Sirolimus in renal transplant recipients with malignancies in Germany.

BACKGROUND: Renal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited. METHODS: We retrospectively analysed 726 renal allograft recipients converted to SRL from 10 German transplant centres. Patient and graft survival were analysed depending on malignancy status prior to conversion and tumour entity. RESULTS: Malignancy before conversion to SRL was reported in 230 patients, with 137 patients having skin cancers and 101 having solid cancers. Cancer occurred 4.6 ± 9.4 (median 3.0) years after transplantation. Basal cell carcinoma, squamous cell carcinoma and Bowen's disease were the most prevalent skin cancers, while carcinomas of the kidney, colon and breast were the most prevalent solid cancers before conversion. Patients with prior malignancy were older and had better renal function at conversion compared with patients without a history of cancer. After conversion to SRL, cancer incidence rates (IRs) of all tumours were lower compared with rates before conversion. Cancer IRs after conversion were higher in patients with malignancy before conversion compared with those without. Patient survival was worse in patients with solid cancers compared with patients with skin cancers or without malignancies. Biopsy-proven acute rejections in the first year after conversion were less frequent in patients with malignancy compared with those without. Graft survival and renal function in all cancer types were better than in patients converted to SRL without cancers. CONCLUSIONS: Conversion to SRL in patients with a history of cancer is safe regarding renal function and graft survival, while patient survival is largely dependent on tumour entity.

Determinants of Successful Use of Sirolimus in Renal Transplant Patients.

BACKGROUND: Sirolimus is an established immunosuppressant in renal transplantation with antineoplastic and antiviral features, but side effects like proteinuria limit its use. The aim of this retrospective multicenter observational study is to define predictors for determining which patients most likely benefit from a sirolimus-based therapy. METHODS: All patients from 10 German centers that were switched to a sirolimus-containing maintenance immunosuppression in 2000 to 2008 after 3 months or later post-transplantation were enrolled (n = 726). Observation times after switching to sirolimus ranged from 4 days to 9 years (median: 24.3 months). With multinomial logistic regression, risk factors for the endpoints terminal graft failure and withdrawal of sirolimus therapy compared to successful therapy were identified. RESULTS: Successful sirolimus therapy was observed in 304 patients. Forty patients died with functioning graft. Therapy failures included graft loss (n = 106) and sirolimus-discontinuation for various reasons (n = 276). Successful sirolimus-use was predicted in 83% and graft failure in 65%, whereas prediction of deliberate sirolimus-discontinuation was poor (48%). Most favorable results for sirolimus-use were observed in patients switched in 2006 to 2008. Using ROC analysis, an estimated glomerular filtration rate (eGFR) below 32 mL/min was shown to be the cut-off in patients withdrawing from therapy as a result of renal reasons, as well as in patients with graft loss. Proteinuria above 151 mg/L was shown to be predictive for patients with graft failure. CONCLUSIONS: eGFR and proteinuria are the major determinants for successful sirolimus-therapy. Our findings help stratifying patients who will benefit most from this therapy and avoid toxicities in patients without potential benefits for this therapy.

Proteinuria and sirolimus after renal transplantation: a retrospective analysis from a large German multicenter database.

The German Sirolimus Study Group has established a database among 10 transplant centers throughout Germany to study the outcomes in 726 renal transplant patients being converted to a sirolimus-containing therapy between 2000 and 2008 with a total of more than 1500 recorded patient years on therapy. In this study, we present a detailed description of the cohort, of characteristic changes over the observation period, proteinuria and graft survival, and new-onset proteinuria after conversion. Over the study period, age, graft function at the time of conversion, and the proportion of patients switched to sirolimus because of malignancy increased, whereas the proportion of patients with significant proteinuria at conversion decreased. Already modest proteinuria (151-268 mg/L) at conversion and new-onset proteinuria (>500 mg/L) after conversion were associated with inferior graft survival. Even mild proteinuria (>71 mg/L) at conversion was associated with new-onset proteinuria (>500 mg/L) post-conversion. Serum creatinine and urinary protein excretion at conversion together with age at transplantation had a significant impact on patient and graft survival. This large data set confirms and extends previous observations that proteinuria is an important indicator for graft outcome after conversion to sirolimus. We conclude that patients without any proteinuria have the greatest benefit from conversion to sirolimus.

Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy.

The present study examined non-insulin-treated streptozotocin (STZ)-induced diabetic rats to determine the role of kinins in diabetic nephropathy. Their involvement in the renoprotective effect of the angiotensin-converting enzyme inhibitor (ACEI) ramipril was investigated using the bradykinin (BK) B(2)-receptor antagonist, icatibant (HOE 140), or a combination of the two drugs.Although, none of the treatments prevented the decline of the glomerular filtration rate (GFR) in diabetic rats, ramipril (3 mg/kg/day), but not icatibant (HOE 140; 500 microg/kg/day), prevented proteinuria in these animals. However, the antiproteinuric effect of ramipril was reduced by 45% when combined with icatibant. To explore whether the renal kallikrein-kinin system (KKS) belongs to the underlying mechanisms of these findings, we also determined urinary BK levels, renal kallikrein (KLK) and angiotensin-converting enzyme (ACE) activity as well as renal cortical mRNA levels of neutral endopeptidase 24.11 (NEP) and low-molecular weight (LMW) kininogen. STZ led to a reduction of renal KLK and ACE activity and NEP expression and to a three-fold increase of urinary BK excretion and renal kininogen expression. Icatibant given alone had no effect on these parameters. In contrast, ramipril treatment normalized urinary protein and BK excretion as well as kininogen mRNA expression without affecting NEP mRNA expression or KLK and ACE activity. Our data demonstrate that renal BK is increased in severe STZ-induced diabetes mellitus, but may affect glomerular regulation only to a minor degree under this condition. However, kinins are partly involved in the antiproteinuric action of ACEI at this stage of diabetic nephropathy.

Increased activity of the renal kallikrein-kinin system in autosomal dominant polycystic kidney disease in rats, but not in humans.

The kallikrein-kinin system (KKS) was investigated in autosomal dominant polycystic kidney disease (ADPKD)-affected rats (PKD) and compared to unaffected controls (SD) and 5/6 nephrectomized rats (5/6 Nx). In addition, patients with ADPKD compared to patients with nonpolycystic kidney disease and healthy controls have been investigated. Plasma and urine samples for determination of creatinine, protein, kallikrein (KAL) and bradykinin (BK) were taken in male 3- and 9-month-old PKD, SD and 9-month-old 5/6 Nx. The same parameters were determined in young (age: 20-40 years) and old (41-65 years) male patients with ADPKD and compared to age-matched patients with nonpolycystic kidney disease and age-matched healthy controls. Plasma and urine KAL were measured by chromogenic peptide substrate, and kininswere determined by radioimmunoassay. Urine KAL and BK levels were increased i n PKD compared to age-matched SD. No differences with respect to serum KAL were found between PKD and SD. In 5/6 Nx, urinary BK levels showed a trend towards higher compared to old SD (p = 0.06). KAL and BK were not increased in serum and urine of patients with ADPKD, in contrast to rats. Urinary KAL excretion was reduced in patients with ADPKD and advanced renal failure. Our results demonstrate an age-dependent activation of the renal KKS in rats with ADPKD, whereas the KKS is not activated in patients with ADPKD and advanced renal failure. These data indicate that there are fundamental differences in the factors influencing the course of the disease in human and rat ADPKD.

Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat.

UNLABELLED: Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat. BACKGROUND: The kallikrein-kinin-system is a complex multienzymatic system that has been implicated in the control of systemic blood pressure, glomerular filtration rate, and proteinuria. The present study investigated its functional role in rat polycystic kidney disease (PKD), which is characterized by progressive renal failure and proteinuria in the absence of systemic hypertension and stimulated renin-angiotensin-system. METHODS: Kallikrein and bradykinin levels were measured in plasma and urine of rats with polycystic kidneys and compared to non-affected controls (SD) and rats with reduced renal mass. The functional relevance of the kallikrein-kinin system (KKS) was assessed by the effects of a short-term treatment with either a selective bradykinin (BK) B1-receptor antagonist (des-Arg9-[Leu8]-BK), a B2-receptor antagonist (HOE 140), an angiotensin converting enzyme inhibitor (ramipril), or an angiotensin II-receptor blocker (HR 720) on systemic and renal parameters. RESULTS: Urine levels of kallikrein were increased threefold in 9-month-old PKD, and BK excretion was increased tenfold in 3-month and 30-fold in 9-month-old PKD compared to age-matched SD rats. Blood pressure in 9-month-old PKD rats was decreased to the same degree by ramipril and HR 720. In contrast, only ramipril and HOE 140 significantly reduced proteinuria and albuminuria, independent from creatinine clearance. This effect was accompanied by an increased excretion of bradykinin. The B1 receptor antagonist had no influence on functional renal parameters. CONCLUSIONS: The present study demonstrates an age-dependent activation of the renal KKS in rats with polycystic kidney disease. The bradykinin B2-receptor is involved in the pathogenesis of proteinuria, independent from systemic blood pressure or creatinine clearance. The antiproteinuric effect of ramipril in this model is angiotensin II-independent and related to its influence on the renal KKS.