phenanthrenes and Renal-Insufficiency

Chinese herbs nephropathy is characterized by an extensive interstitial fibrosis and by a rapid evolution to end-stage renal failure. We thus decided to try steroid therapy (prednisolone 1 mg/kg for 1 month, tapered off 0.1 mg/kg every 2 weeks) in cases with moderate renal failure and evidence of deterioration in renal function. Our steroid group (SG) consisted of 12 female patients with biopsy-proven renal fibrosis who were followed for at least 12 months after the initiation of steroids. Plasma creatinine level (Pcreat) ranged from 1.8 to 3.9 mg/dL (mean +/- SEM, 2.8 +/- 0.2 mg/dL) when steroids were initiated at t = 0. Renal failure was in progression since Pcreat was 2.1 +/- 0.1 mg/dL (P = 0.022) 3 months before t = 0. Our control group (CG; N = 23) was selected retrospectively from among the 81 patients in the Belgian Register of Chinese Herbs Nephropathy. Compared with the CG, renal function was better preserved in the SG (Pcreat; mean +/- SEM): SG v CG, 2.9 +/- 0.3 mg/dL v 5.3 +/- 0.5 mg/dL at 6 months (P = 0.0024) and 4.0 +/- 0.7 mg/dL v 7.1 +/- 0.5 mg/dL at 1 year (P = 0.001). The slope of the reciprocal serum creatinine concentration was similar in both groups before t = 0 (-0.0463 mg/dL/mo in the SG v -0.0438 mg/dL/mo in the CG; P = 0.83), but it became less steep after initiation of steroid therapy (between 0 and 6 months, -0.000742 mg/dL/mo in the SG v -0.0284 mg/dL/mo in the CG; P < 0.001). Finally, only two of the 12 patients in the SG required dialysis at 1 year compared with 16 of the 23 patients in the CG (P = 0.0045). We conclude that steroid therapy slows the progression of renal failure in a disease characterized by an interstitial fibrosis that progresses quickly despite the fact that the insulting agent has been withdrawn. This supports the hypothesis that renal interstitial fibrosis may be an immune-mediated process.

Topics: Aristolochic Acids; Case-Control Studies; Disease Progression; Drugs, Chinese Herbal; Female; Fibrosis; Follow-Up Studies; Glucocorticoids; Humans; Kidney; Middle Aged; Nephritis, Interstitial; Phenanthrenes; Pilot Projects; Prednisolone; Renal Insufficiency; Time Factors

Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese Medicine, is effective in treating rheumatoid arthritis (RA), but its severe nephrotoxicity limits its extensive application. The nephrotoxic mechanism of Triptolide (TP), the main pharmacological and toxic component of TwHF, has not been fully revealed. This study was designed to explore the nephrotoxicity of TP in the RA state and the potential molecular mechanism. A rat collagen-induced arthritis (CIA) model was constructed and administered with TP for 28 days in vivo. Results showed that the kidney injury induced by TP was aggravated in the CIA state, the concentration of TP in the renal cortex was higher than that of the medulla after TP administration in the CIA rats, and the expression of organic cation transporter 2 (Oct2) in kidney was up-regulated under CIA condition. Besides, rat kidney slice study demonstrated that TP was transported by Oct2 and this was confirmed by transient silencing and overexpression of OCT2 in HEK-293T cells. Furthermore, cytoinflammatory models on HK-2 and HEK-293T cell lines were constructed by exposure of TNF-α or IL-1β to further explore the TP's renal toxicity. Results suggested that TNF-α exposure aggravated TP's toxicity and up-regulated the protein expression of OCT2 in both cell lines. TNF-α treatment also increased the function of OCT2 and finally OCT2 silencing confirmed OCT2 mediated nephrotoxicity of TP in HEK-293T cells. In summary, the exposure of TNF-α in RA state induced the expression of OCT2, which transported more TP into kidney cortex, subsequently exacerbated the kidney injury.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cell Line; Cytokines; Diterpenes; Epoxy Compounds; Female; HEK293 Cells; Humans; Kidney; Medicine, Chinese Traditional; Organic Cation Transporter 2; Phenanthrenes; Rats; Rats, Wistar; Renal Insufficiency; Tripterygium; Up-Regulation

Chinese herbs nephropathy (CHN), a unique type of nephropathy has been associated with the intake of weight-reducing pills containing the Chinese herb Aristolochia fangchi. Moreover, an association between the use of A. fangchi and urothelial cancer in CHN patients has been reported indicating that aristolochic acid (AA) the major alkaloid of A. fangchi might be the causal agent. Similarities of CHN to the Balkan endemic nephropathy (BEN) have led to the hypothesis of a common etiological agent for both diseases. Evidence has accumulated that BEN is an environmentally-induced disease strongly associated with the fungal mycotoxin ochratoxin A (OTA). Both, AA and OTA are nephrotoxic and carcinogenic and induce the formation of DNA adducts. As OTA has been suspected as fungal contaminant in the herbal batches used for the preparation of the weight-reducing pills we analysed tissues from CHN patients by the 32P-postlabeling procedure for the presence of DNA adducts related to both OTA and AA exposure. Whereas, AA-specific DNA adducts were detected in all five urinary tract tissues from five patients (total RAL: 32-251 adducts per 10(9) nucleotides), OTA-related DNA adducts were detectable in two kidneys and one ureter only (total RAL: 1.5-3.7 adducts per 10(9) nucleotides). Thus, OTA-related DNA adduct levels were about 50 times lower than AA-DNA adduct levels. In female and male rats that were treated with the slimming regimen in the same way like the CHN patients except that the amount of Chinese herbs was 10 times higher, AA-DNA adducts were found in kidney tissues (total RAL ranging from 51 to 83 adducts per 10(9) nucleotides) but adducts derived from OTA were not observed. These results demonstrate that OTA-related DNA adducts do not play a key role in CHN or CHN-associated urothelial cancer.

Topics: Adult; Animals; Anti-Obesity Agents; Aristolochic Acids; Balkan Nephropathy; Belgium; DNA Adducts; Drugs, Chinese Herbal; Female; Humans; Male; Middle Aged; Mycotoxins; Ochratoxins; Phenanthrenes; Rats; Rats, Wistar; Renal Insufficiency

Topics: Aristolochic Acids; Drugs, Chinese Herbal; Humans; Kidney; Phenanthrenes; Renal Insufficiency; Terminology as Topic

The causal role of aristolochic acid (AA) in the so-called Chinese herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.

Topics: Aristolochic Acids; DNA Adducts; Drugs, Chinese Herbal; Female; Humans; Kidney; Middle Aged; Phenanthrenes; Renal Insufficiency; Terminology as Topic