Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb ( Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7 mg/kg body weight DXF (DXF group), 7 mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days. Six animals per group were killed on day 10 and the remaining six on day 35. Renal function was evaluated by determining serum creatinine and urinary leucine aminopeptidase activity. Histological evaluation of kidney samples was performed and tubulointerstitial injuries were semiquantified. The DXF group did not differ from controls for any parameter. Similarly elevated serum creatinine levels, decreased leucine aminopeptidase enzymuria, and renal lesions were observed in the AA and the AA+DXF groups after both 10 and 35 days. The formation of specific AA-DNA adducts in liver and renal tissue samples was assessed by the (32)P-postlabelling method. Specific AA-DNA adduct levels were significantly increased in kidney tissues from AA+DXF rats compared with AA rats. These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA-DNA adduct formation.

Experimental aristolochic acid nephropathy is characterized by transient acute proximal tubule necrosis and inflammatory cell infiltrates followed by interstitial fibrosis and tubular atrophy. The respective role of T-cell subpopulations has never been studied in the acute phase of the mouse model, and was heretofore exclusively investigated by the use of several depletion protocols. As compared to mice injected with aristolochic acids alone, more severe acute kidney injury was observed after CD4+ or CD8+ T-cells depletion. TNF-alpha and MCP-1 mRNA renal expressions were also increased. In contrast, regulatory T-cells depletion did not modify the severity of the aristolochic acids induced acute kidney injury, suggesting an independent mechanism. Aristolochic acids nephropathy was also associated with an increased proportion of myeloid CD11bhighF4/80mid and a decreased proportion of their counterpart CD11blowF4/80high population. After CD4+ T-cell depletion the increase in the CD11bhighF4/80mid population was even higher whereas the decrease in the CD11blowF4/80high population was more marked after CD8+ T cells depletion. Our results suggest that CD4+ and CD8+ T-cells provide protection against AA-induced acute tubular necrosis. Interestingly, T-cell depletion was associated with an imbalance of the CD11bhighF4/80mid and CD11blowF4/80high populations.

BackgroundRenal toxicity induced by cisplatin (CisPt) is a clinical issue in patients with or without chronic kidney disease (CKD). Proximal tubular injury can result in acute kidney injury (AKI), which may compromise the course of chemotherapy and the prognosis. The purpose of this study was to investigate the time course of urinary markers of acute tubulotoxicity and to assess the usefulness of such monitoring in a routine clinical setting.MethodsThis work is an open prospective pilot study carried out among 23 patients receiving a platinum-based chemotherapy. Individual comorbidities, plasma parameters of kidney function (urea, creatinine) and estimated glomerular filtration rate were registered. Urinary excretion of leucine aminopeptidase, neutrophil gelatinase-associated lipocalin, cystatin C, liver fatty acid-binding protein and interleukin-18 were monitored during successive chemotherapy cycles. Episodes of AKI were identified according to KDIGO (Kidney Disease Improving Global Outcomes) 2012 guidelines.ResultsA total of 28 patients were recruited; among them 23 agreed to be part of the study, of whom 18 received CisPt and 5 carbo- or oxaliplatin. Of the 18 CisPt patients, 12 had a preexisting CKD. Sixteen AKI episodes were observed in 13 patients receiving CisPt with a pejorative evolution in seven cases (partial recovery of the renal function); a transient but dramatic increase in urinary biomarkers was observed 3 h after chemotherapy initiation, whereas plasma creatinine rise appeared 72 h after the end of CisPt treatment. Identified precipitating factors included: dehydration due to lack of fluid intake or diuretic use, exposure to high CisPt doses, regular use of nonsteroidal anti-inflammatory drugs and/or iodinated contrast agents and sepsis.ConclusionEven if numerous precipitating factors could be avoided, the monitoring of urinary markers seemed helpful for the early detection of subclinical AKI induced during CisPt chemotherapy.

BackgroundThe platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.AimsIn this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN.Materials and MethodsNeutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily.ResultsAt Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.ConclusionsThe early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation.

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