Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized controlled open-label multi-center trial (INTERCEPT study).

BACKGROUND: Chronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area. METHODS: The INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05. The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection. DISCUSSION: No effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term. TRIAL REGISTRATION: ClinicalTrials.gov NCT04561986. Registered on September 24, 2020.

Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression?

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2 genes, is the most common hereditary renal disease. Renal manifestations of ADPKD are gradual cyst development and kidney enlargement ultimately leading to end-stage renal disease. ADPKD also causes extrarenal manifestations, including endothelial dysfunction and hypertension. Both of these complications are linked with reduced nitric oxide levels related to excessive oxidative stress (OS). OS, defined as disturbances in the prooxidant/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen and nitrogen free radicals. Next to endothelial dysfunction and hypertension, there is cumulative evidence that OS occurs in the early stages of ADPKD. In the current review, we aim to summarize the cardiovascular complications and the relevance of OS in ADPKD and, more specifically, in the early stages of the disease. First, we will briefly introduce the link between ADPKD and the early cardiovascular complications including hypertension. Secondly, we will describe the potential role of OS in the early stages of ADPKD and its possible importance beyond the chronic kidney disease (CKD) effect. Finally, we will discuss some pharmacological agents capable of reducing reactive oxygen species and OS, which might represent potential treatment targets for ADPKD.

Oxidative stress in chronic kidney disease.

Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the balance is not disturbed, OS has a role in physiological adaptations and signal transduction. However, an excessive amount of ROS and RNS results in the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease (CKD), increased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients.

Association of HO-1 (GT)n Promoter Polymorphism and Cardiovascular Disease: A Reanalysis of the Literature.

BACKGROUND: Heme-oxygenase 1 (HO-1), an inducible heme-degrading enzyme, has antiatherogenic effects through its enzymatic end products. HO-1 gene expression is modulated by a guanidine thymidine dinucleotide ([GT]n) repeat polymorphism in the promoter region. Shorter repeats with (GT)n < 25 are associated with higher inducibility and activity of HO-1. METHODS: We performed a systematic review of all literature from 1997 to 2013 on the association of the HO-1 (GT)n and cardiovascular disease (CVD). On the basis of predefined criteria (patient characteristics, genotype data format, allelic distribution, repeat length cutoff) 41 articles were selected. Patients were redistributed into 4 homogeneous subpopulations: patients with CVD (CVD group), patients without CVD (nonCVD), 'controls' with unknown cardiovascular status (unspecified) and children younger than 20 years of age (unselected). Genotype distributions (homozygous short [SS] or long [LL], and heterozygous) of the 4 patient categories were compared and odds ratios (ORs) for CVD were calculated using logistic regression analysis. RESULTS: Overall, the proportion of the SS genotype was lower in CVD compared with nonCVD and unspecified. The ORs for CVD was highest in patients carrying the LL genotype (OR LL vs SS, 1.769 [95% confidence interval, 1.594-1.963]). Furthermore, genotype distribution differed between Caucasian and Asian individuals, the latter having a much higher proportion of the SS genotype (22% vs 11%). CONCLUSIONS: This review of the available literature on the epidemiological association between the HO-1 (GT)n repeat polymorphism and CVD supports the presumed protective effects of HO-1. The second but probably even more relevant finding of our review is that racial disparities in HO-1 (GT)n repeat length distribution exist and might influence the associations of the genotype with CVD status.

Microscopic nephrocalcinosis in chronic kidney disease patients.

BACKGROUND: Experimental data indicate that microscopic calcium phosphate deposition in the kidney (nephrocalcinosis) may accelerate progression of chronic kidney disease (CKD). Data on the prevalence, risk factors and implications of nephrocalcinosis in CKD patients are scarce. A mineral metabolism disorder could play an important pathogenetic role, as suggested by recent protocol biopsy findings in incident renal transplant recipients. METHODS: Kidney biopsy cylinders of CKD patients, collected between January 1989 and December 2007, were screened for the presence of nephrocalcinosis. Only patients with ≥1 parathyroid hormone (PTH) level available within 180 days of the biopsy were eligible for inclusion (n = 211). Demographics and mineral metabolism parameters were retrieved from medical files. Data on renal death (up to December 2012) were obtained from the Flemish ESRD registry. Baseline biopsies from 110 deceased kidney transplant donors served as controls. RESULTS: The prevalence of nephrocalcinosis in kidney donors and patients with CKD 1-2, CKD 3-4 and CKD 5-5D was 4.6, 14.3, 20.2 and 54.0%, respectively (P < 0.0001). Among CKD patients, patients with nephrocalcinosis were characterized by lower estimated GFR, lower serum bicarbonate level and higher serum PTH and calcium level. In multivariate regression analysis, high serum PTH, calcium and creatinine level, and low serum bicarbonate level were all significantly and independently associated with nephrocalcinosis. Serum phosphorus level, but not nephrocalcinosis predicted renal death, independent of renal function. CONCLUSIONS: Our data demonstrate that prevalence rates of nephrocalcinosis increase with increasing CKD stage to reach more than 50% in end-stage renal disease patients and suggest that acid-base and mineral metabolism disturbances are implicated in its pathogenesis.