Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies.

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.

The importance of tubulointerstitial injury in the early phase of primary glomerular disease.

OBJECTIVES: As tubulointerstitial damage is regarded secondary to glomerular injury in primary glomerulopathies, we assessed lesions to renal tubulointerstitium in recently diagnosed primary glomerular diseases and evaluated their impact on progression of the disease during the first 2 years after diagnosis. DESIGN: A nonrandomized prospective study assessing tubulointerstitial morphometry at diagnosis, markers of tubular function within the next 6 months and progression of the disease (creatinine clearance) during 24 months' follow-up. SETTING: Single tertiary referral centre. SUBJECTS: Forty-six patients with primary glomerular disease, the diagnostic oligobiopsy performed within 2 months of the onset of clinical symptoms. INTERVENTIONS: All patients were subjected to antiinflammatory/immunosuppressive treatment. MAIN OUTCOME MEASURES: Alterations in results of tubulointerstitial morphometry and tubular function tests, correlations between these variables and parameters of nephrosis/renal function, selection of the most accurate predictor of disease progression within 24 months after diagnostic biopsy. RESULTS: Function of proximal tubules, markedly deteriorated at the time of diagnosis, significantly improved 6 months later (urinary beta2-microglobulin: P < 0.0025), along with reduction in proteinuria (P < 0.00125). No appreciable alterations in function of distal tubules were noted. Morphometric indices revealing interstitial expansion and tubular atrophy significantly correlated with creatinine clearance at 6 months (P = 0.032) and were the best predictors of deteriorating renal function at 24 months. Excretion of beta2-microglobulin at the time of diagnosis was the best marker for impairment of glomerular filtration 6 months later. CONCLUSIONS: Significant damage to cortical tubulointerstitium occurs concurrently with glomerular injury in primary glomerulopathies and may predict the clinical course of the disease already in its initial phase.