Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy.

Renal fibrosis is a common pathway for the progression of various chronic kidney diseases (CKD), and the formation and deterioration will eventually lead to end-stage renal failure, which brings a heavy medical burden to the world. HeidihuangWan (HDHW) is a herbal formulation with stable and reliable clinical efficacy in the treatment of renal fibrosis. However, the mechanism of HDHW in treating renal fibrosis is not clear. In this study, we aimed to investigate the mechanism of HDHW to improve renal fibrosis. Wistar rats were randomly divided into the normal control group, 5/6 Nephrectomy group, astragaloside IV (AS-IV) group, HDHW group, and HDHW + IGF-1R inhibitor (JB1) group. Except for the normal control group, the rat renal fibrosis model was established by 5/6 nephrectomy and intervened with drugs for 8 weeks. Blood samples were collected to evaluate renal function. Hematoxylin-Eosin (HE), Periodic Acid-Schiff (PAS), Modified Masson's Trichrome (Masson) staining were used to evaluate the pathological renal injury, and immunohistochemistry and Western blotting were used to detect the protein expression of renal tissue. The results showed that HDHW was effective in improving renal function and reducing renal pathological damage. HDHW down-regulated the levels of fibrosis marker proteins, including α-smooth muscle actin (α-SMA), vimentin, and transforming growth factors-ß(TGF-ß), which in turn reduced renal fibrosis. Further studies showed that HDHW down-regulated the expression of autophagy-related proteins Beclin1 and LC3II, indicating that HDHW inhibited autophagy. In addition, we examined the activity of the class I phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway, an important signaling pathway regulating autophagy, and the level of insulin-like growth factor 1 (IGF-1), an upstream activator of PI3K/Akt/mTOR. HDHW upregulated the expression of IGF-1 and activated the PI3K/Akt/mTOR pathway, which may be a vital pathway for its inhibition of autophagy. Application of insulin-like growth factor 1 receptor (IGF-1R) inhibitor further confirmed that the regulation of autophagy and renal fibrosis by HDHW was associated with IGF-1-mediated activation of the PI3K/Akt/mTOR pathway. In conclusion, our study showed that HDHW inhibited autophagy by upregulating IGF-1 expression, promoting the binding of IGF-1 to IGF-1R, and activating the PI3K/Akt/mTOR signaling pathway, thereby reducing renal fibrosis and protecting renal function. This study provides support for the application and further study of HDHW.

[The safety analysis of living-related kidney donors in short term after transplantation].

OBJECTIVE: To evaluate the safety of living related donors in short term after transplantation. METHODS: Two hundred and fifty-one cases of living related donor kidney transplantation from May 2000 to July 2007 were analysed retrospectively. There were 117 male and 134 female aged from 22 to 72 years old, with a mean of 46.6 years old. The indexes were compared including serum creatinine (SCr), creatinine clearance (CCr), glomerular filtration rate (GFR) and quality of life before and after donation. Surgical complications were followed-up. RESULTS: Donors' SCr was (75.9 +/- 17.2) micromol/L before donation, (107.4 +/- 21.2) micromol/L on 7 d after donation, (130.4 +/- 58.2) micromol/L at the 1(st) month and (116.1 +/- 24.1) micromol/L at the 3(rd) month. There were significant difference between any 2 time points (P < 0.01). CCr was (94.4 +/- 17.5) ml/min before donation and (63.5 +/- 17.8) ml/min on 10 d after donation (P < 0.01). In 62 donors, total GFR was (82.4 +/- 21.8) ml/min before donation. On 10 d after donation, GFR of remaining kidney was (57.4 +/- 14.1) ml/min which was 34.7% higher than GFR of this kidney before donation (42.6 +/- 11.8) ml/min. There was no significant difference in quality of life before living related donors and non-donor populations (P = 0.116). Surgical complications included splenic rupture in 1 case, descending colon rupture in 1 case and wound infection in 5 cases. CONCLUSION: Living donor kidney transplantation is safe for donors, although part of indexes would vary within normal range during the early time after donation.

Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study.

Calcineurin inhibitors, including tacrolimus, are largely responsible for advances in allotransplantation. However, the nephrotoxicity associated with these immunosuppressants impairs patients' long-term survival after renal allograft. Therefore, novel regimens that minimize or even eliminate calcineurin inhibitors could improve transplantation outcomes. In this pilot study, we investigated the use of low-dose tacrolimus in combination with mesenchymal stem cells (MSCs), which are immunosuppressive and prolong allograft survival in experimental organ transplant models. Donor-derived, bone marrow MSCs combined with a sparing dose of tacrolimus (0.04-0.05 mg/kg/day) were administered to 16 de novo living-related kidney transplant recipients; 16 other patients received a standard dose of tacrolimus (0.07-0.08 mg/kg/day). The safety of MSC infusion, acute rejection, graft function, graft survival, and patient survival were evaluated over ≥24 months following kidney transplantation. All patients survived and had stable renal function at the 24 month follow-up. The combination of low-dose tacrolimus and MSCs was as effective as standard dose tacrolimus in maintaining graft survival at least 2 years after transplantation. In addition, both groups had similar urea, urine protein, urinary RBC, urinary WBC, 24-h urine protein, and creatinine clearance rates from 7 days to 24 months after transplantation. Furthermore, no differences in the proportion of lymphocytes, CD19, CD3, CD34, CD38, and natural killer cells were detected between the control and experimental groups. None of the MSC recipients experienced immediate or long-term toxicity from the treatment. This preliminary data suggests that the addition of MSCs permits the use of lower dosages of nephrotoxic calcineurin inhibitors following renal transplantation.