A Prospective, Randomized Study to Compare the Effect of Combination Therapy With Campath-1H on Peripheral Blood Mononuclear Cells in Kidney Transplant Recipients

Induction therapy with Campath-1H, a humanized anti-CD52 monoclonal antibody depleting T and B lymphocytes, has been used in organ transplantation with the final goal of resetting the immune system in order to promote a tolerance-permissive environment and, at the same time, to reduce the need for chronic maintenance immunosuppression. To explore whether thisO may result from the capability of Campath-1H, in association with different maintenance regimens, to promote regulatory T cells (Treg) expansion and to assess whether this may translate into better graft outcomes in the long-term, 21 renal transplant patients receiving Campath-1H induction were randomized to low-dose SRL (n=11) or low-dose CsA (n=10), both in addition to low-dose mycophenolate mofetil (MMF) as maintenance immunosuppressive therapy and monitored for over 30 month follow-up. SRL-treated patients showed an important expansion of circulating CD4+CD25highFOXP3+ Treg that, at one and two years after transplant, were significantly more abundant than in the CsA group. T cells isolated from peripheral blood long-term post-transplant were hyporesponsive to donor alloantigens in both treatment arms. In SRL-, but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic to donor antigens. Despite higher Treg counts, SRL-treated patients had a faster GFR and RPF decline, more clinical proteinuria, significantly higher tubular C4d staining score and a trend to higher chronic allograft damage index score, compared to CsA-treated patients. There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each treatment group. These data suggest that, after Campath-1H induction, maintenance therapy with low-dose SRL and MMF promotes Treg expansion, but this is not paralleled by long-term improved graft outcomes. Conversely, maintenance immunosuppression with low-dose CsA and MMF is associated with better graft function and structure than low-dose SRL plus MMF, possibly through the induction of T cell anergy toward donor antigens

Monitoring alloimmune response in kidney transplantation

Currently, immunosuppressive therapy in kidney transplant recipients is generally performed by protocols and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients are likely to receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. Developing reliable biomarkers is crucial for individualizing therapy aimed at extending allograft survival. Emerging data indicate that many assays, likely used in panels rather than single assays, have potential to be diagnostic and predictive of short and also long-term outcome. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Of note, some prospective, randomized, multicenter biomarker-driven studies are currently on-going aiming at confirming such preliminary data. These works as well as other future studies are highly warranted to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice

The role of renin angiotensin system inhibition in kidney repair

Chronic kidney diseases share common pathogenic mechanisms that, independently from the initial injury, lead to glomerular hyperfiltration, proteinuria, and progressive renal scarring and function loss. Inhibition of the renin angiotensin system (RAS) has been consistently found to reduce or halt the progressive deterioration of renal function through reduction of blood pressure and proteinuria, the two main determinants of renal function decline. In few instances, RAS inhibition may even promote amelioration of the glomerular filtration rate. Animal data suggest that chronic therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor type I blockers promotes regression of glomerulosclerosis, even in later phases of the disease. In humans, studies investigating the effect of angiotensin II inhibition on renal structural changes have shown inconsistent results, possibly due to small numbers and/or short duration of follow-up. Whether regression of glomerulosclerosis relies on a direct regenerative effect of RAS inhibition or on spontaneous kidney self-repair after the injury has been removed is still unknown. Improved understanding of mechanisms that promote renal regeneration may help in designing specific therapies to prevent the development of end-stage renal disease. This is a desirable goal, considering the economic burden of chronic kidney diseases and their effect on morbidity and mortality

HCV-Associated Nephropathies in the Era of Direct Acting Antiviral Agents

Hepatitis C virus (HCV) infection is a systemic disorder that frequently associates with extrahepatic manifestations, including nephropathies. Cryoglobulinemia is a typical extrahepatic manifestation of HCV infection that often involves kidneys with a histological pattern of membranoproliferative glomerulonephritis. Other, less common renal diseases related to HCV infection include membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, fibrillary and immunotactoid glomerulopathy. Over the last decades, the advent of direct-acting antiviral therapies has revolutionized treatment of HCV infection, dramatically increasing the rates of viral clearance. In patients where antiviral therapy alone fails to induce renal disease remission add-on B-cell depleting agents represent an alternative to counteract the synthesis of pathogenic antibodies. Immunosuppressive therapies, such as steroids, alkylating agents, and plasma exchanges, may still represent an effective option to inhibit immune-complex driven inflammatory response, but the potentially associated increase of HCV replication and worsening of liver disease represent a serious limitation to their use

Review: Ischemia Reperfusion Injury?A Translational Perspective in Organ Transplantation

Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI

Perioperative Minimal Induction Therapy: A Further Step toward More Effective Immunosuppression in Transplantation

Dual induction with low doses of rabbit anti-human thymoglobulin (RATG) and basiliximab effectively and safely prevented allograft rejection in high-risk renal transplant recipients. To assess whether treatment timing affects efficacy and tolerability, in this single-center, matched-cohort study, we compared posttransplant outcomes in 25 patients and 50 gender-, age-, and treatment-matched reference patients induced with the same course of 7 daily RATG infusions (0.5 mg/kg/day) started before or after engraftment, respectively. All subjects received basiliximab (20 mg) before and 4 days after transplantation, withdrew steroids within 6 days after surgery, and were maintained on steroid-free immunosuppression with cyclosporine and mycophenolate mofetil or azathioprine. Over 12 months after transplant, 1 patient (4%) and 13 reference patients (26%) had acute rejection episodes. One patient and 5 reference-patients required dialysis therapy because of delayed graft function. In all patients circulating CD4+ and CD8+ T lymphocytes were fully depleted before engraftment. Both treatments were well tolerated. In kidney transplantation, perioperative RATG infusion enhances the protective effect of low-dose RATG and basiliximab induction against graft rejection and delayed function, possibly because of more effective inhibition of early interactions between circulating T cells and graft antigens

Pretransplant Donor-specific IFN gamma ELISPOT as a Predictor of Graft Rejection: A Diagnostic Test Accuracy Meta-analysis

Background. Pretransplant interferon-gamma enzyme-linked immunospot (IFN-gamma ELISPOT) has been proposed as a tool to quantify alloreactive memory T cells and estimate the risk of acute rejection (AR) after kidney transplantation, but studies have been inconclusive so far. We performed a meta-analysis to evaluate the association between pretransplant IFN-gamma ELISPOT and AR and assess its predictive accuracy at the individual level. Methods. We estimated the pooled summary of odds ratio for AR and the joined sensitivity and specificity for predicting AR using random-effects and hierarchical summary receiver-operating characteristic models. We used meta-regression models with the Monte Carlo permutation method to adjust for multiple tests to explain sensitivity and specificity heterogeneity across studies. The meta-analytic estimates of sensitivity and specificity were used to calculate positive and negative predictive values across studies. Results. The analysis included 12 studies and 1181 patients. IFN-gamma ELISPOT was significantly associated with increased AR risk (odds ratio: 3.29; 95% confidence interval (CI), 2.34-4.60); hierarchical summary receiver operating characteristic jointly estimated sensitivity and specificity values were 64.9% (95% CI, 53.7%-74.6%) and 65.8% (95% CI, 57.4%-73.5%), respectively, with moderate heterogeneity across studies. After adjusting for multiple testing, meta-regression models showed that thymoglobulin induction, recipient black ethnicity, living versus deceased donors, and geographical location did not affect sensitivity or specificity. Because of the varying AR incidence of the studies, positive and negative predictive values ranged between 16%-60% and 70%-95%, respectively. Conclusions. Pretransplant IFN-gamma ELISPOT is significantly associated with increased risk of AR but provides suboptimal predictive ability at an individual level. Prospective randomized clinical trials are warranted

Effect of Trandolapril on Regression of Retinopathy in Hypertensive Patients with Type 2 Diabetes: A Prespecified Analysis of the Benedict Trial

Background. The effect of angiotensin converting enzyme inhibitors (ACEi) on regression of retinopathy in type 2 diabetics is still ill defined. Methods. We compared the incidence of retinopathy regression in 90 hypertensive type 2 diabetics randomized to at least 3-year blinded ACEi with trandolapril (2 mg/day) or non-ACEi therapy who had preproliferative or proliferative retinopathy at baseline. Results. Over a median (interquartile range) follow-up period of 35.8 (12.4–60.7) months, retinopathy regressed in 27 patients (30.0%). Regression occurred in 18 of 42 patients (42.9%) on ACEi and in 9 of 48 (18.8%) on non-ACEi therapy (adjusted for predefined baseline covariates HR (95% CI): 2.75 (1.18–6.42), P = .0193). Concomitant treatment with or without Non-Dihydropyridine Calcium Channel Blockers (ndCCBs) did not appreciably affect the incidence of retinopathy regression. Conclusions. Unlike ndCCB, ACEi therapy may have an additional effect to that of intensified BP and metabolic control in promoting regression of diabetic retinopathy

Liquid biopsy for non-invasive monitoring of patients with kidney transplants

The current tools for diagnosing and monitoring native kidney diseases as well as allograft rejection in transplant patients are suboptimal. Creatinine and proteinuria are non-specific and poorly sensitive markers of injury. Tissue biopsies are invasive and carry potential complications. In this article, we overview the different techniques of liquid biopsy and discuss their potential to improve patients’ kidney health. Several diagnostic, predictive, and prognostic biomarkers have been identified with the ability to detect and monitor the activity of native kidney diseases as well as early and chronic allograft rejection, such as donor-derived cell-free DNA, exosomes, messenger RNA/microsomal RNA, proteomics, and so on. While the results are encouraging, additional research is still needed as no biomarker appears to be perfect for a routine application in clinical practice. Despite promising advancements in biomarkers, the most important issue is the lack of standardized pre-analytical criteria. Large validation studies and uniformed standard operating procedures are required to move the findings from bench to bedside. Establishing consortia such as the Liquid Biopsy Consortium for Kidney Diseases can help expedite the research process, allow large studies to establish standardized procedures, and improve the management and outcomes of kidney diseases and of kidney transplant recipients

Clinical Study Effect of Trandolapril on Regression of Retinopathy in Hypertensive Patients with Type 2 Diabetes: A Prespecified Analysis of the Benedict Trial

Background. The effect of angiotensin converting enzyme inhibitors (ACEi) on regression of retinopathy in type 2 diabetics is still ill defined. Methods. We compared the incidence of retinopathy regression in 90 hypertensive type 2 diabetics randomized to at least 3-year blinded ACEi with trandolapril (2 mg/day) or non-ACEi therapy who had preproliferative or proliferative retinopathy at baseline. Results. Over a median (interquartile range) follow-up period of 35.8 (12.4-60.7) months, retinopathy regressed in 27 patients (30.0%). Regression occurred in 18 of 42 patients (42.9%) on ACEi and in 9 of 48 (18.8%) on non-ACEi therapy (adjusted for predefined baseline covariates HR (95% CI): 2.75 (1.18-6.42), P = .0193). Concomitant treatment with or without Non-Dihydropyridine Calcium Channel Blockers (ndCCBs) did not appreciably affect the incidence of retinopathy regression. Conclusions. Unlike ndCCB, ACEi therapy may have an additional effect to that of intensified BP and metabolic control in promoting regression of diabetic retinopathy