GLOMERULONEPHRITIS II By: Dr. Zaidan Jayed NEPHROTIC SYNDROME DEFINITION The nephrotic syndrome is a clinical complex characterized by a number of renal and extrarenal features, the most prominent of which are 1-proteinuria of 3.5 g per 1.73 m2 per 24 h (in practice, 3.0 to 3.5 g per 24 h), 2-hypoalbuminemia, 3-edema, 4-hyperlipidemia, 5-lipiduria, and 6-hypercoagulability. Six entities account for 90% of cases of nephrotic syndrome in adults: 1-minimal change disease (MCD), 2- focal and segmental glomerulosclerosis (FSGS), 3-membranous glomerulopathy, 4-membranoproliferative glomerulonephritis (MPGN), 5- diabetic nephropathy,and 6-amyloidosis. Renal biopsy is a valuable tool in adults with nephrotic syndrome for: 1-establishing a definitive diagnosis, 2-guiding therapy, and 3-assessing prognosis. Renal biopsy is not required in the majority of children with nephrotic syndrome as most cases are due to MCD and respond to empirical treatment with glucocorticoids. It should be stressed that the key component of nephrotic syndrome is proteinuria, which results from altered permeability of the glomerular filtration barrier for protein, namely the GBM and the podocytes and their slit diaphragms. The other components of the nephrotic syndrome and the ensuing metabolic complications are all secondary to urine protein loss and can occur with lesser degrees of proteinuria or may be absent even in patients with massive proteinuria. PATHOPHYSIOLOGY In general, the greater the proteinuria, the lower the serum albumin level. Hypoalbuminemia is compounded further by increased renal catabolism and inadequate, albeit usually increased, hepatic synthesis of albumin. GENERAL MANAGEMENT OF NEPHROTIC SYNDROME AND COMPLICATIONS The treatment of nephrotic syndrome involves : (1) specific treatment of the underlying morphologic entity and, when possible, causative disease; (2) general measures to control proteinuria if remission is not achieved through immunosuppressive therapy and other specific measures; and (3) general measures to control nephrotic complications. Nonspecific measures that may reduce proteinuria include ACE inhibitors, ARBs, and nonsteroidal antiinflammatory drugs (NSAIDs). ACE inhibitors and ARBs reduce proteinuria and slow the rate of progression of renal failure by lowering intraglomerular pressure and preventing the development of hemodynamically mediated focal segmental glomerulosclerosis. There is conclusive evidence that these drugs are renoprotective in human diabetic nephropathy and many other proteinuric glomerulopathies, including secondary FSGS. NSAIDs also reduce proteinuria in some patients with nephrotic syndrome, probably by altering glomerular hemodynamics and GBM permeability characteristics. This potential benefit must be balanced against the risk of inducing acute renal failure, hyperkalemia, salt and water retention, and other side effects. Edema should be managed cautiously by moderate salt restriction, usually 1 to 2 g per day, and the judicious use of loop diuretics. It is unwise to remove 1.0 kg of edema per day without close monitoring as more aggressive diuresis may precipitate intravascular volume depletion and prerenal azotemia. Administration of salt-poor albumin is not recommended as most is excreted within 24 to 48 h. The potential value of dietary protein restriction for reducing proteinuria must be balanced against the risk of contributing to malnutrition. Vitamin D supplementation is advisable in patients with clinical or biochemical evidence of vitamin D deficiency. MINIMAL CHANGE DISEASE (MINIMAL CHANGE GLOMERULOPATHY) MCD accounts for about 80% of nephrotic syndrome in children younger than 16 years and 20% in adults. The peak incidence is between 6 and 8 years. Patients typically present with nephrotic syndrome and benign urinary sediment. Microscopic hematuria is present in 20 to 30%. Hypertension and renal insufficiency are very rare. MCD (also called nil disease, lipoid nephrosis, or foot process disease) is so named because glomerular size and architecture are normal by light microscopy. Immunofluorescence studies are typically negative for immunoglobulin and C3. Electron microscopy reveals characteristic diffuse effacement of the foot processes of visceral epithelial cells. TREATMENT MCD is highly steroid-responsive and carries an excellent prognosis. Spontaneous remission occurs in 30 to 40% of childhood cases but is less common in adults.Approximately 90% of children and 50% of adults enter remission following 8 weeks of high- dose oral glucocorticoids. If relapse occur shortly after steroid discontinuation cyclophosphamide (2 to 3 mg/kg per day) or chlorambucil (0.1 to 0.2 mg/kg per day) is started after steroid-induced remission and continued for 8 to 12 weeks. Cytotoxic agents may also induce remission in occasional steroid-resistant cases. These benefits must be balanced against the risk of infertility, cystitis, alopecia, infection, and secondary malignancies, particularly in children and young adults. Azathioprine has not been proven to be a useful adjunct to steroid therapy. Cyclosporine induces remission in 60 to 80% of patients; it is an alternative to cytotoxic agents and an option in patients who are resistant to cytotoxic agents. Unfortunately, relapse is usual when cyclosporine is withdrawn, and long-term therapy carries the risk of nephrotoxicity and other side effects. Long-term renal and patient survival is excellent in MCD. FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS The pathognomonic morphologic lesion in FSGS is sclerosis with hyalinosis involving portions (segmental) of fewer than 50% (focal) of glomeruli on a tissue section. The incidence of idiopathic (primary) FSGS has increased over the past two decades so that it now accounts for about one-third of cases of nephrotic syndrome in adults and as many as one-half of cases of nephrotic syndrome in blacks. Secondary FSGS can complicate a number of systemic diseases and sustained glomerular capillary hypertension following nephron loss from any cause. Idiopathic FSGS typically presents as nephrotic syndrome (66%) or subnephrotic proteinuria (33%) in association with hypertension, mild renal insufficiency, and an abnormal urine sediment that contains red blood cells and leukocytes. Proteinuria is nonselective in most cases. Light microscopy of renal biopsy tissue reveals FSGS with entrapment of amorphous hyaline material, a process that shows a predilection for juxtamedullary glomeruli. Electron microscopy reveals evidence of damage to visceral epithelial cell. TREATMENT Spontaneous remission of primary FSGS is rare and renal prognosis is relatively poor. Proteinuria remits in only 20 to 40% of patients treated with glucocorticoids for 8 weeks. Uncontrolled studies suggest that up to 70% respond when steroid therapy is prolonged for 16 to 24 weeks. Cyclophosphamide and cyclosporine, when used at doses described above for MCD, induce partial or complete remission in 50 to 60% of steroid-responsive patients but are generally ineffective in steroid-resistant cases. Mycophenolate mofetil is another option in resistant cases. Poor prognostic factors at presentation include : 1-hypertension, 2-abnormal renal function, 3- black race, and 4-persistent heavy proteinuria. Renal transplantation is complicated by recurrence of FSGS in the allograft in about 50% of cases and graft loss in about 10%. MEMBRANOUS GLOMERULOPATHY (MEMBRANOUS NEPHROPATHY ) This morphologic lesion is a leading cause of idiopathic nephrotic syndrome in adults (30 to 40%) and a rare cause in children (5%). It has a peak incidence between the ages of 30 to 50 years and a male-female ratio of 2:1 Membranous glomerulopathy derives its name from the characteristic light-microscopic appearance on renal biopsy, namely diffuse thickening of the GBM. Most patients (80%) present with nephrotic syndrome, proteinuria usually being nonselective. Microscopic hematuria is present in up to 50% of cases. Hypertension is documented in only 10 to 30% of patients at the outset but is common later in patients with progressive renal failure. Light microscopy of renal biopsy sections reveals diffuse thickening of the GBM without evidence of inflammation or cellular proliferation. Nephrotic syndrome remits spontaneously and completely in up to 40% of patients. The natural history of another 30 to 40% is characterized by repeated relapses and remissions. The final 10 to 20% suffer a slow progressive decline in GFR that typically culminates in ESRD after 10 to 15 years. Presenting features that predict a poor prognosis include : 1- male gender, 2-older age, 3-hypertension, 4-severe proteinuria and hyperlipidemia, and 5-impaired renal function. Controlled trials of glucocorticoids have failed to show consistent improvement in proteinuria or renal protection. Cyclophosphamide, chlorambucil, and cyclosporine have each been shown to reduce proteinuria and/or slow the decline in GFR in patients with progressive disease in small or uncontrolled studies. These observations need to be confirmed in controlled prospective studies. Transplantation is a successful treatment option for patients who reach ESRD. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS This morphologic entity, also known as mesangiocapillary glomerulonephritis, is characterized by thickening of the GBM and proliferative changes on light microscopy. Two major types are identified; both are characterized by a diffuse increase in mesangial cellularity and matrix, and by thickening and reduplication of the GBM such that the lobular pattern of the glomerular tuft is exaggerated. The hallmark of type I MPGN is the presence of subendothelial and mesangial deposits on electron microscopy that contain C3 and IgG or IgM; rarely, IgA deposits are demonstrated by immunofluorescence microscopy. The hallmark of type II MPGN (dense deposit disease) is the presence of electron-dense deposits within the GBM and other renal basement membranes (shown by electron microscopy) that stain for C3, but little or no immunoglobulin. Most patients with type I MPGN present with heavy proteinuria or nephrotic syndrome, active urinary sediment, and normal or mildly impaired GFR. C3 levels are usually depressed, and C1q and C4 levels are borderline or low. Type I MPGN usually has a protracted course, and as many as 50% of patients reach ESRD by 10 years. There is no proven therapy for patients with progressive disease beyond eradicating the underlying infection, malignancy, or systemic disease, when possible. The incidence of type I MPGN appears to be falling, possibly because the overall incidence of HCV infection has fallen dramatically in western society over the past decade. Type II MPGN can also present with proteinuria and nephrotic syndrome; however, some patients present with nephritic syndrome, RPGN, or recurrent macroscopic hematuria. Type II MPGN is an autoimmune disease in which patients have an IgG autoantibody, termed C3 nephritic factor, that binds to C3 convertase, the enzyme that metabolizes C3, and renders it resistant to inactivation. Type II MPGN runs a variable course; the GFR remains stable in some patients and declines gradually to ESRD over 5 to 10 years in others. There is no effective therapy for this disease, which may be associated with partial lipodystrophy, although corticosteroids are sometimes used. A third, rarer form of MPGN is associated with subepithelial immune deposits. Thank you for listening