C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy.

The deposition of antipodocyte autoantibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN.

Ofatumumab in Rituximab-Resistant and Rituximab-Intolerant Patients With Primary Membranous Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Rituximab is the first-choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 7 rituximab-intolerant and 10 rituximab-resistant patients with MN who consented to receive ofatumumab (50-300mg, single intravenous infusion) and were followed at the nephrology unit of Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII (Bergamo, Italy) between September 2015 and January 2019. FINDINGS: Over a median (IQR) follow-up of 5.0 (3.0-9.8) months, all 7 rituximab-intolerant and 3 of the 10 rituximab-resistant patients exhibited complete (proteinuria<0.3g/d) or partial (proteinuria<3.5g/d with≥50% reduction vs baseline) remission of nephrotic syndrome. Circulating B cells were similarly depleted in all patients by 1 week, and serum anti-phospholipase A2 receptor antibody concentrations decreased to<2.7 relative units/mL in 3 of 4 rituximab-intolerant and 4 of 8 rituximab-resistant patients with phospholipase A2 receptor-related disease. Ofatumumab significantly reduced 24-hour urinary protein and immunoglobulin G excretion and increased serum albumin and immunoglobulin G levels. These effects were greater in rituximab-intolerant than in rituximab-resistant patients. Measured glomerular filtration rate significantly increased by an average of 13.4% at 24 months compared with baseline (P=0.036) among all patients in the series. There were 14 nonserious infusion-related adverse events in 9 patients that recovered with temporary infusion interruption. LIMITATIONS: Retrospective design, limited number of patients. CONCLUSIONS: Ofatumumab may represent an effective and safe treatment for rituximab-intolerant cases of MN. Larger prospective studies will be needed to validate these preliminary findings and explore the effectiveness of other second-generation anti-CD20 antibodies in this clinical setting. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome (NS) in adults. In this case series, we explored the efficacy of ofatumumab, a fully human second-generation anti-CD20 antibody, in 17 patients with MN and NS who were intolerant or unresponsive to rituximab. All 7 rituximab-intolerant patients exhibited complete or partial clinical remission, compared with only 3 of the 10 rituximab-resistant patients. Autoantibody levels decreased in all patients with phospholipase A2 receptor-related disease. Ofatumumab achieved a significant reduction in urinary protein and immunoglobulin G excretion while increasing serum albumin and immunoglobulin G levels. Ofatumumab may be a promising option for patients with MN who are rituximab-intolerant. Further investigations are warranted to validate these preliminary findings.

Role of complement in humoral immunity.

PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) after solid organ transplantation remains an unsolved problem and leads to poor early and late patient outcomes. The complement system is a well recognized pathogenic mediator of AMR. Herein, we review the known molecular mechanisms of disease and results from ongoing clinical testing of complement inhibitors after solid organ transplant. RECENT FINDINGS: Activation and regulation of the complement cascade is critical not only for the terminal effector function of donor-specific antibodies, but also for the regulation of T and B cell subsets to generate the antidonor humoral response. Donor-specific antibodies (DSA) have heterogenous features, as are their interactions with the complement system. Clinical testing of complement inhibitors in transplant patients have shown good safety profiles but mixed efficacy to date. SUMMARY: The complement cascade is a critical mediator of AMR and clinical trials have shown early promising results. With the steady emergence of novel complement inhibitors and our greater understanding of the molecular mechanisms linking complement and AMR, there is greater optimism now for new prognostic and therapeutic tools to deploy in transplant patients with AMR.

Endogenous erythropoietin has immunoregulatory functions that limit the expression of autoimmune kidney disease in mice.

Background: Administration of recombinant erythropoietin (EPO), a kidney-produced hormone with erythropoietic functions, has been shown to have multiple immunoregulatory effects in mice and humans, but whether physiological levels of EPO regulate immune function in vivo has not been previously evaluated. Methods: We generated mice in which we could downregulate EPO production using a doxycycline (DOX)-inducible, EPO-specific silencing RNA (shEPOrtTAPOS), and we crossed them with B6.MRL-Faslpr/J mice that develop spontaneous lupus. We treated these B6.MRL/lpr shEPOrtTAPOS with DOX and serially measured anti-dsDNA antibodies, analyzed immune subsets by flow cytometry, and evaluated clinical signs of disease activity over 6 months of age in B6.MRL/lpr shEPOrtTAPOS and in congenic shEPOrtTANEG controls. Results: In B6.MRL/lpr mice, Epo downregulation augmented anti-dsDNA autoantibody levels and increased disease severity and percentages of germinal center B cells compared with controls. It also increased intracellular levels of IL-6 and MCP-1 in macrophages. Discussion: Our data in a murine model of lupus document that endogenous EPO reduces T- and B-cell activation and autoantibody production, supporting the conclusion that EPO physiologically acts as a counterregulatory mechanism to control immune homeostasis.

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome.

Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for adults. In these patients, treatment with rituximab allows safe discontinuation of steroids, but long-term efficacy is variable, and some patients experience NS relapses after B cell reconstitution. In this study, we aimed to determine disease-associated changes in the B and T cell phenotype of adult patients with SDND/FRNS after steroid-induced remission. We also investigated whether any of these changes in immune cell subsets could discriminate between patients who developed NS relapses after steroid-sparing treatment with rituximab from those who did not. Lymphocyte subsets in SDNS/FRNS patients (n = 18) were compared to those from patients with steroid-resistant NS (SRNS, n = 7) and healthy volunteers (HV, n = 15). Before rituximab, SDND/FRNS patients showed increased frequencies of total and memory B cells, mainly with a CD38-negative phenotype. Within the T-cell compartment, significantly lower levels of FOXP3+ regulatory T cells (Tregs) were found, mostly due to a reduction in CD45RO+ memory Tregs compared to both SRNS and HV. The levels of CD45RO+ Tregs were significantly lower at baseline in patients who relapsed after rituximab (n = 9) compared to patients who did not (n = 9). In conclusion, patients with SDND/FRNS displayed expansion of memory B cells and reduced memory Tregs. Treg levels at baseline may help identify patients who will achieve sustained remission following rituximab infusion from those who will experience NS relapses.

SGLT2 Inhibitors in Diabetic and Non-Diabetic Chronic Kidney Disease.

Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin-angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection.

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study.

OBJECTIVES: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. METHODS: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. RESULTS: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [ß (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [ß (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [ß (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]. CONCLUSIONS: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses.

Sexual dimorphic response to rituximab treatment: A longitudinal observational study in a large cohort of patients with primary membranous nephropathy and persistent nephrotic syndrome.

Rituximab is one of the first-line therapies for patients with membranous nephropathy (MN) at high risk of progression towards kidney failure. We investigated whether the response to Rituximab was affected by sex and anti-PLA2R antibody levels in 204 consecutive patients (148 males and 56 females) with biopsy-proven MN who were referred to the Nephrology Unit of the Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII from March 2001 to October 2016 and managed conservatively for at least 6 months. The primary outcome was a combined endpoint of complete (proteinuria <0.3 g/24 h) or partial (proteinuria <3.0 g/24 h and >50% reduction vs. baseline) remission. Patients gave written informed consent to Rituximab treatment. The study was internally funded. No pharmaceutical company was involved. Anti-PLA2R antibodies were detectable in 125 patients (61.3%). At multivariable analyses, female gender (p = 0.0198) and lower serum creatinine levels (p = 0.0108) emerged as independent predictors of better outcome (p = 0.0198). The predictive value of proteinuria (p = 0.054) and anti-PLA2R titer (p = 0.0766) was borderline significant. Over a median (IQR) of 24.8 (12.0-36.0) months, 40 females (71.4%) progressed to the combined endpoint compared with 73 males (49.3%). Anti-PLA2R titers at baseline [127.6 (35.7-310.8) vs. 110.1 (39.9-226.7) RU/ml] and after Rituximab treatment were similar between the sexes. However, the event rate was significantly higher in females than in males [HR (95%): 2.12 (1.44-3.12), p = 0.0001]. Forty-five of the 62 patients (72.3%) with anti-PLA2R titer below the median progressed to the combined endpoint versus 35 of the 63 (55.6%) with higher titer [HR (95%): 1.97 (1.26-3.07), p < 0.0029]. The highest probability of progressing to the combined endpoint was observed in females with anti-PLA2R antibody titer below the median (86.7%), followed by females with anti-PLA2R antibody titer above the median (83.3%), males with titer below the median (68.1%), and males with titer above the median (44.4%). This trend was statistically significant (p = 0.0023). Similar findings were observed for complete remission (proteinuria <0.3 g/24 h) and after analysis adjustments for baseline serum creatinine. Thus, despite similar immunological features, females were more resilient to renal injury following Rituximab therapy. These findings will hopefully open new avenues to identify the molecular pathways underlying sex-related nephroprotective effects.

Immune responses to SARS-CoV-2 in dialysis and kidney transplantation.

Despite progressive improvements in the management of patients with coronavirus disease 2019 (COVID-19), individuals with end-stage kidney disease (ESKD) are still at high risk of infection-related complications. Although the risk of infection in these patients is comparable to that of the general population, their lower rate of response to vaccination is a matter of concern. When prevention strategies fail, infection is often severe. Comorbidities affecting patients on maintenance dialysis and kidney transplant recipients clearly account for the increased risk of severe COVID-19, while the role of uremia and chronic immunosuppression is less clear. Immune monitoring studies have identified differences in the innate and adaptive immune response against the virus that could contribute to the increased disease severity. In particular, individuals on dialysis show signs of T cell exhaustion that may impair antiviral response. Similar to kidney transplant recipients, antibody production in these patients occurs, but with delayed kinetics compared with the general population, leaving them more exposed to viral expansion during the early phases of infection. Overall, unique features of the immune response during COVID-19 in individuals with ESKD may occur with severe comorbidities affecting these individuals in explaining their poor outcomes.

Autophagy in lupus nephritis: A delicate balance between regulation and disease.

Autophagy is a highly regulated process wherein an unwanted cargo of damaged and dysfunctional cytoplasmic components is removed, delivered to lysosomes for degradation, and released back into the cytoplasm. Accumulating evidence suggests an important role of autophagy in the pathophysiology of systemic lupus erythematosus, with profound effects on both innate and adaptive immunity. Autophagy downregulation results in the inhibition of antigen presenting cells, reduced release of neutrophil extracellular traps and decreased activation of effector T and B cells, leading to reduced autoantibody production and attenuated type 1 interferon signaling. However, defective autophagy may accelerate the production of other inflammatory cytokines and reduce the clearance of apoptotic cells, promoting lupus development. In addition, autophagy dysfunction can concur to the pathogenesis of kidney injury in lupus nephritis. Autophagy is a pivotal mechanism to maintain podocyte integrity and endothelial cell survival. Several animal models have demonstrated that defective autophagy leads to podocyte injury and can promote an endothelial pro-inflammatory and atherogenic phenotype. Moreover, autophagy is a key homeostatic regulator of renal tubular cells, and recent evidence has pointed out that chronic autophagy deficiency may accelerate kidney fibrosis. Targeting autophagy may theoretically improve lupus nephritis outcomes, but novel, non-invasive methods to measure and monitor autophagic activity are urgently needed. In addition, the extent and timing of autophagy inhibition still require additional studies before clinical translation may be attempted. In this review, we will also discuss the effect of several clinically available drugs that can regulate the autophagic flux and their effect in lupus nephritis patients.

Calciphylaxis after kidney transplantation: a rare but life-threatening disorder.

Calciphylaxis is a rare disorder characterized by vascular calcification and thrombosis of the subcutaneous microcirculation, leading to painful necrotic skin lesions and bearing a dreadfully high mortality rate. This syndrome is frequently also termed uraemic calcific arteriolopathy, since most cases are observed in patients with kidney failure. However, it is increasingly clear that calciphylaxis may also affect patients with normal or only slightly impaired renal function, including kidney transplant recipients. A precise definition of the characteristics and risk factors of calciphylaxis developing after kidney transplantation has been hindered by the extreme rarity of this condition, which also hampered the development of effective therapeutic strategies. In the present issue of CKJ, Guillén and colleagues report the largest case series of calciphylaxis in kidney transplant recipients to date, outlining several features that are apparently specific to this population. In this editorial, we briefly present the epidemiology and pathogenesis of calciphylaxis in different patient populations and discuss recent findings for its therapeutic management.

Cardiovascular calcifications in kidney transplant recipients.

Vascular and valvular calcifications are highly prevalent in kidney transplant recipients (KTRs) and are associated with an increased risk of cardiovascular events, which represent the leading cause of long-term mortality in these patients. However, cardiovascular calcification has been traditionally considered as a condition mostly associated with advanced chronic kidney disease stages and dialysis, and comparatively fewer studies have assessed its impact after kidney transplantation. Despite partial or complete resolution of uraemia-associated metabolic derangements, KTRs are still exposed to several pro-calcifying stimuli that favour the progression of pre-existing vascular calcifications or their de novo development. Traditional risk factors, bone mineral disorders, inflammation, immunosuppressive drugs and deficiency of calcification inhibitors may all play a role, and strategies to correct or minimize their effects are urgently needed. The aim of this work is to provide an overview of established and putative mediators involved in the pathogenesis of cardiovascular calcification in kidney transplantation, and to describe the clinical and radiological features of these forms. We also discuss current evidence on preventive strategies to delay the progression of cardiovascular calcifications in KTRs, as well as novel therapeutic candidates to potentially prevent their long-term deleterious effects.

Sodium Levels Predict Disability at Discharge in Guillain-Barré Syndrome: A Retrospective Cohort Study.

Guillain-Barré syndrome (GBS) is an inflammatory polyradiculopathy with potentially severe complications. Clinical tools for risk stratification have been developed, but no definitive prognostic biomarker has been reported. Hyponatremia is frequent in GBS patients, but the impact of serum sodium levels on clinical outcomes is still ill-defined. In this retrospective cohort study, we included all adult patients diagnosed with GBS spectrum disorders at our center from January 2010 to July 2020. Disability at discharge was assessed with the GBS Disability Score (GDS), and all clinical and laboratory data was retrieved from medical charts. Thirty (58.8%) of the 51 subjects included in the study were discharged with severe residual disability (GDS ≥ 3). After accounting for relevant confounders, the odds of experiencing severe disability decreased by 27% (p = 0.027) for each unitary increase in serum sodium concentration. Thirteen (25.5%) patients were diagnosed with mild to moderate hyponatremia; the use of intravenous immune globulin (IVIG) independently increased the odds of developing hyponatremia. In conclusion, we found a significant, independent association between baseline serum sodium levels and severe disability at discharge in GBS patients. In our cohort, hyponatremia was more frequently observed after treatment with IVIG, suggesting dilutional pseudohyponatremia as a probable cause.

Membranous Nephropathy: It Is Time to Go Back to the Future.

CONTEXT: Membranous nephropathy (MN) is an immune-mediated glomerular disease that can lead to nephrotic syndrome and progressive kidney function loss. The cyclic steroid-cyclophosphamide regimen (the modified Ponticelli protocol) and the monoclonal anti-CD20 antibody rituximab have been advocated as effective therapies to improve renal outcomes, but a direct comparison of these treatments had never been carried out in a prospective study. Subject of Review: Scolari et al. [J Am Soc Nephrol. 2021;32:972-82] recently reported the results of a pilot randomized controlled trial (RI-CYCLO) designed to provide direct estimates of the effect of rituximab (1 g × 2) compared to the cyclic steroid-cyclophosphamide regimen in 74 patients with MN. The proportion of patients with complete remission at 12 months was higher in the cyclic regimen arm than that of rituximab (32 and 16%, respectively), but the difference was not statistically significant in intention-to-treat analyses. Interestingly, differences in the cumulative incidence of complete and partial remissions between treatment arms progressively reduced over the follow-up and became virtually nonexistent from 24 months (>80% in both groups). The frequency of serious and nonserious adverse events was similar between the 2 treatment arms. Infusion reactions and drug discontinuation were more common with rituximab, while infections and leukopenia were more frequently observed with the cyclic regimen. The risk of cancer was similar in the 2 allocation groups, but the limited follow-up length did not allow to draw definitive conclusions. Independent of treatment allocation, 18% of patients experienced at least 1 relapse after achieving complete or partial remission. Second Opinion: Notwithstanding the intrinsic limitations of a pilot study, the RI-CYCLO trial represents an important milestone in the treatment of MN. Findings from this study support the hypothesis that the cyclic regimen and rituximab may have comparable efficacy in inducing disease remission over the long term. Considering its potentially better-albeit not yet formally proven-long-term safety profile, rituximab could be considered as a first-line therapy for most patients with MN. Several questions remain to be addressed, including rituximab ideal dose and its efficacy in patients with a significant reduction in glomerular filtration rate. In light of RI-CYCLO results, a large-scale trial to assess rituximab noninferiority to the cyclic regimen would require the enrollment of thousands of patients, and it would be probably unfeasible within a reasonable time frame. In our opinion, resources should be allocated to provide an answer to the pressing matter of treatment nonresponse and intolerance, which may be addressed in the near future with novel therapeutic strategies.

COVID-19 in Chronic Kidney Disease: The Impact of Old and Novel Cardiovascular Risk Factors.

Cardiovascular disease is a frequent complication and the most common cause of death in patients with CKD. Despite landmark medical advancements, mortality due to cardiovascular disease is still 20 times higher in CKD patients than in the general population, which is mainly due to the high prevalence of risk factors in this group. Indeed, in addition to traditional cardiovascular risk factors, CKD patients are exposed to nontraditional ones, which include metabolic, hormonal, and inflammatory alterations. The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has brought novel challenges for both cardiologists and nephrologists alike. Emerging evidence indicates that coronavirus disease 2019 (COVID-19) increases the risk of cardiovascular events and that several aspects of the disease may synergize with pre-existing cardiovascular risk factors in CKD patients. A better understanding of these mechanisms is pivotal for the prevention and treatment of cardiovascular events in this context, and we believe that additional clinical and experimental studies are needed to improve cardiovascular outcomes in CKD patients with COVID-19. In this review, we provide a summary of traditional and nontraditional cardiovascular risk factors in CKD patients, discussing their interaction with SARS-CoV-2 infection and focusing on CO-VID-19-related cardiovascular complications that may severely affect short- and long-term outcomes in this high-risk population.

Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. RESULTS: At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m2; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. CONCLUSIONS: Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.

Immunosuppression-related neurological disorders in kidney transplantation.

A large number of neurological disorders can affect renal transplant recipients, potentially leading to disabling or life-threatening complications. Prevention, early diagnosis and appropriate management of these conditions are critical to avoid irreversible lesions. A pivotal role in the pathogenesis of common post-transplant neurological disorders is played by immunosuppressive therapy. The most frequently administered regimen consists of triple immunosuppression, which comprises a calcineurin inhibitor (CNI), a purine synthesis inhibitor and glucocorticoids. Some of these immunosuppressive drugs may lead to neurological signs and symptoms through direct neurotoxic effects, and all of them may be responsible for the development of tumors or opportunistic infections. In this review, after a brief summary of neurotoxic pathogenetic mechanisms encompassing recent advances in the field, we focus on the clinical presentation of more common and severe immunosuppression-related neurological complications, classifying them by characteristics of urgency and anatomic site. Our goal is to provide a general framework that addresses such clinical issues with a multidisciplinary approach, as these conditions require.