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Aims: Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft–Gault‐based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft–Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT‐enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. Methods: Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT‐ and CG‐based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. Results: In total, 108 patients were included in the analysis. Addition of the CRAFT‐ and CG‐based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26‐point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 μmol/L, the calculated carboplatin dose was 233 mg higher using the CG. Conclusions: Carboplatin clearance is better predicted by CRAFT vs. CG‐based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha‐ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide–cysteamine combination treatment as a novel dual‐target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient‐derived kidney tubuloids and cystinotic zebrafish. SYNOPSIS: Nephropathic cystinosis is a severe genetic disorder caused by mutations in the lysosomal cystine transporter, cystinosin. Although several cellular defects have been associated with cystinosis, the mechanism linking cystinosin loss, and epithelial dysfunction remains largely unknown. CRISPR‐generated isogenic cystinotic renal proximal tubule cells recapitulate the disease pathology and allow direct evaluation of the effect of cystinosin loss, independent of chronic exposure to disease‐related changes in the body.Alpha‐ketoglutarate (αKG), an important intermediate of the tricarboxylic acid cycle, is a part of a unifying mechanism linking cystinosin loss, lysosomal autophagy disruption and proximal tubule impairment in cystinotic renal proximal tubule cells.Cysteamine‐bicalutamide combination therapy restores proximal tubule function in advanced in vitro models and corrects cystinosis related defects in cystinotic zebrafish. Our findings demonstrate that the combination therapy is a novel potential treatment for patients with nephropathic cystinosis. [ABSTRACT FROM AUTHOR]

In earlier days, periarticular accumulations of calcium phosphate causing tumor-like depositions were considered the result of passive precipitation and referred to as metastatic calcifications. From sophisticated computer tomographic studies and growing insight, we have learned that calcifications in the cardiovascular system are far more threatening and in fact one of the most important sequela of end-stage renal disease. The histologic characteristic of uremia-related calcification is arteriosclerosis of the media. In addition, there is atherosclerosis of the intima, due to the high prevalence of classic cardiovascular risk factors in renal disease. The two vascular features can frequently exist at different sites in the vasculature. Novel diagnostic techniques are helping to elucidate the pathogenetic mechanisms of active conversion of vascular smooth muscle cells to osteochondritic cells. Through this process, extensive calcification of the central and peripheral vasculature ensues, influenced by different promotors and inhibitors. Calciphylaxis is a special form of extraosseous calcification leading to skin necrosis. The factors that trigger the development of calciphylaxis are not completely understood, but this syndrome shares part of the pathophysiologic basis of extraosseous calcification in general. However, the therapeutic approach must be prompt and aggressive, because of the poor prognosis. Frequently, a fatal outcome cannot be avoided in calciphylaxis. [ABSTRACT FROM AUTHOR]

Acute Tubular Injury (ATI) is the leading cause of Delayed Graft Function (DGF) after renal transplantation (RTX). Biopsies taken 1 week after RTX often show extensive tubular damage, which in most cases resolves due to the high regenerative capacity of the kidney. Not much is known about the relation between histological parameters of renal damage and regeneration immediately after RTX and renal outcome in patients with DGF. We retrospectively evaluated 94 patients with DGF due to ATI only. Biopsies were scored for morphological characteristics of renal damage (edema, casts, vacuolization, and dilatation) by three independent blinded observers. The regenerative potential was quantified by tubular cells expressing markers of proliferation (Ki67) and dedifferentiation (CD133). Parameters were related to renal function after recovery (CKD‐EPI 3, 6, and 12 months posttransplantation). Quantification of morphological characteristics was reproducible among observers (Kendall's W ≥ 0.56). In a linear mixed model, edema and casts significantly associated with eGFR within the first year independently of clinical characteristics. Combined with donor age, edema and casts outperformed the Nyberg score, a well–validated clinical score to predict eGFR within the first year after transplantation (R2 = 0.29 vs. R2 = 0.14). Although the number of Ki67+ cells correlated to the extent of acute damage, neither CD133 nor Ki67 correlated with renal functional recovery. In conclusion, the morphological characteristics of ATI immediately after RTX correlate with graft function after DGF. Despite the crucial role of regeneration in recovery after ATI, we did not find a correlation between dedifferentiation marker CD133 or proliferation marker Ki67 and renal recovery after DGF. Acute tubular injury is the leading cause of delayed graft function after kidney transplantation and is associated with worse long–term outcome. Although the underlying mechanisms of damage and ensuing regeneration are progressively identified, predicting outcome in these patients remains challenging. In this study we found that the morphological characteristics of acute tubular injury but not characteristics of regeneration were associated with recovery. [ABSTRACT FROM AUTHOR]