Possible role of mitochondrial injury in Caulis Aristolochia manshuriensis-induced chronic aristolochic acid nephropathy.

CONTEXT: The proximal tubular epithelial cells (PTECs) are the primary target of aristolochic acids and especially vulnerable to mitochondrial injury from insults of toxic xenobiotics. OBJECTIVES: This study aimed to investigate the possible role of mitochondrial injury in Caulis Aristolochia manshuriensis (CAM)-induced aristolochic acid nephropathy (AAN). MATERIALS AND METHODS: Male Sprague-Dawley rats were gavaged with CAM extract every other week for 1, 4, 8 and 12 weeks, respectively. RESULTS: The rats in the model group showed chronic AAN as evidenced by worsening kidney function evaluated by blood urea nitrogen, creatinine and proteinuria levels, and severe tubulointerstitial injury marked by massive tubular atrophy and interstitial fibrosis in kidney tissues. Moreover, overt apoptosis and impaired regeneration of PTECs were observed in AAN rats. Furthermore, the study revealed that mitochondria in PTECs were fragmented into small, punctuate suborganelles in AAN rats. Two mitochondrial respiratory chain proteins, mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit І (COX-І) and nuclear DNA-encoded nicotinamide adenine dinucleotide dehydrogenase (ubiquinone)-1ß subcomplex 8 (NDUFß8), were both down-regulated after one week of CAM treatment. However, with AAN progression, NDUFß8 level restored, while COX-І level maintained low. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), master regulator of mitochondrial biogenesis, was significantly down-regulated at week 4 and week 8, but significantly up-regulated at week 12. In addition, mtDNA copy number reduced markedly along with AAN progression. DISCUSSION AND CONCLUSION: A rat model of chronic AAN was successfully reproduced by gavage with CAM extract. Dynamic changes of mitochondrial injury induced by CAM might contribute to the AAN progression.

Urinary neutrophil gelatinase-associated lipocalin: A potential biomarker for predicting rapid progression of drug-induced chronic tubulointerstitial nephritis.

INTRODUCTION: The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in drug-induced chronic tubulointerstitial nephritis (D-CTIN) has not been well described. METHODS: A total of 36 patients with D-CTIN were enrolled in the study. The baseline urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL), alpha1-microglobin (alpha1-MG), albumin (mAlb) and total protein were measured, and estimated glomerular filtration rate change rates within a period of 6 to 33 (mean: 24 months) follow-up months were recorded. RESULTS: Areas under the receiver-operator characteristic curve of urinary NGAL, alpha1-MG, mAlb and total protein for predicting deterioration of estimated glomerular filtration rate were 0.707, 0.631, 0.685 and 0.678, respectively. The cutoff points that maximized the combined sensitivity and specificity for NGAL, alpha1-MG, mAlb and total protein were 37.71 ng/mL, 33.20 microg/mL, 6.91 mg/L and 60.00 mg/L, respectively. At these thresholds, the sensitivity and specificity was 64.7% and 78.9% for NGAL, 66.7% and 50.0% for alpha1-MG, 80.0% and 50.0% for mAlb and 70.6% and 63.2% for total protein, respectively. The median renal survival time (years) of patients with urinary NGAL level exceeding 37.705 ng/mL was shorter than that of patients with urinary NGAL level below 37.705 ng/mL (1.59 +/- 0.79 versus 2.09 +/- 0.63, P = 0.040, chi(2) = 4.218). CONCLUSIONS: Increase of baseline urinary NGAL was better than alpha1-MG, mAlb and total protein in predicting renal function deterioration in patients with D-CTIN. This noninvasive approach has potential to serve as a practical tool in D-CTIN prognosis.

[Significance of urinary biomarkers in differential diagnosis of acute tubulointerstitial nephritis].

OBJECTIVE: To find some urinary biomarkers with significance in the differentiation of drug-induced tubulointerstitial nephritis (DTIN). METHODS: Forty patients with biopsy-proven DTIN were enrolled. The urine samples of DTIN patients were collected on the day of biopsy and all urine samples were measured for the following different biomarkers as indicated, respectively: urinary TGF-beta by ELISA; urinary IL-6 by radio-immunoassay; NAG by an enzyme-substrate colorimetric assay; alpha1-MG by immune transmission turbidity method. Receiver operating characteristic curves (ROC curve) were constructed to calculate the sensitivity and specificity of those biomarkers in distinguishing acute (A-DTIN) and chronic DTIN (C-DTIN). RESULTS: Urinary NAG and alpha1-MG levels in patients with A-DTIN were as 2.5 and 2.1 times as those in C-DTIN (P<0.05), while urinary TGF-beta levels in the two groups had no statistical difference. The areas under ROC curve (AUC) of urinary NAG and alpha1-MG for differentiating A-DTIN were 0.720 (P=0.029) and 0.714 (P=0.034) respectively, while the AUCs for TGF-beta and IL-6 were 0.536 (P=0.767) and 0.150 (P=0.004) respectively. Combined measurement of NAG and alpha1-MG could make sensitivity and specificity reach 78.6% and 75.0 % respectively. CONCLUSION: Urinary alpha1-MG and NAG levels can reflect the acute lesions of DTIN, and combined measurement of both could enhance efficiency in differentiating A-DTIN.

Drug-induced acute tubulointerstitial nephritis: a case with elevated urinary cadmium.

Acute tubulointerstitial nephritis (ATIN) has many different causes, but is most frequently caused by drugs. We report a 13-year-old vegetarian girl with drug-induced ATIN, confirmed by renal biopsy, and simultaneous occurrence of elevated urinary cadmium. Four weeks prior to admission she had been treated with antibiotics and acetaminophen for respiratory infection, and remaining febrile, was treated with different "home-made" herbal mixtures. She presented with acute non-oliguric renal failure, tubular dysfunction, and sterile pyuria, but without skin rash or edema. Laboratory data showed a raised erythrocyte sedimentation rate, normal white blood count with eosinophilia, and a serum creatinine of 245 micromol/l. Urinalysis was remarkable for glycosuria, tubular proteinuria, and elevated beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase excretion. Immunoserological tests characteristic of acute glomerulonephritis and systemic diseases were negative. She was treated with steroids and her renal function improved. Follow-up analyses disclosed normal urinary cadmium and enzyme excretion within 6 months. Heavy metal analysis of herbal preparations that she had taken confirmed the presence of cadmium, but within approved concentrations. In conclusion, elevated urinary cadmium in the case of drug-induced ATIN may be assumed to be an accidental finding. However, consumption of different herbs containing cadmium and cadmium-induced nephro-toxicity could be the reason for such serious renal damage.