Sita Gourishankar

Evidence for antibody-mediated injury as a Major determinant of late kidney allograft failure

Background. Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF. Methods. One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3±6.0 years) had a baseline serum creatinine level of 1.4±0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7±1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations. Results. Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF. Conclusions. Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Herpes Zoster Infection Following Solid Organ Transplantation: Incidence, Risk Factors and Outcomes in the Current Immunosuppressive Era

Herpes zoster (HZ) infection is a frequent and serious complication of organ transplantation that has not been examined in the current era of immunosuppression.

Inflammation in Areas of Tubular Atrophy in Kidney Allograft Biopsies: A Potent Predictor of Allograft Failure

The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new‐onset late graft dysfunction (N = 337). We found inflammation (‘iatr’) and tubulitis (‘tatr’) in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death‐censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10–4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16–5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.

Long-Term Deterioration of Kidney Allograft Function

Although long‐term survival after kidney transplantation is critically dependent on maintaining stable allograft function, few studies have examined renal allograft function over time. Using pooled data from 10 278 consecutive transplants at five centers, we calculated slopes of estimated glomerular filtration rates (eGFR) measured after 1, 6 and 12 months in 9515, 8861 and 7359 patients surviving ≥1, ≥6 and ≥12 months, respectively. Slopes of eGFR progressively diminished for patients transplanted during 1984–1989, 1990–1993, 1994–1998 and 1999–2002 (analysis of variance p < 0.0001 and p = 0.1245 for slopes measured after 1 and 6 months, respectively). Slopes measured after 12 months were less in the most recent era: −2.2 ± 7.2 mL/min/1.73 m2/year, −2.3 ± 6.6 mL/min/1.73 m2/year, −2.4 ± 7.4 mL/min/1.73 m2/year and −1.4 ± 10.9 mL/min/1.73 m2/year, respectively, p = 0.0058. Slopes measured after 1, 6 and 12 months each were less for transplantations during 1999–2002, after adjusting for multiple transplantation characteristics (p < 0.0001). Similarly, in Cox proportional hazards analysis, the risk (95% CI) for a 25% reduction in eGFR was 0.92 (0.85–1.01), p = 0.0736 during 1990–1994; 0.94 (0.82–1.08), p = 0.4111 during 1995–1998 and 0.78 (0.64–0.95), p = 0.0110 during 1999–2002 (compared to 1984–1989). We conclude that the rate of decline in allograft function after kidney transplantation has improved, suggesting that stable, long‐term function may be achievable.

Pathological and Clinical Characterization of the ‘Troubled Transplant’: Data from the DeKAF Study

We are studying two cohorts of kidney transplant recipients, with the goal of defining specific clinicopathologic entities that cause late graft dysfunction: (1) prevalent patients with new onset late graft dysfunction (cross‐sectional cohort); and (2) newly transplanted patients (prospective cohort). For the cross‐sectional cohort (n = 440), mean time from transplant to biopsy was 7.5 ± 6.1 years. Local pathology diagnoses included CAN (48%), CNI toxicity (30%), and perhaps surprisingly, acute rejection (cellular‐ or Ab‐mediated) (23%). Actuarial rate of death‐censored graft loss at 1 year postbiopsy was 17.7%; at 2 years, 29.8%. There was no difference in postbiopsy graft survival for recipients with versus without CAN (p = 0.9). Prospective cohort patients (n = 2427) developing graft dysfunction >3 months posttransplant undergo ‘index’ biopsy. The rate of index biopsy was 8.8% between 3 and 12 months, and 18.2% by 2 years. Mean time from transplant to index biopsy was 1.0 ± 0.6 years. Local pathology diagnoses included CAN (27%), and acute rejection (39%). Intervention to halt late graft deterioration cannot be developed in the absence of meaningful diagnostic entities. We found CAN in late posttransplant biopsies to be of no prognostic value. The DeKAF study will provide broadly applicable diagnostic information to serve as the basis for future trials.

The Stability of the Glomerular Filtration Rate after Renal Transplantation Is Improving

The 6-mo function and the stability of function posttransplantation in 429 cadaver renal transplants was investigated from 1990 to 2000. The 6-mo creatinine clearance (CrCl) and the rate of change of CrCl beyond 6 mo posttransplantation were calculated. The mean 6-mo CrCl was 64.6 +/- 1.1 ml/min and was stable between 1990 and 2000. The net slope of CrCl was -1.4 +/- 0.5 ml/min per yr. The slope has improved in recent years, such that the mean slopes in the period after 1997 are actually positive (+3.5 ml/min per yr). The slope of CrCl beyond 6 mo was not related to the actual value of the 6 mo CrCl, i.e., there was no accelerated loss of function at low CrCl levels. The 6-mo CrCl was independently determined by donor factors (age, gender), recipient factors (age, gender), and immune factors (rejection episodes, regraft status). The slope of the CrCl correlated independently with the transplant year, recipient gender, rejection episodes, diastolic BP, and the choice of immunosuppressive drugs. Cytomegalovirus infection and mismatch status and lipid levels and treatment were not independently associated with slope or 6-mo CrCl. Thus, the most striking change in the course of renal transplants over the past decade is the new stability of function, correlating with reduced rejection and probably due at least in part to the new immunosuppressive agents. Despite continued calcineurin inhibitor use, late improvement in function now occurs in many cadaver kidney transplants, suggesting a previously unappreciated capacity for functional adaptation.

Development of Diabetes Mellitus Following Kidney Transplantation: A Canadian Experience

The onset of diabetes mellitus following kidney transplantation or post‐transplant diabetes mellitus (PTDM) is now recognized as being an increasingly common complication that is associated with poor graft and patient survival. The incidence and clinical correlates of PTDM in a Canadian kidney transplant population has not been examined and may vary based on differences in demographics (i.e. race). Furthermore, little information exists on the association of variables such as cmulative dose of corticosteroids and trough calcineurin inhibitor levels and PTDM. We examined all recipients of a kidney transplant in our center between 1995 and 2001 and found an overall PTDM rate of 9.8%. Five clinical factors were independently associated with PTDM: older recipient age, deceased donor, hepatitis C antibody status, rejection episode and use of tacrolimus (vs. cyclosporine). Furthermore, cmulative corticosteroid dose and calcineurin inhibitor trough level were not associated with PTDM. This study demonstrates that in a Canadian kidney transplant population that there is a significant risk of PTDM following kidney transplantation, and it is therefore advisable to minimize this risk.

Peritubular capillary changes and C4d deposits are associated with transplant glomerulopathy but not IgA nephropathy.

We examined our renal transplant population for glomerular diseases demonstrated on biopsy between January 1993 and April 2002, focusing on transplant glomerulopathy (TGP). Of 1156 patients followed in our clinics during this period, glomerular disease was diagnosed in 132 cases (11.4%). Glomerulonephritis was diagnosed in 86 transplants (7.4%), with IgA nephropathy (IgAN) being the commonest diagnosis [32 cases (2.8%)]. Thirty‐one cases (2.7%) of biopsy‐proven TGP were analyzed for associated factors compared with 27 cases (2.3%) of recurrent IgAN. Transplant glomerulopathy was less frequent with mycophenolate mofetil (MMF) and/or tacrolimus, whereas recurrent IgAN showed no such tendency (P= 0.02). Peritubular capillary (PTC) C4d deposition was observed in six of 24 cases (25%) with TGP but none with recurrent IgAN (P= 0.02). Peritubular capillary basement membrane (BM) multilayering was significantly greater in TGP (4.92 ± 2.94) than in recurrent IgAN (1.86 ± 1.04) (P < 0.001). The graft survival of TGP was worse than recurrent IgAN (P= 0.05). The association of TGP with BM multilayering and C4d deposits in PTC suggests a generalized disorder of the graft microcirculation and its BM, owing to antibody‐mediated rejection in at least some cases. Transplant glomerulopathy has a serious prognosis but is less frequent in patients on newer immunosuppression, unlike recurrent IgAN.

Death and renal transplantation among Aboriginal people undergoing dialysis

Background: Despite the increase in the number of Aboriginal people with end-stage renal disease around the world, little is known about their health outcomes when undergoing renal replacement therapy. We evaluated differences in survival and rate of renal transplantation among Aboriginal and white patients after initiation of dialysis. Methods: Adult patients who were Aboriginal or white and who commenced dialysis in Alberta, Saskatchewan or Manitoba between Jan. 1, 1990, and Dec. 31, 2000, were recruited for the study and were followed until death, transplantation, loss to follow-up or the end of the study (Dec. 31, 2001). We used Cox proportional hazards models to examine the effect of race on patient survival and likelihood of transplant, with adjustment for potential confounders. Results: Of the 4333 adults who commenced dialysis during the study period, 15.8% were Aboriginal and 72.4% were white. Unadjusted rates of death per 1000 patient-years during the study period were 158 (95% confidence interval [CI] 144–176) for Aboriginal patients and 146 (95% CI 139–153) for white patients. When follow-up was censored at the time of transplantation, the age-adjusted risk of death after initiation of dialysis was significantly higher among Aboriginal patients than among white patients (hazard ratio [HR] 1.15, 95% CI 1.02–1.30). The greater risk of death associated with Aboriginal race was no longer observed after adjustment for diabetes mellitus and other comorbid conditions (adjusted HR 0.89, 95% CI 0.77–1.02) and did not appear to be associated with socioeconomic status. During the study period, unadjusted transplantation rates per 1000 patient-years were 62 (95% CI 52–75) for Aboriginal patients and 133 (95% CI 125–142) for white patients. Aboriginal patients were significantly less likely to receive a renal transplant after commencing dialysis, even after adjustment for potential confounders (HR 0.43, 95% CI 0.35–0.53). In an additional analysis that included follow-up after transplantation for those who received renal allografts, the age-adjusted risk of death associated with Aboriginal race (HR 1.36, 95% CI 1.21–1.52) was higher than when follow-up after transplantation was not considered, perhaps because of the lower rate of transplantation among Aboriginals. Interpretation: Survival among dialysis patients was similar for Aboriginal and white patients after adjustment for comorbidity. However, despite universal access to health care, Aboriginal people had a significantly lower rate of renal transplantation, which might have adversely affected their survival when receiving renal replacement therapy.

Late deterioration of organ transplants: a problem in injury and homeostasis.

The late deterioration of allografts remains a problem despite improvements in short-term and long-term graft survival. The previous concept that late deterioration reflects a specific disease -- chronic rejection -- is being replaced. The new view is that many factors are involved in late deterioration, including the age and pretransplant condition of the organ, injury from brain death, injury from the transplant process, T cell-mediated and antibody-mediated rejection (in some cases reflecting poor compliance with immunosuppressive drugs) and post-transplant organ-specific stresses in the new environment, including drug toxicity, infectious agents, hypertension and lipids. Ultimately these stresses interact with the intrinsic limitations in repair and homeostasis in the tissues of the organ, producing characteristic syndromes. The most important recent advance has been the emergence of potent immunosuppressive drug combinations that have greatly reduced rejection.