagulability and thus should be used only if Na restriction is ineffective.
Statins are indicated for hyperlipidemia.
Limitation of saturated fat and cholesterol intake is recommended to help control hyperlipidemia.
Anticoagulants are indicated for treatment of thromboembolism, but few data exist to support their use as primary prevention.
All patients should receive pneumococcal vaccination if not otherwise contraindicated.
Rarely, bilateral nephrectomy is necessary in severe nephrotic syndrome because of persistent hypoalbuminemia. The same result can sometimes be achieved by embolizing the renal arteries with coils, thus avoiding surgery in high-risk patients. Renal replacement therapy is used as necessary.
Congenital Nephrotic Syndromes
Congenital and infantile nephrotic syndromes are those that manifest during the first year of life. They include diffuse mesangial sclerosis and Finnish-type nephrotic syndrome.
Diffuse mesangial sclerosis:
This nephrotic syndrome is rare. Inheritance is variable. Progression to end-stage renal failure occurs by age 2 or 3 yr.
Patients with severe proteinuria may require bilateral nephrectomy because of severe hypoalbuminemia; dialysis should be initiated early to ameliorate nutritional deficits and mitigate failure to thrive. The disorder usually recurs in a renal graft.
Finnish-type nephrotic syndrome:
This syndrome is an autosomal recessive disorder that affects 1/8200 Finnish neonates and is caused by a mutation in the NPHS1 gene, which codes for a podocytic slit-diaphragm protein (nephrin).
Finnish-type nephrotic syndrome is rapidly progressive and usually necessitates dialysis within 1 yr. Most patients die within 1 yr, but a few have been supported nutritionally until renal failure occurs and then managed with dialysis or transplantation. However, the disorder may recur in a renal graft.
Several other rare congenital nephrotic syndromes are now genetically characterized. These include corticosteroid-resistant nephrotic syndrome (defective NPS2 gene coding for podocin), familial focal segmental glomerulosclerosis (defective ACTN 4 gene coding for α-actin 4), and Denys-Drash syndrome, which is characterized by diffuse mesangial sclerosis, male pseudohermaphroditism, and Wilms' tumor (defective WT1 gene).
(See also Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic nephropathy.)
Diabetic nephropathy (DN) is glomerular sclerosis and fibrosis caused by the metabolic and hemodynamic changes of diabetes mellitus. It manifests as slowly progressive albuminuria with worsening hypertension and renal insufficiency. Diagnosis is based on history, physical examination, urinalysis, and urine albumin/creatinine ratio. Treatment is strict glucose control, angiotensin inhibition (ACE inhibitors or angiotensin II receptor blockers), and control of BP and lipids.
DN is the most common cause of nephrotic syndrome in adults and of end-stage renal disease in the US, accounting for up to 80% of cases of the latter. The prevalence of renal failure is probably about 40% among patients with type 1 diabetes mellitus. The prevalence of renal failure among patients with type 2 diabetes mellitus is usually stated as 20 to 30%, but this figure is probably low. Renal failure is particularly common in certain ethnic groups, such as blacks, Mexican-Americans, Polynesians, and Pima Indians. Other risk factors include the following:
Renal failure usually takes ≥ 10 yr after the onset of nephropathy to develop; however, because type 2 diabetes is often present for several years before being recognized, nephropathy often develops < 10 yr after diabetes is diagnosed.
Pathogenesis begins with small vessel disease. Pathophysiology is complex, involving glycosylation of proteins, hormonally influenced cytokine release (eg, transforming growth factor-β), deposition of mesangial matrix, and alteration of glomerular hemodynamics. Hyperfiltration, an early functional abnormality, is only a relative predictor for the development of renal failure.
Hyperglycemia causes glycosylation of glomerular proteins, which may be responsible for mesangial cell proliferation and matrix expansion and vascular endothelial damage. The GBM classically becomes thickened.
Lesions of diffuse or nodular intercapillary glomerulosclerosis are distinctive. There is marked hyalinosis of afferent and efferent arterioles as well as arteriosclerosis; interstitial fibrosis and tubular atrophy may be present. Only mesangial matrix expansion appears to correlate with progression to end-stage renal disease.
DN begins as glomerular hyperfiltration (increased GFR); GFR normalizes with early renal injury and mild hypertension, which worsens over time. Microalbuminuria, urinary excretion of albumin in a range of 30 to 300 mg albumin/day, then occurs. Urinary albumin in these concentrations is called microalbuminuria because detection of proteinuria by dipstick on routine urinalysis usually requires > 300 mg albumin/day. Microalbuminuria progresses to proteinuria > 0.5 g/day at a variable course, usually over years. Nephrotic syndrome (proteinuria ≥ 3 g/day) precedes end-stage renal disease, on average, by about 3 to 5 yr, but this timing is also highly variable. Other urinary tract abnormalities commonly occurring with DN that may accelerate the decline of renal function include papillary necrosis, type IV renal tubular acidosis, and UTIs. In DN, the kidneys are usually of normal size or larger.
Symptoms and Signs
DN is asymptomatic in early stages. Sustained microalbuminuria is the earliest warning sign. Hypertension and some measure of dependent edema eventually develop in most untreated patients. In later stages, patients develop symptoms and signs of uremia (eg, nausea, vomiting, anorexia) earlier (ie, with higher GFR) than do patients without DN, possibly because the combination of end-organ damage due to diabetes (eg, neuropathy) and renal failure worsens symptoms.
The diagnosis is suspected in patients with diabetes who have proteinuria, particularly if they have diabetic retinopathy (indicating small vessel disease) or risk factors for DN. Other renal disorders should be considered if there are any of the following:
Patients are tested for proteinuria by routine urinalysis; if proteinuria is present, testing for microalbuminuria is unnecessary because the patient already has macroalbuminuria suggestive of diabetic renal disease. In patients without proteinuria on urinalysis, an albumin/creatinine ratio should be calculated from a mid-morning urine specimen. A ratio ≥ 0.03 mg/mg (≥ 30 mg/g) indicates microalbuminuria if it is present on at least 2 of 3 specimens within 3 to 6 mo and if it cannot be explained by infection or exercise. Some experts recommend that microalbuminuria be measured from a 24-h urine collection, but this approach is less convenient, and many patients have difficulty accurately collecting a specimen. The random urine albumin/creatinine ratio overestimates 24-h collection of microalbuminuria in up to 30% of patients > 65 due to reduced creatinine production from reduced muscle mass. Inaccurate results can also occur in very muscular patients or if vigorous exercise precedes urine collection.
For most patients with diabetes who have proteinuria, the diagnosis is clinical. Renal biopsy can confirm the diagnosis but is rarely necessary.
Patients with type 1 diabetes without known renal disease should be screened for proteinuria and, if proteinuria is absent on routine urinalysis, for microalbuminuria, beginning 5 yr after diagnosis and at least annually thereafter.
Patients with type 2 diabetes should be screened at the time of diagnosis and annually thereafter.
Prognosis is good for patients who are meticulously treated and monitored. Such care is often difficult in practice, however, and most patients slowly lose renal function; even prehypertension (BP 120 to 139/80 to 89 mm Hg) or stage 1 hypertension (BP 140 to 159/90 to 99 mm Hg) may accelerate injury. Systemic atherosclerotic disease (stroke, MI, peripheral arterial disease) predicts an increase in mortality.
Primary treatment is strict glucose control to maintain HbA1c
≤ 7.0; maintenance of euglycemia reduces microalbuminuria but may not retard disease progression once DN is well established. Glucose control must also be accompanied by strict control of BP to < 130/80 mm Hg. Some experts suggest BP should be 110 to 120/65 to 80 mm Hg, particularly in patients with protein excretion of > 1 g/day; however, others claim that BP values < 120/85 mm Hg are associated with increased cardiovascular mortality and heart failure. Dyslipidemia should also be treated.
Angiotensin inhibition is first-line therapy. Thus, ACE inhibitors or angiotensin II receptor blockers are the antihypertensives of choice; they reduce BP and proteinuria and slow the progression of DN. ACE inhibitors are usually less expensive, but angiotensin II receptor blockers can be used instead if ACE inhibitors cause persistent cough. Treatment should be started when microalbuminuria is detected regardless of whether hypertension is present; some experts recommend drugs be used even before signs of renal disease appear.
Diuretics are required by most patients in addition to angiotensin inhibition to reach target BP levels. Dose should be decreased if symptoms of orthostatic hypotension develop or serum creatinine increases by more than 30%.
Nondihydropyridine Ca channel blockers (diltiazem and verapamil) are also antiproteinuric and renoprotective and can be used if proteinuria does not meaningfully decrease when target BP is reached or as alternatives for patients with hyperkalemia or other contraindications to ACE inhibitors or angiotensin II receptor blockers. In contrast, dihydropyridine Ca channel blockers (eg, nifedipine, felodipine, amlodipine) are relatively contraindicated because they may worsen proteinuria and renal function. ACE inhibitors and nondihydropyridine Ca channel blockers have greater antiproteinuric and renoprotective effects when used together, and their antiproteinuric effect is enhanced by Na restriction. Nondihydropyridine Ca channel blockers should be used with caution in patients taking β-blockers.
Dietary protein restriction yields mixed results. The American Diabetic Association recommends that people with diabetes and overt nephropathy be restricted to 0.8 g protein/kg/day. Significant protein restriction should be done only with close dietary monitoring to ensure a balanced supply of amino acids, because undernutrition may be a significant risk.
Kidney transplantation with or without simultaneous or subsequent pancreas transplantation (see Transplantation: Kidney Transplantation) is an option for patients with end-stage renal disease. The 5-yr survival rate for patients with type 2 diabetes receiving a kidney transplant is almost 60%, compared with 2% for dialysis-dependent patients who do not undergo transplantation (though this statistic probably represents significant selection bias). Renal allograft survival rate is > 85% at 2 yr.
Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is scattered (segmental) mesangial sclerosis in some but not all (focal) glomeruli. It is most often idiopathic but may be secondary to use of heroin or other drugs, HIV infection, obesity, sickle cell disease, atheroembolic disease, or nephron loss (eg, in reflux nephropathy or subtotal nephrectomy). It manifests mainly in adolescents but also in young and middle-aged adults. Patients have insidious onset of proteinuria, mild hematuria, hypertension, and azotemia. Diagnosis is confirmed by renal biopsy. Treatment is with angiotensin inhibition and, for idiopathic disease, corticosteroids and sometimes cytotoxic drugs.
FSGS is now the most common cause of idiopathic (or primary) nephrotic syndrome among adults in the US. It is especially common in black men. Though usually idiopathic, FSGS can occur in association with other factors (secondary FSGS), including drugs (eg, heroin, interferon alfa, pamidronate, cyclosporine, or acetaminophen or NSAIDs [causing analgesic nephropathy]), atheroembolic disease affecting the kidneys, obesity, HIV infection (see Glomerular Disorders: HIV-associated nephropathy), and disorders causing nephron loss (eg, reflux nephropathy, subtotal nephrectomy, renal dysgenesis). Familial cases exist.
In FSGS, because charge as well as size ultrafiltration barriers are defective, proteinuria is typically nonselective, affecting high molecular-weight proteins (eg, Igs) as well as albumin. Kidneys tend to be small.
Symptoms and Signs
FSGS patients commonly present with heavy proteinuria, hypertension, renal dysfunction, edema, or a combination; however, asymptomatic, non-nephrotic–range proteinuria is sometimes the only sign. Microscopic hematuria is occasionally present.
FSGS is suspected in patients with nephrotic syndrome, proteinuria, or renal dysfunction with no obvious cause, particularly patients who have disorders or use drugs associated with FSGS.
Urinalysis is done and BUN, serum creatinine, and 24-h urinary protein excretion are measured. Diagnosis is confirmed by renal biopsy, which shows focal and segmental hyalinization of the glomeruli, often with immunostaining showing IgM and complement (C3) deposits in a nodular and coarse granular pattern. Electron microscopy reveals diffuse effacement of podocyte foot processes. Global sclerosis may be visible, along with secondary atrophic glomeruli. Biopsy may be falsely negative if areas of focal abnormalities are not sampled.
Prognosis is poor. Spontaneous remissions occur in < 10% of patients. Renal failure occurs in > 50% of patients within 10 yr; in 20%, end-stage renal disease occurs within 2 yr despite treatment. The disorder is more rapidly progressive in adults than in children. The presence of segmental sclerosis consistently at the glomerular pole where the tubule originates (tip lesion) may portend a more favorable response to corticosteroid therapy. Another variant, in which the capillary walls are wrinkled or collapsed (collapsing glomerulopathy, which is typical in association with IV drug abuse or HIV infection), suggests more severe disease and rapid progression to renal failure. Pregnancy may exacerbate FSGS.
FSGS may recur after renal transplantation; proteinuria sometimes returns within hours of transplantation. Of patients whose transplant was for end-stage renal disease caused by FSGS, about 8 to 20% lose their graft due to recurrent FSGS; risk is highest in young children, patients who develop renal failure < 3 yr after disease onset, and patients with mesangial proliferation.
Heroin addicts with nephrotic syndrome due to FSGS can experience complete remission if they cease taking heroin early in the disease.
Treatment often is not effective. Patients with FSGS should be treated with angiotensin inhibition (an ACE inhibitor or an angiotensin II receptor blocker) unless contraindicated by angioedema or hyperkalemia. Patients with nephrotic syndrome should be treated with a statin. In patients with secondary FSGS, the primary disorder should be treated. A trial of immunosuppressive therapy is indicated in idiopathic FSGS if proteinuria reaches the nephrotic range or if any degree of renal dysfunction is present.
Corticosteroids (eg, prednisone 1 mg/kg po once/day or 2 mg/kg every other day) are recommended for at least 2 mo, although some experts recommend use for up to 9 mo. Response rates of 30 to 50% have been reported with prolonged therapy. After a 2-wk remission of proteinuria, the corticosteroid is slowly tapered over ≥ 2 mo. Secondary and familial cases are more likely to be corticosteroid-resistant.
If only slight improvement or relapse occurs with corticosteroid therapy, cyclosporine (1.5 to 2 mg/kg po bid for 6 mo) or, alternatively, mycophenolate mofetil (750 to 1000 mg po bid for 6 mo in patients > 1.25 m2 BSA or 600 mg/ m2 BSA bid up to 1000 mg bid) may induce remission. In patients with contraindications to high-dose corticosteroids (eg, diabetes, osteoporosis), cyclosporine can be given along with a lower dose of corticosteroids (eg, prednisone 0.15 mg/kg po once/day). An alternative is plasmapheresis with tacrolimus immunosuppression.
HIV-associated nephropathy (HIVAN) is characterized by clinical findings similar to those of focal segmental glomerulosclerosis and often biopsy features of collapsing glomerulopathy (a variant of focal segmental glomerulosclerosis).
HIVAN seems to be more common among black patients with HIV who are injection drug users. Infection of renal cells with HIV may contribute.
Most clinical findings are similar to those of FSGS, but hypertension is less common and the kidneys remain enlarged. Most patients experience rapid progression to end-stage renal disease within 1 to 4 mo.
HIVAN is suspected in patients with nephrotic syndrome or nephropathy who have AIDS or symptoms of AIDS. HIVAN should be distinguished from the many other disorders that occur with higher frequency in HIV-infected patients and cause renal disease, such as thrombotic microangiopathy (hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura), immune complex–mediated glomerulonephritis, and drug-induced interstitial nephritis (due to indinavir and ritonavir) and rhabdomyolysis (due to statins).
In HIVAN, ultrasonography, if done, shows that the kidneys are enlarged and highly echogenic. Renal biopsy typically is done. Light microscopy shows capillary collapse of varying severity (collapsing glomerulopathy) and differing degrees of increased mesangial matrix. Tubular cells show marked degenerative changes and tubular atrophy or microcytic dilation. Interstitial immune cell infiltrate, fibrosis, and edema are common. Tubular reticular inclusions, similar to those in SLE, are found within endothelial cells but are now rare with more effective HIV therapy. Normotension and persistently enlarged kidneys help to differentiate HIVAN from FSGS.
Control of the HIV infection may help minimize renal damage. ACE inhibitors are probably of some benefit. The role of corticosteroids is not well defined. Dialysis is usually required. At some centers, outcomes after transplantation have been excellent.
Membranous nephropathy (MN) is deposition of immune complexes on the GBM with GBM thickening. Cause is usually unknown, although secondary causes include drugs, infections, autoimmune disorders, and cancer. Manifestations include insidious onset of edema and heavy proteinuria with benign urinary sediment, normal renal function, and normal or elevated BP. Diagnosis is by renal biopsy. Spontaneous remission is common. Treatment of patients at high risk of progression is usually with corticosteroids and cyclophosphamide or chlorambucil.
MN mostly affects adults, in whom it is a common cause of nephrotic syndrome.
MN is usually idiopathic but may be secondary to any of the following:
Depending on the patient's age, 4 to 20% have an underlying cancer, including solid cancers of the lung, colon, stomach, breast, or kidney; Hodgkin or non-Hodgkin lymphoma; chronic lymphocytic leukemia; and melanoma.
MN is rare in children and, when it occurs, is usually due to hepatitis B virus infection or SLE.
Renal vein thrombosis is especially frequent in MN but is usually clinically silent unless it progresses to pulmonary embolism.
Symptoms and Signs
Patients typically present with edema and nephrotic-range proteinuria and occasionally with microscopic hematuria and hypertension. Symptoms and signs of a disorder causing MN (eg, a cancer) may be present initially.
Diagnosis is suggested by development of nephrotic syndrome, particularly in patients who have potential causes of MN. The diagnosis is confirmed by biopsy.
Proteinuria is in the nephrotic range in 80%. Laboratory testing is done as indicated for nephrotic syndrome. The GFR, if measured, is normal or decreased. Immune complexes are seen as dense deposits on electron microscopy (see Fig. 1: Glomerular Disorders: Electron microscopic features in immunologic glomerular disorders.). Subepithelial dense deposits occur with early disease, with spikes of lamina densa between the deposits. Later, deposits appear within the GBM, and marked thickening occurs. A diffuse, granular pattern of IgG deposition occurs along the GBM without cellular proliferation, exudation, or necrosis.
Evaluation of patients diagnosed with MN usually includes the following:
The search for occult cancer is usually limited to age-appropriate screening (eg, colonoscopy for patients age > 50 or with other symptoms or risk factors, mammogram for women age > 40, prostate-specific antigen measurement for men age > 50 [age > 40 for blacks], chest x-ray and possibly chest CT for patients at risk of lung cancer).
About 25% of patients undergo spontaneous remission, 25% develop persistent, non-nephrotic–range proteinuria, 25% develop persistent nephrotic syndrome, and 25% progress to end-stage renal disease. Women, children, and young adults with non-nephrotic–range proteinuria and patients with persistently normal renal function 3 yr after diagnosis tend to have little disease progression. More than 50% of patients with nephrotic-range proteinuria who are asymptomatic or who have edema that can be controlled with diuretics will have a partial or complete remission within 3 to 4 yr.
Risk of progression to renal failure is highest among patients with
Primary treatment is that of the causes. Among patients with idiopathic MN, asymptomatic patients with non-nephrotic–range proteinuria do not require treatment; renal function should be monitored periodically (eg, twice yearly when apparently stable). Patients with nephrotic-range proteinuria who are asymptomatic or who have edema that can be controlled with diuretics should be treated for nephrotic syndrome. Patients with hypertension should be given an ACE inhibitor or angiotensin II receptor blocker; these drugs may also benefit patients without hypertension by reducing proteinuria.
Immunosuppressants should be considered only for patients with symptomatic idiopathic nephrotic syndrome and for those most at risk of progressive disease. Older and chronically ill patients are at greater risk of infectious complications from immunosuppressants. No consensus protocol exists, but one approach uses methylprednisolone 1 g IV for 3 days, after which prednisone 0.5 mg/kg po once/day is given for the next 27 days. The following month, chlorambucil 0.1 to 0.2 mg/kg po once/day is given for 1 mo. These 2 monthly regimens are alternated for a total of 6 mo. This protocol remains controversial (see the Cochrane abstract review There is no strong evidence that adults with nephrotic syndrome have a long-term benefit from treatment with immunosuppressive drugs
) and should be used with caution, especially in the elderly because of the increased risk of infection. Some experts favor use of combinations of cyclophosphamide and corticosteroids because of their better safety profile.
For patients who are intolerant of cytotoxic drugs or who do not respond to them, cyclosporine 4 to 6 mg/kg po once/day for 4 mo may be beneficial. Therapies of unproven long-term value include IV immune globulin and NSAIDs.
Minimal Change Disease
(Lipoid Nephrosis; Nil Disease)
Minimal change disease (MCD) causes abrupt onset of edema and heavy proteinuria, mostly in children. Renal function is typically normal. Diagnosis is based on clinical findings or renal biopsy. Prognosis is excellent. Treatment is with corticosteroids or, in patients who do not respond, cyclophosphamide or cyclosporine.
MCD is the most common cause of nephrotic syndrome in children 4 to 8 yr (80 to 90% of childhood nephrotic syndrome), but it also occurs in adults (10 to 20% of adult nephrotic syndrome). The cause is almost always unknown, although rare cases may occur secondary to drug use (especially NSAIDs) and hematologic cancers (especially Hodgkin lymphoma).
MCD causes nephrotic syndrome, usually without hypertension or azotemia; microscopic hematuria occurs in about 20% of patients, mainly adults. Azotemia can occur in secondary cases and in patients > 60 yr. Albumin is lost in the urine of patients with MCD more so than larger serum proteins probably because MCD causes changes in the charge barrier that affect albumin selectively.
In children, the following:
Renal biopsy is required in atypical cases and in adults. Electron microscopy demonstrates edema with diffuse swelling (effacement) of foot processes of the epithelial podocytes (see Fig. 1: Glomerular Disorders: Electron microscopic features in immunologic glomerular disorders.). Complement and Ig deposits are absent on immunofluorescence. Although effacement is not observed in the absence of proteinuria, heavy proteinuria may occur with normal foot processes.
Spontaneous remissions occur in 40% of cases, but most patients are given corticosteroids. About 80 to 90% of patients respond to initial corticosteroid therapy (eg, prednisone 60 mg/m2 po once/day for 4 to 6 wk in children and 1 to 1.5 mg/kg po once/day for 6 to 8 wk in adults), but 40 to 60% of responders relapse. Patients who respond (ie, have cessation of proteinuria or a diuresis if edema is present) should continue prednisone for another 2 wk and change to a maintenance regimen to minimize toxicity (2 to 3 mg/kg on alternate days for 4 to 6 wk in children and for 8 to 12 wk in adults, tapering during the next 4 mo). More prolonged initial therapy and slower tapering of prednisone lower relapse rates. Nonresponsiveness may be due to underlying focal sclerosis that was missed on biopsy due to sampling error.
In corticosteroid nonresponders (< 5% of children and > 10% of adults), frequent relapsers, and corticosteroid-dependent patients, prolonged remission may be achieved with an oral cytotoxic drug (usually cyclophosphamide 2 to 3 mg/kg once/day for 12 wk or chlorambucil 0.15 mg/kg once/day for 8 wk). (See the Cochrane abstract review Non-corticosteroid treatment for nephrotic syndrome in children.) However, these drugs may suppress gonadal function (most serious in prepubertal adolescents), cause hemorrhagic cystitis, have mutagenic potential, and suppress bone marrow and lymphocyte function. Dosage should be monitored with frequent CBCs, and hemorrhagic cystitis should be sought by urinalysis. Adults, particularly if older or hypertensive, are more prone to adverse effects from these cytotoxic drugs. Another alternative is cyclosporine 3 mg/kg po bid, adjusted to obtain a whole-blood trough concentration of 50 to 150 μg/L (40 to 125 nmol/L).
Complete remission occurs in > 80% of patients treated with corticosteroids, and treatment is usually continued for 1 to 2 yr. However, half or more relapse, requiring treatment with the same or a different regimen. Patients responsive to cyclosporine frequently relapse when the drug is stopped.
Most patients who are unresponsive to these interventions respond to alternative therapies, including ACE inhibitors, thioguanine, levamisole, azathioprine, and mycophenolate mofetil; < 5% progress to renal failure.
Last full review/revision January 2010 by James I. McMillan, MD
Content last modified November 2012