Paul Trevillian

Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data

BACKGROUND Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation. METHODS Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age. RESULTS One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6-1.8 for >/=3 HLA-A, -B, -DR mismatches compared with those with <3 mismatches) and age (OR = 1.2-1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0-2.3). Three polymorphisms of the IL-10 gene at -1082, -819, -592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6-1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6). CONCLUSION Pooled results to date suggest possible association between both the TGF-beta1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.

Potential roles of erythropoietin in the management of anaemia and other complications diabetes

Erythropoietin (EPO) is a haematopoietic cytokine, mainly generated in the renal cortex, and its secretion and action is impaired in chronic kidney disease (CKD). Early renal damage in diabetes mellitus (DM) is usually not detected because diabetes‐induced nephron hypertrophy maintains glomerular filtration rate (GFR) and an elevated plasma creatinine concentration is a relatively late manifestation of diabetic nephropathy. However, anaemia occurs more frequently in subjects with DM when compared with those with non‐DM renal disease. While reduced production and a blunted response to EPO occurs in DM with early renal damage, other factors including chronic inflammation, autonomic neuropathy and iron deficiency are also important. Although recombinant human erythropoietin (rhEPO) has been an effective therapeutic agent in CKD anaemia, it appears to be more effective in patients with DM, even in earlier stages. Nevertheless, patients with DM are also more likely to be iron deficient, a barrier to effective rhEPO therapy. The effect of treatment on the reliability of haemoglobin A1c as an index of glycaemic control must be remembered. It is proposed that anaemia and its causes must be important components of care in subjects with early diabetic renal damage.

Assessment of the Bioequivalence of a Generic Cyclosporine A by a Randomized Controlled Trial in Stable Renal Recipients

Background. The aim of this study was to determine the bioequivalence of Cysporin, a generic cyclosporine A, compared with Neoral in stable renal transplant recipients. Methods. Study design consisted of an open label, two-way crossover, randomized controlled trial of Cysporin versus Neoral in stable renal transplant recipients. In all, 33 patients were enrolled; 31 were randomized and 28 were evaluable. AUCs 0–12 were done on day 14 and 28; C0 and C2 were done on days 0, 7, 21 and 35. Dose conversion was 1:1. Outcome measures for serum cyclosporin A concentrations expressed as the mean±SD were AUC 0–12 (&mgr;g.hr/L), Cmax (&mgr;g/L), C2 (&mgr;g/L), Tmax (hr) and T1/2 (hr). Mean and 90% CI of the ratio Cysporin/Neoral of log-transformed data were calculated using a general linear model. Results. The main pharmacokinetic features were: AUC0–12: Cysporin 3495±1319, Neoral 3853±1378 (P<0.05); Cmax: Cysporin 755±301, Neoral 881±368 (P<0.05); C2: Cysporin 613±235, Neoral 672±255 (P>0.05); Tmax: Cysporin 1.9±0.8, Neoral 1.4±0.6 (P<0.005); and T1/2: Cysporin 8.8±4.3, Neoral 8.7±6.2 (P>0.05). Estimated ratios of Cysporin/Neoral were: AUC 0.93 (90% CI 0.88–0.98; P<0.05); Cmax 0.88 (90% CI 0.80–0.97; P<0.05); and Tmax 1.32 (90% CI 1.14–1.53; P<0.005). Conclusions. Both the extent and rate of absorption of Cysporin are significantly less than those of Neoral. The 90% CI for the ratios of Cysporin/Neoral for AUC and Cmax lie within 0.80–1.25. Hence in this clinical context Cysporin is pharmacologically bioequivalent with Neoral. This study illustrates the importance of testing bioequivalence of generic cyclosporine A products in transplant recipients not healthy volunteers.

Evidence-based guidelines for the nutritional management of adult kidney transplant recipients.

OBJECTIVE The present article summarizes the key recommendations of the evidence-based guidelines developed for the nutritional management of adult kidney transplant recipients. BACKGROUND AND METHODS Nutrition interventions play an important role in preventing and managing common health problems associated with renal transplantation such as obesity, hypertension, diabetes, and cardiovascular disease. Two sets of guidelines were developed by a working group of renal dietitians and nephrologists. They were subject to expert panel review, and public consultation by renal clinicians and consumers before final endorsement by 2 authorities in Australia--Caring for Australasians with Renal Impairment (CARI) and Dietitians Association of Australia (DAA). Protocol and rigor of guideline development were previously described and published in the Journal of Renal Nutrition, 2009. RESULTS AND OUTCOMES These guidelines address 13 priority topics identified by the renal community and complement each other with different emphasis, from research translation to day to day clinical practice recommendations. The published guidelines are available to the public through web-access of CARI and DAA, and journal publications. Information includes the guidelines themselves with level of evidence stated, grading of recommendations, suggestions for clinical care, search strategy, background and summary of evidence, recommendations of other guidelines, practice recommendations, appendices of useful tools, and suggestions for audits and future research. CONCLUSIONS Two sets of comprehensive evidence-based nutrition guidelines from CARI and DAA are now available to help improve health outcomes of adult kidney transplant recipients.

Monoclonal gammopathy and glomerulopathy associated with chronic lymphocytic leukemia.

Background A 42-year-old previously healthy man was referred to hospital with an 8-week history of fevers, night sweats, fatigue, and unintentional weight loss. There was no past history of medical illness or any medication use. Physical examination was unremarkable. On urinalysis, the patient had hematuria (grade 4+) and proteinuria (grade 4+).Investigations Urine phase-contrast microscopy, full blood count, renal function tests, 24-h urine collection for protein, serum immune electrophoresis, renal biopsies, phase-contrast microscopy, serological tests for antinuclear antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies, hepatitis B, hepatitis C and HIV, cryoglobulin test, complement testing, flow cytometry of the peripheral blood, and bone marrow biopsy.Diagnosis Monoclonal gammopathy and a glomerulopathy, with microtubular deposits, associated with chronic lymphocytic leukemia.Management Treatment with prednisone and cyclophosphamide did not improve proteinuria, although lymphocyte count returned to normal. The patient did not tolerate high-dose cyclophosphamide and was started on rituximab. His proteinuria completely resolved and there was complete disappearance of the microtubules.

Development of Evidence-Based Guidelines for the Nutritional Management of Adult Kidney Transplant Recipients

OBJECTIVE This article documents the development of evidence-based guidelines for the nutritional management of adult kidney transplant recipients. Dietary interventions play an important role in preventing and managing common post-transplant health problems, such as cardiovascular disease and diabetes. However, there are currently no comprehensive, evidence-based guidelines for the nutritional management of kidney transplant recipients. METHODS AND RESULTS Thirteen guideline topics were identified, including obesity, diabetes, dyslipidemia, and bone disease, following broad consultation with clinicians and transplant recipients in Australia and New Zealand. A systematic review of the scientific literature was undertaken, the protocol for which is published in the Cochrane Library. The evidence was graded and synthesized, and evidence-based recommendations formulated consistent with National Health and Medical Research Council of Australia standards. A total of 119 scientific papers were assessed. CONCLUSION There was no level I or II evidence to support any guideline; however, there was sufficient level III and IV evidence to support Grade C and D recommendations for six guideline topics. Experts from 18 transplant units in Australia and New Zealand were consulted to generate consensus-based recommendations for the remaining seven topics, using the Delphi method. Using evidence from a comprehensive literature search and expert opinion, guidelines that represent current best practice have been produced. These guidelines have been evaluated in transplant units throughout Australia and New Zealand and have been submitted to the Dietitians Association of Australia (DAA) and Caring for Australasians with Renal Impairment (CARI) for endorsement.

Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study.

Background To measure the risk of cancer in renal transplantation for recipients who had previously been treated with immunosuppressive agents for primary renal disease. Methods A retrospective population-based cohort study of 5970 renal transplant recipients in Australia registered on the Australia and New Zealand Dialysis and Transplant Registry between 1982 and 1997 and followed until 2007. Data about the incidence of a range of cancer types from this Registry were compared with cancer incidence data for the general population matched for cancer type, year of incidence, age, and gender derived from national cancer records. Outcome measures for each cancer group with or without pretransplantation immunosuppression were cancer-specific standardized incidence ratios and a multivariate hazard ratio (HR) standardized to 1. Results For those treated with pretransplantation immunosuppression, the risks for four cancer groups during renal transplantation were significantly increased: anogenital cancer (HR, 3.13; confidence interval [CI], 1.92–5.11; P<0.0001), non–Hodgkin’s lymphoma (HR, 2.37; CI, 1.53–3.68; P=0.0001), breast cancer (HR, 2.52; CI, 1.13–5.61; P=0.024), and urinary tract cancer (excluding kidney) (HR, 1.84; CI, 1.13–3.01; P=0.015). However, the risks of cancer in the oral cavity and pharynx, kidney, thyroid, colon, leukemia, lung, melanoma, prostate, and stomach were not significantly increased. Conclusions Pretransplantation immunosuppression for primary renal disease increases the risks of four cancer types in renal transplantation while sparing the others. Patients in whom this treatment is being considered should be informed of these risks.

Salvaging kidneys with renal allograft compartment syndrome.

Renal allograft compartment syndrome is an under recognized cause of early allograft dysfunction which can be reversed by early intervention. It occurs early after renal transplantation where closure of the anterior abdominal wall seems to compress the transplant in the limited retroperitoneal space. The literature about this syndrome in renal transplantation is sparse. Our report describes the diagnostic criteria and the management of two renal transplant recipients with this syndrome. Its diagnosis depends upon duplex vascular scan findings of reversed or absent diastolic flow in the renal vasculature in the absence of any perigraft collection or severe acute tubular necrosis. In our hands emergency laparotomy, decompression of the transplant and closure with interposition mesh salvaged these kidneys.

Nutritional management of overweight and obesity in adult kidney transplant recipients

Date written: June 2008

Nutritional management of diabetes mellitus in adult kidney transplant recipients

Date written: June 2008