GLOMERULONEPHRITIS III By Dr.zaidan Jayed Zaidan بسم الله الرحمن الرحيم GLOMERULONEPHRITIS III By Dr.zaidan Jayed Zaidan

DIABETIC NEPHROPATHY Diabetic nephropathy is the leading cause of ESRD in western societies and accounts for 30to 35% of patients on renal replacement therapy in North America. Type 1 diabetes mellitus (DM; formerly, insulin-dependent diabetes mellitus) and type 2 DM (formerly, non-insulin-dependent diabetes mellitus) affect approximately 0.5 and 4% of the population, respectively. Nephropathy complicates 30% of cases of type 1 DM and approximately 20% of cases of type 2 DM. However, most diabetic patients with ESRD have type 2 DM because of the greater prevalence of type 2 DM worldwide (90% of all individuals with diabetes).

Risk factors for the development of diabetic nephropathy include: 1-hyperglycemia, 2-systemic hypertension, 3-glomerular hypertension and hyperfiltration, 4-proteinuria, and possibly 5-cigarette smoking, 6-hyperlipidemia, and 7-gene polymorphisms affecting the activity of the renin-angiotensin- aldosterone axis.

For reasons that are unclear, ESRD from diabetic nephropathy is more common in blacks with type 2 DM than in whites (4:1 ratio), whereas the reverse is true for type 1 DM.

Pathophysiology The pathophysiology, clinical features, and morphology of diabetic nephropathy appears similar in type 1 and type 2 DM, although the true incidence and precise time course of nephropathy in type 2 DM is still debated. Glomerular hypertension and hyperfiltration are the earliest renal abnormalities in experimental and human diabetes and are observed within days to weeks of diagnosis. Microalbuminuria, so named because the abnormal albumin excretion of 30 to 300 mg/24 h is below the limits of detection of standard dipsticks, develops after approximately 5 years of sustained glomerular hypertension and hyperfiltration in type 1 DM.

Microalbuminuria is the first manifestation of injury to the glomerular filtration barrier and predicts the development of overt nephropathy. Dipstick-positive proteinuria, ultimately reaching nephrotic levels, typically develops 5 to 10 years after the onset of microalbuminuria (i.e., 10 to 15 years after the onset of diabetes) and is associated with hypertension and progressive loss of renal function.

In addition, patients can display features of tubulointerstitial disease such as hyperkalemia and type IV renal tubular acidosis. ESRD typically develops 5 to 10 years after the development of overt nephropathy. As noted above, the course of diabetic nephropathy may be shorter in type 2 DM, and many patients present with established nephropathy and hypertension. Diabetic nephropathy is usually diagnosed on clinical grounds without a renal biopsy. Supportive clues are : 1-the presence of normal sized or enlarged kidneys, 2-evidence of proliferative diabetic retinopathy, and 3-a bland urinary sediment. Retinopathy is found in 90% and 60% of patients with type 1 and type 2 DM, respectively, who develop nephropathy

Pathologic Changes The earliest morphologic abnormalities in diabetic nephropathy are thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix. With time, matrix accumulation becomes diffuse and is evident as eosinophilic, PAS positive glomerulosclerosis on renal biopsy. Prominent areas of nodular matrix expansion (nodular glomerulosclerosis, the classic Kimmelsteil-Wilson lesion) are often superimposed on this background. The glomeruli and kidneys are typically normal or increased in size, distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency (renal amyloidosis and polycystic kidney disease being other important exceptions).

TREATMENT Therapy is aimed at retarding the progression of nephropathy through control of blood sugar, systemic blood pressure, and glomerular capillary pressure. Glycemic control is achieved through regulation of diet and administration of oral hypoglycemic agents and insulin. ACE inhibitors and ARBs are the drugs of choice as they control both systemic hypertension and intraglomerular hypertension by inhibiting the actions of angiotensin II on the systemic vasculature and renal efferent arterioles. In addition, these agents also attenuate the stimulatory effect of angiotensin II on glomerular cell growth and matrix production.

Because ACE inhibitors conclusively delayed the time to ESRD by 50% in patients with type 1 DM in several randomized controlled trials and probably delay progression in type 2 DM, it is recommended that all patients with diabetes over the age of 12 should be screened annually for microalbuminuria and should receive an ACE inhibitor on the development of microalbuminuria, even in the absence of systemic hypertension. ARBs slowed the rate of progression of diabetic nephropathy in patients with type 2 DM in two recent randomized controlled trials and are an alternative to ACE inhibitors for renoprotection. Approximately 80% of patients with DM require more than one drug to control systemic hypertension, and aggressive lowering of blood pressure in these patients retards the rate of progression of nephropathy and other diabetic complications.

Diabetic nephropathy is the most common cause of ESRD requiring renal replacement therapy, and patients with DM have the highest annual mortality rate (20 to 30%) of any group on dialysis, in large part as a result of accelerated atherosclerosis. The survival rates of younger patients undergoing either peritoneal dialysis or hemodialysis are comparable; however, older patients with DM appear to have a higher mortality rate on peritoneal dialysis. Renal transplantation, with or without pancreas transplantation, is the preferred mode of renal replacement therapy in patients who are otherwise medically suitable.

GLOMERULAR DEPOSITION DISEASES 1- AMYLOIDOSIS. 2-MULTIPLE MYELOMA. 3-WALDENSTRO¨ M’S MACROGLOBULINEMIA

Renal Amyloidosis Amyloidosis is classified according to the major component of its fibrils. There is substantial overlap in the renal clinicopathologic presentations of amyloid (AL) and amyloid A (AA) disease. Glomeruli are involved in 75 to 90% of patients, usually in association with involvement of other organs. The clinical correlate of glomerular amyloid deposition is nephrotic-range proteinuria. In addition, 50% of patients have impaired glomerular filtration at diagnosis.

Hypertension is present in about 20 to 25% Hypertension is present in about 20 to 25%. Renal size is usually normal or slightly enlarged.Rectal biopsy and abdominal fat pad biopsy reveal amyloid deposits in about 70% of patients and may obviate the need for renal biopsy.

Renal biopsy gives a very high yield if there is clinical evidence of renal involvement. The earliest pathologic changes are mesangial expansion by amorphous hyaline material and thickening of the GBM. Further amyloid deposition results in the development of large nodular eosinophilic masses. When stained with Congo red, these deposits show apple-green birefringence under polarized light.

TREATMENT Most patients with renal involvement by AL amyloidosis develop ESRD within 2 to 5 years. No treatment has been shown consistently to improve this prognosis; however, some success has been reported with a combination of melphalan and prednisone. Preliminary studies have reported a benefit of high-dose melphalan with autologous stem cell transplantation. Colchicine delays the onset of nephropathy in patients with familial Mediterranean fever but has not proved useful in patients with established disease or with other forms of amyloid. Remissions may be achieved in AA amyloidosis by eradication of the underlying cause.

Renal replacement therapy is offered to patients who reach ESRD; however, the 1-year survival rate on dialysis is low (66%) by comparison with other causes of ESRD. Most patients die from extrarenal complications, particularly cardiovascular disease. Renal transplantation is a viable option in patients with AA amyloidosis whose primary disease has been eradicated. Transplantation is also an option for patients with AL amyloidosis, although a poor prognosis because of extrarenal organ involvement may preclude them as candidates. Here again, the survival rate is lower by comparison with other causes of ESRD; most of the excess mortality is due to infectious and cardiovascular complications. Recurrence of amyloidosis in the allograft is common but rarely leads to graft loss.

ASYMPTOMATIC ABNORMALITIES OF THE URINARY SEDIMENT Many cases of glomerular disease are diagnosed when asymptomatic hematuria or proteinuria are detected on routine examination of the urinary sediment as part of preemployment or insurance-related medical assessments.

HEMATURIA Most asymptomatic glomerular hematuria is due to IgA nephropathy (Berger’s disease) or thin basement membrane (TBM) disease (benign hematuria). A rarer but more ominous cause of isolated hematuria is Alport’s syndrome. Asymptomatic hematuria may also be the presenting feature of indolent forms of most other primary and secondary proliferative glomerulopathies.

Glomerular hematuria must be distinguished from a variety of renal parenchymal and extrarenal causes of hematuria. Important clues to the presence of glomerular hematuria are the presence of urinary red blood cell casts; dysmorphic urinary red blood cells; proteinuria 2.0 g per 24 h; and clinical or serologic evidence of nephritic syndrome, RPGN, or a compatible systemic disease.

THIN BASEMENT MEMBRANE DISEASE (BENIGN HEMATURIA) This disorder can be heredofamilial or sporadic and is as common as IgA nephropathy in some series of asymptomatic hematuria. When familial, it is usually inherited as an autosomal dominant trait and is due to a defect in the gene encoding the 4 chain of type IV collagen.

The molecular basis for the sporadic form of TBM disease has not been determined. TBM disease typically manifests in childhood as persistent hematuria. Intermittent hematuria and exacerbation of hematuria during upper respiratory tract infections have also been reported. The kidney is normal on light and immunofluorescence microscopy. The GBM is thin by comparison with normal subjects. TBM disease is usually a benign condition, and progressive renal impairment or proteinuria should prompt a search for an alternative diagnosis. A small proportion of patients do, however, appear to develop hypertension and focal glomerulosclerosis upon long-term follow-up, and ACE inhibitors are usually prescribed in this group in an effort to attenuate renal injury.

ALPORT’S SYNDROME (HEREDITARY NEPHRITIS) Alport’s syndrome is the most common hereditary nephritis and is usually transmitted as an Xlinked dominant trait. The genetic defect resides in the gene for the 5 chain of type IV collagen located on the long arm of the X chromosome; type IV collagen is a major structural component of the GBM. Alport’s syndrome is associated with sensorineural deafness and ocular abnormalities . Typical light-microscopic features on renal biopsy include mesangial hypercellularity, focal and segmental glomerulosclerosis, chronic tubulointerstitial fibrosis, atrophy, and accumulation of foam cells. Electron microscopy reveals thickening, fragmentation, and lamellation of the lamina densa of the GBM.

Males with the disease tend to progress to ESRD and are suitable candidates for dialysis and transplantation. ACE inhibitors are typically prescribed in the predialysis phase in an effort to slow the decline in GFR. About 5% of transplant recipients develop anti-GBM disease in the renal allograft; their immune system recognizes normal GBM of the transplanted kidney as a foreign antigen. In the majority of patients this posttransplant anti-GBM disease does not significantly compromise GFR.

PROTEINURIA Between 0.5 and 10% of the population have isolated proteinuria, defined as proteinuria in the presence of an otherwise normal urinary sediment, a radiologically normal urinary tract, and the absence of known renal disease. The majority of these patients excrete 2 g of protein per day, and more than 80% have an excellent prognosis (benign isolated proteinuria). A minority (10 to 25%) are found to have persistent proteinuria (persistent isolated proteinuria), some of whom develop progressive renal insufficiency over 10 to 20 years.

Benign Isolated Proteinuria The major categories of benign isolated proteinuria are idiopathic transient proteinuria, functional proteinuria, intermittent proteinuria, and postural proteinuria. Idiopathic transient proteinuria is usually observed in young adults and refers to dipstickpositive proteinuria in an otherwise healthy individual that disappears spontaneously by the next clinic visit. Functional proteinuria refers to transient proteinuria during fever, exposure to cold, emotional stress, congestive cardiac failure, or obstructive sleep apnea.

This phenomenon is presumed to be mediated through changes in glomerular ultrafiltration pressure and/or membrane permeability. Patients with intermittent proteinuria have proteinuria in approximately half of their urine samples in the absence of other renal or systemic abnormalities. Postural proteinuria is proteinuria (usually 2.0 g per 24 h) that is evident only in the upright position. This disorder affects 2 to 5% of adolescents and may be transient (80%) or fixed (20%). Fixed postural proteinuria resolves within 10 to 20 years in most cases. In each of these conditions, renal biopsy reveals either normal renal parenchyma or mild and nonspecific changes involving podocytes or the mesangium. All carry an excellent prognosis.

Persistent Isolated Proteinuria Isolated proteinuria detected on multiple ambulatory clinic visits in both the recumbent and upright position usually signals a structural renal lesion. Virtually all glomerulopathies that induce nephrotic syndrome can cause persistent isolated proteinuria.

The most common lesion on renal biopsy is mild mesangial proliferative glomerulonephritis with or without focal and segmental glomerulosclerosis (30 to 70%), followed by focal or diffuse proliferative glomerulonephritis (15%) and interstitial nephritis (5%). Although this clinical entity carries a worse prognosis than benign isolated proteinuria, the prognosis is still relatively good, with only 20 to 40% of patients developing renal insufficiency after 20 years. Furthermore, progression to ESRD is extremely rare. It is wise to exclude monoclonal gammopathy by urinary electrophoresis in older patients.

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