Separate risk factors for the development of transplant glomerulopathy vs chronic tubulointerstitial rejection

Kupin, Warren; Nakhleh, Raouf E.; Lee, M.; Venkat, K. K.; Goggins, M.; Mozes, Martin F.; Escobar, F; Abouljoud, Marwan

doi:10.1016/s0041-1345(96)00081-4

Cited by 12 publications

(9 citation statements)

References 7 publications

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“…3,4 Its pathogenesis is unknown, but it is thought to be related to glomerular endothelial cell injury, as described for transplant glomerulitis and antibody-mediated rejection. 20 -22 However, by electron microscopy the endothelium does not always appear to be damaged, as is the case in our rat renal allograft model.…”

Section: Discussionmentioning

confidence: 99%

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Antibody Response Against Perlecan and Collagen Types IV and VI in Chronic Renal Allograft Rejection in the Rat

Joosten

Dixhoorn

Borrias

et al. 2002

The American Journal of Pathology

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Chronic rejection is the leading cause of late renal transplant failure. Various structural lesions are observed in grafts undergoing chronic rejection including glomerular basement membrane (GBM) duplications. The well-established Fisher (F344) to Lewis (LEW) rat renal transplant model for chronic rejection was used to assess the presence and role of the humoral immune response against graft antigens during chronic rejection. LEW recipients of F344 allografts develop transplant glomerulopathy and produce IgG1 antibodies directed against F344 GBM preparations that are detectable 3 weeks after transplantation. Glomerular IgG1 deposition was observed that in vitro co-localized with a rabbit anti-rat GBM antiserum in rejecting F344 grafts; elution experiments of isolated glomeruli yielded IgG1 antibodies reactive in vitro with F344 GBM, but not LEW GBM. 1 The glomeruli may show a myriad of lesions, including chronic transplant glomerulopathy, which is characterized by duplication of the glomerular basement membrane (GBM) with interposition of electron-lucent material.2,3 Transplant glomerulopathy is observed in up to 20% of kidney grafts with CR. 4 It has been postulated that CR results from immune reactions of the recipient against yet poorly defined antigens exposed in the graft. 5 Nonimmune factors, such as hypertension or ischemia/reperfusion injury, may lead to unmasking or alteration of graft antigen(s).1 In syngeneic transplants with comparable degrees of nonimmune injury, CR does not develop within the same time span compared with allogeneic grafts, underlining the importance of immunological mechanisms.6 -8 We hypothesize that immune reactions such as antibody formation after previous damage play a role in the perpetuation of CR in renal allografts. In a mouse model of chronic cardiac graft rejection, antibodies are crucial for disease development.7 Immunoglobulin heavy chain (IGH) knockout mice that receive a cardiac allograft do not develop CR in contrast to immunoglobulin heavy chain wild-type mice.7 Moreover, transfer of posttransplantation (Tx) IgG antibodies or antigen-reactive immune serum into transplanted SCID mice results in transplant atherosclerosis. 6,8 A well-established model to study CR in renal allografts is the F344 to LEW rat model. All LEW recipients of F344 grafts develop acute rejection at approximately day 30 resulting in 50% graft loss. The surviving animals show histopathological and functional characteristics of CR from day 50. The reverse combination, ie, LEW kidneys transplanted into F344 rats all exhibit long-term surviving kidney grafts in the absence of histological abnormalities, despite early acute rejection episodes. In this model, antibody responses specific for lymph node-derived lymphocytes have been described. 9 These antibodies disappeared at 8 weeks after Tx and were described to

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Section: Discussionmentioning

confidence: 99%

“…2,3 Transplant glomerulopathy is observed in up to 20% of kidney grafts with CR. 4 It has been postulated that CR results from immune reactions of the recipient against yet poorly defined antigens exposed in the graft. 5 Nonimmune factors, such as hypertension or ischemia/reperfusion injury, may lead to unmasking or alteration of graft antigen(s).…”

mentioning

confidence: 99%

Antibody Response Against Perlecan and Collagen Types IV and VI in Chronic Renal Allograft Rejection in the Rat

Joosten

Dixhoorn

Borrias

et al. 2002

The American Journal of Pathology

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“…The observation that different risk factors were associated with Vvintima/artery and with Vvinterstitium/cortex points out that the susceptibility of the different renal allograft compartments to a given insult is rather variable (7,10,35) and raises the possibility that strategies aimed to prevent transplant vasculopathy could be rather inefficient to prevent the glomerular or tubulointerstitial chronic damage.…”

Section: Progression Of Chronic Allograft Nephropathymentioning

confidence: 99%

Serial Protocol Biopsies to Quantify the Progression of Chronic Transplant Nephropathy in Stable Renal Allografts

Moreso

López

Vallejos

et al. 2001

American Journal of Transplantation

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Aim: To evaluate the utility of intimal thickness and interstitial width as a primary efficacy variable in the design of clinical trials aimed to modify the natural history of chronic allograft nephropathy. Methods: A donor and a 4-month protocol biopsy were evaluated in 40 stable grafts according to the Banff schema. In 27 patients, a second protocol biopsy was done at 1 yr. Arterial intimal volume fraction (Vvintima/ artery) and cortical interstitial volume fraction (Vvinterstitium/cortex) were estimated with a point counting technique. Results: Chronic Banff scores increased during followup, while acute scores reached its peak at 4 months. Vvintima/artery and Vvinterstitium/cortex significantly increased at 4 months, but not at 1 yr. Vvintima/artery at 4 months correlated with donor Vvintima/artery (r Ω0.57, p ∞0.001), histocompatibility (r Ω0.38, p Ω 0.01) and serum cholesterol (r Ω0.31, p Ω0.047). Vvinterstitium/cortex at 4 months correlated with recipient body surface area (r Ω0.44, p Ω0.004) and delayed graft function (p Ω0.016). Power calculations showed that Vvintima/artery and Vvinterstitium/cortex allow an important reduction in minimum sample size of a hypothetical trial aimed to prevent chronic allograft nephropathy. Conclusions: Intimal thickening and interstitial widening progresses rapidly during the first 4 months after transplantation and slowly thereafter. These parameters can be considered as a primary efficacy variable in trials aimed to prevent chronic allograft nephropathy.

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“…A recent study separately analyzed the risk factors of tubulo-interstitial fibrosis or transplant glomerulopathy and nephrotic proteinuria in patients with chronic transplant nephropathy. 19 The incidence of black recipients, female donors, and preceding steroid-sensitive rejection was significantly higher in patients with transplant glomerulopathy, whereas the donor/recipient surface area ratio, as a good indicator of donor/recipient size-matching, was significantly lower in this group than in patients with interstitial fibrosis or controls, suggesting that glomerular hyperfiltration and glomerular hypertension play an important role in the development of transplant glomerulopathy. 19 Transplant glomerulopathy appears to be related to both immunologic and non-immunologic influences, particularly those affecting renal mass, e.g., a donor surface area/recipient surface area ratio of less than 0.8 and female donor to male recipient.…”

Section: Non-immunologic Causes Of Chronic Allograft Dysfunctionmentioning

confidence: 83%

“…Proteinuria is a well known indicator of poor graft outcome, irrespective of the cause of the proteinuria. 19 The long-term outcome of recipients with daily proteinuria in excess of 1 g protein/day and/or with elevation of serum creatinine of more than 2 mg/dl at 1 year post-transplant is significantly poorer than that of patients without proteinuria and/or with serum creatinine values of less than 1.5 mg/dl. 20 Proteinuria and/or deterioration of graft function are valuable clinical indicators for loss of graft function.…”

Section: Clinical Aspects Of Chronic Allograft Nephropathymentioning

confidence: 99%

Chronic renal allograft nephropathy

2000

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Chronic rejection/chronic allograft nephropathy is the most prevalent cause of renal graft loss after the first year posttransplant. Chronic rejection/chronic allograft nephropathy is characterized by a slow progressive deterioration of graft function, often in combination with proteinuria and hypertension. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as delayed graft function, nephron-dosing mismatch, repeated acute rejection episodes, and pathologically severe rejection. However, the precise pathogenesis of chronic allograft nephropathy remains elusive. The differential diagnosis of immunologically mediated chronic rejection and chronic rejection caused by non-immunologic factors is usually not possible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis and remodelling of the vascular wall, and these findings are nonspecific. However, typical chronic transplant glomerulopathy, which affects glomerular tufts, as well as the multilayering of the peritubular capillary basement membrane, are characteristic of immunologic chronic rejection. Furthermore, in long-surviving patient with an allograft treated with a potent immunosuppressive agent, a calcineurin inhibitor, two or more concomitant independent lesions often develop. Therefore, the term "chronic allograft nephropathy" may be clinically preferable to "chronic rejection" to describe the gradual decline in graft function months or years after transplantation, in the absence of a well defined mechanism of graft dysfunction. The most effective way to prevent chronic allograft nephropathy is to avoid any kind of graft damage via either immunologic or non-immunologic mechanisms.

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Separate risk factors for the development of transplant glomerulopathy vs chronic tubulointerstitial rejection

Cited by 12 publications

References 7 publications

Antibody Response Against Perlecan and Collagen Types IV and VI in Chronic Renal Allograft Rejection in the Rat

Antibody Response Against Perlecan and Collagen Types IV and VI in Chronic Renal Allograft Rejection in the Rat

Serial Protocol Biopsies to Quantify the Progression of Chronic Transplant Nephropathy in Stable Renal Allografts

Chronic renal allograft nephropathy

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