Rafael Poveda

New immunosuppresor strategies in the treatment of murine lupus nephritis

Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Although treatment with corticosteroids and cytotoxic drugs may be useful in many cases, morbidity associated with these drugs and the relapsing nature of the disease make it necessary to develop new treatment strategies. Five-month old female NZB/W F1 mice were divided into the following groups: CYP group (n = 10), cyclophosphamide (CYP) 50 mg/kg intraperitoneally every 10 days; RAPA 1 group (n = 10) oral daily sirolimus (SRL), 1 mg/kg; RAPA 12 group (n = 13), oral daily SRL, 12 mg/kg; FTY group (n = 10), oral fingolimod (FTY720), 2 mg/kg three times per week. An additional group of 13 non-treated mice were used as a control (control group). Follow-up was performed over four months. Animal survival, body weight, anti-DNA antibodies and proteinuria were determined. Kidneys were processed for conventional histology and immunofluorescence for IgG and complement. Total histological score (HS) was the sum of mesangial expansion, endocapillary proliferation glomerular deposits, extracapillary proliferation, interstitial infiltrates, tubular atrophy and interstitial fibrosis. All treated groups had lower proteinuria at the end of the follow-up with respect to the control group (P < 0.0001). Serum anti-DNA antibodies were appropriately controlled in RAPA 1 and CYP groups, but not in FTY or RAPA 12 groups. SRL and CYP arrested, and perhaps reversed almost all histological lesions. FTY720 ameliorated histological lesions but did not control mesangial expansion or interstitial infiltrates. SRL produces great improvement in murine lupus nephritis, while FTY720 seems a promising alternative if used in appropriate doses.

Interstitial Nephritis in Sarcoidosis: Simultaneous Multiorgan Involvement

Two cases of sarcoidosis with interstitial nephritis (lymphocytic and granulomatous) are described. In contrast to the majority of reported cases, patients simultaneously exhibited renal failure and multiple extrarenal manifestations, including bone marrow granulomas. Pretreatment gallium-67 gamma scan of the kidneys produced negative results. Patients were treated with steroids. Treatment resulted in a normal renal function after 1 year in the patient with lymphocytic interstitial nephritis. Renal function improved in the patient with granulomatous interstitial nephritis, and a second renal biopsy performed 13 months after diagnosis revealed granuloma disappearance and residual interstitial fibrosis. These cases provide evidence that interstitial nephritis in sarcoidosis may appear simultaneously with multiorgan involvement. The absence of gallium-67 renal intake does not guarantee that the disease is not active in the kidneys.

Long-term outcome of antineutrophil cytoplasmic antibody-associated small vessel vasculitis after renal transplantation

The survival after renal transplantation of patients with antineutrophil cytoplasmic antibody (ANCA)‐associated to systemic vasculitis is as good as in other diseases, although most of the reports are based on small numbers of patients. Furthermore, it is not known whether comorbidities (cardiovascular [CV] disease and cancer) are more frequent than in general population. We report our experience and the analysis of the published data on this topic. The outcome after transplantation in 49 patients with ANCA‐associated small vessel vasculitis was compared with a control group. The relapse rate of vasculitis was 0.01 per patient per year. Comparison with the control patients revealed no difference in long‐term outcome, CV mortality or incidence of malignancies. In the published literature, patients with ANCA at transplantation and with Wegeners granulomatosis are at greater risk of relapse. Taking our own results together with the review of the literature, we conclude that patient and graft survival rates compare favorably with those in control group that the recurrence rate is very low and that there is no increase in the incidence of cancer or in CV mortality. Patients with ANCA at transplantation and with Wegeners granulomatosis have a higher relapse rate.

Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy

BACKGROUND There is a lack of new therapeutic strategies for IgA nephropathy. Low-dose sirolimus inhibits mesangial cell proliferation and renal fibrosis in animal models. METHODS We performed a pilot, randomized controlled trial to evaluate the efficacy and safety of low-dose sirolimus in patients with a high-risk IgA nephropathy. Twenty-three patients with a glomerular filtration rate (GFR) within 30-60 mL/min and/or proteinuria >1 g/day were randomly assigned to low-dose sirolimus plus enalapril and atorvastatin (SRL group, n = 14) or enalapril plus atorvastatin (CONTROL group, n = 9). Primary composite end point was variation of haematuria, proteinuria and blood pressure. Secondary end points were isotopic GFR, renal histology evaluated by Oxford classification and safety parameters evaluated at 6 and 12 months. RESULTS Primary end point improved significantly in the SRL group at 12 months. Regarding isotopic GFR, patients included in the CONTROL group lost 8 mL/min/1.73 m(2), whereas those in the SRL arm improved 5 mL/min/1.73 m(2) (P = 0.03). Proteinuria decreased similarly in both study groups. At 1 year, SRL treatment was associated with a significant reduction of mesangial and endocapillary proliferation, whereas glomerular sclerosis, tubular atrophy and interstitial fibrosis were similar. Sirolimus was well tolerated; all patients remained on therapy at 12 months. CONCLUSION The addition of low-dose sirolimus to enalapril and statin is safe, stabilizes renal function and reduces glomerular proliferative lesions in patients with poor prognosis IgA nephropathy.

Use of mycophenolate in ANCA-associated renal vasculitis: 13 years of experience at a university hospital

INTRODUCTION Standard therapy with corticosteroids (CS) and cyclophosphamide (CYC) followed by azathioprine has been shown to improve renal and patient survival in ANCA-associated renal vasculitis (rAAV). Mycophenolate mofetil (MF) has been progressively introduced for the treatment of rAAV in the last years because of its immunosuppressive efficacy combined with a lower toxicity profile. In this study, we retrospectively analyse the results of the introduction of MF for maintenance and induction therapy in rAAV in our institution from 2001 to 2013. RESULTS We reported 67 patients treated with MF as a maintenance treatment, divided by baseline serum creatinine (>500 µmol/L: Group 1 and <500 µmol/L: Group 2) and treatment schedule. Twenty-nine of the 67 patients were also treated with MF as induction treatment, mostly in Group 2. During the follow-up (2 years after the diagnosis) creatinine levels for serum glomerular filtration rate, ANCA titres, C-reactive protein and percentage of haematuria decreased in all groups. In Group 2, parameters and also relapse rates were similar at 24 months in patients treated with CYC or MF as an induction treatment (Subgroups 2a and 2b, respectively). Median dose of MF in maintenance treatment was 1000 mg daily and prednisone dose was tapered to 10 mg daily from Month 3. After 24 months, 82% of patients remained on MF therapy, 18% had discontinued the treatment, seven of them due to medical indication and two because of gastrointestinal intolerance. The percentage of patients that started renal replacement therapy was irregular in Group 1 depending on the subgroup (25-100%), and 10% in Group 2. Adverse effects, such as neutropenia, infections and neoplasia, were more prevalent in groups treated with CYC. CONCLUSION In conclusion, in our patients with rAAV, MF demonstrated to be an effective and well-tolerated option for maintenance treatment. As an induction treatment, MF seems to be similar to CYC for patients with moderate renal failure in the diagnosis.

Fracaso renal agudo inducido por nefritis intersticial aguda secundario a cocaína

Elías Jatem, Irene Agraz, M. Eugenia Semidei, Berta Ferrer, Rosa Ramos, Joan Fort 1 Servicio de Nefrología. Hospital Universitari Vall d’Hebron. Barcelona. (Spain). 2 Servicio de Anatomía Patológica. Hospital Universitari Vall d’Hebron. Barcelona. (Spain). Correspondence: Elías Jatem Servicio de Nefrología. Hospital Universitari Vall d’Hebron, Idumea. 08035 Barcelona. (Spain). jatemelias@gmail.com eliasjatem@ymail.com

Efficacy of mycophenolate treatment in adults with steroid-dependent/frequently relapsing idiopathic nephrotic syndrome

Abstract Background This study assessed the efficacy of therapy with mycophenolate (MF) and reduced doses of steroids in adults with steroid-dependent/frequently relapsing idiopathic nephrotic syndrome (SD/FR-INS). Methods Twenty-nine nephrotic patients (including 16 males and 13 females; mean age: 40 years, range: 18–74) were treated. Starting doses of MF were 2000 mg/day for mofetil MF (1500 mg/day in one patient) or 1440 mg/day for sodium MF. The initial prednisone (PDN) dose was 10 mg/day in 14 patients, 5 mg/day in two patients and no steroids in one patient. In the remaining 12 patients, moderate initial doses of PDN were administered (mean: 23.7 mg/day, range: 15–40), tapering to 10 mg/day after 1 month. Results Nephrotic syndrome remission was achieved in 27/29 cases (93.1%) (25 complete, 2 partial). Two patients showed resistance to the prescribed schedule. The first cycle of MF therapy was concluded in 20 patients after a mean (range) of 16.9 months (12–49). Maintenance of remission was observed in 11 of these 20 cases (55%) after a mean follow-up of 32.8 months (12–108). In nine patients with nephrotic syndrome relapse after tapering of MF (MF dependency), the same MF-PDN schedule was restarted, leading again to remission in all nine. The remaining seven MF-sensitive patients are still receiving their first therapeutic cycle. To date, the mean time under therapy in the 27 MF-sensitive patients is 38 months (4–216). Regarding complications, only minor digestive disorders and a slight decrease in blood haemoglobin levels were observed in a few patients. Conclusions MF plus reduced doses of PDN is an effective and well-tolerated therapy for adult SD/FR-INS. Though MF dependence is observed, its low toxicity could allow long periods of therapy if it is required to maintain nephrotic syndrome remission.