Stress Response Gene Nupr1 Alleviates Cyclosporin A Nephrotoxicity In Vivo.

Acute tubular damage is a major cause of renal failure, especially at the early phase of kidney transplant when ischemia-reperfusion injury and cyclosporin A toxicity may coexist. The mechanisms of the latter are largely unknown. Using an mRNA microarray on microdissected tubules from a rat model of cyclosporin A toxicity to describe the related epithelial-specific transcriptional signature in vivo, we found that cyclosporin A induces pathways dependent on the transcription factor ATF4 and identified nuclear protein transcriptional regulator 1 (Nupr1), a stress response gene induced by ATF4, as the gene most strongly upregulated. Upon cyclosporin A treatment, Nupr1-deficient mice exhibited worse renal tubular lesions than wild-type mice. In primary cultures treated with cyclosporin A, renal tubular cells isolated from Nupr1-deficient mice exhibited more apoptosis and ATP depletion than cells from wild-type mice. Furthermore, cyclosporin A decreased protein synthesis and abolished proliferation in wild-type tubular cells, but only reduced proliferation in Nupr1-deficient cells. Compared with controls, mouse models of ischemia-reperfusion injury, urinary obstruction, and hypertension exhibited upregulated expression of renal NUPR1, and cyclosporin A induced Nupr1 expression in cultured human tubular epithelial cells. Finally, immunohistochemical analysis revealed strong expression of NUPR1 in the nuclei of renal proximal tubules of injured human kidney allografts, but not in those of stable allografts. Taken together, these results suggest that epithelial expression of NUPR1 has a protective role in response to injury after renal transplant and, presumably, in other forms of acute tubular damage.

Evaluation of the ability of bone marrow derived cells to engraft the kidney and promote renal tubular regeneration in mice following exposure to cisplatin.

It has been suggested that bone marrow derived stem cells have the ability to engraft the kidney and improve the outcome of severe acute kidney injury (AKI) in mice exposed to high doses of cisplatin, providing hope for cancer patients in whom irreversible renal damage occasionally occurs following the use of this highly effective anti-tumor drug. We tested the therapeutic potential of bone marrow derived cells injected during the acute phase (day 3 after cisplatin administration) of experimentally-induced AKI in C57Bl6/J mice, characterized by massive tubular necrosis, apoptosis, and a low proliferation capacity. We failed to show any benefit of bone marrow derived cells versus a regular homogenate of intact renal cells, or normal saline. Using cell tracers and flow cytometry, we demonstrated that bone marrow derived cells did indeed home to the bone marrow of the recipients but failed to settle in the kidney. Conversely, renal cells homed to injured kidneys. However, neither cell therapy protected the animals against cisplatin-induced death. We therefore question the short-term efficacy of bone marrow derived cells used to repair established injuries of the tubular epithelium.

Urinary TIMP2 and IGFBP7 Identifies High Risk Patients of Short-Term Progression from Mild and Moderate to Severe Acute Kidney Injury during Septic Shock: A Prospective Cohort Study.

BACKGROUND: To examine whether the new urinary biomarkers TIMP2 and IGFBP7 can predict progression within 24 hours and 72 hours from mild and moderate (KDIGO 1 or 2) to severe (KDIGO 3) AKI in patients with septic shock. METHODS: A prospective, multicenter observational study performed in three French ICUs. The urinary biomarkers TIMP2∗IGFBP7 were analyzed at the early phase (<6 hours) of patients admitted for septic shock with mild and moderate AKI. RESULTS: Among the 112 patients included, 45 (40%) progressed to the KDIGO 3 level 24 hours after inclusion (KDIGO 3 H24) and 47 (42%) 72 hours after inclusion (KDIGO 3 H72). The median urinary TIMP2∗IGFBP7 at inclusion (baseline) were higher in the KDIGO 3 group than in the KDIGO<3 group at H24 and H72. All covariates with a p value < 0.1 in the univariate analysis were included in stepwise multiple logistic regression models to identify factors independently associated with the risk of KDIGO 3 at H24 and H72. TIMP2∗IGFBP7 remained independently associated with KDIGO 3 at H24 and H72. Baseline posology of norepinephrine, baseline urine output, and baseline serum creatinine remained also significantly associated with progression to KDIGO 3 at H24. Baseline TIMP2∗IGFBP7 and baseline urinary output had the best AUC ROC. A baseline TIMP2∗IGFBP7 > 2.0 (ng/ml)2/1,000 identified the population at high risk of KDIGO 3 H24 (relative risk 4.19 (1.7-10.4)) with a sensitivity of 76% (60-87) and a specificity of 81% (69-89). But the diagnostic performance at H72 of baseline TIMP2∗IGFBP7 was poor (AUC: 0.69 (0.59-0.77)). CONCLUSION: The urinary TIMP2∗IGFBP7 concentration and the urine output at the early phase of septic shock are independent factors to identify the population at high risk of progression from mild and moderate to severe AKI over the next 24 but not 72 hours. A TIMP2∗IGFBP7 concentration > 2.0 (ng/ml)2/1,000 quadruples the risk of KDIGO 3 AKI within 24 hours. This trial is registered with (NCT03547414).

Evidence of dipstick superiority over urine microscopy analysis for detection of hematuria.

BACKGROUND: There is an unresolved debate on the best screening method for hematuria as a symptom of glomerulonephritis or urological malignancies. The urinary dipstick is generally considered as an imperfect surrogate for urine microscopy analysis. RESULTS: We designed a study to compare urine microscopy analysis, urinary dipstick and flow cytometry, using controlled dilutions of blood in urine samples from volunteers collected in two different physiologically-relevant conditions (basal state and hyperhydration). We found that although all techniques were 100 % effective in detecting hematuria at basal state, these results were variably reproduced when testing the same final amount of hematuria in urine collected after hyperhydration. Our data shows a variable sensitivity for the detection of hematuria by urine microscopy analysis or flow cytometry, but not by urinary dipstick. CONCLUSIONS: Urinary dipstick qualifies as a better screening test for hematuria than urine microscopy analysis or flow cytometry, as it is sensitive and performs better in unstandardized conditions. It is universally available and also faster and cheaper than cytometric techniques.

[Fanconi syndrome in a 22-year-old African patient]. / Syndrome de Fanconi chez un patient de 22 ans d'origine africaine.

Acquired Fanconi syndrome can occur in patients with monoclonal gammopathy or after exposure to heavy metals or drug agents such as ifosfamide, and some antiretroviral therapies. Fanconi syndrome is characterized by a dysfunctional of the proximal tubular responsible in its complete form for polyuria, hypokalemia, glycosuria, hypophosphatemia and low molecular weight proteinuria. We report the case of a 22-year-old patient hospitalized with an acute renal failure secondary to a tubulo-interstitial nephritis associated with a complete Fanconi syndrome in a context of a poor general condition and fever. We described and analyzed the process leading to the diagnosis.

Impact of renal graft nephrectomy on second kidney transplant survival.

PURPOSE: To determine the impact of non-functional renal graft nephrectomy on second kidney transplantation survival. METHODS: We performed a retrospective study on patients managed in our department from April 1989 to April 2011. We compared the number of acute graft rejections and graft survival between patients undergoing second transplantation with (Group I) or without (Group II) prior graft nephrectomy. RESULTS: A total of ninety-one patients received a second renal graft: 43 underwent graft nephrectomy and 48 kept their non-functional renal graft. There were 5 episodes of acute graft rejection in Group I and 12 in Group II (p = 0.3). Six (13.9 %) grafts failed in Group I and eight (16.6 %) in Group II. Five and 10 years actuarial graft survival in Group I were, respectively, 91 and 85 %, while in Group II were 82.7 % and 69 % (p = 0.2). PRA level and number of acute rejection episodes did not have a statistically significant influence on graft survival, whether the patient had a nephrectomy or not (p = 0.2). CONCLUSION: Nephrectomy of a failed allograft did not significantly improve the survival of a subsequent graft. Graft nephrectomy should be indicated in case of graft-related pain or a chronic inflammation syndrome.