Transplantation in Diabetic Kidney Failure Patients: Modalities,Outcomes, and Clinical Management

Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre‐emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre‐existent DM or NODAT involves a multi‐pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re‐transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.     

Clinical issues in renal transplantation in the elderly

Kidney transplantation is the best renal replacement therapy option and is superior to dialysis in elderly end‐stage renal disease (ESRD) patients. Furthermore, the outcome of transplantation in the elderly is comparable to younger patients in terms of allograft survival. The exact nature of this phenomenon is not completely clear. As the elderly population continues to grow, it becomes more important to identify specific issues associated with kidney transplantation. In particular, elderly transplant recipients might have a lower chance of acute rejection as their immune systems seem to be less reactive. This might predispose elderly recipients to greater risk of post‐transplant infectious complications or malignancies. Furthermore, due to differences in pharmacokinetics, elderly recipients might require lower doses of immunosuppressive medication. As the main cause of graft failure in the elderly is death with a functioning graft and also considering the scarcity of donor organs, it might make sense to recommend transplanting elderly recipients with extended criteria donor kidneys. This approach would balance shorter patient survival compared to younger recipients. In conclusion, old age should not preclude ESRD patients from kidney transplantation. However, specific differences that have to do with immunosuppression and other aspects of managing elderly transplant recipients should be considered.     

Evolution of Causes and Risk Factors for Mortality Post‐Liver Transplant: Results of the NIDDK Long‐Term Follow‐Up Study

Although mortality rates following liver transplantation (LT) are well described, there is a lack of detailed, prospective studies determining patterns of and risk factors for long‐term mortality. We analyzed the multicenter, prospectively obtained The National Institute of Diabetes and Digestive and Kidney Diseases LT Database of 798 transplant recipients from 1990 to 1994 (follow‐up 2003). Overall, 327 recipients died. Causes of death >1 year: 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, 6% renal failure. Renal‐related death increased dramatically over time. Risk factors for death >1 year (univariate): male gender, age/decade, pre‐LT diabetes, post‐LT diabetes, post‐LT hypertension, post‐LT renal insufficiency, retransplantation >1 year, pre‐LT malignancy, alcoholic disease (ALD) and metabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation, post‐LT diabetes, hypertension and renal insufficiency were significant risk factors for liver‐related death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre‐LT hypertension and post‐LT renal insufficiency. In summary, the leading causes of late deaths after transplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age, diabetes and renal insufficiency identified patients at highest risk of poor survival overall. Diligent management of modifiable post‐LT factors including diabetes, hypertension and renal insufficiency may impact long‐term mortality.     

A simulation model to investigate the impact of cardiovascular risk in renal transplantation

Premature cardiovascular (CV) disease is the leading cause of death following renal transplantation and, as a consequence of death with a functioning graft, it is a major cause of graft loss. Renal transplant recipients have a high prevalence of CV risk factors that influence both patient and graft survival. We used data on the relationship between CV risk factors and graft and patient survivals to develop a discrete event simulation model to study the possible impact of CV risk factor reduction on transplant outcome. The simulation was based on a renal unit in a population that has the risk factor profile of patients from the West of Scotland. We studied the dynamic between patient numbers on the waiting list compared to the transplanted list. After establishing results pertinent to the renal unit, we investigated in what way potential changes to transplant policy affected patient numbers. These perturbations included changing the number of transplants performed, changing the incidence of acute rejection, and interventional policies where patients on the waiting list were selectively transplanted taking into account their CV risk factor profiles. Overall, the model predicts that reducing CV risk in the population with end-stage renal failure awaiting kidney transplantation will have comparable benefits to foreseeable developments in immunosuppression or attainable increases in transplant numbers. Moreover, addressing CV risk has benefits for all patients regardless of whether or not they ultimately receive a kidney transplant.     

Antiphospholipid antibodies after renal transplantation and cardiovascular disease

Abstract: Background: The aim was to assess the presence of pre‐ or post‐transplant serum antiphospholipid antibodies (APA) and its association with the development of cardiovascular disease (CVD) in renal transplantation. Methods: We studied 138 patients transplanted with a cadaver kidney graft between 1990 and 1998 and with a graft functioning for longer than one yr. One pre‐transplant sample and another obtained after transplantation from our serum bank were analyzed. The ELISA used were set up in our laboratory, following established international guidelines, and results were confirmed in three different runs. Results: 23.9% and 31.2% of patients had pre‐ and post‐transplant positive titers of APA, respectively. 16% developed those antibodies de novo after transplantation. Post‐transplant CVD was observed in 20.3% of patients but they were not associated with the production of APA in the whole population studied. However, multivariate analysis demonstrated an increased risk (RR 2.27; p = 0.02) for CVD when APA were produced after acute rejection. Conclusions: The presence of serum APA alone was not an independent risk factor for CVD after kidney transplantation. Nonetheless, in kidney recipients who produced APA de novo after acute rejection, the control of cardiovascular risk factors must be intensified.     

Incidence,risk factors,and outcomes of stroke post‐transplantation in patients receiving a steroid sparing immunosuppression protocol

Corticosteroid use after transplantation is associated with an increased incidence of cardiovascular events and death. Cerebrovascular disease is a common cause of morbidity and mortality post‐renal transplantation; however, a dedicated analysis of cerebrovascular disease in recipients of a steroid sparing protocol has not been reported. The aim of this study was to examine the incidence, risk factors, and outcomes of CVA in transplant recipients receiving a steroid sparing protocol. We retrospectively analyzed 1237 patients who received a kidney alone or a simultaneous pancreas and kidney (SPK) transplant. Fifty‐six of 1237 (4.53%) patients had a CVA post‐transplant. All‐cause mortality was significantly higher in the CVA group compared with the non‐CVA group, OR: 3.4 (1.7–7.0), p < 0.001. Factors found to be associated with increased risk of CVA by multivariate analysis were older age, HR: 1.07 (1.04–1.09), p < 0.001; diabetes at the time of transplantation, HR: 2.83 (1.42–5.64), p = 0.003; corticosteroid use pre‐transplant, HR: 3.27 (1.29–8.27), p = 0.013 and recipients of a SPK, HR: 4.03 (1.85–8.79), p < 0.001. This study has identified subgroups of patients who are at increased risk of CVA post‐transplant in patients otherwise receiving a steroid sparing immunosuppression protocol.     

Risk factors for cardiovascular disease after renal transplantation

Cardiovascular diseases (CVD) have become the leading cause of mortality in renal transplant recipients. Well-known cardiovascular (CV) risk factors and graft dysfunction both play an important role in the development of the posttransplantation CV events. We studied 233 stable kidney transplant patients to establish the prevalence of CVD and to assess CV risk factors that can be evaluated (and modified) in daily clinical practice. While 6.2% of the patients had coronary heart disease (CHD) before the transplantation, 16% displayed at least 1 CV event posttransplantation. The most significant factors associated with CV events were as follows: gender, length of smoking, diabetes mellitus, hepatitis C virus antibodies (HCV), dyslipidemia, proteinuria, and serum creatinine levels.     

Restoration of Renal Function Does Not Correct Impairment of Uremic HDL Properties

Cardiovascular disease remains the leading cause of death in renal transplant recipients, but the underlying causative mechanisms for this important problem remain elusive. Recent work has indicated that qualitative alterations of HDL affect its functional and compositional properties in ESRD. Here, we systematically analyzed HDL from stable renal transplant recipients, according to graft function, and from patients with ESRD to determine whether structural and functional properties of HDL remain dysfunctional after renal transplantation. Cholesterol acceptor capacity and antioxidative activity, representing two key cardioprotective mechanisms of HDL, were profoundly suppressed in kidney transplant recipients independent of graft function and were comparable with levels in patients with ESRD. Using a mass spectroscopy approach, we identified specific remodeling of transplant HDL with highly enriched proteins, including α-1 microglobulin/bikunin precursor, pigment epithelium-derived factor, surfactant protein B, and serum amyloid A. In conclusion, this study demonstrates that HDL from kidney recipients is uniquely altered at the molecular and functional levels, indicating a direct pathologic role of HDL that could contribute to the substantial cardiovascular risk in the transplant population.     

Outcomes of renal transplantation in recipients with Wegener’s granulomatosis

Shen J, Gill J, Shangguan M, Sampaio MS., Bunnapradist S. Outcomes of renal transplantation in recipients with Wegener’s granulomatosis.
Clin Transplant 2011: 25: 380–387. © 2010 John Wiley & Sons A/S. Abstract: Wegener’s granulomatosis (WG) is the leading cause of rapidly progressive glomerulonephritis‐induced end‐stage renal disease (ESRD). In this study, we compared transplant outcomes between recipients with ESRD caused by WG to recipients with ESRD secondary to other causes. Using OPTN/UNOS data from 1996 to 2007, 919 recipients with WG were identified. Post‐transplant outcomes included rates of delayed graft function, acute rejection within one‐yr post‐transplant, overall and death‐censored graft survival, and patient survival and were compared between recipients with ESRD secondary to WG versus ESRD from other causes. Recipients with ESRD because of WG had superior unadjusted and adjusted rates of graft loss, patient death, and functional graft loss (adjusted hazard ratio [HR] 0.711, 0.631, and 0.625 respectively, p < 0.001). When we compared the WG cohort to a non‐WG, non‐diabetic population, the HR for graft loss was still significant, but patient death and death‐censored graft loss were not. Subgroup analysis of recipients aged over 60 confirmed that WG recipients had better unadjusted outcomes. This study supports the notion that renal transplantation is an effective treatment option for patients with ESRD secondary to WG. They fare similarly, if not better, than other patients.     

Combined Pancreatic Islet and Kidney Transplantation in a Child With Unstable Type 1 Diabetes and End‐Stage Renal Disease

Islet transplantation after successful kidney transplantation is a recognized treatment for adults with diabetes and end‐stage renal disease (ESRD), but has not been considered an option in the pediatric population. To our knowledge, we report the first combined islet and kidney transplant in a child. The patient was born with bilateral renal hypoplasia and was diagnosed with type 1 diabetes mellitus at age 13 months. He had erratic glycemic control and hypoglycemia unawareness. At 6 years of age, the child safely underwent simultaneous islet and live donor kidney transplantation. Although function of the islet graft was transient, the combined transplant provided significant benefits in terms of glucose control and overall growth and development. Such an approach represents a viable treatment option for pediatric patients with ESRD and unstable diabetes.     

Chronic kidney disease progression in kidney transplant recipients: A focus on traditional risk factors

Kidney transplant recipients are a subset of patients with chronic kidney disease (CKD) that remain at high risk for progression to dialysis and mortality. Recent advances in immunosuppression have only partially improved long‐term graft and patient survival. Discovery of new immunosuppressive regimens is a slow and resource‐intensive process. Hence, recognition and management of modifiable allogeneic and non‐allogeneic risk factors for progression to CKD among kidney transplant recipients is of major interest for improving long‐term outcomes. Graft survival is mainly determined by the quality of the allograft and by the patient’s alloimmune response, which is influenced by human leukocyte antigen matching and the presence of donor‐specific antibodies. Alloimmune responses manifest as acute and chronic forms of cell‐ and antibody‐mediated rejection, which can be worsened by patient non‐adherence or under‐immunosuppression. However, donor and patient ages, glomerular disease recurrence, time on dialysis, pre‐existing cardiovascular burden, medication side‐effects and traditional risk factors, such as hypertension, proteinuria, anaemia, dyslipidaemia, diabetes and bone mineral disorder, which can ultimately lead to severe endothelial derangement, also contribute to graft loss and mortality. These traditional risk factors, common to pre‐dialysis patients, often are considered of secondary importance when compared to alloimmunity and immunosuppression concerns. In this review article, we focus on the epidemiological, pathophysiological and therapeutic features of non‐allogeneic traditional risk factors for CKD. We also discuss the benefit of adopting a multidisciplinary approach to pursue the same therapeutic targets recommended for pre‐dialysis patients.     

Steroid-Free Immunosuppression Since 1999: 129 Pediatric Renal Transplants with Sustained Graft and Patient Benefits

Despite early promising patient and graft outcomes with steroid-free (SF) immunosuppression in pediatric kidney transplant recipients, data on long-term safety and efficacy results are lacking. We present our single-center experience with 129 consecutive pediatric kidney transplant recipients on SF immunosuppression, with a mean follow-up of 5 years. Outcomes are compared against a matched cohort of 57 concurrent recipients treated with steroid-based (SB) immunosuppression. In the SF group, 87% of kidney recipients with functioning grafts remain corticosteroid - free. Actual intent-to-treat SF (ITT-SF) and still-on-protocol SF patient survivals are 96% and 96%, respectively, actual graft survivals for both groups are 93% and 96%, respectively and actual death-censored graft survivals for both groups are 97% and 99%, respectively. Unprecedented catch-up growth is observed in SF recipients below 12 years of age. Continued low rates of acute rejection, posttransplant diabetes mellitus (PTDM), hypertension and hyperlipidemia are seen in SF patients, with sustained benefits for graft function. In conclusion, extended enrollment and longer experience with SF immunosuppression for renal transplantation in low-risk children confirms protocol safety, continued benefits for growth and graft function, low acute rejection rates and reduced cardiovascular morbidity.     

Fellows’ Forum: Cardiac Evaluation Prior to Kidney Transplantation

Kidney transplantation is the treatment of choice for most patients with stage 5 chronic kidney disease and end‐stage renal disease (ESRD), offering improved quality of life and overall survival rates. However, the limited supply of available organs makes this a scarce resource. Cardiovascular complications continue to be the leading cause of mortality in the kidney transplant population, accounting for over 30% of deaths with a functioning allograft. Thus, preoperative cardiac risk assessment is critical to optimize patient selection and outcomes. Currently there is no consensus for cardiovascular evaluation in the chronic kidney disease and ESRD population prior to kidney transplantation; the recommendations of the American Society of Nephrology and American Society of Transplantation differ from those of the American Heart Association and the American College of Cardiology. Previously developed risk scores have also been used to risk stratify this population. In this review, we discuss two cases that illustrate the difficulties of interpreting the prognostic value of current testing strategies. We also discuss the importance of different tests for cardiovascular evaluation as well as previous nonkidney transplant specific risk scores used in the pre‐kidney transplant population.     

Pre‐existing diabetes significantly increases the risk of graft failure and mortality following renal transplantation

The aim of this study was to examine the impact of pre‐existing diabetes mellitus (DM) on acute rejection, graft loss, and mortality following kidney transplant and whether glycemic control or cardiovascular disease (CVD) risk control with medications influenced outcomes. This was a cohort study of 1002 renal transplants conducted between 2000 and 2008. Patients were included if they received a kidney transplant within the allotted time and were at least 18 yr of age. Cox regression was used to assess acute rejection, graft failure, or death controlling for relevant sociodemographic, clinical, and post‐transplant variables. Five‐yr patient survival (83% vs. 93%, p < 0.001) and graft survival (74% vs. 79%, p = 0.005) were significantly lower in patients with pre‐existing DM. Sequential Cox regression models demonstrated that pre‐existing DM was consistently associated with a higher risk of death (HR 2.3–3.0, p < 0.01) and graft failure (HR 1.5–1.8, p < 0.04) in all models except after adjusting for CVD medication use (HR 1.9, p = 0.174 and HR 1.5, p = 0.210, respectively). These data suggest pre‐existing DM is a significant risk factor for graft failure and death following renal transplantation and aggressive CVD risk reduction with medications may be an important strategy to reduce mortality and graft failure.     

Risk factors for cardiovascular disease in renal transplant recipients and strategies to minimize risk

Cardiovascular disease is the leading cause of death following renal transplantation, and renal transplant patients have a greatly increased cardiac risk compared with the general population. Death with a functioning graft caused by cardiovascular disease also represents a substantial cause of graft loss. Decreased renal function in transplant recipients is a major contributor to increased cardiac risk, both as an independent risk factor and because of its negative effects on hypertension, anemia, left ventricular hypertrophy, and dyslipidemia. Graft loss and diabetes mellitus are also significant risk factors for cardiac death. Although critical for maintaining the transplanted organs, standard immunosuppressants have toxicities that exacerbate cardiac risk. Preservation of renal function, prevention of graft loss, and reductions in cardiovascular risk factors via improvements in both patient management and immunosuppressive therapies constitute critical strategies for optimizing patient and graft survival over the long term.     

Cardioprotective medication use after renal transplantation

Dawson KL, Patel SJ, Putney D, Suki WN, Gaber AO. Cardioprotective medication use after renal transplantation.
Clin Transplant 2010: 24: E253–E256. © 2010 John Wiley & Sons A/S. Abstract: Cardiovascular disease is the leading cause of death in renal transplant patients. This study compares the use of cardioprotective medications in adult kidney transplant recipients at a single center with recommendations, which have been validated in the general population. Cardioprotective medication use was retrospectively collected post‐renal transplant. Patients were defined as high risk if they had pre‐transplant coronary heart disease or equivalent risk. “Optimal” treatment was defined as a patient receiving aspirin, statin, angiotensin‐converting enzyme inhibitors/angiotensin receptor blocker, and a beta‐blocker according to cardiovascular risk. The percentage of high‐risk patients optimally treated at one, three, six, and 12 months was 7.7%, 11.5%, 17.6%, and 18.8%, respectively. Although the use of cardioprotective medications was evident in transplant recipients, opportunities exist to increase the use of optimal cardioprotective regimens after renal transplantation.     

Post-transplantation diabetes mellitus

Post-transplant diabetes mellitus is a frequent and serious complication after organ transplantation. Its ethiopathogenesis is complex, with interaction between intrinsic factors (older age, body mass index, individual and family history, hepatitis C virus infection) and graft related factors (immunosuppressive regimen, HLA status). In kidney transplant recipients, new onset diabetes mellitus is associated with an adverse effect upon patient survival, with an increased incidence of infectious and cardiovascular complications. Furthemore, post transplant diabetes mellitus clearly affects long-term allograft survival. Management of new onset diabetes mellitus after transplantation includes: screening for risk factors before transplantation (to propose lifestyle modifications and adaptation of immunosuppressive therapy); regular monitoring of glycemia after transplantation; non pharmacologic and pharmacologic therapies associated with management of others cardiovascular risk factors (hypertension, dyslipidemias).     

Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study

Kidney transplantation is one of the therapeutic options for end‐stage renal disease (ESRD) in systemic sclerosis (SS). Current evidence demonstrates poorer patient and graft survival after transplantation in SS than in other primary kidney diseases. All the patients presenting ESRD associated with SS who had received a kidney allograft between 1987 and 2013 were systematically included from 20 French kidney transplantation centres. Thirty‐four patients received 36 kidney transplants during the study period. Initial kidney disease was scleroderma renal crisis in 76.4%. Extrarenal involvement of SS was generally stable, except cardiac and gastrointestinal involvements, which worsened after kidney transplantation in 45% and 26% of cases, respectively. Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post‐transplant, respectively. Pulmonary involvement of SS was an independent risk factor of death after transplantation. Death‐censored graft survival was 97.2% after 1 and 3 years, and 92.8% after 5 years. Recurrence of scleroderma renal crisis was diagnosed in three cases. In our study, patient and graft survivals after kidney transplantation can be considered as excellent. On this basis, we propose that in the absence of extrarenal contraindication, SS patients presenting with ESRD should be considered for kidney transplantation.     

Impact of pre-transplant dialysis modality on post-transplant diabetes mellitus after kidney transplantation

Courivaud C, Ladrière M, Toupance O, Caillard S, de Ligny BH, Ryckelynck J‐P, Moulin B, Rieu P, Frimat L, Chalopin J‐M, Chauvé S, Kazory A, Ducloux D. Impact of pre‐transplant dialysis modality on post‐transplant diabetes mellitus after kidney transplantation.
Clin Transplant 2011: 25: 794–799. © 2010 John Wiley & Sons A/S. Abstract: Post‐transplant diabetes mellitus (PTDM) is a well‐known complication in renal transplant recipients (RTRs). While a number of risk factors for PTDM have been identified, the potential impact of pre‐transplant dialysis modality on subsequent development of PTDM has not yet been explored. We performed a multicenter retrospective study on 2010 consecutive RTRs who did not have a history of diabetes prior to renal transplantation. PTDM was defined as a need for anti‐diabetic therapy in an RTR without a history of diabetes prior to transplantation. Analysis of the risk factors for development of PTDM was performed with respect to pre‐transplant dialysis modality. A total of 137 (6.8%) patients developed PTDM; 7% in the hemodialysis group and 6.5% in the peritoneal dialysis (PD) group (p = 0.85). In the multivariate analysis, age (p < 0.001), body mass index (BMI) (p < 0.001), use of tacrolimus (p = 0.002), and rejection episodes (p < 0.001) were identified as independent risk factors for development of PTDM. Patients in the PD group were younger (p = 0.004), had lower BMI (p = 0.07), and were less likely to have a history of hepatitis C (p = 0.007) and autosomal dominant polycystic kidney disease (p = 0.07). Adjustment for these variables did not modify the results. The results of this study suggest that pre‐transplant dialysis modality does not have an impact on the subsequent development of PTDM in RTRs.