HYPERTENSIVE NEPHROSCLEROSIS: Essential hypertension is an ever increasing cause of ESRD despite widespread awareness of the risk of hypertension to certain end organs and as kidney, heart and brain. Although hypertension is common in TP patients (80% in the immediate post transplant period and 50% in patients with stable renal function) only 10-20% have severe or accelerated forms. Establishing recurrent essential hypertension as the cause for hypertension in a TP patient is complicated by the numerous potential causes such as:

Steroids, cyclosporine	Rejection
Renal artery stenosis	De novo disease
Native kidneys	Recurrent essential

Morphologic recognition of recurrent disease is complicated by the common presence of donor related vascular disease and the similarity of chronic rejection and cyclosporine arteriopathy to hypertensive alterations. In patients in which HT has been implicated as the original cause for ESRD, a well functioning allograft may cure their HT especially if native nephrectomies are performed, implicating a renal contribution to their original essential hypertension. In patients beyond one year, chronic rejection appears to be the most common cause of hypertension.

DIABETES: Although all patients with diabetes will eventually develop alterations attributable to glucose intolerance in their allograft, no objective morphologic abnormalities in mesangial matrix or capillary loop basement membrane thickening are detectable until 2 years. Prior to this linear staining for IgG along glomerular and tubular basement membranes may be detectable. Afferent and efferent arteriolar thickening develops in 5 years in 50% of grafts. Nodular glomerulosclerosis is uncommon but may develop in the second decade. Pancreas or islet cell transplantation are the only modalities with the potential to eliminate risk of recurrent disease.

ANALGESIC NEPHROPATHY: Although a certain fraction of patients continue to use analgesics (5-25%), most discontinue the drugs. Recurrent chronic interstitial nephritis and papillary necrosis in the graft has only rarely been reported.

B. "No Deposit - No Return"

Despite successfully persuading the immune system to tolerate the presence of the allograft, persistance of the original immunologic aberration which damaged the native kidneys may result in recurrent glomerulonephritis. Recurrent GN represents the most common cause of nondiabetic recurrent disease in allograft, developing in 20-30% of patients and causing graft loss in 10% of affected patients. The incidence and risk of recurrent disease varies considerably between the various types of GN.

Glomerulonephritis
Recurrence Rate Graft Loss
With Recurrence

Diabetic nephropathy	100%	<5%
Focal segmental glomerulosclerosis	20-30%	30-50%
IgA nephropathy	50%	10%
Membranoproiferative GN - Type I	20-30%	10-40%
Dense Deposit Disease	80-100%	10-20%
*Membranous GN	3/4 10%	rare
AGBM/ANCA	Ab positive - common Ab negatibe - rare	significant
Henoch - Schñlein Purpura	50%	rare
Lupus	rare	rare
Hemolytic-Uremic Syndrome	15-25%	40-50%
Amyloid, paraprotein, cryoglobulenemia	5-30%	variable

______________________________________________________________________________________
*75% of MGN in allograft represents de novo disease

Since the original disease resulting in ESRD was unsuccessfully controlled, it may be surprising that the incidence and threat to allograft survival is not greater than the data indicates. It has been hypothesized that the immunosuppressive effects of chronic renal failure coupled with the immunosuppressive therapy to prevent rejection reduce the incidence of recurrent GN. A contribution related to the susceptibility of the donor kidney itself, particularly variation in HLA and other antigens, may also play a significant role.

Glomerular abnormalities in a renal allograft may reflect recurrent or de novo GN, glomerular forms of rejection such as transplant glomerulitis or chronic transplant glomerulopathy or cyclosporine microangiopathy affecting glomeruli. Establishing the cause of glomerular abnormalities requires knowledge of the original disease, urinary findings, pertinent serologies, and ideally, a complete evaluation of the biopsy by light, DIF and EM. Proteinuria is the usual clinical finding, which may be associated with either hematuria or renal insufficiency. The etiology of allograft glomerular disease may vary between adults and children. However regardless of cause, when heavy proteinuria develops, allografts usually fail within one year.

	Chronic Rejection	Recurrent GN	De Novo GN
Adults	65%	25%	10%
Children	24%	33%	43%

TRANSPLANT GLOMERULOPATHY is the most common glomerular lesion in long-term grafts. It appears to represent a glomerular form of rejection and was described in detail by Porter, et al. and Harlen, et al. in 1967. It is usually associated with characteristic findings of chronic rejection in the vascular and tubulointerstitial compartments. It resembles a proliferative GN initially (transplant glomerulitis) which may evolve into a lesion resembling membranoproliferative GN (chronic transplant glomerulopathy). The absence of immune complexes by IF and dense deposit disease alterations by EM, is necessary for accurate diagnosis.

The presence of SEGMENTAL GLOMERULAR SCARS in an established, well functioning allograft, represents a common diagnostic dilemma, especially if the original cause of ESRD was never established. Segmental scars are nonspecific and can develop in a variety of situations. Resolution requires careful scrutiny of the biopsy, ancillary studies and hopefully some knowledge of the clinical evolution of renal dysfunction and proteinuria and any prior complications, especially CSA thrombotic microangiopathy.

Tips in the Evaluation of a Segmental Glomerular Scar

Recurrent FSGS	original disease <3 years, recurrent proteinuria within 3 months
Rejection	Insidius onset of proteinuria, features of chronic rejection - vascular sclerosis, glomeruopathy, peritubular capillary reduplication
CSA relate	Prior severe thrombotic microangiopathy affecting glomeruli
De Novo FSGS	Original disease not FSGS, chronic rejection excluded
Other GN	Characteristic DIF and EM findings

The development of recurrent GN in transplants has established a role for humoral factors in the evolution of many original diseases. This is not surprising for those original diseases associated with immune complexes or nephrotoxic antibodies. It is more interesting however that diseases such as focal segmental sclerosis and dense deposit disease, in which antibodies and immune deposits are not demonstrable can develop quickly following transplantation. Unidentified humoral factor(s) are thus implicated in their pathogenesis.

C. Tubulointerstitial Disease Resulting in ESRD

Analgesic nephropathy (discussed above)

Congenital anomalies and obstruction affecting kidney and lower urinary tract

Metabolic disease: oxalosis, cystinosis

CONGENITAL ANOMALIES AND OBSTRUCTION of kidney and lower urinary tract comprise a heterogeneous group of diseases which require individualized management in anticipation of graft placement. The urethra, bladder and ureters may be abnormal either because of the intrinsic anomaly or like the native kidneys, may be damaged secondarily. Patients frequently require surgical procedures designed to provide a suitable urinary reservoir, urinary continence and functional ureters. Recurrent disease in the form of infection, reflux or obstruction are a common problem. The risk to the allograft is dependent upon the functional status of the lower urinary tracts.

OXALOSIS resulting in nephrocalcinosis, nephrolithiasis and renal failure may be congenital or acquired. Recurrent disease is a complication of the congenital forms in which there is an abscence of hepatic alanine-glyoxylate amino-transfersase. By the time end stage renal disease has developed, patients have a large tissue store of oxalate. Early transplantation, stringent dietary control, drugs such as pyridoxine and aggressive pretransplant dialysis to deplete the oxalate pool, are employed to prevent the rapid deposition of calcium oxalate in the allograft. In functioning allografts, high urinary flow rates are important. Rapid deposition of calcium oxalate occurs in the situation of primary nonfunction and may recur during a rejection episode. The only true prevention and cure is a combined liver and kidney transplant, to replace both the enzyme deficient organ and the functionally affected organ.

CYSTINOSIS rarely recurs in a renal transplant in a functionally significant fashion since the allograft possesses the necessary enzyme to metabolize cystine. However in 10-25% of patients , host macrophages containing cystine crystals are deposited in the renal interstitium and in glomerular mesangium.

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