USMLE/1
Textbook
4.7.1.3 Glomerular disorders
Glomerular disorders: Glomerular diseases include many conditions with a variety of genetic and environmental causes that interfere with the function of the glomerulus. They may present as glomerulonephritis or inflammation of the glomerulus or glomerulosclerosis which shows scarring and deposition of hyaline material in the glomerular arterioles and /or mesangium. Glomerular disease interferes with selective filtration at the glomerulus with the result of hematuria, proteinuria and loss of other blood components that are normally not filtered. It is determined by the nature and severity of the disease and can clinically present as either nephrotic or nephritic syndromes. Some patients may have a mixed presentation e.g. in MPGN.
Nephrotic syndrome: It is comprised of proteinuria, edema, hypoalbuminemia, hyperlipidemia and lipiduria. Nephrotic range proteinuria is > 3.5 gm/24 hours. Urine may appear foamy. Loss of anticoagulants such as antithrombin III leads to hypercoagulable state and increased platelet aggregation, with high risk of venous and arterial thromboembolism. Hyperlipidemia is due to increased hepatic synthesis of cholesterol, triglycerides, and lipoproteins, decreased activity of lipoprotein lipase, decreased LDL receptor activity and an increased urinary loss of HDL.
Nephritic syndrome: It is comprised of hematuria, reduced renal function, hypertension, edema and non-nephrotic proteinuria. Hematuria may present as cola colored urine on gross examination.
Minimal change disease (MCD) or lipoid nephrosis: It is the most common cause of nephrotic syndrome in children. Clinical symptoms are typically preceded by an upper respiratory infection or recent use of medication. It is also seen in adults. It may be secondary to HIV, lymphomas, hypersensitivity reactions to drugs like NSAIDS, bee stings etc. No changes are seen on light microscopy. Microscopic lipid droplets are seen in urine and tubular cells. Electron microscopy shows effacement of foot processes. Underlying pathology is abnormal T cell function with cytokine induced damage to podocytes. There is an increased Th2 response, overexpression of IL13 and decreased regulatory T cell response. B cell response may be increased. Hemopexin, a plasma protein that binds to sialoglycoproteins in podocytes and causes cytoskeletal rearrangement may lead to fusion and effacement of foot processes. Patients are at increased risk of infections such as cellulitis, pneumonia and peritonitis. Treatment is with corticosteroids, ACE inhibitors and ARBs. Recurrent disease or steroid-resistant cases are treated with cyclophosphamide, chlorambucil, rituximab, cyclosporine, tacrolimus, azathioprine or mycophenolate mofetil. NSAIDS may reduce proteinuria in some cases. Low salt diet and diuretics may be used to control edema. Prognosis is typically good.
Electron microscopy of renal biopsy with paramesangial deposits (arrows) and foot process effacement (arrow heads).
Focal segmental glomerulosclerosis or FSGS: It is characterized by scarring and hardening or sclerosis in scattered regions of the kidney, typically limited to one part of the glomerulus and to a minority of glomeruli in the affected region. Most cases are idiopathic. FSGS may be secondary to obesity, sickle cell anemia, sleep apnea, diabetes, cyanotic heart disease, unilateral renal agenesis, IUGR, VUR, drugs like interferons, anthracyclines, calcineurin inhibitors, sirolimus, lithium, bisphosphonates and anabolic steroids and viruses such as HIV, Hep C, Parvovirus B19, SV 40, EBV and CMV. Some cases are genetic and are associated with mutations in the APOL1 gene. FSGS is more common in the African American community. Podocyte injury is seen in all types of FSGS, from cytokines, relative hyperfiltration at the glomerulus and effect of interferons following a viral illness. FSGS is a common cause of nephrotic syndrome. Some patients with an aggressive form of FSGS reach kidney failure in 2 to 3 years. The juxtamedullary or inner cortical glomeruli are affected first. Biopsy shows focal and segmental glomerular and mesangial sclerosis, foam cells with lipid inclusions in the capillaries, tubulo-interstitial fibrosis, hyalinization of afferent arteriole. Multiple areas need to be biopsied due to focal nature of the lesion. Histologically, perihilar variant of FSGS has the best prognosis while the collapsing variant has the worst. IgM and C3 deposits are seen in the sclerotic segments. Electron microscopy shows detachment of epithelial cells from the glomerular basement membrane (GBM). Extensive effacement of foot processes of podocytes is seen. Collapsing variant shows collapsed glomerular loops. Treatment is with steroids, ARBs or ACE inhibitors, immunosuppressive drugs like cyclosporine, tacrolimus, mycophenolate mofetil, low salt and low protein diet and diuretics as needed. Severe cases may need dialysis and renal transplantation.
Membranous nephropathy: It is the second most common overall and most common primary renal disease causing nephrotic syndrome in US adults. Majority of the cases are idiopathic, others are caused by SLE, Hep B, Hep C, some forms of cancer, drugs and toxins like penicillamine, gold, mercury, NSAIDS, COX 2 inhibitors, lithium or captopril. It is more common in caucasians and in those with HLA-DQ1. It has an autoimmune etiology. Most patients develop antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A). Complement mediated damage to podocytes may occur. Biopsy reveals deposits of immunoglobulin G, mainly IgG4 and complement C3, present uniformly in the glomerular capillaries in a subepithelial distribution. Subepithelial “spikes” and GBM thickening may be seen later on. The EM appearance of the “spike and dome” pattern is characteristic. Serum anti-PLA2R or THSD7A may be positive. About 20 percent of patients recover without treatment. Some patients may progress to ESRD (end-stage renal disease). ACE inhibitors and ARBs are generally used to reduce proteinuria. Symptomatic control with low salt and low protein diet, statins and diuretics is done. Resistant cases are treated with steroids, cyclophosphamide, cyclosporine, tacrolimus, rituximab, tetracosactrin (ACTH analogue) or corticotropin. Persistence of anti-PLA2R/THSD7A antibodies is associated with a bad prognosis. Renal transplant may be required.
Diabetic nephropathy (DN): Overall, the most common cause of nephrotic syndrome in adults. It is also the most common cause of end-stage renal disease. It is more common in males, African Americans and Mexican Americans. Co-existent hypertension aggravates nephropathy.
Hyperglycemia causes hyperfiltration at the glomerulus and increased glomerular hydrostatic pressure. There is activation of the renin-angiotensin-aldosterone system. Oxidative stress and reactive oxygen species activate cellular pathways such as MAPK, NF-kB and protein kinase C. Conversion of excess glucose to sorbitol increases the NADH/NAD+ ratio. Hyperglycemia also causes non-enzymatic glycation of proteins, lipids and nucleic acids with increased expression of pro-inflammatory cytokines and growth factors like TGF-beta, PDGF, VEGF. There is recruitment and activation of T cells and macrophages. Accumulation of interstitial macrophages correlated strongly with proteinuria, interstitial fibrosis, and GFR decline.
DN develops slowly over the period of many years . Asymptomatic microalbuminuria occurs 5-10 years after disease onset, it is followed a few years later by overt proteinuria of 0.5-3 gm/day and then nephrotic range proteinuria of > 3.5 gm/day. In type 2 diabetics, more patients have DN at the time of diagnosis of diabetes as type 2 diabetes can go unrecognized for years. The GFR also decreases concomitantly. A spot urine albumin/creatinine ratio ( normal >30 mg/g creatinine) can be used for screening for DN. Serum TNF alpha receptor and uric acid levels correlate with disease prognosis. Biopsy shows mesangial expansion, thickening of the basement membrane, arteriolar hyalinosis and characteristic nodular glomerulosclerosis (Kimmelstiel–Wilson lesion). Tubular atrophy and interstitial fibrosis is seen. An infiltrate of T cells and macrophages may be seen. EM shows podocyte loss and decreased endothelial cell fenestration.
Management involves blood sugar control, control of hypertension, ACE inhibitors and ARBs are renoprotective, pioglitazone, rosiglitazone and sitagliptin have beneficial effects on proteinuria and glomerular function, aldosterone antagonists like spironolactone (additional anti-inflammatory effect) , verapamil and diltiazem (reduce proteinuria), thiazides or loop diuretics (increase efficacy of ACEI and ARBs). Supportive treatment is with Vit D supplementation, keeping cholesterol levels in normal range, maintaining ideal body weight, aerobic exercise, low salt and low protein diet. Gene therapy, direct renin inhibitors like aliskiren, endothelin inhibitors like atrasentan, PKC inhibitors like ruboxistaurin, phosphodiesterase inhibitors like cilostazol and pentoxifylline are some of the novel therapeutic agents for diabetic nephropathy. Renal transplantation and dialysis is needed once ESRD develops.