mycophenolic-acid and Ureteral-Obstruction

Idiopathic retroperitoneal fibrosis (IRF) is a rare condition characterized by the development of a peri-aortic and peri-iliac tissue showing chronic inflammatory infiltrates and pronounced fibrosis. Ureteral entrapment with consequent obstructive uropathy is one of the most common complications of IRF, which can lead to acute renal failure and, in the long term, to varying degrees of chronic kidney disease. IRF may be isolated or develop in association with autoimmune diseases (e.g. Hashimoto's thyroiditis and psoriasis) and other fibro-inflammatory disorders (often within the spectrum of immunoglobulin G4-related disease), which suggests that it should be considered as a potentially systemic condition. IRF is an immune-mediated disease: genetic variants (e.g. human leukocyte antigen (HLA)-DRB1*03) and environmental agents (mainly exposure to asbestos and smoking) are strongly associated with an increased risk of developing the disease, while a complex network of chemokines (e.g. CXCL12 and C-C moti chemokine 11 (CCL11)) and cytokines [e.g. interleukin (IL)-6, IL-12 and IL-13] is likely to orchestrate the inflammatory response and simultaneously promote fibrosis. Glucocorticoids, alone or in combination with traditional immunosuppressants such as methotrexate and mycophenolate mofetil, are usually efficacious and promptly induce disease remission; however, up to 50% of patients relapse, thus requiring repeat immunosuppressive courses. Biologic drugs, namely rituximab, are being explored for the treatment of IRF. In addition to medical therapies, interventional procedures (mainly ureteral stenting) are required to relieve ureteral obstruction, whereas surgical ureterolysis is generally reserved to refractory cases. If appropriately treated, then the overall and renal prognosis of IRF are good, with <5% patients developing end-stage renal disease.

Topics: Chemokines; Cytokines; Glucocorticoids; Humans; Methotrexate; Mycophenolic Acid; Nephrologists; Retroperitoneal Fibrosis; Rituximab; Ureteral Obstruction

Renal interstitial fibrosis (IF) is an important pathologic manifestation of disease progression in a variety of chronic kidney diseases (CKD). However, the quantitative and reproducible analysis of IF remains a challenge, especially in experimental animal models of progressive IF. In this study, we compare traditional polarized Sirius Red morphometry (SRM) to novel Second Harmonic Generation (SHG)-based morphometry of unstained tissues for quantitative analysis of IF in the rat 5 day unilateral ureteral obstruction (UUO) model. To validate the specificity of SHG for detecting fibrillar collagen components in IF, co-localization studies for collagens type I, III, and IV were performed using IHC. In addition, we examined the correlation, dynamic range, sensitivity, and ability of polarized SRM and SHG-based morphometry to detect an anti-fibrotic effect of three different treatment regimens. Comparisons were made across three separate studies in which animals were treated with three mechanistically distinct pharmacologic agents: enalapril (ENA, 15, 30, 60 mg/kg), mycophenolate mofetil (MMF, 2, 20 mg/kg) or the connective tissue growth factor (CTGF) neutralizing antibody, EX75606 (1, 3, 10 mg/kg). Our results demonstrate a strong co-localization of the SHG signal with fibrillar collagens I and III but not non-fibrillar collagen IV. Quantitative IF, calculated as percent cortical area of fibrosis, demonstrated similar response profile for both polarized SRM and SHG-based morphometry. The two methodologies exhibited a strong correlation across all three pharmacology studies (r2 = 0.89-0.96). However, compared with polarized SRM, SHG-based morphometry delivered a greater dynamic range and absolute magnitude of reduction of IF after treatment. In summary, we demonstrate that SHG-based morphometry in unstained kidney tissues is comparable to polarized SRM for quantitation of fibrillar collagens, but with an enhanced sensitivity to detect treatment-induced reductions in IF. Thus, performing SHG-based morphometry on unstained kidney tissue is a reliable alternative to traditional polarized SRM for quantitative analysis of IF.

Topics: Animals; Antibodies, Monoclonal; Azo Compounds; Collagen; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Kidney Diseases; Male; Mycophenolic Acid; Non-Fibrillar Collagens; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Ureteral Obstruction

Topics: Decompression, Surgical; Diagnosis, Differential; Drug Administration Schedule; Humans; Immunoglobulin G; Mycophenolic Acid; Nephrostomy, Percutaneous; Prednisone; Retroperitoneal Fibrosis; Tomography, X-Ray Computed; Ureteral Obstruction

Small series and case reports suggest that a combination of mycophenolate mofetil and prednisone is an efficatious and safe treatment for patients with retroperitoneal fibrosis.. To describe the outcomes of patients with retroperitoneal fibrosis treated with a combination of prednisone and mycophenolate mofetil.. Prospective, case series.. 31 patients with retroperitoneal fibrosis.. Single-center tertiary care facility.. Prednisone 40 mg administered daily and tapered over 6 months and mycophenolate mofetil 1,000 mg given twice daily.. Clinical course, laboratory assessment, measurement of periaortic mass.. Systemic symptoms resolved in all patients. Eighty-nine percent of patients had a 25% or greater reduction in periaortic mass. Eighteen patients had 32 obstructed ureters. Thirty of these ureters were free of obstruction after an average of 513 days of therapy. Laboratory abnormalities of elevated erythrocyte sedimentation rate and serum creatinine and decreased hemoglobin levels normalized in all patients. Recurrent disease occurred in 2 of 28 patients.. Combined prednisone and mycophenolate mofetil appears to be an effective therapeutic option for patients with retroperitoneal fibrosis.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Aortic Diseases; Disease Management; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Retroperitoneal Fibrosis; Retrospective Studies; Tertiary Care Centers; Treatment Outcome; Ureteral Obstruction

Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. One morphological characteristic of CAN is renal interstitial fibrosis. Mycophenolate mofetil (MMF), the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, has been reported to attenuate the progression of renal interstitial fibrosis. However, the question of whether the newly synthesized IMPDH inhibitors with structures different from MMF have an antifibrotic effect remains unanswered. We evaluated the antifibrotic effects of BMS-566419, a chemically synthesized IMPDH inhibitor, using an experimental rat model, unilateral ureteral obstruction (UUO), in comparison with those of MMF. Expression levels of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-β1), which play important roles in UUO-induced renal fibrosis, were also investigated to determine the mechanism by which BMS-566419 affects the progression of renal fibrosis. After 14 days of UUO, interstitial fibrosis was frequently observed in the renal cortex of rats administered vehicle control. BMS-566419 by oral administration showed a significant and dose-dependent suppressive effect on UUO-induced renal fibrosis in histopathological experiments. BMS-566419 treatment also decreased collagen content, as indicated by hydroxyproline concentration, and the expression of collagen type 1 mRNA. BMS-566419 also decreased the expression of mRNA for both MCP-1 and TGF-β1. The antifibrotic effects of treatment with BMS-566419 at 60 mg/kg seemed comparable to those with MMF at 40 mg/kg. These results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in the treatment of fibrotic renal disease, including CAN.

Topics: Acridines; Animals; Chemokine CCL2; Chronic Disease; Collagen; Fibrosis; Hydroxyproline; IMP Dehydrogenase; Kidney Cortex; Kidney Diseases; Male; Mycophenolic Acid; Piperazines; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1; Ureteral Obstruction

[corrected] Idiopathic retroperitoneal fibrosis (IRF) is an uncommon disease characterized by a retroperitoneal fibrotic tissue that often involve the ureters, leading to the obstructive nephropathy and variable impairment of renal function. Findings strongly suggest an autoimmune etiology. Surgery, medical treatment with immunosuppressive drugs, or a combination of both are proposed. The optimal treatment has not been established yet. The aim of this study was to present our experience with combined immunosuppressive therapy of IRF, steroids (S) and mycophenolate mofetil (MMF).. We prospectively followed four patients with IRF from January 2004 to December 2006. Three patients had an active disease with bilateral hydronephrosis. In the two of them acute renal failure was presented, and ureteral catheters were inserted in one in order to manage ureteral obstruction. One patient has came to our unit with a relapse of IRF and incipient chronic renal failure after the prior therapy with ureterolysis and immunosuppressive drugs (azathioprine and tamoxifen). All patients received steroids and MMF. Two patients were treated with intravenous methylprednisolone pulses (250 mg each), for three consecutive days, followed by oral prednisone 0.5 mg/kg/day. The other two patients received oral prednisone at the same dose. Prednisone was gradually tappered to a maintenance dose of 10 mg/kg/day. Simultaneously, all patients received MMF, initially 1 g/day with the increase to 2 g/day.. After four weeks of the therapy all symptoms disappeared, as well as a hydronephrosis with a decrease of erythrocyte sedimentation rate and Creactive protein (CRP) to normal level in all patients. Three patents remain in remission untill the end of the follow up. One patient had a relapse because of stopping taking the therapy after six months. He was treated by oral prednisone 0.5 mg/kg/day, which was gradually decreased. After twelve weeks hydronephrosis disappeared and CRP returns to the normal level.. The combination of steroids and mycophenolate mofetil led to the remission of IRF with a strong and quick immunosuppressive effect. It also provided avoiding the long-term use of high steroid dose and surgical procedures.

Topics: Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prednisone; Retroperitoneal Fibrosis; Ureteral Obstruction

The effect of mycophenolate mofetil (MMF) and azathioprine (AZA) in reducing renal interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) was studied. Fifty-nine rats with surgically induced UUO received oral MMF (n=19), AZA (n=19), or no treatment (n=21). The obstructed kidneys were analyzed by histology and morphometry on days 21 and 60 post UUO. Fibronectin- and collagen-stained areas were significantly lower in both treatment groups when compared with the control group 21 days post surgery. Transforming growth factor (TGF)-beta expression was significantly lower in the MMF-treated group than in the AZA-treated (P<0.01) and the control (P<0.001) groups. There was no significant difference in TGF-beta expression between the AZA-treated and the control groups 21 days post surgery (P>0.05). No significant difference was found in TGF-beta and fibronectin expression between treated and untreated groups on the 60th day post surgery. However, collagen expression was significantly lower in both treated groups than in the untreated group on the 60th day (P<0.005). We observed that MMF is more effective in preventing fibrosis than AZA in the UUO model in the short term; however, there is a less significant anti-fibrotic effect of these drugs in long-term than in short-term obstruction.

Topics: Animals; Azathioprine; Collagen; Fibronectins; Fibrosis; Immunohistochemistry; Kidney Diseases; Mycophenolic Acid; Rats; Rats, Wistar; Transforming Growth Factor beta; Ureteral Obstruction

To investigate the effects of mycophenolate mofetil (MMF) on the process of renal interstitial fibrosis, unilateral ureteral obstruction (UUO) model was established in rats. Twenty Sprague-Dawley rats underwent UUO and received vehicle (n = 10) or MMF (20 mg.kg-1.d-1, by daily gastric gavage, n = 10) during a period of 5 days following surgery, and the additional 10 rats were served as sham-operated group. The rats were killed 5 days after surgery. Immunohistochemistry was performed on renal tissue for proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alpha-SMA) and type I and III collagen (col I, col III). Histological studies were also done by MASSON staining. Five days after surgery, proliferating cells in tubules, interstitium as well as interstitial myofibroblast (MyoF) infiltration and interstitial col I, col III deposition were all significantly reduced by MMF treatment. MMF also alleviated the histological changes of UUO rats. These results suggested that the reduction of interstitial MyoF infiltration may be an important event by which MMF prevents renal injury caused by UUO and MMF could be used to limit the progression of renal fibrosis.

Topics: Animals; Female; Fibrosis; Kidney; Kidney Diseases; Mycophenolic Acid; Random Allocation; Rats; Rats, Sprague-Dawley; Ureteral Obstruction

Topics: Creatine; Cyclosporine; Diabetes Complications; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Stents; Ureteral Obstruction