Calcineurin inhibitors (CNIs), including tacrolimus and cyclosporine, are immune‐modulating agents used in autoimmune disorders, glomerulonephritides, and after transplantation. CNIs are implicated ...as diabetogenic drugs but the mechanism is not clearly elucidated. Calcineurin is a cytosolic‐phosphatase critical for T‐lymphocyte activation. Calcineurin is widely distributed in different tissues responsible for glucose‐regulation including pancreas, liver, skeletal muscle, adipocytes, brain, and gut. We describe the pharmacologic effects of CNIs in different tissues and impact on glucose regulation.
Immunosuppressants are critical after transplantation and prescribed as immune‐modulators for autoimmune disorders and glomerulonephritides. Immunosuppressants include large (e.g., thymoglobulin, ...alemtuzumab, and rituximab) and small molecules (e.g., corticosteroids, calcineurin inhibitors, antimetabolites, and mammalian target of rapamycin (mTOR) inhibitors). The majority of the small molecules worsen traditional cardiovascular risks. This review describes cardiovascular risks of small molecule immunosuppressants: corticosteroids, calcineurin inhibitors (tacrolimus and cyclosporine), and mTOR inhibitors (rapamycin), by categorizing these risks into two categories: ischemic heart disease and nonischemic cardiac effects.
Our aim was to study the impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy (IF/TA) on a 1‐year protocol biopsy in patients on rapid steroid withdrawal ...(RSW). A total of 256 patients were classified based on protocol biopsy findings at months 1 or 4. Group 1 is 172 patients with no inflammation, group 2 is 50 patients with subclinical inflammation (SCI), group 3 is 19 patients with subclinical acute rejection (SAR) and group 4 is 15 patients with clinical acute rejection (CAR). On the 1‐year biopsy, more patients in group 2 (SCI) (34%, p = 0.004) and group 3 (SAR) (53%, p = 0.0002), had an IF/TA score > 2 compared to group 1 (control) (15%). IF/TA was not increased in group 4 (CAR) (20%). The percent with IF/TA score > 2 and interstitial inflammation (Banff i score > 0) was higher in group 2 (16%, p = 0.004) and group 3 (37%, p < 0.0001) compared to group 1 (3%). In a multivariate analysis, patients in groups 2 or 3 had a higher risk of IF/TA score > 2 on the 1‐year biopsy (OR 6.62, 95% CI 2.68–16.3). We conclude that SCI and SAR increase the risk of developing IF/TA in patient on RSW.
Protocol biopsy findings during the first 4 months after kidney transplantation in a cohort of patients on rapid steroid withdrawal show that patients with earlier subclinical inflammation manifest a significantly higher risk of interstitial fibrosis and tubular atrophy on a subsequent one‐year protocol biopsy.
Our aim was to determine outcomes with transplanting kidneys from deceased donors with acute kidney injury, defined as a donor with terminal serum creatinine ≥2.0 mg/dL, or a donor requiring acute ...renal replacement therapy. We included all patients who received deceased donor kidney transplant from June 2004 to October 2013. There were 162 AKI donor transplant recipients (21% of deceased donor transplants): 139 in the standard criteria donor (SCD) and 23 in the expanded criteria donor (ECD) cohort. 71% of the AKI donors had stage 3 (severe AKI), based on acute kidney injury network (AKIN) staging. Protocol biopsies were done at 1, 4, and 12 months posttransplant. One and four month formalin‐fixed paraffin embedded (FFPE) biopsies from 48 patients (24 AKI donors, 24 non‐AKI) underwent global gene expression profiling using DNA microarrays (96 arrays). DGF was more common in the AKI group but eGFR, graft survival at 1 year and proportion with IF/TA>2 at 1 year were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (p‐value <0.005; FDR <10%), but by 4 months there were no differences. Transplanting selected kidneys from deceased donors with AKI is safe and has excellent outcomes.
The authors show that transplanting select kidneys from deceased donors with severe acute injury results in excellent outcomes, including graft survival, and resolution of early differences in allograft gene expression for tissue damage, cell death, and inflammation.
The aim of this study was to determine the clinical and histologic outcomes related to transplanting kidneys from deceased donors with glomerular fibrin thrombi (GFT). We included all cases ...transplanted between October 2003 and October 2014 that had either a preimplantation biopsy or an immediate postreperfusion biopsy showing GFT. The study cohort included 61 recipients (9.9%) with GFT and 557 in the control group without GFT. Delayed graft function occurred in 49% of the GFT group and 39% in the control group (p = 0.14). Serum creatinine at 1, 4, and 12 months and estimated GFR at 12 months were similar in the two groups. Estimated 1‐year graft survival was 93.2% in the GFT group and 95.1% in the control group (p = 0.22 by log‐rank). Fifty‐two of the 61 patients in the GFT group (85%) had a 1‐month protocol biopsy, and only two biopsies (4%) showed residual focal glomerular thrombi. At the 1‐year protocol biopsy, the prevalence of moderate to severe interstitial fibrosis and tubular atrophy was 24% in the GFT group and 30% in the control group (p = 0.42). We concluded that GFT resolves rapidly after transplantation and that transplanting selected kidneys from deceased donors with GFT is a safe practice.
Deceased donor kidneys with glomerular fibrin thrombi can have excellent graft survival, as fibrin thrombi resolve by one month in most cases without any deleterious effect on renal function or biopsy findings at one year.
Whether the high incidence of ischemic heart disease (IHD) among renal transplant patients can be attributed to the same risk factors that have been identified in the general population is unclear. ...The risk for major IHD events occurring >1 yr after transplantation among 1124 transplant recipients was estimated by using the risk calculated from the Framingham Heart Study (FHS). The FHS risk predicted IHD (relative risk, 1.28; 95% confidence interval, 1.20 to 1.40; P: < 0.001); however, the FHS risk tended to underestimate the risk of IHD for renal transplant recipients. This was largely attributable to increased risks associated with diabetes mellitus and, to a lesser extent, age and cigarette smoking for renal transplant recipients. For men, the relative risks for diabetes mellitus were 2.78 (1.73 to 4.49) and 1.53 for the transplant recipient and FHS populations, respectively; the relative risks for age (in years) were 1.06 (1.04 to 1.08) and 1.05, respectively, and those for smoking were 1.95 (1.20 to 3.19) and 1.69, respectively. For women, the relative risks for diabetes mellitus were 5.40 (2.73 to 10.66) and 1.82, respectively. There was a tendency for the risk associated with cholesterol levels to be higher for transplant recipients, compared with the FHS population, but the risks associated with high-density lipoprotein cholesterol levels and BP appeared to be comparable. Independent of these and other risk factors, the adjusted risk of IHD for the transplant recipient population has decreased. Compared with the era before 1986, transplantation between 1986 and 1992 was associated with a lower relative risk of 0.60 (0.39 to 0.92); transplantation after 1992 was associated with an even lower relative risk of 0.27 (0.11 to 0.63) for IHD. Of concern was the fact that dihydropyridine calcium channel antagonists were associated with an increased risk for IHD (relative risk, 2.26; 95% confidence interval, 1.24 to 4.12; P: = 0. 008), and this association was independent of other antihypertensive agents and risk factors. Therefore, although the FHS risk predicts IHD after renal transplantation, it tends to underestimate the risks, especially the risk associated with diabetes mellitus. The unexpected finding that dihydropyridine calcium channel antagonists were associated with an increased IHD risk merits further evaluation.
Abstract Tacrolimus pharmacokinetics vary due to single nucleotide polymorphisms (SNPs) in metabolizing enzymes and membrane transporters that alter drug elimination. Clinically we observed that ...Native Americans require lower dosages of tacrolimus to attain trough levels similar to Caucasians. We previously demonstrated that Native Americans have decreased oral clearance of tacrolimus, suggesting that Native Americans may have more variant SNPs and, therefore, altered tacrolimus pharmacokinetic parameters. We conducted 12-hour pharmacokinetic studies on 24 adult Native American kidney transplant recipients on stable doses of tacrolimus for at least 1 month posttransplantation. Twenty-four Caucasian kidney transplant recipients were compared as controls. SNPs encoding the genes for the enzymes (CYP3A4, CYP3A5) and transporters (ABCB1, BCRP, and MRP1) were typed using TaqMan. The mean daily tacrolimus dose in the Native Americans was 0.03 ± 0.02 compared with the Caucasians 0.5 ± 0.3 (mg/kg/d; P = .002), with no significant differences in trough levels, (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P = .4). Many Native Americans, but not Caucasians, demonstrated the 3/*3 - C3435T CC and the *3/*3 -G2677T GG genotype combination previously associated with low tacrolimus dosing. Native Americans required significantly lower tacrolimus doses than Caucasians to achieve similar tacrolimus trough levels, in part due to lower tacrolimus clearance from decreased drug metabolism and excretion.
Since the publication of previous meta-analyses of cyclosporine (CsA) and prednisone withdrawal in renal transplant recipients, several additional randomized controlled trials with longer follow-up ...have been reported. Currently, in nine prednisone withdrawal trials (n = 1461), the proportion of patients with acute rejection was increased by 0.14 (95% confidence interval = 0.10 to 0. 17, P < 0.001). In nine prednisone withdrawal trials (n = 1899), the relative risk (RR; RR = 1.0 indicates no risk) of graft failure after withdrawal was also increased (RR = 1.40; range, 1.09 to 1.70, P = 0.012). There was no evidence of between-study heterogeneity for either acute rejection or graft failure in the prednisone withdrawal trials by a chi(2) test (P > 0.05). In 10 CsA withdrawal trials (n = 1049), the proportion of patients with acute rejection was increased by 0.11 (0.07 to 0.15, P < 0.001). In 12 trials (n = 1151), the RR of graft failure after CsA withdrawal was 1.06 (95% confidence interval, 0.82 to 1.29, P = 0.646), but a chi(2) test indicated that there was study heterogeneity. However, there was no evidence of heterogeneity in the six studies (n = 632) with at least 4.0 yr (5.8 +/- 1.7) of follow-up (RR = 0.92; range, 0.64 to 1.20, P = 0.569) or in the seven trials (n = 962) published in peer-reviewed journals (RR = 0.95; range, 0.70 to 1.20 P = 0.682). Finally, in three trials (n = 259) that compared CsA and prednisone withdrawal, there was a nonsignificant trend for less graft failure with CsA withdrawal (RR = 0.63; range, 0.08 to 1.16, P = 0.190). Thus, unlike prednisone withdrawal, CsA withdrawal in select patients seems to impart little risk of long-term graft failure.
Abstract Background Earlier studies reporting outcomes after pancreas transplantation have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus ...(T2DM). However, because the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate the type of diabetes in patients with kidney disease. Methods To improve the discriminative power and better classify the type of diabetes, we used a composite definition to identify T2DM: presence of C-peptide, negative glutamic acid decarboxylase antibody, absence of diabetic ketoacidosis, and use of oral hypoglycemics. Additionally among T2DM patients with end-stage renal disease (ESRD), body mass index of <30 kg/m2 and use of <1 u/kg of insulin per day were selection criteria for suitablity for simultaneous pancreas and kidney transplantation (SPKT). We compared graft and patient survival between T1DM and T2DM after SPKT. Results Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) or patient survival between the 2 groups. The mean creatinine clearance at 1 year estimated by the modification of Diet in Renal Disease (MDRD) equation was not significantly different between the 2 groups. Among those with 1 year of follow-up, all patients with T2DM had glycosylate hemoglobin of <6.0 at 1 year versus 92% of those with T1DM. Conclusion SPKT should be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Use of C-peptide measurements for ESRD patients can be misleading as the sole criterion to determine the type of diabetes.
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