Chronic kidney disease: novel insights from genome-wide association studies

Chronic kidney disease (CKD) is common, affecting about 10% of the general population, and causing significant morbidity and mortality. Apart from the risk conferred by traditional cardiovascular risk factors, there is a strong genetic component. The method of a genome-wide association study (GWAS) is a powerful hypothesis-free approach to unravel this component by association analyses of CKD with several million genetic variants distributed across the genome. Since the publication of the first GWAS in 2005, this method has led to the discovery of novel loci for numerous human common diseases and phenotypes. Here, we review the recent successes of meta-analyses of GWAS on renal phenotypes. UMOD, SHROOM3, STC1, LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2/SH2B3, DACH1, UBE2Q2, and SLC7A9 were uncovered as loci associated with estimated glomerular filtration rate (eGFR) and CKD, and CUBN as a locus for albuminuria in cross-sectional data of general population studies. However, less than 1.5% of the total variance of eGFR and albuminuria is explained by the identified variants, and the relative risk for CKD is modified by at most 20% per locus. In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA(2)R1 implicate most of the risk for idiopathic membranous nephropathy. In contrast, genetic findings in the analysis of diabetic nephropathy are inconsistent. Uncovering variants explaining more of the genetically determined variability of kidney function is hampered by the multifactorial nature of CKD and different mechanisms involved in progressive CKD stages, and by the challenges in elucidating the role of low-frequency variants. Meta-analyses with larger sample sizes and analyses of longitudinal renal phenotypes using higher-resolution genotyping data are required to uncover novel loci associated with severe renal phenotypes.     

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.     

Rat heart-aorta cluster transplantation: a novel model to study transplant rejection

The purpose of this study was to develop a microsurgical cluster model of heart plus entire thoracic aorta transplantation and to compare it to the isolated model of heart transplantation as a tool to study transplant rejection. Thirty-six syngeneic (DAxDA and LewxLew) and allogeneic (DAxPVG and DAxLew) cluster heart-aorta transplants were compared to 43 syngeneic and allogeneic isolated heart grafts. Graft survival, recipient survival and histological data on myocardial and aortic tissues were assessed. There was no statistically significant difference in graft survival between the two models studied (P>0.05). In the cluster transplants, the aortic component was spared the severity of acute rejection noted for the myocardial counterpart. In conclusion, the results demonstrated that the cluster model was technically feasible and highly reproducible. Additionally, it was possible to apply this model to the study of experimental allograft rejection using novel immunosuppressants. The success of the cluster model in strongly mismatched transplant strain combinations underscores its potential for application in slower rejection combinations, making it particularly suited for chronic rejection studies. The inherent capacity for sampling a broader range of vessel sizes in one animal makes the cluster model more suitable than the isolated models of aorta or heart for application to experimental protocols.This paper was presented in part at the 6th ESOT Congress in Rhodes, Greece, in October 1993     

大鼠肾移植急性排斥反应模型的建立

目的建立大鼠肾移植急性排斥反应(AR)模型,了解大鼠肾移植AR病理进程.方法异基因移植组由Wistar大鼠为供体,雄性SD大鼠为受体.同基因对照组供受体均为SD大鼠.肾移植术后第1、3、5、7天取移植肾组织,进行HE染色、Masson染色、PAS染色、PASM染色,光镜下观察病理改变,参照Banff 97标准进行诊断,根据Watanabe的方法进行AR严重程度的半定量评分.结果术后第1、3、5、7天异基因移植组和同基因对照组的半定量评分分别为(0.50±0.54)、(1.33±0.82)、(3.50±1.05)、(4.33±0.82)和(0.33±0.52)、(0.67±0.52)、(0.67±0.52)、(0.67±0.52).异基因移植组与同基因对照组评分比较差异均有统计学意义(P＜0.05).异基因移植组中两两比较结果第3、5、7天评分与第1天评分比较差异有统计学意义(P＜0.05),第3天与第5、7天评分差异有统计学意义(P＜0.05),第5天和第7天评分差异无统计学意义(P＞0.05).同基因对照组各天的评分差异无统计学意义(P＞0.05). 结论SD大鼠间组织相容性高,SD大鼠作为供受体的大鼠肾移植排斥反应轻微,可作为同基因对照组;Wistar-SD大鼠间肾移植AR发生快,程度重,是良好的AR动物模型.     

Heart valve dysfunction resulting from cellular rejection in a novel heterotopic transplantation rat model

Abstract Structural failure of heart valve allografts may be related to technical factors or immunological reactions. To circumvent nonimmunological factors a new rat implantation model was developed to study whether alloreactivity results in histopathological changes and valve dysfunction. Syngeneic (WAG‐WAG, DA‐DA) and allogeneic (WAG‐BN, WAG‐DA) transplantation was carried out using this new technique, and the function of explanted valves was assessed 21 days later by retrograde comptence testing. Additionally, grafts were examined using standard histological and immunohistochemical techniques. There was no leakage during retrograde injection in nine of tem syngeneic and two of ten allogeneic grafts. Microscopically, syngeneic valves appeared normal without fibrosis or intimal thickening, although CD8⁺ lymphocytes and macrophages were found in necrotic myocardial rim and adventitia. In contrast, allogeneic valves were deformed and noncellular, with extensive infiltration of CD4⁺, CD8⁺ and CD68⁺ cells in adventitia and media. Absence of fibrosis and intimal thickening in syngeneic transplanted valves indicated circumvention of nonimmunological factors. Allogeneic valve transplantation induces cellular infiltration in the graft with subsequent graft failure.     

Acute cellular rejection and HLA mismatch in heart transplantation: insights from a developing country

The notable evolution of heart transplant (HTX) has paralleled the capacity of diagnosing rejection and, consequently, initiating timely treatment. Acute cellular rejection, diagnosed by endomyocardial biopsy, is the most frequent in the first 6 months after HTX. HLA matching is not routinely performed in HTX due to the absence of consensus regarding its usefulness. However, the use of HLA typing might be underscored if it could predict an increased risk of rejection. Therefore, the aim of this study was to evaluate, at a public cardiology center in Brazil, the association between HLA mismatches and the incidence of acute cellular rejection in the first 6 months after HTX. Data were obtained from hospital records and from the National Transplant System. Overall, there was no association between the number of HLA mismatches and the frequency of acute cellular rejection, but there was a tendency toward a higher incidence of rejection with HLA‐DR incompatibility.     

Chronic rejection in renal transplantation

With renal transplantation, chronic rejection is currently the most prevalent cause of late transplant failure. Clinically, chronic rejection presents as chronic transplant dysfunction, characterized by a slow loss of function, often in combination with hypertension and proteinuria. Transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic for chronic rejection. Risk factors have been identified and include young recipient age, black race, presensitization, histoincompatibility, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral immune responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking play an important role. At the tissue level, senescence conditioned by ischemia/reperfusion may contribute to the development of chronic rejection. The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.     

Chronic rejection in renal transplantation

Chronic rejection in renal transplantation is an alloantigen-dependent immune process ultimately leading to graft failure. We reviewed the literature on the basis of the case history of a patient who lost her renal allograft apparently from chronic interstitial rejection. Chronic rejection presents clinically as chronic transplant dysfunction starting at various intervals after transplantation. The histopathologic features consist of chronic allograft nephropathy with or without transplant vasculopathy or glomerulopathy. Chronic rejection should be differentiated from chronic toxicity of calcineurin inhibitors, de novo or recurrent glomerulonephritis, polyoma (BK) virus nephropathy, transplant renal artery stenosis, and nephrosclerosis. Young recipient age, black race, presensitization, histoincompatibility, and acute, especially vascular, and late acute rejection episodes are dominant risk factors, compatible with immunologic mechanisms. Cellular and humoral responses resulting from indirect recognition of alloantigens with subsequent fibrotic sequelae play a central role in the pathogenesis. Circulating donor-specific antibodies and staining for C4d can detect humoral chronic rejection. The prognosis depends on alloreactivity and the presence of progression factors such as old donor age, renal dysfunction, proteinuria, hyperlipidemia, and smoking. A multifactorial approach directed to the risk and progression factors is needed to prevent premature graft loss from chronic rejection.     

Gemcitabine--a novel immunosuppressive agent--prevents rejection in a rat cardiac transplantation model.

BACKGROUND: 2',2' -difluorodeoxycytidine (dFdC, gemcitabine) is a pyrimidine antimetabolite with antineoplastic activity against a wide range of solid tumors. The immunosuppressive activities of this compound have not been described to date. METHODS: The in vitro effects on activated T lymphocytes were studied with a lymphocyte colony-forming assay in a microagar culture system. Heart transplantations were performed in the fully allogeneic Lewis/ Brown Norway combination. dFdC was administered once daily at various dosages from the time of surgery until day 50. RESULTS: Phytohemagglutinin-induced lymphocyte proliferation was inhibited 50% by dFdC at a concentration of 3.25+/-0.9 nmol/L. Allografts of untreated animals survived for 7.5 (7-8) days and those with 25, 50, and 75 microg/kg body weight dFdC for 7.3 (7-8), 9.3 (8-10), and 16.3 (10-38) days, respectively. Treatment with 100 or 125 microg/kg body weight of dFdC, however, prolonged allograft survival until day 152.8 (129-178). Dose-dependent leukopenia was the main toxicity. CONCLUSIONS: DFdC is a new immunosuppressive agent that can successfully prevent cardiac rejection in a rat transplantation model.     

Chronic rejection of mouse kidney allografts

BACKGROUND: Chronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined. METHODS: To explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection. RESULTS: We found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-beta (TGF-beta), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-beta up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-beta expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens. CONCLUSIONS: Reduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-beta expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-beta expression within the allograft.     

Post-renal transplantation hypophosphatemia: a review and novel insights

PURPOSE OF REVIEW: This review intends to elucidate the pathophysiologic mechanism of renal phosphorus loss in the post-renal transplantation population. This review will provide new insight in to the pathophysiologic mechanism(s) responsible for the development of this phenomenon and will also explore the pathogenetic role of persistent phosphorus wasting in the development of post-renal transplantation osteodystrophy. RECENT FINDINGS: Recently, the phosphaturic hormone, fibroblast growth factor-23, has been ascertain to be increased in the sera of patients with chronic kidney and end-stage renal disease. There is new evidence that a non-PTH humoral factor is persistently present in post-renal transplantation patients that is likely responsible for the observed persistent renal phosphorus loss. We offer that fibroblast growth factor-23 (and/or other phosphatonins) is the culprit factor responsible for the phenomenon of persistent hypophosphatemia in post-renal transplantation patients. Moreover, we believe that the phenomenon of persistent renal phosphorus wasting is an important but overlooked cause of osteodystrophy and increased fracture risk in this patient population. SUMMARY: The pathophysiology of post-renal transplantation phosphorus wasting is complex and to date is still not fully recognized. Further studies of the regulatory mechanism of fibroblast growth factor-23 and its metabolism may offer additional insights into phosphorus homeostasis and its clinical application in the post-renal transplantation population.     

Chronic rejection: an enduring enigma of transplantation biology

Renal transplantation has achieved reasonably good success over the years in controlling acute rejection episodes; however, the immunology of chronic rejection is still not well understood. The problem haunts transplanters across the globe. We describe the presentation, brief immunopathological events, and recent advances suggested by pathologists to define chronic rejection and differentiate it from chronic allograft nephropathy. Our experience using tolerance induction is briefly mentioned including a reduced incidence of acute rejection episodes, chronic rejection events, or calcineurin inhibitor toxicity using lower drug levels.     

Compliance and late acute rejection after kidney transplantation: a psycho-medical perspective

INTRODUCTION: We examined the relationship between late acute rejection (LAR) after cadaveric kidney transplantation and medical compliance utilizing a modified version of the Long-term Medication Behaviour Self-efficacy Scale (LTMBS-scale), a validated patient self-report questionnaire. The original LTMBS-scale uses a five-point scale, however, our pilot study showed that patients found it difficult to discriminate between the five options. We therefore modified this to a three-point scale. PATIENTS AND METHODS: We carried out a retrospective analysis of all patients who received a kidney transplant in our unit in the cyclosporin (CyA) era. We divided rejections into early and late rejection based on the time interval after transplantation. Graft rejection was confirmed by biopsy; LAR was defined as acute rejection occurring after 90 d. We retrospectively administered the modified LTMBS-scale to determine individual patient confidence and self-efficacy in taking their medications in a variety of situations (home, work, leisure, psychological and physical). Individual patient confidence and self-efficacy was analysed in relationship to compliance behaviour. RESULTS: Twenty-four questionnaires were distributed, 22 (92%) were returned fully completed. The overall results suggested that our patients surveyed were not particularly confident (mean score 2.17 out of maximum possible 3) in taking their medications in a variety of contexts. They demonstrated significantly less confidence (mean score 1.0) when experiencing physical (brittle bones, feeling 'ill') and psychological ('sadness') side-effects of medication and emotional reactions to the experience of chronic illness. CONCLUSION: Negative physical and psychological states were related to low self-efficacy with the taking of immunosuppressive medication, non-compliance and subsequent LAR in our cohort of patients.     

Treatment of humoral rejection in kidney transplantation

Acute antibody-mediated rejection (acute humoral rejection [AHR]) of organ allografts presents most of the time as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition is diagnostic of AHR in kidney allografts and is associated with circulating donor-specific anti-HLA alloantibodies. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), mycophenolate mofetil, tacrolimus, and/or intravenous immunoglobulins have been used to successfully treat AHR. The optimal protocol to treat humoral rejection remains to be defined. Anti-CD20 monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as a rescue therapy in some episodes of refractory humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully “desensitize” selected high-immunologic risk patients who were in anticipation of crossmatch-positive (or ABO-incompatible) kidney transplantation. Recent data suggest that chronic kidney allograft rejection might also be monitored by complement C4d in biopsies. The efficacy and safety of immunosuppressive drugs such as tacrolimus, mycophenolate mofetil (or enteric-coated mycophenolic acid), sirolimus, or everolimus in controlling antidonor humoral responses in patients with chronic allograft dysfunction remains to be studied prospectively. The combination of tacrolimus and mycophenolate mofetil appears to effectively suppress antidonor antibody production. In the near future, the possible role of specific anti–B-cell approaches with drugs, such as rituximab, or possibly of new anti–T-cell activation approaches using selective agents such as belatacept should be assessed to refine the management of chronic allograft dysfunction.     

Cadaveric kidney transplantation: a model with limitations

The first successful kidney transplant in Spain was performed in 1965. It's been forty years already and currently Spain is the country with the highest cadaver donation rates worldwide. The so-called Spanish model of transplantation is well known for its organization and excellent results. These results are the consequence of a perfect network organization. Furthermore, the organ procurement organization--Organización Nacional de Trasplantes--, regional coordinators, national health system hospital network, hospital transplant coordinators, and all professionals involved in the process of donation and transplantation have perfectly well defined functions and work with the common objective of optimizing resources and making the most of the opportunities. Provided that one of the main characteristics of the Spanish model is the possibility of adaptation to the moments necessities, we proceed to review and evaluate it from its beginning to current days.     

Quantification of donor-derived DNA in serum: a new approach of acute rejection diagnosis in a rat kidney transplantation model

Clinical and laboratory findings of acute rejection (AR) are often late and misleading. Core needle biopsy, the most reliable diagnostic method, is usually performed late in the course of AR and is associated with several complications. Therefore noninvasive approaches to monitor the immune system for detection of early AR is one of the major aims in transplant medicine. In a fully MHC-mismatched renal allograft model in the rat, we quantified donor-derived DNA (ddDNA) in the recipient serum using real-time RT-PCR as an alternative screening procedure for the early diagnosis of acute rejection. We also investigated the influence of different immunosuppressive protocols on the levels of ddDNA. Our results show that donor-derived DNA is present in the serum of kidney allograft recipients prior to acute rejection. Animals that received a syngeneic graft and animals that received a mismatched allograft but were treated with immunosuppressive drugs did not show significant elevations of ddDNA. When steroid therapy failed to avoid acute rejection, the animals showed a delayed peak of ddDNA. In summary, the detection of ddDNA in recipient serum offers a noninvasive diagnostic approach to uncover ongoing rejection processes in the graft.     

Clinical efficacy of rituximab for acute rejection in kidney transplantation: a meta-analysis

Objectives

This meta-analysis was undertaken to compare the efficacy and safety of pretransplant treatment with rituximab in sensitized patients receiving kidney transplantation.

Methods

PubMed, EMBASE, and Cochrane databases were searched to identify studies that used pretransplantation rituximab in eligible patients. The major outcomes included antibody-mediated rejections (AMR) after kidney transplantation and one-year graft survival rate. The meta-analysis was performed using fixed-effects model.

Results

Seven studies were identified including a total of 589 patients, of whom 312 were treated without rituximab, while 277 were treated with rituximab. In our meta-analysis, patients treated with rituximab had significantly fewer AMR after kidney transplantation [odds ratio (OR) 0.52, 95 % CI 0.28, 0.98, P = 0.04] and higher rate of one-year graft survival rates (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03), indicating that rituximab is effective against acute rejection and enhances graft survival in kidney transplantation. No differences were noted in other efficacy and safety parameters in these two patient groups.

Conclusions

We demonstrated that preinduction with rituximab could significantly improve AMR and graft survival rates in sensitized patients undergoing kidney transplantation. Future prospective controlled studies are warranted to further understand rituximab’s role in kidney transplantation.