Characterized by albuminuria (>3.5 g/d) and hypoalbuminemia (<30 g/L) and accompanied by edema, hyperlipidemia, and lipiduria. Protein excretion should be quantified by 24-h urine collection, but can be monitored by measurement of the urine protein:creatinine ratio or albumin:creatinine ratio on a random spot urine. The measurement of creatinine excretion helps define the adequacy of 24-h urine collections: daily creatinine excretion should be 20-25 mg/kg lean body weight in men and 15-20 mg/kg lean body weight in women. For random urine samples, the ratio of protein or albumin to creatinine in mg/dL approximates the 24-h urine protein excretion, since creatinine excretion is only slightly >1000 mg/d per 1.73 m2 . A urine protein:creatinine ratio of 5 is thus consistent with 5 g/d per 1.73 m2 . Quantification of urine protein excretion on spot urines has largely supplanted formal 24-h urine collections for monitoring or screening, due to the greater ease and the need to verify a complete 24-h collection. The total protein:creatinine ratio does not detect microalbuminuria, a level of albumin excretion that is below the level of detection by tests for total protein; urine albumin:creatinine measurement is therefore preferred as a screening tool for lesser proteinuria.
In addition to edema, the complications of NS can include renal vein thrombosis and other thromboembolic events, infection, vitamin D deficiency, protein malnutrition, and drug toxicities due to decreased protein binding.
In adults, the most common cause of NS is diabetes. A minority of cases are secondary to SLE, amyloidosis, drugs, neoplasia, or other disorders (Table 145-3 Causes of Nephrotic Syndrome (NS)). By exclusion, the remainder are idiopathic. With the exception of diabetic nephropathy, suggested by a compatible natural history of proteinuria in a diabetic pt, a renal biopsy is required to make the diagnosis and determine therapy in NS.
Causes about 10-15% of idiopathic NS in adults, but 70-90% of NS in children. Blood pressure is normal; GFR is normal or slightly reduced; urinary sediment is benign or may show few RBCs. Protein selectivity is variable in adults. Recent upper respiratory infection, allergies, or immunizations are present in some cases; nonsteroidal anti-inflammatory drugs can cause minimal change disease with interstitial nephritis. Acute renal failure due to associated acute tubular necrosis may rarely occur, particularly among elderly persons. Renal biopsy shows only foot process fusion on electron microscopy. Remission of proteinuria with glucocorticoids carries a good prognosis; cytotoxic therapy or calcineurin inhibitor or anti-CD20 (e.g., rituximab) therapy may be required for relapsing pts. Progression to renal failure is uncommon. Focal sclerosis should be suspected in cases that are refractory to steroid therapy; these pts are more likely to progress to end-stage renal disease (ESRD). Children with steroid-resistant MCD/FSGS are more likely to have an underlying genetic cause.
Characterized by subepithelial IgG deposits; accounts for ∼30% of idiopathic adult NS. Pts present with edema and nephrotic proteinuria. Blood pressure, GFR, and urine sediment are usually normal at initial presentation. Hypertension, mild renal insufficiency, and abnormal urine sediment develop later. Renal vein thrombosis can occur, with low but greater frequency than with other forms of NS. Underlying diseases such as SLE, hepatitis B, and solid tumors and exposure to such drugs as high-dose captopril or penicillamine should be sought. The majority of pts with “primary” (previously “idiopathic”) membranous GN have detectable circulating autoantibodies to the M-type phospholipase A2 (PLA2R), which is expressed in glomerular podocytes; the PLA2R titer can be monitored during therapy or utilized as a screening tool for idiopathic membranous GN in NS. Approximately 10% of pts with primary membranous GN who test negative for anti-PLA2R antibodies will have antibodies against the alternative podocyte antigen THSD7A (thrombospondin type-1 domain-containing 7A protein). Some pts progress to ESRD; however, 20-33% may experience a spontaneous remission. Male gender, older age, hypertension, and persistence of significant proteinuria (>6 g/d) are associated with a higher risk of progressive disease. Optimal immunosuppressive therapy is controversial. Glucocorticoids alone are ineffective. Cytotoxic agents may promote complete or partial remission in some pts, as may cyclosporine. Anti-CD20 antibody therapy with rituximab has recently shown considerable promise, consistent with a role for B cells and anti-podocyte antibodies in the pathophysiology. Reduction of proteinuria with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) is also an important mainstay of therapy. Venous thromboembolic events (DVTs, renal vein thrombosis, etc.) occur in about 7% of pts with membranous nephropathy; hypoalbuminemia is the most significant independent predictor of venous thrombotic risk. Prophylactic anticoagulation is not recommended for all pts, but should be considered in pts at very high risk for venous thrombosis (albumin <2.0 g/dL) with low or intermediate bleeding risk.
Focal Glomerulosclerosis (Fgs) 
Can be primary or secondary. Primary tends to be more acute, similar to minimal change disease in abruptness of NS, but with added features of hypertension, renal insufficiency, and hematuria. Involves fibrosis of portions of some (primarily juxtamedullary) glomeruli and is found in ∼35% of pts with NS. There are several different pathologic subtypes of idiopathic FGS, with prognostic implications. In particular, the “collapsing glomerulopathy” variant has pathologic similarity to HIV-associated nephropathy (HIVAN); both nephropathies cause rapidly progressive disease.
African Americans are disproportionately affected by FGS, HIVAN, and other nondiabetic renal disease, with higher incidence, greater susceptibility (HIVAN), and a much higher risk of developing ESRD. “African-specific” variants in the APOL1 gene, which encodes apolipoprotein L1 expressed in glomerular podocytes, have recently been implicated in this enhanced genetic risk.
Treatment of primary FGS typically begins with an extended course of steroids; fewer than half of pts undergo remission. Cyclosporine is an alternative therapy for maintenance of remission and for steroid-resistant pts. As in other glomerulopathies, reduction of proteinuria with ACE inhibitors and/or ARBs is also an important component of therapy. Finally, primary FGS may recur after renal transplant, when it may lead to loss of the allograft.
Secondary FGS can occur in the late stages of any form of kidney disease associated with nephron loss (e.g., remote GN, prior severe pyelonephritis, sickle cell disease, vesicoureteral reflux). Treatment includes anti-proteinuric therapy with ACE inhibition and blood pressure control. There is no benefit of glucocorticoids or other immunsuppressive agents in secondary FGS. Clinical history, kidney size, biopsy findings, and associated conditions usually allow differentiation of primary versus secondary causes.
Membranoproliferative Glomerulonephritis (Mpgn)
Mesangial expansion and proliferation extend into the capillary loop. Two ultrastructural variants exist. In MPGN I, subendothelial electron-dense deposits are present, C3 is deposited in a granular pattern indicative of immune-complex pathogenesis, and IgG and the early components of complement may or may not be present. In MPGN II, the lamina densa of the GBM is transformed into an electron-dense character, as is the basement membrane in Bowman's capsule and tubules. C3 is found irregularly in the GBM. Small amounts of Ig (usually IgM) are present, but early components of complement are absent.
Pts with MPGN may have associated genetic mutations in complement components or complement regulatory factors. MPGN has been proposed to be reclassified into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway).
Serum complement levels are usually decreased. MPGN affects young adults. Blood pressure and GFR are abnormal, and the urine sediment is active. Some have acute nephritis or hematuria. Similar lesions occur in SLE and hemolytic-uremic syndrome. Infection with hepatitis C virus (HCV) has been linked to MPGN, often with associated cryoglobulinemia. Glucocorticoids, cytotoxic agents, antiplatelet agents, and plasmapheresis have been used with limited success in HCV-associated MPGN; rituximab is a newer therapy with greater evident efficacy. Therapy with a direct-acting antiviral regimen should be considered in pts with MPGN and/or cryoglobulinemic vasculitis associated with HCV infection, once the vasculitis and/or MPGN has been controlled with rituximab. Some rare subsets of MPGN associated with activation of the alternative pathway of complement activation can be successfully treated with the C5a inhibitor eculizumab.
The most common cause of NS. Although prior duration of diabetes mellitus (DM) is variable, in type 1 DM proteinuria may develop 10-15 years after onset of diabetes, progress to NS, and then lead to renal failure over 3-5 years. Retinopathy is nearly universal in type 1 diabetics with nephropathy, so much so that the absence of retinopathy should prompt consideration of another glomerular lesion (e.g., membranous nephropathy). In contrast, only ∼60% of type 2 diabetics with diabetic nephropathy have retinopathy. Clinical features include proteinuria, progressive hypertension, and progressive renal insufficiency. Pathologic changes include mesangial sclerosis, diffuse, and/or nodular (Kimmelstiel-Wilson) glomerulosclerosis. However, pts rarely undergo renal biopsy; to the extent that yearly measurement of microalbuminuria is routine management for all diabetics, the natural history is an important component of the diagnosis. Pts typically demonstrate progression from microalbuminuria (30-300 mg/24 h) to dipstick-positive proteinuria (>300 mg albuminuria) and then progressively overt proteinuria and chronic kidney disease. However, proteinuria can be quite variable in diabetic nephropathy, with as much as 25 g/24 h in the absence of profound renal insufficiency or alternatively with progressive renal insufficiency and stable, modest proteinuria.
Treatment with ACE inhibitors delays the onset of nephropathy and of ESRD in type 1 diabetics with microalbuminuria and/or declining renal function and should be instituted in all pts tolerant to that class of drug. If a cough develops in a pt treated with an ACE inhibitor, an ARB is the next best choice. Type 2 diabetics with microalbuminuria or proteinuria can be treated with ACE inhibitors or ARBs. Hyperkalemia, hypotension, and/or worsening GFR can limit single or combined therapy with renin-angiotensin-aldosterone (RAA) system inhibitors. If hyperkalemia develops and cannot be controlled with (1) optimizing glucose control, (2) loop diuretics (if otherwise appropriate), or (3) treatment of metabolic acidosis (if present), then potassium binder therapy with sodium zirconium cyclosilicate (ZS-9) or patiromer should be considered, so as to maintain RAA inhibition.
Evaluation of NS is shown in Table 145-4 Evaluation of Nephrotic Syndrome.