Rahul M. Jindal

Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients

End-stage renal disease (ESRD) is a growing public health concern and non-adherence to treatment has been associated with poorer health outcomes in this population. Depression, likely to be the most common psychopathology in such patients, is associated with increased morbidity and mortality. We compared psychological measures and self-reported medication adherence of 94 kidney transplant recipients to those of 65 patients receiving hemodialysis in a major medical center in Brooklyn, New York. Compared to the transplant group, the hemodialysis cohort was significantly more depressed as determined by the Beck Depression Inventory score. They also had a significantly lower adherence to medication as reported on the Medication Therapy Adherence Scale. Using hierarchical multiple regression analysis, the variance in depression was the only statistically significant predictor of medication adherence beyond gender and mode of treatment, accounting for an additional 12% of the variance. Our study strongly suggests that a depressive affect is an important contributor to low medication adherence in patients with ESRD on hemodialysis or kidney transplant recipients.

Post-transplant diabetes mellitus. The role of immunosuppression.

SummaryImmunosuppressive agents increase the risk of death due to coronary disease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants. As recipients of organ transplants survive longer, the secondary complications of diabetes mellitus have assumed greater importance.There is a need for a precise definition of post-transplant diabetes mellitus to facilitate inter-centre comparison and to study the natural history of post-transplant diabetes mellitus. We recommend broad criteria to define hyperglycaemia, as a fasting blood glucose level of >400 mg/dl at any point or >200 mg/dl for 2 weeks, or a need for insulin treatment for at least 2 weeks. We also recommend serial measurements of HbA1c.Cyclosporin and tacrolimus cause post-transplant diabetes mellitus by a number of mechanisms, including decreased insulin secretion, increased insulin resistance or a direct toxic effect on the beta cell. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mechanism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimens which may result in decreased metabolic complications.Corticosteroid sparing regimens have been shown to reduce the metabolic complications of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections.Post-transplant diabetes mellitus may be organ-specific, irrespective of the immunosuppressant used. Tacrolimus causes a high incidence of post-transplant diabetes mellitus in recipients of kidney transplants (up to 20% in some reports); the diabetogenicity of cyclosporin-based regimens is comparable with that of tacrolimus-based regimens in recipients of liver transplants. A few clinical studies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected patients with liver transplants. However, post-transplant recipients who may benefit from this approach are difficult to identify.In some early series, patients received doses of tacrolimus that were approximately 2 to 3 times higher than those currently used, which may have resulted in a higher incidence of post-transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvaging whole pancreatic grafts which were maintained on cyclosporin. Tacrolimus-based immunosuppression as primary therapy was also used with remarkable success in solitary whole pancreas transplants.Strategies to reduce the metabolic complications of immunosuppressants should be pursued aggressively as this will directly lead to a decrease in long term cardiovascular adverse effects.

Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation

Aims. To investigate the outcomes in patients who have pre‐existing diabetes and those who develop post‐transplant diabetes mellitus (PTDM). 
Methods. We retrospectively reviewed the charts of 939 patients who received a first functioning renal transplant in the cyclosporine (CyA) era between 1984 and 1999. 
Results. Sixty‐six (7%) patients had renal failure due to insulin‐dependent diabetes mellitus (IDDM) and 7 (0.8%) patients due to non‐insulin‐dependent diabetes mellitus (NIDDM). Ten (1.1%) patients had coexistent diabetes and 48 (5.1%) recipients developed PTDM. The mean graft survival for the patients with PTDM was 9.7 yr versus 11.3 yr for the non‐diabetic patients, while mean graft survival was 10.1 yr for patients with IDDM and 2.9 yr with NIDDM and 8.3 yr for those with coexistent diabetes (p=ns). However, there was a statistically significant difference in patient survival between patients who developed PTDM and in those who did not develop this complication. The mean survivals of patients with IDDM, NIDDM, coexistent diabetics and PTDM were 8.4, 3.7, 8.6 and 10.3 yr, respectively. The mean survival of the patients without pre‐existing diabetes or PTDM was 12.8 yr (p<0.001). The survival of patients older than 55 yr with PTDM was no different to the control group. However, in those younger than 55 yr, PTDM was associated with a higher risk of death (relative risk of 2.54, p<0.001). Fifty percent of patients with IDDM developed acute rejection episodes, whereas rejection rate was 57.1% in NIDDM group, 50.0% in the PTDM group, 20.0% in the coexistent diabetes group and 44.3% in the control group (p=ns). 
Conclusion. Patient survival, but not graft survival, was adversely affected by both pre‐existing diabetes and by PTDM, particularly in those with an age less than 55 yr.

Progressive Multifocal Leukoencephalopathy and Use of Mycophenolate Mofetil After Kidney Transplantation

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

Kidney Transplantation and Gender Disparity

Gender inequity in access to hemodialysis and kidney transplantation has created a public health crisis in the US. Women have a lower chance of receiving hemodialysis and kidney transplant than men, but they constitute the majority of living kidney donors. Research has shown that economic factors such as greater income of men may encourage females to be donors; while gender-bias on part of physicians or institutions, lack of social support networks and differences in health-seeking behaviors compared to men are cited as reasons for this imbalance. We suggest various strategies to improve participation of women in the transplant process by education; raising awareness by publishing gender-specific data for dialysis and transplant centers; education and workshops to eliminate gender-bias within institutions and health-care providers and establishment of gender-specific support groups. Transplant teams that are more sensitive to the social complexities of women’s lives may lead to increased understanding of the effects of renal disease and indicate measures that need to be in place in order to address this gender disparity in the treatment of renal failure. Research needs to be done to elucidate the underlying medical, societal or psychological processes that lead to gender bias in the field of kidney transplantation.

The impact of late acute rejection after cadaveric kidney transplantation

Background: Acute graft rejection (AR) following renal transplantation results in reduced graft survival. However, there is uncertainty regarding the definition, aetiology and long‐term graft and patient outcome of AR occurring late in the post‐transplant period. 
Aim: To determine if rejection episodes can be classified by time from transplantation by their impact on graft survival into early acute rejection (EAR) and late acute rejection (LAR). 
Materials and methods: 687 consecutive adult renal transplant recipients who received their first cadaveric renal transplant at a single centre. All received cyclosporine (CyA)‐based immunosuppression, from 1984 to 1996, with a median follow‐up of 6.9 yr. Details were abstracted from clinical records, with emphasis on age, sex, co‐morbid conditions, HLA matching, rejection episodes, patient and graft survival. 
Analysis: Patients were classified by the presence and time to AR from the date of transplantation. Using those patients who had no AR (NAR) as a baseline, we determined the relative risk of graft failure by time to rejection. The characteristics of patients who had no rejection, EAR and LAR were compared. 
Results: Compared with NAR, the risk of graft failure was higher for those patients who suffered a rejection episode. A much higher risk of graft failure was seen when the first rejection episode occurred after 90 d. Thus, a period of 90 d was taken to separate EAR and LAR (relative risk of 3.06 and 5.27 compared with NAR as baseline, p<0.001). Seventy‐eight patients (11.4%) had LAR, 271 (39.4%) had EAR and 338 (49.2%) had NAR. The mean age for each of these groups differed (LAR 39.6 yr, EAR 40.8 yr compared with NAR 44 yr, p<0.003). The 5‐yr graft survival for those who had LAR was 45% and 10‐yr survival was 28%. HLA mismatches were more frequent in those with EAR vs. NAR (zero mismatches in HLA‐A: 36 vs. 24%, HLA‐B: 35 vs. 23% and HLA‐DR: 63 vs. 41%, p<0.003). There was no difference in mismatching frequency between NAR and LAR. 
Conclusions: AR had a deleterious impact on graft survival, particularly if occurring after 90 d. AR episodes should therefore be divided into early and late phases. In view of the very poor graft survival associated with LAR, it is important to gain further insight into the main aetiological factors. Those such as suboptimal CyA blood levels and non‐compliance with medication should be further investigated with the aim of developing more effective immunosuppressive regimens in order to reduce the incidence of LAR.

Analysis of USRDS: Incidence and Risk Factors for Pneumocystis jiroveci Pneumonia

Background. To investigate the effect of modern immunosuppression on the incidence, risk factors, morbidity, and mortality of Pneumocystis pneumonia (PCP) in recipients of kidney transplants. Methods. We conducted a retrospective cohort study of 32,757 Medicare primary transplant recipients in the United States Renal Data System from January 1, 2000 through July 31, 2004. PCP infection was defined by Medicare claims using International Classification of Disease, 9th Revision codes. The incidence of PCP infections, graft loss, and death were measured. Results. There were a total of 142 cases (cumulative incidence 0.4%) of PCP after kidney transplantation during the study period. By using multivariate analysis with Cox regression, expanded criteria donor, donation after cardiac death, and earlier year of transplant were associated with development of PCP disease. Induction immunosuppression and acute rejections were not associated with risk for PCP infections. However, based on adjusted hazard ratio (AHR), maintenance immunosuppression regimens containing the combination of tacrolimus and sirolimus (AHR 3.60, confidence interval [CI] 2.03–6.39), Neoral and mycophenolate mofetil (AHR 2.09, CI 1.31–3.31), and sirolimus and mycophenolate mofetil (AHR 2.77, CI 1.40–5.47), were associated with development of PCP. As a time dependent variable, PCP was associated with an increased risk of both graft loss and death. Conclusion. PCP infections are rare in the modern era of prophylaxis; however, these infections are a serious risk factor for graft loss and patient death, in particular, in patients who are on sirolimus as part of the immunosuppressive regimen. The median time to development of PCP after transplant was 0.80±0.95 years, suggesting a longer period of PCP prophylaxis.

Incidence, Predictors and Outcomes of Transplant Renal Artery Stenosis after Kidney Transplantation: Analysis of USRDS

Objective: We analyzed the United States Renal Data System registry to study the risks, predictors, and outcomes of transplant renal artery stenosis (TRAS) in contemporary practice. Methods: The study sampled comprised adults with Medicare primary insurance who received kidney transplants in 2000–2005. We examined associations of recipient, donor and transplant factors with time-to-TRAS by the Kaplan-Meier method and multivariate Cox regression. Survival analysis methods were employed to estimate graft survival after TRAS, and to model TRAS as a time-dependent outcome predictor. Kaplan-Meier analysis was used to estimate time to allograft loss in patients who did or did not have an angioplasty procedure for TRAS. Results: There were 823 cases of TRAS among 41,867 transplant patients, with an incidence rate of 8.3 (95% CI 7.8–8.9) cases per 1,000 patient-years. Mean time to diagnosis of TRAS was 0.83 ± 0.81 years after transplant. Factors associated with TRAS were older recipient and donor age, extended criteria donors, induction immunosuppression, delayed graft function, and ischemic heart disease. There was no association of TRAS with deceased donors, prolonged cold ischemia time, acute rejection or cytomegalovirus status. TRAS was associated with increased risk of graft loss (including death; adjusted hazard ratio 2.84, 95% CI 1.70–4.72). Among the 823 patients with TRAS, 145 (17.6%) underwent angioplasty. Graft survival after TRAS was not significantly different in patients treated with angioplasty compared to those without angioplasty. Conclusions: TRAS is an important complication that predicts adverse patient and graft outcomes. Treatment strategies for TRAS warrant prospective investigation in clinical trials.

Emotional issues after kidney transplantation: a prospective psychotherapeutic study.

Abstract: Background:  Negative emotional states are the single most influential factor in determining quality of life after a successful kidney transplant. We designed a prospective study using psychotherapeutic principles to understand and intervene in emotional issues in adult recipients of first cadaver kidney transplants.

Quality of Life After Kidney and Pancreas Transplantation: A Review

There is an increasing amount of data on quality of life (QOL) in most chronic illnesses; some of the instruments used are generic, but recently, there is a tendency to use disease-specific instruments. We propose that recipients of organ transplants be assessed routinely for QOL by means of the 36-Item Short-Form Health Survey or a disease-specific instrument; for compliance, by means of the Long-Term Medication Behavior Self-Efficacy Scale; and for psychological status, by means of the Beck Depression Inventory Brief Symptom Inventory or the Symptom Checklist. The widespread use of QOL data in recipients of organ transplants will increase accountability of service providers and eventually increase patient satisfaction because these instruments are patient reported.