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Nephrotic
syndrome is urinary excretion of > 3 g
of protein/day due to glomerular disease. It is more common in children
and has both primary and secondary causes. Diagnosis is by measurement
of a spot urine protein/creatinine ratio or a 24-h urinary protein;
underlying causes are diagnosed based on history, physical examination,
and renal biopsy. Treatment and prognosis vary by cause.
Etiology
and Pathophysiology
Nephrotic syndrome (NS) occurs at any age but is more prevalent in children, mostly between ages 1 1⁄2 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 Diseases: Glomerular Diseases by Age and Presentation ). The most common primary causes are minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Secondary causes account for < 10% of childhood cases but > 50% of adult cases, most commonly diabetic nephropathy and preeclampsia (see Table 3: Glomerular Diseases: Causes of Nephrotic Syndrome). Amyloidosis is an underrecognized cause of 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 glomerular disease, but evidence suggests that T cells up-regulate a circulating permeability factor or down-regulate an inhibitor of permeability factor in response to unidentified immunogens and cytokines. The result is urinary loss of macromolecular proteins, primarily albumin but also opsonins, immunoglobulins, erythropoietin, transferrin, hormone-binding proteins, and antithrombin III in conditions that cause nonselective proteinuria. As a result, patients with NS develop peripheral edema, ascites, and effusions and are at increased risk for infection (especially cellulitis and, in 2 to 6%, spontaneous bacterial peritonitis); anemia; abnormal thyroid function; and thromboembolism (especially renal vein thrombosis and pulmonary embolism in up to 5% of children and 40% of adults). Thromboembolism may develop not only because of urinary loss of antithrombin III but also because of increased hepatic synthesis of clotting factors, platelet abnormalities, and hyperviscosity from hypovolemia. Chronic complications of NS include malnutrition in children, coronary artery disease in adults, chronic renal failure, and bone disease. Malnutrition may mimic kwashiorkor, including brittle hair and nails, alopecia, and stunted growth. Coronary artery disease develops because NS causes hyperlipidemia, hypertension, and hypercoagulability. Complications of chronic renal failure are discussed in Renal Failure: Symptoms and Signs. Bone disease develops because of vitamin D deficiency and corticosteroid use. Other chronic complications include hypothyroidism from loss of thyroid-binding globulin and proximal tubular dysfunction causing glucosuria, aminoaciduria, K depletion, phosphaturia, and renal tubular acidosis.
Renal failure is rarely a presenting finding but may occur after a prolonged illness. However, patients with NS due to a secondary cause frequently have renal insufficiency at onset or soon thereafter.
Symptoms and Signs
Primary symptoms include anorexia, malaise, and frothy urine caused by high concentrations of protein. Edema may cause dyspnea (pleural effusion or laryngeal edema), chest discomfort (pericardial effusion), arthralgia (hydrarthrosis), or abdominal pain (ascites or, in children, mesenteric edema). 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 NS (see above).
Diagnosis
Diagnosis is suspected in patients with edema and proteinuria on urinalysis and confirmed by 24-h measurement of urinary protein. The cause may be suggested by history (eg, cancer); when the cause is unclear, serologic testing and renal biopsy are indicated.
A finding of 3 g protein in a 24-h urine collection is diagnostic. The protein/creatinine ratio in a random specimen 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 on a random urine sample are equivalent to the finding of 4 g/1.73 m2 in a 24-h specimen). The use of spot urine protein/creatinine ratio may be less reliable when creatinine excretion is extremely high (eg, during athletic training) or low (eg, in cachexia) and in disorders in which proteinuria may vary daily (eg, in diabetic nephropathy).
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, is primarily present with glomerular disease causing NS. Urinary cholesterol can be detected with plain microscopy and demonstrates a “Maltese cross” pattern under polarized light; Sudan staining must be used to show triglycerides. WBCs are prominent in exudative diseases and SLE.
Adjunctive testing helps characterize severity and complications. BUN and creatinine concentrations vary by degree of renal impairment. Albumin often is < 2.5 g/dL. Total cholesterol and triglyceride levels are typically increased. It is not routinely necessary to measure levels of α- and γ-globulins, immunoglobulins, hormone binding proteins, ceruloplasmin, transferrin, and complement components, but these may also be low.
The role of testing for secondary causes (see Table 3: Glomerular Diseases: Causes of Nephrotic Syndrome) is controversial, because yield may be low. Tests, including serum glucose or glycosylated hemoglobin (HbA1c), antinuclear antibodies, and hepatitis B and C serologic tests, are indicated by clinical context and 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), whereas demonstration of a monoclonal protein on serum or urine protein electrophoresis suggests a monoclonal gammopathy (eg, multiple myeloma), especially in patients > 50 yr.
In adults, a renal biopsy is indicated to diagnose the underlying cause of idiopathic NS. Idiopathic NS in children is most likely minimal change disease and is usually presumed without biopsy unless the patient fails to improve on a trial of corticosteroids. Specific biopsy findings are discussed under individual disease entities below.
Prognosis
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 infection; hypertension; significant azotemia; hematuria; or thromboses in cerebral, pulmonary, peripheral, or renal veins. The recurrence rate is high in kidney transplantation patients with focal segmental glomerulosclerosis, SLE, IgA nephropathy, and membranoproliferative glomerulonephritis (especially type II).
Treatment
Specific treatment is discussed under individual disorders below. Supportive therapy includes treatment of secondary causes when they exist and dietary restrictions, antihypertensives, and measures to prevent complications. Rarely, severe NS requires nephrectomy because of persistent hypoalbuminemia.
Treatment of underlying causes may include prompt treatment of infections (eg, staphylococcal and Streptococcus
viridans endocarditis, vascular prosthetic nephritis, 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 NS in specific instances.
Protein restriction is no longer recommended because of lack of demonstrated effect on disease progression. However, saturated fat and cholesterol intake should be limited, and Na restriction (< 100 mmol/day) is recommended to control symptomatic edema.
ACE inhibitors are indicated to reduce systemic and intraglomerular BP and proteinuria. They may cause or exacerbate hyperkalemia in patients with moderate to severe renal insufficiency.
Loop diuretics are usually required to control edema but may worsen preexisting renal insufficiency and hypovolemia, hyperviscosity, and hypercoagulability.
Anticoagulants are indicated for thromboembolism, but few data exist to support their use as primary prevention. Statins are indicated for hyperlipidemia. All patients should receive pneumococcal vaccination; the use of prophylactic penicillin is controversial.
Congenital
Nephrotic Syndromes
Congenital
nephrotic syndromes include diffuse mesangial sclerosis and Finnish-type
nephrotic syndrome.
Diffuse mesangial sclerosis is rare. Inheritance is unknown. A patient with severe proteinuria may require bilateral nephrectomy because of severe hypoalbuminemia; dialysis should be initiated early in the disease to ameliorate nutritional deficits and mitigate failure to thrive. The disease usually recurs in a renal graft.
Finnish-type NS, an autosomal recessive disease, affects 1/8200 Finnish newborns and is caused by a mutation in the NPHS1 gene, which codes for a podocytic slit-diaphragm protein (nephrin). Finnish-type NS 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.
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 alpha-actin 4), and Denys-Drash syndrome (defective WT1 gene).
Diabetic
Nephropathy
(See also Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic nephropathy.)
Diabetic
nephropathy 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 serum creatinine. Treatment is strict glucose control, ACE inhibitors and/or
angiotensin receptor blockers, and control of BP and lipids.
Diabetic nephropathy (DN) is the most common cause of NS and of end-stage renal disease in the US, accounting for up to 80% of cases of the latter. The prevalence of renal failure among patients with type 2 diabetes mellitus is most likely underestimated at 20 to 30%; renal failure is particularly common in blacks, Asians, and Hispanics with type 2 diabetes. Prevalence increases with duration and poor control of disease; renal failure usually takes ≥ 10 yr to develop.
Pathophysiology
Pathogenesis 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 it cannot be detected by routine urinalysis. Microalbuminuria progresses to proteinuria > 0.5 g/day, and NS usually precedes end-stage renal disease by 3 to 5 yr. Overall progression to chronic renal failure takes 10 to 20 yr. 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.
Symptoms,
Signs, and Diagnosis
DN is asymptomatic in early stages. Proteinuria (especially with albumin) on routine urinalysis is often the earliest warning. 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.
Diagnosis is suggested by proteinuria, diabetic retinopathy and/or hypertension, and a history of diabetes. Other renal diseases should be considered if there is heavy proteinuria with a short diabetic history, absence of diabetic retinopathy, rapid onset of heavy proteinuria, gross hematuria, RBC casts, or a rapid decline in GFR. Renal biopsy can confirm the diagnosis but is rarely necessary.
If proteinuria is evident on urinalysis, testing for microalbuminuria is unnecessary because the patient already has macroalbuminuria suggestive of diabetic renal disease. Patients with type 1 diabetes without known renal disease should be screened for microalbuminuria and proteinuria 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.
In patients without proteinuria on urinalysis, a microalbumin-to-creatinine ratio should be measured on a 1st morning void urine specimen. A ratio ≥ 0.03 (≥ 30 mg/g) indicates microalbuminuria if it is present on at least 2 of 3 measures 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 spot 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.
Prognosis
and Treatment
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 glycosylated hemoglobin ≤ 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 110 to 120/< 75 mm Hg). ACE inhibitors or angiotensin receptor blockers are the antihypertensives of choice; they reduce BP and proteinuria and slow the progression of DN. The combination of both drugs may exert greater antiproteinuric and renoprotective effects than either drug alone. They should be started when microalbuminuria is detected regardless of whether hypertension is present; some experts recommend they be used even before signs of renal disease appear. Angiotensin receptor blockers can be used alone if persistent cough precludes the use of ACE inhibitors.
Nondihydropyridine Ca channel blockers ( diltiazem and verapamil ) are also antiproteinuric and renoprotective and are reasonable alternatives for patients with hyperkalemia or other contraindications to ACE inhibitors or angiotensin 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.
Dietary restriction of protein yields mixed results. The American Diabetic Association recommends that people with diabetes and overt nephropathy be restricted to ≤ 0.8 g protein/kg/day. Some experts recommend restriction to 0.6 g/kg when disease progression is documented. Significant protein restriction should be done only with close dietary monitoring to ensure a balanced supply of amino acids, because malnutrition 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 is scattered (segmental) mesangial
sclerosis in some but not all (focal) glomeruli. It is most often
idiopathic but may be secondary to heroin use, HIV infection, obesity,
or nephron loss (eg, in reflux nephropathy or subtotal nephrectomy). Manifestations
are insidious onset of proteinuria, mild hematuria, hypertension,
and azotemia, mainly in adolescents but also in young and middle-aged
adults. Diagnosis is indicated by history, physical examination,
and urinalysis; it is confirmed by renal biopsy. Treatment is with
corticosteroids and occasionally cytotoxic drugs.
Focal segmental glomerulosclerosis (FSGS) is now the most common cause of idiopathic NS among adults in the US. It is especially common in black men. Though usually idiopathic, FSGS can occur in association with injection drug use, obesity, analgesic nephropathy, and diseases causing nephron loss (eg, reflux nephropathy, subtotal nephrectomy). Familial cases exist. HIV-associated nephropathy (HIVAN) is characterized by a lesion similar to FSGS and seems to be more common in black patients with HIV who are injection drug users. Infection of renal cells with HIV may contribute. 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 ( indinavir , ritonavir ) and rhabdomyolysis (statins).
Symptoms,
Signs, and Diagnosis
FSGS patients commonly present with heavy proteinuria, hypertension, and renal dysfunction, although asymptomatic non-nephrotic–range proteinuria is sometimes the only sign. Microscopic hematuria is occasionally found. Proteinuria is typically nonselective (both size and charge ultrafiltration barriers are defective). IgG levels are frequently depressed. Diagnosis is confirmed by renal biopsy, which shows focal and segmental hyalinization of the glomeruli, often with immunostaining showing IgM and C3 deposits in a nodular and coarse granular pattern. Electron microscopy reveals diffuse effacement of podocyte foot processes. Global sclerosis may occur, leading to atrophic glomeruli.
HIVAN may accompany symptoms of AIDS. At presentation, mild azotemia and signs of NS, including nephrotic-range proteinuria, are often found. The kidneys are enlarged and highly echogenic on ultrasonography. 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 persistent enlarged kidneys help to differentiate HIVAN from FSGS.
Prognosis
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 disease 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), suggests more severe disease and rapid progression to renal failure. Pregnancy may exacerbate FSGS.
FSGS recurs after renal transplantation in 20 to 30% of patients; proteinuria sometimes returns within hours of transplantation. Of patients with recurrent FSGS, 30 to 50% lose their graft; risk is highest in young children, patients who develop renal failure < 3 yr after disease onset, and patients with mesangial proliferation.
Heroin addicts with NS due to FSGS can experience complete remission if they cease taking heroin early in the disease.
Most patients with HIVAN experience rapid progression to end-stage renal disease within 1 to 4 mo.
Treatment
Treatment often is not effective. 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 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, cyclophosphamide (2 to 3 mg/kg po once/day for 12 wk) or cyclosporine (5 mg/kg po once/day in adults or 6 mg/kg once/day in children for 16 wk) may induce remission. Patients with corticosteroid-resistant, advanced primary FSGS should be treated with a prolonged course of ACE inhibitors. An alternative is plasmapheresis with tacrolimus immunosuppression.
Treatment of HIVAN is antiretroviral therapy. Control of the underlying HIV infection may improve the renal lesion. ACE inhibitors are probably of some benefit. The role of corticosteroids is not well defined. Dialysis is usually required.
Membranous
Nephropathy
Membranous
nephropathy is deposition of immune complexes on the GBM with GBM thickening.
Cause is usually unknown, although secondary causes include
drugs, infections, autoimmune diseases, and cancer. Symptoms and
signs include insidious onset of edema, heavy proteinuria, benign
urinary sediment, normal renal function, and normal or elevated
BP. Diagnosis is by renal biopsy. Treatment is usually with corticosteroids
and cyclophosphamide, although many patients undergo spontaneous
remission.
Membranous nephropathy (MN) mostly affects adults. It is usually idiopathic but may be caused by drugs (eg, gold, penicillamine , NSAIDs), infections (eg, hepatitis B virus), autoimmune disease (eg, SLE), thyroiditis, or cancer. 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,
Signs, and Diagnosis
Patients typically present with edema and nephrotic-range proteinuria and occasionally with microscopic hematuria and hypertension. Symptoms and signs of chronic immune complex or connective tissue disease, chronic infection, or tumor may be present initially.
Diagnosis is indicated by history and urinalysis and confirmed by biopsy. Only 20% have non-nephrotic–range proteinuria. C3 and C4 levels are normal. The GFR is normal or decreased. Immune complexes are seen as dense deposits on electron microscopy (see Fig. 1: Glomerular Diseases: Electron microscopic features in immunologic glomerular diseases. ). 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.
A search for occult cancer should be undertaken, particularly in a patient who has lost weight, has unexplained anemia or heme-positive stools, or is elderly. Drug-induced MN should also be considered.
Prognosis
About 25% of patients undergo spontaneous remission, 25% develop persistent non-nephrotic–range proteinuria, 25% develop persistent NS, and 25% progress to end-stage renal disease. Women, children, and young adults with non-nephrotic–range proteinuria and those with persistent normal renal function 3 yr after diagnosis tend to have little disease progression.
Men > 50 yr with proteinuria ≥ 10 g/day, patients with increased β-microglobulinuria, and patients with an initially elevated serum creatinine are at greatest risk of progression to renal failure.
Treatment
Primary treatment is that of underlying causes. Among patients with idiopathic MN, asymptomatic patients with non-nephrotic–range proteinuria do not require treatment; renal function should be monitored periodically, however. Patients with nephrotic-range proteinuria who are asymptomatic or who have edema that can be controlled with diuretics should be followed, because ≥ 50% will have a partial or complete remission within 3 to 4 yr.
Immunosuppressants should be considered only for patients with symptomatic idiopathic NS and for those most at risk of progressive disease (see Prognosis, above). 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 for the next 27 days is given. The following month, chlorambucil 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 Immunosuppressive
treatment for idiopathic membranous nephropathy in adults with nephrotic
syndrome) and should be used with caution, especially in the elderly because of the increased risk of infection.
For patients intolerant of cytotoxic drugs, cyclosporine 4 to 6 mg/kg po once/day for 4 mo may be beneficial. Patients with hypertension should be given an ACE inhibitor or angiotensin receptor blocker; these drugs may also benefit patients without hypertension by reducing proteinuria. Therapies of unproven long-term value include IV immune globulin and NSAIDs.
Minimal
Change Disease
(Lipoid Nephrosis; Nil Disease)
Minimal
change disease causes abrupt onset of edema and heavy proteinuria,
mostly in children. Renal function is typically normal. Diagnosis
is made empirically or by renal biopsy. Prognosis is excellent.
Treatment is with corticosteroids or, in patients who do not respond, cyclophosphamide
or cyclosporine.
Minimal change disease (MCD) is the most common cause of NS in children 4 to 8 yr (80 to 90% of childhood NS), but it also occurs in adults (20% of adult NS). The cause is almost always unknown, although rare cases may occur secondary to drug use (especially NSAIDs) and hematologic malignancies (especially Hodgkin lymphoma).
MCD causes NS without hypertension or azotemia; microscopic hematuria occurs in about 20% of patients. Azotemia can occur in nonidiopathic 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 rather than the size barrier in the glomerular capillary wall.
Diagnosis
Diagnosis in children is most often clinical, but 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 Diseases: Electron microscopic features in immunologic glomerular diseases.). Although effacement is not observed in the absence of proteinuria, heavy proteinuria may occur with normal foot processes.
Treatment
Spontaneous remissions occur in 40% of cases, but most patients are given corticosteroids. About 80 to 90% of patients respond to initial corticosteroid therapy ( 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, 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.
In corticosteroid nonresponders (< 5% of children; > 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), and cyclophosphamide may cause hemorrhagic cystitis 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 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, and treatment is usually continued for 1 to 2 yr. Patients responsive to cyclosporine frequently relapse when the drug is stopped.
For patients unresponsive to these interventions, most respond to alternative therapies, including ACE inhibitors, thioguanine , levamisole, azathioprine , and mycophenolate mofetil ; < 5% progress to renal failure.
Last full review/revision November 2005
Content last modified November 2005
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