Doença cardiovascular em pacientes transplantados renais: associação com fatores da coagulação e seus polimorfismos genéticos

As doenças decorrentes da aterosclerose apresentam uma prevalência mais elevada entre pacientes submetidos a transplante de órgãos sólidos comparativamente à população em geral. Os motivos para esta discrepância podem estar na maior exposição dos pacientes transplantados a fatores de risco cardiovascular. Recentemente identificou-se a participação de fatores da coagulação na patogênese da aterosclerose, tanto em estudos populacionais quanto em pacientes transplantados. No presente estudo aferiram-se diversos fatores da coagulação e a exposição a fatores de risco convencionais para doença cardiovascular em um grupo de 270 pacientes transplantados renais comparativamente a um grupo de indivíduos saudáveis. Adicionalmente, compararam-se pacientes transplantados renais com e sem o diagnóstico de doença cardiovascular quanto a exposição a características ambientais e genéticas relacionadas aos fatores da coagulação e fatores de risco clássicos para doença cardiovascular. As variáveis estudadas foram: idade, sexo, tabagismo, história familiar de doença cardiovascular, índice de massa corporal, pressão arterial sistólica e diastólica, esquema imunossupressor, glicemia, colesterol total, triglicerídios, fibrinogênio, interleucina-6 (IL-6), inibidor do ativador do plasminogênio tipo 1 (PAI- 1 ), fator VIl coagulante (FVIIc), polimorfismos genéticos do fator VIl c (Arg/Gin 353), alfa (TIA 312) e beta (G/A-445 ) fibrinogênio, PAI-1 (4G/5G), IL-6 (intron-4). O grupo de 270 pacientes transplantados renais foi similar ao grupo de 31 indivíduos saudáveis em relação à idade, sexo e índice de massa corporal. Entre os pacientes transplantados a proporção de tabagistas foi menor (15,9% vs 38,7%) e pressão arterial mais elevada (146/84 vs 133/71 mmHg). Os níveis de colesterol total, triglicerídios, fibrinogênio, interleucina 6, fator VIl coagulante e dímero-D foram mais elevados nos pacientes transplantados comparativamente aos indivíduos saudáveis. Sessenta e três (23,3%) pacientes transplantados tinham o diagnóstico de doença cardiovascular, sendo que 22 já apresentavam doença previamente ao transplante. Estes pacientes eram mais idosos e apresentavam maior freqüência de história familiar positiva para doença cardiovascular e tabagismo comparativamente aos pacientes transplantados sem doença cardiovascular. Não houve diferença entre os 2 grupos em relação a sexo, índice de massa corporal e pressão arterial. Os esquemas de medicações imunossupressoras foram similares nos 2 grupos. Os pacientes com doença cardiovascular apresentaram níveis significativamente mais elevados de fibrinogênio [415 (230-1050) mg/dl vs 360 (211-650) mg/dl P<0,001], interleucina-6 [2,4 (0,26-25) pg/ml vs 2,0 (0,19-23,9) P=0,017], glicose [6 ,6+-2,7 mmoi/L vs 5,9+-1 ,3 mmoVL P=0,007), triglicerídios [1 ,8(0,7-7,5) mmoi/L vs 1,5 (0,4- 12,3) mmoi/L P=0,023] e mais baixos de albumina (40,5+3,3 g/L vs 42,5+3,6 g/L P<0,001). Os níveis de fator Vllc [97(29,8-214)% vs 96 (40,7-226) %; P=0,31], PAI- 1 [9 ,9(2,0-34,6) AU/ml vs 9,0{0,8-50) AU/ml; P=0,248] e colesterol total [6 ,0(4,0- 11 ,0) mmoi/L vs 5,9 (2,9-10,2) mmoi/L P=0,454) foram similares. A freqüência dos alelos raros dos polimorfismos genéticos dos genes do beta fibrinogênio (A/G -445), alfa fibrinogênio (A/T 312), IL-6 (intron-4 A/G), fator Vllc (Arg/Gin-353) e PAI-1 (4G/5G) foram similares entre os pacientes transplantados renais com e sem doença cardiovascular. A interação do a leio A-445 do beta fibrinogênio e tabagismo associou-se com maior prevalência de doença cardiovascular nos pacientes transplantados renais. Em análise de covariância observou-se associação dos níveis de fibrinogênio com a idade, níveis de IL-6 e ciclosporinemia. Os níveis de fator Vllc associaram-se com os niveis de trigliceridios e colesterol e com o genótipo, sendo mais baixo nos portadores do alelo raro (Gin353). Os níveis de PAI-1 associaramse com os níveis de glicose e triglicerídios e com o genótipo, sendo mais elevado nos portadores do alelo 4G. Os nlveis de IL-6 associaram-se com ciclosporinemia. Em análise de regressão logística observou-se associação independente de doença cardiovascular com idade, história familiar positiva para doença cardiovascular, tabagismo e níveis séricos de fibrinogênio e albumina. Em conclusão, identificou-se alterações no sistema de coagulação de pacientes transplantados renais à longo prazo. A prevalência de doença cardiovascular associou-se com estas alterações e com fatores de riscos clássicos para doença cardiovascular, como idade, história familiar e tabagismo. Não detectou-se associação entre a freqüência dos diversos polimorfismos genéticos e prevalência de doença cardiovascular entre os pacientes transplantados. A associação entre a interação de tabagismo e presença do alelo raro (A-445) do beta-fibrinogênio com o diagnóstico de doença cardiovascular merece futura investigação.The prevalence of clinicai consequences of atherosclerosis is increased in patients submitted to solid organs transplantation, in comparison to the general population. The reason of this is not completely understood. The exposition to a higher prevalence of classical risk factors for cardiovascular disease has been considered. Recently, abnormalities in the coagulation factors are also thought to play a role in the pathogenesis of the atherosclerosis, both in unselected populations and transplant patients. In this study, we studied coagulation factors and the exposition to classical risk factors for cardiovascular disease in a group of 270 renal transplant recipients and compared them to a sample of 31 healthy subjects. Additionally, we analysed those risk factors for cardiovascular disease in transplant patients with and without a diagnosis of cardiovascular disease. In this setting, we evaluated the distribution of the coagulation factors leveis and polymorphisms of the respective genes. The variables studied were: age, gender, smoking, family history of cardiovascular disease, body mass index, blood pressure, immunosuppressor agents, glicemia, total cholesterol, tryglicerides, fibrinogen, interleukin-6 (IL-6), plasminogen activator inhibitor type 1 (PAI-1 ), facto r VIl coagulant (FVIIc), D-dimer, and genetic polymorphisms of factor Vllc (Arg/Gin 353) , alpha (T/A 312) and beta (G/A445 ) fibrinogen, PAI-1 (4G/5G), IL- 6 (intron-4). Age, gender and body mass index were similar in renal transplant recipients and control group. However, in the transplant group the frequency of smokers was lower (15,9% vs 38,7%) and the blood pressure was higher (146/84 vs 133/71 mmHg). The total cholesterol, tryglicerides, fibrinogen, IL-6, facto r VIl c and Ddimer leveis were significantly increased in transplant recipients compared to healthy controls. Cardiovascular disease was present in sixty-three (23,3%) transplant patients. Twenty-two of them have had the diagnosis previous to transplantation. The former patients were older and the frequency of smoking and positive family history of cardiovascular disease was higher compared to transplant patients without cardiovascular disease. There were no differences between these 2 groups related to sex, body mass index and blood pressure. The immunosuppressive regimes were similar in both groups. The patients with cardiovascular disease presented significantly higher leveis of fibrinogen [415 (230-1050) mg/dl vs 360 (21 1-650) mg/dl P<0,001], IL-6 [2,4 (0,26-25) pg/ml vs 2,0 (0,19-23,9) P=0,017], glucose [6,6+- 2,7 mmol/1 vs 5,9+-1 ,3 mmol/1 P=0,007) and tryglicerides [1 ,8(0,7-7,5) mmol/1 vs 1,5 (0,4-12,3) mmol/1 P=0,023]. and lower leveis of albumin (40,5+3,3 g/1 vs 42,5+3,6 g/1 P<0,001). The leveis offactor Vllc [ 97(29,8-214)% vs 96 (40,7-226) %; P=0,31]. PAI-1 [9,9(2,0-34,6) AU/ml vs 9,0{0,8-50) AU/ml; P=0,248] and total cholesterol [6,0(4,0-11 ,0) mmol/1 vs 5,9 (2,9-1 0,2)] mmol/1 P=0,454] were similar. The frequency of the rare alleles of the polymorphic genes of beta fibrinogen (A/G -445), alpha fibrinogen (AIT 312), IL-6 (intron-4 A/G), factor Vllc (Arg/Gin-353) and PAI-1 (4G/5G) were similar in both groups of transplant patients. The interaction of the beta fibrinogen allele A-445 and smoking was associated with a higher prevalence of cardiovascular disease. Fibrinogen leveis were associated with age, IL-6 leveis and trough leveis of cyclosporin. Difference in plasma factor Vllc leveis were associated with factor VIl genotype, tryglicerides and cholesterol. Carriers of the Gln353 allele had lower Vllc when compared with Arg353 homozygous, which may conter a reduced thrombotic risk. Difference in PAI-1 leveis was associated with glucose, tryglicerides and 4G/5G genotype. Carriers of the 4G allele had higher PAI-1 leveis compared with 5G homozygous. IL-6 leveis were associated with trough cyclosporin leveis. Cardiovascular disease was independently associated with age, positive family history for cardiovascular disease, smoking, fibrinogen and albumin in multivariate analysis. In conclusion, long-term renal transplant recipients manifest alterations in coagulation system. Cardiovascular disease was associated with these conditions, as well as with the classical risk factors such as age, positive family history and smoking. There was no association between the polymorphic genes coding for beta and alpha fibrinogen, IL-6, factor Vllc and PAI-1 with a higher prevalence of cardiovascular disease in the transplant recipients presently studied. The association between the prevalence of cardiovascular disease and interaction of smoking and the 13-fibrinogen A-445 allele deserves further investigation

Interventions performed by clinical pharmacist in the renal transplant ambulatory care

Introdução: O desenvolvimento de novos agentes imunossupressores e outros medicamentos de suporte têm aumentado à complexidade dos tratamentos. Consequentemente, interações medicamentosas potenciais, reações adversas e custos podem comprometer o resultado terapêutico. Embora os farmacêuticos tenham sido envolvidos no cuidado de pacientes após transplantes, poucas equipes de transplante renal podem contar com serviços farmacêuticos. Objetivos: Descrever as intervenções farmacêuticas realizadas para melhorar os resultados do tratamento de pacientes submetidos à transplante renal. Métodos: Trata-se de um ensaio clínico randomizado que foi realizado em um hospital especializado em transplantes no sul do Brasil. O farmacêutico clínico acompanhou 64 pacientes durante um período de 12 meses e realizou intervenções quando identificava um problema relacionado a medicamento. As intervenções farmacêuticas foram categorizadas em “significante”, “muito significante” ou “extremamente significante”. Os Resultados Negativos associados ao uso dos Medicamentos (RNM) foram classificados em relação à efetividade, segurança e necessidade. Resultados: Foram realizadas 226 intervenções farmacêuticas, com uma média de 3,25 ± 2,37 por paciente. Entre elas, 159 (70,4%) foram orientadas ao paciente e 67 (29,6%) à equipe de saúde. Trinta e oito por cento foram classificados como muito significantes. Algumas das intervenções farmacêuticas frequentes foram sugerir a redução de dose do imunossupressor para os médicos, educar pacientes com diabetes mellitus pós-transplante ou em caso de omissão de doses. Foram identificados 114 RNM, 43% relacionados à efetividade, 36% à segurança e 21% à necessidade. O número de rejeição aguda confirmada por biópsia foi 33 (51,6%). A sobrevida livre de rejeição aguda foi de 59,4% no primeiro mês, 53,1% no terceiro mês e 48,3% em 12 meses. Conclusões: O farmacêutico tem um papel importante no ambulatório de transplante renal, identificando problemas e atuando como um dos principais atores para a redução dos RNM.Introduction: The development of new immuno-suppressant agents and other supporting medications has increased the complexity of medical regimes. Therefore, potential drug interactions, adverse reactions and costs may jeopardize a successful outcome. Although pharmacists have been involved in the care of patients after transplants, only a few kidney transplant teams can count with dedicated pharmaceutical services. Objective: The goal of this study was to describe the pharmaceutical interventions performed to improve treatment outcomes of patients who underwent kidney transplantation. Methods: This study was a randomized clinical trial and was carried out in a specialized transplant hospital in southern Brazil. The clinical pharmacist followed up 64 patients during a period of 12 months and performed interventions when identifying a drug related problem. The pharmaceutical interventions were categorized as “significant”, “very significant” or “extremely significant”. Medication-related negative outcomes were classified in relation to their effectiveness, safety and necessity. Results: Two hundred and twenty-six (226) pharmaceutical interventions were performed, with a mean of 3.25 ± 2.37 per patient. Among them, 159 (70.4%) were patient-oriented, and 67 (29.6%) were health team-oriented. Thirty eight percent were classified as very significant. Frequent pharmaceutical interventions performed were to suggest the reduction of immuno-suppressant doses to the physicians, educate patients with post-transplant diabetes mellitus or in case of skipping doses. One hundred and fourteen (114) medication-related negative outcomes were identified, 43% related to effectiveness, 36% to safety and 21% to necessity. The number of acute rejection confirmed by biopsy was 33 (51.6%). The free survival of acute rejection was 59.4% in the first month, 53.1% in the third month and 48.3% in 12 months. Conclusions: The pharmacist has an important role in the ambulatory care of kidney transplant, identifying problems and acting as a major player towards the reduction of medication-related negative outcomes

The Halifax flow Crossmatch Protocol Results According to the Class and MFI of the DSA

Introduction: The main strategy to reduce the immunogenicity of transplanted grafts is to seek maximum compatibility betweenalloantigens in the donor-recipient pair. It is understood that the virtual crossmatch (VXM) can be a good tool in the evaluation of the donor / recipient pair and that a broader application of these protocols will improve the pre-transplant immunological risk assessment. The aim of this study was to correlate the physical flow crossmatches results, looking at different mean fluorescence intensity (MFI) values of the donor specific antibodies (DSA), and the probability of a positive crossmatch. We also aimed to validate this tool using a well standardized flow crossmatch protocol. Methods: We performed a total of 15,217 FCXM between 2015 and 2019. All were tested by the Halifax Flow Cytometer Crossmatch (FCXM) protocol, with cells from deceased donors and serum from renal recipients. For this analysis we selected only samples that had one or two DSA per locus (N = 1,081), when the MFI was above 1,000, and they were divided according to the allelic group recognized by the antibody (anti-HLA-A, B, C, DR or DQ) looking at the probability of a positive crossmatch with different MFI values of the DSAs. Combinations among them were alsoanalyzed in the same way (N=175). Results: In the presence of an exclusive DSA against the allelic groups A, B and DR, with an index MFI above 5,000, all the FCXM were positives. With exclusively antibodies against groups C or DQ, all cases with DSAsabove 15,000 MFIs were positives. With two or more DSAs anti A and/or B, and/or DR, when their MFIs sums exceeded 5,000,all FCXM results against B cells were positive. The presence of anti-Class I DSAs (A, B and A+B), regardless of the MFI value, was responsible for 71% (N=424 of 601) of the T cell positivity and 77% (N=460 of 661) in the B cell crossmatches. The presence of only anti-Class II DSAs (DR and DQ) accounted for 55% (N=168 of 303) of FCXM positivity in B cells. The overall mean of the MFI of the DSAs was higher in the FCXM positive group when compared to negative crossmatch. The group with sum of DSAs A (N=217) showed that when the sum was 4,000 MFI or higher, there was a 24 times higher probability for a positive B cell crossmatch when compared with lowers MFIs. Conclusions: Our results show a strong association between the DSA MFI and the FCXM result. The data here presented confirm the results of our previous studies, justifying the VXMstandard used by our center, proving to be a good tool to streamline the selection of transplant recipients and facilitate the sharing of organs from national donors

BKV-infection in kidney graft dysfunction

AbstractIntroductionBKV nephropathy (BKN) causes kidney graft loss, whose specific diagnosis is invasive and might be predicted by the early detection of active viral infection.ObjectiveDetermine the BKV-infection prevalence in late kidney graft dysfunction by urinary decoy cell (DC) and viral DNA detection in urine (viruria) and blood (viremia; active infection).MethodsKidney recipients with >1 month follow-up and creatinine >1.5mg/dL and/or recent increasing >20% (n=120) had their urine and blood tested for BKV by semi-nested PCR, DC searching, and graft biopsy. PCR-positive patients were classified as 1+, 2+, 3+. DC, viruria and viremia prevalence, sensitivity, specificity, and likelihood ratio (LR) were determined (Table 2×2). Diagnosis efficacy of DC and viruria were compared to viremia.ResultsDC prevalence was 25%, viruria 61.7%, and viremia 42.5%. Positive and negative patients in each test had similar clinical, immunossupressive, and histopathological characteristics. There was no case of viremia with chronic allograft nephropathy and, under treatment with sirolimus, patients had a lower viruria prevalence (p=0.043). Intense viruria was the single predictive test for active infection (3+; LR = 2.8).1,6-4,9ConclusionDC, BKV-viruria and -viremia are commun findings under late kidney graft dysfunction. Viremia could only be predicted by intense viruria. These results should be considered under the context of BKN confirmation

Early HHV-6 replication is associated with morbidity non-related to CMV infection after kidney transplantation

AbstractHuman herpesvirus type 6-(HHV-6) has been associated with morbidity after liver transplantation.ObjectiveThe aim of this study was to determine the HHV-6 seroprevalence among donorrecipient pairs, analyze the incidence of early active infection, its clinical manifestation, interaction with CMV, and the related morbidity in the first year after kidney transplantation.Methods46 donor-recipient pairs had IgG evaluated by ELISA before transplantation: HHV-6-(Pambio – USA) and CMV-(Roche – USA). A frozen whole blood sample collected weekly (from the 1st to the 6th week) was retrospectively tested for HHV-6 viral load (VL) determination by real time quantitative PCR (qPCR, Nanogen – Italy). Patients were preemptively surveyed for CMV by pp65 antigenemia (Ag, APAAP, immunohistochemistry, Biotest – Germany) from the 4th to the 12th week after transplantation. Active infection was defined as qPCR-HHV6+ (viral-load/mL-VL) and Ag+ (+cells/100.000 granulocytes), for HHV-6 and CMV, respectively. DCMV was defined as simultaneous positive antigenemia and suggestive signs/symptoms. Concerning +qPCR-HHV6, associated factors, clinical manifestation, interaction with CMV and morbidity were searched.ResultsPre-transplant HHV-6 seroprevalence was significantly higher among kidney recipients compared to their donors (82.6×54.8%; p=0.005 [3.9 (1.4–10.4)]). Active infection by this virus occurred in 26.1% (12/46), with no association with previous IgG (p=0.412). Median VL was 125 copies/mL (53–11.264), and the median Ag was 21 +cells (2–740). There was no association between HHV-6 and CMV activation after transplantation (p=0.441), neither concerning DCMV (p=0.596). Median highest Ag+ and days of ganciclovir treatment were similar between qPCR-HHV6 + or − (p=0.206 and p=0.124, respectively). qPCR-HHV6+ was associated with higher incidence of bacterial (p=0.009) and fungal (p = 0.001) infections, and higher number (p=0.001) of hospital admission and longer duration of hospitalization over the first 6 and 12 months post-transplantation (p=0.033 and p=0.001).ConclusionLatent HHV-6 infection is more common among recipients than donors before transplantation. Early active infection by this pathogen after transplantation does not increase DCMV incidence or severity during the first 3 months of follow-up. However, early HHV-6 replication is associated with other infections and hospitalizations in the first year

Real-world effectiveness and safety of direct-acting antivirals for the treatment of hepatitis C virus in kidney and liver transplant recipients: experience of a large transplant center in Brazil

Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments

Detecção quantitativa de vírus BK em receptores de transplante renal : um estudo prospectivo de validação

Introduction: BK virus (BKV) infection in renal transplant patients may cause kidney allograft dysfunction and graft loss. Accurate determination of BKV viral load is critical to prevent BKV-associated nephropathy (BKVAN) but the cut-off that best predicts BKVAN remains controversial. Objective: To evaluate the performance of a commercial and an in-house qPCR test for quantitative detection of BK virus in kidney transplant recipients. Methods: This was a prospective study with kidney transplant recipients from two large university hospitals in Brazil. Patients were screened for BKV infection every 3 months in the first year post-transplant with a commercial and an in-house real time polymerase chain reaction (qPCR) test. BKVAN was confirmed based on histopathology. The area under the curve for plasma qPCR was determined from receiver operating characteristic analysis. Results: A total of 200 patients were enrolled. Fifty-eight percent were male, 19.5% had diabetes mellitus, and 82% had the kidney transplanted from a deceased donor. BKV viremia was detected in 32.5% and BKVAN was diagnosed in 8 patients (4%). BKVAN was associated with viremia of 4.1 log copies/ mL, using a commercial kit. The cut-off for the in-house assay was 6.1 log copies/ mL. The linearity between the commercial kit and the in-house assay was R2 =0.83. Conclusion: Our study shows that marked variability occurs in BKV viral load when different qPCR methodologies are used. The in-house qPCR assay proved clinically useful, a cheaper option in comparison to commercial qPCR kits. There is an urgent need to make BKV standards available to the international community.Introdução: A infecção pelo vírus BK (BKV) em pacientes de transplante renal pode levar a disfunção do aloenxerto renal e perda do enxerto. A determinação precisa da carga viral do BKV é fundamental para prevenir a nefropatia associada ao BKV (BKVAN), mas o ponto de corte de melhor valor preditivo para BKVAN ainda é foco de debates. Objetivo: Avaliar o desempenho de um teste de qPCR comercial e outro desenvolvido internamente para detecção quantitativa de vírus BK em receptores de transplante renal. Métodos: O presente estudo prospectivo incluiu receptores de transplante renal de dois grandes hospitais universitários no Brasil. Os pacientes foram testados para infecção por BKV a cada três meses no primeiro ano pós-transplante com um teste comercial de reação em cadeia de polimerase quantitativa em tempo real (qPCR) e outro desenvolvido internamente. A presença de BKVAN foi confirmada com base na histopatologia. A área sob a curva para o qPCR plasmático foi determinada a partir da análise da característica de operação do receptor. Resultados: Um total de 200 pacientes foram incluídos. Cinquenta e oito por cento eram do sexo masculino, 19,5% tinham diabetes mellitus e 82% tiveram seus rins transplantados de doadores falecidos. Viremia de BKV foi detectada em 32,5% dos pacientes e oito (4%) foram diagnosticados com BKVAN. BKVAN foi associada a viremia de 4,1 log cópias/mL usando o kit comercial. O corte para o ensaio interno foi de 6,1 log cópias/ mL. A linearidade entre o kit comercial e o ensaio interno foi R2 = 0,83. Conclusão: Nosso estudo demonstrou uma acentuada variabilidade na carga viral de BKV quando diferentes metodologias de qPCR foram utilizadas. O ensaio interno de qPCR mostrou- -se clinicamente útil, além de ser uma opção menos onerosa em relação aos kits comerciais de qPCR. Há uma necessidade urgente de se definir padrões de BKV para a comunidade internacional

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years