Outcomes in kidney transplantation

doi:10.1016/S0270-9295(03)00066-4

Seminars in Nephrology

Volume 23, Issue 3, May 2003, Pages 306-316

https://doi.org/10.1016/S0270-9295(03)00066-4 Get rights and content

Abstract

It is estimated that there are greater than 100,000 kidney transplant recipients with a functioning graft in the United States. Recent advances in immunosuppression have improved short-term graft survival rates and decreased early mortality by decreasing the incidence and therapy for acute rejection episodes. For those accepted on the waiting list, transplant prolongs patient survival compared with remaining on dialysis. During the 1990s, 3 new immunosuppressive drugs were introduced in clinical kidney transplantation. All were approved for use by the Food and Drug Administration after large, controlled, randomized trials. Mycophenolate mofetil (MMF), when combined with cyclosporine (CSA) and prednisone, lowered acute rejection rates by nearly 50% compared with control. Tacrolimus compared with CSA also significantly reduced acute rejection rates in kidney transplant recipients, but was associated with a significant increase in posttransplant diabetes mellitus (PTDM) in the early trials. When evaluated in combination with MMF, the incidence of PTDM was much lower. At the end of the decade, sirolimus was shown in several randomized trials to lower acute rejection rates and is believed to be less nephrotoxic compared with calcineurin inhibitors. All of the randomized trials were not statistically powered to assess long-term superiority. Registry analyses have been performed that appear to show some long-term benefit of immunosuppressive therapy with MMF. Other outcome assessments in kidney transplant recipients include risk factors for chronic allograft nephropathy, hypertension, hyperlipidemia, and bone disease. Although there are few randomized trials, understanding of the significance of these common complications has progressed and strategies for therapy and intervention have been developed. This article focuses on the randomized trials of immunosuppressive therapy and complications associated with use of these drugs. In addition, we review the current management and intervention for the comorbidities associated with the long-term clinical management of the kidney transplant recipient.

Section snippets

Azathioprine

Azathioprine (AZA) combined with corticosteroids was the mainstay of immunosuppression until the introduction of cyclosporine (CSA) in the 1980s. AZA then became part of a triple drug regimen of AZA, CSA, and corticosteroids until the mid-1990s when 3 large randomized trials showed the superior efficacy of mycophenolate mofetil (MMF) over AZA for the prevention of acute rejection after renal transplantation.6, 7, 8, 9 Most centers abandoned the use of AZA with the introduction of MMF.

Mycophenolate mofetil

Kidney function

The diagnosis of CAN usually is suggested by slowly increasing plasma creatinine concentration, increasing proteinuria, and worsening hypertension.33 Hariharan et al34 recently showed that the most important predictor of graft outcome in kidney transplantation is the 1-year serum creatinine (Scr) level. In a retrospective analysis of 105,742 kidney transplant recipients, the investigators showed that patients with a 1-year Scr greater than 1.5 mg/dL or a change in creatinine level from 6 to 12

Summary

Nephrologists and primary care physicians are being more involved in the care of kidney transplant recipients. Long-term graft survival depends on long-term patient survival. Similarly, a functioning kidney transplant significantly prolongs life compared with dialysis. Kidney transplant recipients can be considered as a unique group of patients with CKD. Therefore, providers caring for these patients should monitor their kidney function closely and screen and treat risk factors, such as

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Exosomes and microvesicles in kidney transplantation: the long road from trash to gold
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Kidney transplantation significantly enhances the survival rate and quality of life of patients with end-stage kidney disease. The ability to predict post-transplantation rejection events in their early phases can reduce subsequent allograft loss. Therefore, it is critical to identify biomarkers of rejection processes that can be acquired on routine analysis of samples collected by non-invasive or minimally invasive procedures. It is also important to develop new therapeutic strategies that facilitate optimisation of the dose of immunotherapeutic drugs and the induction of allograft immunotolerance. This review explores the challenges and opportunities offered by extracellular vesicles (EVs) present in biofluids in the discovery of biomarkers of rejection processes, as drug carriers and in the induction of immunotolerance. Since EVs are highly complex structures and their composition is affected by the parent cell's metabolic status, the importance of defining standardised methods for isolating and characterising EVs is also discussed. Understanding the major bottlenecks associated with all these areas will promote the further investigation of EVs and their translation into a clinical setting.
Influence of Interferon Gamma +874 T>A (rs2430561) Polymorphism on Renal Allograft Rejection: A Meta-analysis
2021, Transplantation Proceedings
Reported associations of the interferon gamma (IFNG) +874T/A (rs2430561) polymorphism with post-kidney transplantation allograft rejection (AR) have been inconsistent, prompting a meta-analysis to obtain more precise estimates.
Eighteen articles (22 studies) were included in the meta-analysis. Operating on the hypothesis that IFNG rs2430561 either increases or reduces AR risk, we used a genetic model-free approach to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Subgrouping was based on ethnicity (white, Middle Eastern, black, and mixed) and rejection type (ACR: acute rejection and CHR: chronic rejection). Quality of the associative effects was assessed with sensitivity treatment and test for publication bias.
The overall analysis in the dominant model indicated increased risk (OR = 1.26; P^a = .02) was validated in the ACR subgroup (OR = 1.29; P^a = .01), which contrasted with the CHR subgroup, with a nonsignificant effect indicating reduced risk (OR = 0.83; P^a = .68). Only the black subgroup showed significant increased risk (OR = 2.87; P^a = .04), but the association was tenuous on account of low sample size (n = 2) and imprecise effect (95% CI, 1.07-7.73).
Increased risk associations (overall and ACR) of IFNG rs2430561 with AR is significant, robust, statistically powered, and lacking bias. Contrasting ACR (1.3-fold increased risk) and CHR (7% protective) effects may be clinically relevant in the genetics of renal transplantation.
Association between Interleukin-2 -330 T/G Polymorphism and Acute Renal Graft Rejection: A Meta-analysis
2015, Transplantation Proceedings
Interleukin-2 (IL-2) −330 T/G promoter polymorphism is involved in the acute rejection (AR) risk of kidney transplantation. However, results from published studies on the association between recipient IL-2−330 T/G polymorphism and AR risk are conflicting and inconclusive.
We searched Medline, Embase, Web of Science, and Cochrane Central Register from their inceptions through January 2015 for relevant studies. Data concerning publication information, population characteristics, and transplant information were extracted. Odds ratios (ORs) were calculated for the association between IL-2−330 T/G polymorphism and AR risk.
This meta-analysis included 8 case-control studies with 1,405 cases of renal transplant recipients. The pooled estimate showed that IL-2−330 T/G polymorphism was not associated with AR risk: TT vs TG+GG: OR_fixed, 0.93; 95% confidence interval [CI], 0.72–1.21; P = .60; GG vs TG+TT: OR_fixed, 1.15; 95% CI, 0.76–1.72; P = .51; TG vs TT+GG: OR_fixed, 1.01; 95% CI, 0.78–1.31; P = .91; T vs G: OR_fixed, 0.93; 95% CI, 0.77–1.13; P = .48. None of subgroup analyses yielded significant results in the association between IL-2−330 T/G polymorphism and AR risk. Meta-regression confirmed that there was no significant correlation between the preselected trial characteristics and our study results.
This meta-analysis suggests that IL-2−330 T/G polymorphism may not be associated with AR risk in renal transplant recipients.
Study of the cytokine polymorphisms in correlation to rejection and graft survival in renal allograft donors and recipients from a homogenous Saudi population
2014, Transplant Immunology
Citation Excerpt :
Despite recent improvement in immunosuppressive medication and HLA-matching, allograft rejection continues to be problematic and remains the leading cause of graft loss after renal transplantation. Enhanced HLA matching between donors and recipients, optimized immunosuppression, and/or decline of cold ischemia time have improved short-term graft survival rates and decreased early mortality in kidney transplantation [1]. Recent observations signify the importance of the innate immune system in both graft rejection and induction of tolerance following organ transplantation [2].
Allograft outcome can be improved with the discovery of risk factors that influence adverse events and may allow individualization of patients' treatment. Rejection is the main hurdle to successful transplantation and the immune response is the key effecter to rejection development. Hence, the major objective of the present study was to assess the relationship between single nucleotide polymorphisms (SNPs) in 5 cytokine genes, HLA mismatch and graft outcome in a cohort of 100 Saudi kidney transplant recipients and 100 living related donors at a single transplant center.
Genotyping of the following positions: TNFA (− 308 G/A), TGFB1 (codon 10 T/C, codon 25 C/G), IL-10 (− 1082 G/A, − 819 C/T, − 592 C/A), IL-6 (− 174 C/G), and IFNG (+ 874 T/A) were performed.
The majority of the donors whose recipients presented with either cellular or antibody mediated graft rejection (90% and 100%) respectively were found to be significantly (p = 0.0351) associated with intermediate or high IL-10 producing haplotypes, compared to those with stable grafts (58.66%). Haplotypes linked with lower IL-10 production were not detected in the donors or their recipients with antibody mediated graft rejection compared to donors with stable graft (41.33%). The distribution of donor IL-10-1082 haplotypes (GG, GA, AA) showed a statistically significant association of IL-10-1082 GA genotype (p = 0.0351) with rejection, when grouped according to patients' rejection status. No other statistically significant deviations were observed in the donors' genotypes. Analyses of cytokine polymorphisms in the recipients revealed no significant association. Multivariate logistic regression analyses showed that only HLA-DRB1 mismatch significantly influenced graft loss (p = 0.0135).
This study demonstrates that the donor IL-10 genotypes and HLA-DRB1 mismatch are key determinants in graft outcome after renal transplantation.
A reproducible mouse model of chronic allograft nephropathy with vasculopathy
2012, Kidney International
Although short-term outcomes in kidney transplantation have improved dramatically, long-term survival remains a major challenge. A key component of long-term, chronic allograft injury in solid organ transplants is arteriosclerosis characterized by vascular neointimal hyperplasia and inflammation. Establishing a model of this disorder would provide a unique tool not only to identify mechanisms of disease but also to test potential therapeutics for late graft injury. To this end, we utilized a mouse orthotopic renal transplant model in which C57BL/6J (H-2b) recipients were given either a kidney allograft from a completely mismatched Balb/cJ mouse (H-2d) or an isograft from a littermate. A unilateral nephrectomy was performed at the time of transplant followed by a contralateral nephrectomy on post-transplant day 7. Recipients were treated with daily cyclosporine subcutaneously for 14 days and then studied 8 and 12 weeks post transplantation. Renal function was significantly worse in allograft compared with isograft recipients. Moreover, the allografts had significantly more advanced tubulointerstitial fibrosis and profound vascular disease characterized by perivascular leukocytic infiltration and neointimal hyperplasia affecting the intrarenal blood vessels. Thus, we describe a feasible and reproducible murine model of intrarenal transplant arteriosclerosis that is useful to study allograft vasculopathy.
Donor or recipient TNF-A -308G/A polymorphism and acute rejection of renal allograft: A meta-analysis
2011, Transplant Immunology
Citation Excerpt :
It has not been fully explained why patients even with similar matching status and treated with identical immunosuppressive protocols show variation in incidence of acute rejection [55]. On the other hand, immunosuppressive protocol including induction therapy may increase the drug-related side effects, such as nephrotoxicity, infection and cancer [2]. Therefore, it's of great importance to identify risk factors that influence the incidence and severity of AR in transplantation research, considering that it may be helpful to a tailored immunosuppressive protocol.
Results from published studies on the association of donor or recipient TNF-A −308G/A polymorphism with acute rejection (AR) of renal allograft are inconsistent. We performed a meta-analysis to summarize the possible association.
Studies were identified by searching PUBMED, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases until March 22, 2011. Meta-analysis was performed in a fixed/random-effect model using Revman 5.0.25 and STATA10.0.
Eight studies evaluating the association between donor TNF-A −308G/A polymorphism and acute rejection of renal allograft were identified. Pooled OR based on 460 cases (whose recipient developed AR) and 623 controls (whose recipient did not develop AR) was 1.44 (95% CI = 1.05–1.99, p = 0.03). No association was detected in the subgroup analysis based on ethnicity. 28 studies evaluating the association between recipient TNF-A −308G/A polymorphism and acute rejection were identified. Pooled OR based on 1411 cases (patients did not develop AR) and 2088 controls was 1.39 (95% CI = 1.06–1.82, p = 0.02). Two studies evaluating the association between recipient TNF-A −308G/A polymorphism and recurrent acute rejection were identified. Pooled OR based on 225 cases (patients with ≤ 1 AR) and 34 controls (patients with ≥ 2 AR) was 0.28 (95% CI = 0.13–0.62, p = 0.002).
Our meta-analysis provided evidence that TNF2 allele positive genotype of donor or recipient was associated with increased risk of incidence of acute rejection of renal allograft. Recipient TNF2 allele positive genotype is also associated with increased risk of recurrence of acute rejection of renal allograft. However, additional studies with large sample size and better study designs are warranted to verify our finding.

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