Comparing cystatin C and creatinine in the diagnosis of pediatric acute renal allograft dysfunction

Background  

Allograft function following renal transplantation is commonly monitored using serum creatinine. Multiple cross-sectional studies have shown that serum cystatin C is superior to creatinine for detection of mild to moderate chronic kidney dysfunction. Recent data in adults indicate that cystatin C might also be a more sensitive marker of acute renal dysfunction. This study aims to compare cystatin C and creatinine for detection of acute allograft dysfunction in children using pediatric RIFLE (risk of renal dysfunction, injury to the kidney, failure or loss of kidney function, end stage renal disease) criteria for acute kidney injury.     

Predictive factors in chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is characterized by progressive renal dysfunction leading in many cases to graft loss. The pathogenesis of CAN involves both immune and nonimmune factors. Concerning immune factors, one of the most remarkable predictors of CAN is acute rejection, which is associated with a worse prognosis if there are multiple episodes or when late onset occurs. Delayed graft function is also a major risk factor for CAN because of a correlation between late restoration of renal function after transplantation and long-term decreased graft survival. High creatinine levels at 6 months and 1 year after transplantation, proteinuria, viral infections, and cardiovascular risk factors are additional significant parameters for the development of CAN. Recent findings suggest that a high renal segmental arterial resistance index measured by Doppler ultrasonography in intrarenal vessels is associated with poor allograft function. Moreover, the study of patient genetic profile represents a new approach to identify predictive factors for CAN.     

巨噬细胞在移植肾纤维化中的作用研究进展

缺血-再灌注损伤、排斥反应、钙调磷酸酶抑制剂造成的肾毒性等因素会在肾移植术后使肾细胞外基质过度积聚,逐渐造成移植肾纤维化,最终导致肾衰竭。近年来,巨噬细胞在移植肾纤维化中的作用机制逐渐受到关注,有研究表明哺乳动物雷帕霉素靶蛋白抑制剂等药物可以通过巨噬细胞途径减缓肾移植术后移植肾纤维化。本文就移植肾纤维化的主要病因及病理生理学机制、不同巨噬细胞在移植肾纤维化进展中的作用、外周募集巨噬细胞和肾驻留巨噬细胞对肾损伤区域的浸润、巨噬细胞对肌成纤维细胞的诱导作用及巨噬细胞相关的移植肾纤维化潜在治疗方案进行综述,以期为巨噬细胞在移植肾纤维化中的研究提供参考。     

Pathogenesis of chronic renal allograft dysfunction

The pathogenesis of chronic renal allograft dysfunction was reviewed. Chronic rejection/chronic renal allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as glomerular hyper-filtration, delayed graft function, repeated acute rejection, systemic hypertension and hyperlipidemia. However, the precise pathogenesis of chronic allograft nephropathy remains obscure. The differential diagnosis of immunologically mediated chronic rejection and chronic allograft dysfunction caused by non-immunologic factors is usually impossible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis with tubular atrophy and thickening of vascular intima, and these findings are non-specific. Therefore, the term chronic allograft nephropathy may be clinically preferable to chronic rejection to describe the gradual decline in graft function. The most effective way to prevent chronic allograft dysfunction is to avoid any kind of graft damage via immunologic or non-immunologic pathway.     

The lack of Lazarus effect with proteasome inhibition

There have been marked improvements in the short- and long-term outcomes for children after renal transplantation over the past two decades with superior quality and quantity of life. It is encouraging to see increased patient and renal allograft survival rates with initially lower acute renal allograft rejection rates due to improved matching and immunosuppressive regimens. Unfortunately, longer-term renal allograft survival remains unchanged with chronic allograft injury from both immune and non-immune causes, resulting in chronic allograft dysfunction, morbidity from chronic kidney disease, and eventual renal allograft loss. Acute and chronic antibody-mediated rejection remains a clinical dilemma with a growing evidence base of its treatment, including proteasome inhibition using intravenous bortezomib. The future goal is to reduce chronic allograft dysfunction and make renal transplants last longer for pediatric renal transplant recipients who may require retransplantation during their childhood and adult lives, which can become successively more difficult due to sensitization.     

管周毛细血管损伤在肾移植中作用的研究进展

肾脏是一个高度血管化的器官,管周毛细血管网络是其微血管系统中关键组成部分。管周毛细血管作为肾小管及肾间质的主要供应血管,参与肾小管的能量代谢、物质分泌和重吸收等重要生理过程。近年来研究发现,肾移植过程中的缺血-再灌注损伤、排斥反应以及肾脏纤维化过程均会引起管周毛细血管结构完整性破坏、数量减少,并加重移植肾间质纤维化,严重影响肾功能的长期稳定。因此,本文对管周毛细血管的结构与功能,管周毛细血管与缺血-再灌注损伤、排斥反应以及移植肾纤维化进行综述,聚焦肾移植期间管周毛细血管的损伤机制和特异性改变,为防治肾移植围手术期并发症,改善移植物的长期预后提供参考。     

The Emerging Role of DNA Methylation in Kidney Transplantation: A Perspective

Allograft outcome depends on a range of factors, including donor age, the allo‐immune response, ischemia–reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia–reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end‐stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy.     

Chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the leading cause of renal allograft loss in paediatric renal transplant recipients. CAN is the result of immunological and nonimmunological injury, including acute rejection episodes, hypoperfusion, ischaemia reperfusion, calcineurin toxicity, infection and recurrent disease. The development of CAN is often insidious and may be preceded by subclinical rejection in a well-functioning allograft. Classification of CAN is histological using the Banff classification of renal allograft pathology with classic findings of interstitial fibrosis, tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia and arteriolar hyalinosis. Although improvement in immunosuppression has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem. Protocol biopsy monitoring is not current practice in paediatric transplantation for CAN monitoring but may have a place if new treatment options become available. Newer immunosuppression regimens, closer monitoring of the renal allograft and management of subclinical rejection may lead to reduced immune injury leading to CAN in the paediatric population but must be weighed against the risk of increased immunosuppression and calcineurin inhibitor nephrotoxicity.     

移植肾纤维化的诊断和治疗优化方案

移植肾纤维化是肾移植术后常见且严重的并发症之一,严重影响移植肾的功能和存活率,甚至可能导致器官衰竭和患者死亡。目前关于移植肾纤维化的研究非常复杂,包括免疫、缺血-再灌注损伤、感染、药物毒性等,移植肾纤维化的诊断和治疗依然极具挑战性。本文旨在总结当前研究的最新进展,深入探讨移植肾纤维化的成因以及最新的诊断和治疗方法。通过提高诊断的准确率和优化治疗方案,有望改善肾移植受者的预后,也将为临床医师更好地管理肾移植受者提供参考。     

Tubular epithelial syndecan-1 maintains renal function in murine ischemia/reperfusion and human transplantation

Syndecan-1, a heparan sulfate proteoglycan, has an important role in wound healing by binding several growth factors and cytokines. As these processes are also crucial in damage and repair after renal transplantation, we examined syndecan-1 expression in human control kidney tissue, renal allograft protocol biopsies, renal allograft biopsies taken at indication, and non-transplant interstitial fibrosis. Syndecan-1 expression was increased in tubular epithelial cells in renal allograft biopsies compared with control. Increased epithelial syndecan-1 in allografts correlated with low proteinuria and serum creatinine, less interstitial inflammation, less tubular atrophy, and prolonged allograft survival. Knockdown of syndecan-1 in human tubular epithelial cells in vitro reduced cell proliferation. Selective binding of growth factors suggests that syndecan-1 may promote epithelial restoration. Bilateral renal ischemia/reperfusion in syndecan-1-deficient mice resulted in increased initial renal failure and tubular injury compared with wild-type mice. Macrophage and myofibroblast numbers, tubular damage, and plasma urea levels were increased, and tubular proliferation reduced in the kidneys of syndecan-1 deficient compared with wild-type mice 14 days following injury. Hence syndecan-1 promotes tubular survival and repair in murine ischemia/reperfusion injury and correlates with functional improvement in human renal allograft transplantation.     

Molecular mechanisms of renal allograft fibrosis.

BACKGROUND: Chronic graft nephropathy (CGN) remains the leading cause of renal allograft loss after the first year following transplantation. Histologically it is characterized by glomerulosclerosis, intimal hyperplasia and interstitial fibrosis. The pathogenesis is unclear, but is likely to involve both immunological and non-immunological factors. Despite improvements in short-term graft survival rates, new immunosuppressive regimens have made no impact on CGN. METHODS: A review of the current literature on renal transplantation, novel immunosuppression regimens and advances in the molecular pathogenesis of renal allograft fibrosis was performed. RESULTS AND CONCLUSION: Recent advances in understanding of the underlying molecular mechanisms involved suggest autocrine secretion of cytokines and growth factors, especially transforming growth factor beta, are associated with a change in fibroblast phenotype leading to the deposition of extracellular matrix. Repeated insults trigger upregulation of the tissue inhibitors of matrix metalloproteinases, favouring accumulation of extracellular matrix. To date, no drug has proved effective in inhibiting or reducing allograft fibrosis. The deleterious consequences of chronic immunosuppression on the development of such fibrosis are now recognized; newer immunosuppressive drugs, including rapamycin and mycophenolate mofetil, reduce profibrotic gene expression in both experimental and clinical settings, and offer potential strategies for prolonging allograft survival.     

Chronic renal allograft nephropathy

Chronic rejection/chronic allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Chronic rejection/chronic allograft nephropathy is characterized by a slow progressive deterioration of graft function, often in combination with proteinuria and hypertension. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as delayed graft function, nephron-dosing mismatch, repeated acute rejection episodes, and pathologically severe rejection. However, the precise pathogenesis of chronic allograft nephropathy remains elusive. The differential diagnosis of immunologically mediated chronic rejection and chronic rejection caused by non-immunologic factors is usually not possible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis and remodelling of the vascular wall, and these findings are nonspecific. However, typical chronic transplant glomerulopathy, which affects glomerular tufts, as well as the multilayering of the peritubular capillary basement membrane, are characteristic of immunologic chronic rejection. Furthermore, in long-surviving patient with an allograft treated with a potent immunosuppressive agent, a calcineurin inhibitor, two or more concomitant independent lesions often develop. Therefore, the term "chronic allograft nephropathy" may be clinically preferable to "chronic rejection" to describe the gradual decline in graft function months or years after transplantation, in the absence of a well defined mechanism of graft dysfunction. The most effective way to prevent chronic allograft nephropathy is to avoid any kind of graft damage via either immunologic or non-immunologic mechanisms. Received: April 1, 2000 / Accepted: May 2, 2000     

The renin angiotensin system blockade in kidney transplantation: pros and cons.

Besides the immunological mediated damage on the graft, the intrarenal renin-angiotensin system (RAS) is viewed as an additional mechanism in the development and progression of chronic allograft injury. RAS blocking agents efficiently control post-transplant hypertension and are useful to reduce proteinuria and for treating post-transplant erythrocytosis. However, RAS blockade is associated with some potentially relevant adverse events as hyperkalemia, anemia, and even to a decline in renal function. There are consistent experimental data showing that RAS blockade has a therapeutic effect on chronic allograft injury. Some clinical studies have shown that RAS blockade reduces transforming growth factor-beta1 and other markers of fibrosis but, up to now, there is not convincing evidence supporting that RAS blockade has further benefit on the progression of chronic allograft injury in comparison with other antihypertensive interventions. Theoretically, RAS blockade may also improve cardiovascular disease, which constitutes the main cause of mortality and morbidity in renal allograft recipients. Nevertheless, to date there is lack of evidence for supporting that RAS blockade improves neither graft nor patient survival in comparison with other antihypertensive drugs. Randomized, prospective, double blind, placebo-controlled trials with enough sample size and follow-up are needed to address the potential role of RAS blockade to improve graft and patient outcome. Meanwhile, we should empirically balance case to case the pros and cons of RAS blockade in renal transplantation.     

DNA methylation modulates allograft survival and acute rejection after renal transplantation by regulating the mTOR pathway

Acute rejection (AR) can lead to allograft dysfunction following renal transplantation, despite immunosuppressive treatments. Accumulating evidence points out a role for epigenetic modification in immune responses. However, the mechanism and contribution of DNA methylation in allograft survival remain unclear. In this study, we followed up patients who successively experienced end-stage renal disease, renal transplantation with allograft function or dysfunction, and hemodialysis. Peripheral blood mononuclear cells were collected at different time points for analysis of the DNA methylation. Epigenetic modifier analysis was also performed to explore its effect of methylation in a mouse model of AR. Compared with the allograft-stable cohort, patients who experienced AR-induced allograft dysfunction demonstrated more changes in methylation patterns. Pathway analysis revealed that the hypermethylated areas in the allograft dysfunction group were associated with genes related to the mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, in the mouse AR model, treatment with the DNA methyltransferase inhibitor—decitabine regulated the Th1/2/17/regulatory T cell (Treg cell) immune response via its demethylating role in the suppressing the activity of the mTOR pathway, which ultimately ameliorated renal allograft-related inflammatory injuries. These results revealed that changes in methylation accompany AR-induced allograft dysfunction after renal transplantation. Epigenetics may provide new insights into predicting and improving allograft survival.     

2020年肾移植研究大盘点——来自中国的声音

肾移植是终末期肾病患者改善生存质量、回归正常生活的首选途径。随着医疗技术与免疫抑制剂的不断更新发展, 移植肾的短期存活时间显著延长, 但其长期存活问题仍亟待解决。肾缺血-再灌注损伤(IRI)、急性排斥反应、慢性移植肾失功、肾脏纤维化等因素仍是影响移植肾存活的几大难题, 相关研究一直是肾移植领域的热点。同时, 2020年是不平凡的一年, 新型冠状病毒肺炎(新冠肺炎)疫情对各行各业发展的影响巨大, 与肾移植相关的研究报道亦呈百家争鸣之态。本文就我国2020年肾移植相关的临床与基础研究的前沿热点以及肾移植领域新冠肺炎相关的研究做一综述, 以期提供新的治疗思路和策略。     

Chronic allograft nephropathy: An update.

Chronic allograft nephropathy is the most prevalent cause of renal transplant failure in the first post-transplant decade, but its pathogenesis has remained elusive. Clinically, it is characterized by a slow but variable loss of function, often in combination with proteinuria and hypertension. The histopathology is also not specific, but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified, such as advanced donor age, delayed graft function, repeated acute rejection episodes, vascular rejection episodes, and rejections that occur late after transplantation. A common feature of chronic allograft nephropathy is that it develops in grafts that have undergone previous damage, although the mechanism(s) responsible for the progressive fibrosis and tissue remodeling has not yet been defined. Hypotheses to explain chronic allograft nephropathy include the immunolymphatic theory, the cytokine excess theory, the loss of supporting architecture theory, and the premature senescence theory. The most effective option to prevent chronic allograft nephropathy is to avoid graft injury from both immune and nonimmune mechanisms.     

Loss of peritubular capillaries in the development of chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. In this study, we examined the role of peritubular capillary (PTC) injury in the development of CAN. METHODS: We studied renal biopsies (n = 79) obtained from grafts with CAN. PTC injury was examined morphologically by immunohistochemistry for CD34. These findings were correlated with interstitial fibrosis and graft dysfunction. Humoral immunity involved in CAN was studied by C4d staining. RESULTS: The CAN cases in the present study included chronic rejection (CR) (n = 14, 17.8%) and C4d-positive chronic humoral rejection (CHR; n = 6, 42.9% in CR cases). Irrespective of CR, CHR, or other CAN, the development of CAN was characterized by injury to and loss of identifiable PTCs, accompanied with the development of interstitial fibrosis. In CR and CHR cases, the loss of PTCs was prominent and seemed to progress within a relatively short period after transplantation. A decrease in the number of PTCs significantly correlated with the development of interstitial fibrosis (r = -0.75, P < .001) and impairment of graft function (r = -0.69, P < .001). CONCLUSIONS: Irrespective of whether CR, CHR, or other factors contribute to CAN, the processes involved in its development appear similar and are characterized by progressive injury and loss of PTCs, with the development of renal scarring. Immunohistochemistry for CD34 in human renal biopsies is a useful method for the detection of microvascular injury.     

Delayed Graft Function in Renal Transplantation: Etiology, Management and Long-term Significance

Purpose

In cadaveric renal transplantation a period of delayed graft function postoperatively is not uncommon and often associated with a poor outcome. We reviewed the biology of reperfusion injury and delayed graft function in renal transplantation, as well as its prevention, management and long-term effects.

Materials and Methods

The medical literature covering acute tubular necrosis, delayed graft function in renal transplantation and immunology of ischemia reperfusion injury was reviewed.

Results

Delayed graft function is clearly associated with poor allograft survival, and is caused by an interaction of ischemic and immunological factors. Technical and pharmacological maneuvers can improve early function rates. The response to ischemic injury is complex, and may increase graft immunogenicity and promote the chronic proliferative changes seen in chronic allograft nephropathy.

Conclusions

Improvement in early renal function should be a primary goal in renal transplantation to enhance early and long-term results. Basic research into the injury response may yield insights into renal pathophysiology.     

Surveillance Protocol Kidney Transplant Biopsies: Their Evolving Role in Clinical Practice

Protocol renal allograft biopsies at fixed time points from transplantation have aided research and provided insights into the pathogenesis of early and late allograft injury. Their role is evolving from research to a clinical management tool needed to detect subclinical pathology requiring treatment adjustment. They frequently reveal unexpected findings and influence therapy in the majority of patients. Detection of subclinical rejection (SCR) remains important despite declining prevalence with triple therapy, the evidence favors treatment, if found. Surveillance biopsies in steroid avoidance and calcineurin inhibitor (CNI) withdrawal programs provide an important safety net against the increased rates of late acute and SCR. Individualization of therapy in high‐risk patients and safe reduction of immunosuppression in standard risk individuals becomes possible. Other potentially reversible chronic pathologies that may be detected, include chronic T‐cell or antibody‐mediated rejection, recurrent disease, BK virus‐associated nephropathy, interstitial fibrosis and tubular atrophy and CNI nephrotoxicity, allowing modifications of therapy to limit ongoing graft injury. Biopsy is safe and inexpensive compared with costs of earlier graft failure and return to dialysis. This review summarizes current evidence on use of surveillance histology for the clinical practice of renal transplantation.