Sleep-Disordered Breathing Is Associated with Metabolic Syndrome in Outpatients with Diabetes Mellitus Type 2.

BACKGROUND: Metabolic syndrome (MS) and sleep-disordered breathing (SDB) are highly prevalent in patients with diabetes mellitus type 2 (DM2). The present study examined whether there is an independent association between SDB and MS in a sample of outpatients with DM2. METHODS: MS was determined in 679 patients of the DIACORE-SDB substudy, a study of outpatients with DM2. According to the National Cholesterol Education Program (NCEP) criteria, MS is defined by at least three of the following five criteria: waist circumference of >102 cm (men)/>88 cm (women), blood pressure of ≥130/85 mmHg, a fasting triglyceride level of >150 mg/dl, high-density lipoprotein (HDL) of <40 mg/dl (men)/<50 mg/dl (women), and a fasting glucose level of ≥110 mg/dl. The apnea-hypopnea index (AHI) was assessed with a 2-channel ambulatory monitoring device and used to define the severity of SDB (AHI < 15.0: no/mild SDB; AHI 15.0-29.9: moderate SDB; AHI ≥ 30.0: severe SDB). RESULTS: 228 (34%) of the 679 participants (mean age 66 years, mean body mass index (BMI) 31.2 kg/m2, and mean AHI 14/hour) had SDB. MS was significantly more frequent in patients with more severe SDB (no/mild SDB vs. moderate SDB vs. severe SDB: 72% vs. 79% vs. 85%, respectively, p = 0.038). Logistic regression analysis adjusted for sex, age, obesity (BMI ≥ 30 kg/m2), and the HOMA index showed a significant association between the AHI and the presence of MS (OR (95%CI) = 1.039 (1.011; 1.068); p = 0.007). Further, male sex, obesity, and the HOMA index were significantly associated with MS. CONCLUSION: SDB is significantly and independently associated with MS in outpatients with DM2.

Sex Differences in the Prevalence and Modulators of Sleep-Disordered Breathing in Outpatients with Type 2 Diabetes.

In patients with type 2 diabetes, sleep-disordered breathing is a widespread cause of deteriorated quality of life. However, robust prevalence estimates for sleep-disordered breathing in patients with type 2 diabetes are limited due to scarce data. We investigated sex differences in sleep-disordered breathing prevalence and its modulators in the DIACORE SDB substudy, a sample of outpatient type 2 diabetes. 721 participants were tested for sleep-disordered breathing using a two-channel sleep apnoea monitoring device. Patients were stratified according to the severity of sleep-disordered breathing, defined as an apnoea-hypopnoea index < 15, ≥15 to 29, and ≥30 events per hour as no/mild, moderate, and severe sleep-disordered breathing, respectively. In the 679 analysed patients (39% women, age 66 ± 9 years, body mass index 31.0 ± 5.4 kg/m2), the prevalence of sleep-disordered breathing was 34%. The prevalence of sleep-disordered breathing was higher in men than in women (41% versus 22%, p < 0.001) and increased with age (15%, 21%, and 30% in women and 35%, 40%, and 47% in men in those aged 18-59, 60-69, or ≥70, respectively; age trend p = 0.064 in women and p = 0.15 in men). In linear regression analysis, age, BMI, and waist-hip ratio were associated with apnoea-hypopnoea index. Modulators for higher apnoea-hypopnoea index seem to be similar in men and women.

Epstein-Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations.

Background: Recent whole-genome sequencing identified four molecular subtypes of gastric cancer (GC), of which the subgroup of Epstein-Barr virus-associated GC (EBVaGC) showed a significant enrichment of PIK3CA mutations. We here aimed to validate independently the enrichment of PIK3CA mutations in EBVaGC of a Central European GC cohort, to correlate EBV status with clinico-pathological patient characteristics and to test for a major issue of GC, intratumoral heterogeneity. Patients and methods: In a first step, 484 GCs were screened for EBV and PIK3CA hot spot mutations of exon 9/20 using EBER in situ hybridization and pyrosequencing, respectively. Secondly, an extended sequencing of PIK3CA also utilizing next generation sequencing was carried out in all EBVaGCs and 96 corresponding lymph node metastases. Results: Twenty-two GCs were EBER-positive, all being of latency type I. Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P < 0.001). Subsequent extended sequencing of PIK3CA of EBVaGCs showed that 14% harvested three to five different PIK3CA genotypes (including wildtype) in the same primary tumor, albeit in histologically and spatially distinct tumor areas, and that intratumoral heterogeneity of PIK3CA was also present in the corresponding lymph node metastases. Conclusions: Our findings unravel issues of tumor heterogeneity and illustrate that the assessment of the EBV status in tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate molecular tumor classification in a more clinical setting. Moreover, this is the first report of intratumoral heterogeneity of PIK3CA mutations in GC, and our findings lead to the conclusion that PIK3CA mutant and -wildtype tumor subclones are skilled to metastasize independently to different regional lymph nodes.

Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: results from the KORA studies.

BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and antioxidative glycoprotein. Plasma apoA-IV levels are elevated in patients with primary chronic kidney disease (CKD) or renal failure. The association between apoA-IV and kidney function has not been investigated in the general population; therefore, we analysed this relationship in two large population-based cohorts. METHODS: Plasma apoA-IV concentrations were measured in the Cooperative Health Research in the Region of Augsburg (KORA) F3 (n = 3159) and KORA F4 (n = 3061) studies. CKD was defined by the serum creatinine-estimated glomerular filtration rate (eGFR) and/or urine albumin-to-creatinine ratio. RESULTS: Mean (±SD) apoA-IV concentration was 17.3 ± 4.7 mg dL(-1) in KORA F3 and 15.3 ± 4.3 mg dL(-1) in KORA F4. Fully adjusted linear mixed models revealed a significant association between apoA-IV concentration and lower eGFR in the third and fourth versus the first quartile of apoA-IV (ß = -1.78 mL min(-1) /1.73 m², P = 0.0003 and ß = -5.09 mL min(-1) /1.73 m², P = 2.83 × 10(-23) , respectively). ApoA-IV was significantly associated with an eGFR of <60 mL min(-1) /1.73 m², which was observed in 601 of the 6220 study participants [odds ratio (OR) 1.46, P = 0.03 and OR 3.47, P = 6.84 × 10(-15) for the third and fourth vs. the first quartile of apoA-IV, respectively]. Adding apoA-IV (fourth vs. first quartile) to the fully adjusted model significantly improved discrimination of eGFR <60 mL min(-1) /1.73 m² in KORA F3 [integrated discrimination improvement (IDI) 0.03, P = 1.30 × 10(-7) ] and KORA F4 (IDI 0.04, P = 1.32 × 10(-9) ) beyond classical risk factors for CKD. CONCLUSION: The present analysis in two population-based cohorts revealed that high plasma apoA-IV concentrations are strongly associated with low kidney function defined by eGFR independent of major CKD risk factors. ApoA-IV appears to be an early marker of impaired kidney function.

[Surgical technique for laparoscopic kidney donation]. / Die chirurgische Technik der laparoskopischen Nierenlebendspende.

OBJECTIVE: Dialysis cannot fully replace kidney function in patients diagnosed with end-stage renal disease. Patients undergoing dialysis therapy show a significantly reduced quality of life, morbidity and mortality compared to healthy individuals. Every patient diagnosed with end-stage renal disease should be evaluated for a potential kidney transplant, potentially by means of living-donor kidney donation. INDICATIONS: Via living-donor kidney donation, patients diagnosed with end-stage renal disease can receive a kidney transplant already before dialysis therapy needs to be initiated. Those patients show a significantly improved long-term graft and patient survival in comparison to patients transplanted after cadaveric organ donation. PROCEDURE: We here describe the evaluation process of living-donor kidney donation and the procedure of transperitoneal laparoscopic donor-nephrectomy. CONCLUSION: Although technically demanding, laparoscopic donor nephrectomy after careful donor evaluation is a safe procedure. An interdisciplinary medical-surgical management is important for both careful patient selection and life-long aftercare.

Her2/neu testing in gastric cancer: evaluating the risk of sampling errors.

BACKGROUND: We evaluated the risk of sampling errors in specimens of biopsy size, which may be caused by heterogeneous overexpression of Her2/neu in gastric cancer (GC). PATIENTS AND METHODS: The study cohort comprised 454 gastrectomy patients with adenocarcinoma of the stomach or esophago-gastric junction. Tissue micro-arrays (TMAs) served as 'biopsy procedure' and were generated from formalin-fixed and paraffin-embedded tissue: five tissue cylinders were collected randomly from each tumor, rendering 2230 core cylinders. These were compared with 454 whole tissue sections obtained from the same paraffin blocks. Her2/neu expression and gene amplification were analyzed by immunohistochemistry and in situ hybridization. The Her2/neu status was determined according to GC scoring system by two independent observers. RESULTS: In whole tissue sections, 37 (8.1%; observer 1) and 38 (8.4%; observer 2) of the GCs, and in the corresponding TMAs, 28 (6.3%; observer 1) and 28 (6.3%; observer 2) of the GCs were classified as Her2/neu-positive (kappa value 98.5% and 96.2%; P < 0001). Comparison of whole tissue sections with corresponding TMAs showed a false-negative rate of 24% and a false-positive rate of 3% for TMAs. CONCLUSION: Assessment of the Her2/neu status in tissue biopsies carries a significant risk of sampling errors, thereby rendering patients unsuitable for treatment with trastuzumab.

Percutaneous transluminal angioplasty as first-line treatment of transplant renal artery stenosis.

BACKGROUND: Transplant renal artery stenosis (TRAS) is a frequent complication after renal transplantation, however long-term follow-up data after interventional treatment are rare. PATIENTS: In our transplant center 11 of 264 consecutive renal transplant recipients (4.17%) were diagnosed with TRAS. In addition, TRAS occurred in 2 renal transplant recipients that had been transplanted at other centers but who had their follow-up examinations in our center. Either a rise of the serum creatinine level and/or worsened systemic hypertension or routine examination with color Doppler sonography were indications for further diagnostic workup. METHODS: Direct angiography of the transplant renal artery was performed followed by percutaneous transluminal angioplasty (PTA) after the diagnosis of TRAS was confirmed in all of these patients. RESULTS: The immediate success rate for PTA was 92.3% (12/13). Only 1 patient with a severe kinking of the transplant renal artery had to undergo surgery to restore renal function. No complications occurred after the interventions. Thereafter the patients were monitored for a mean observation period of 33.15 months. Serum creatinine levels were significantly lower after the intervention, and estimated glomerular filtration rate (eGFR) increased accordingly. With regard to blood pressure there was only a trend for lower blood pressure levels and less antihypertensive use, whereas the dose of the prescribed drugs decreased significantly with time after interventional treatment of TRAS. In addition, a long-lasting rise of the hemoglobin levels could also be demonstrated. CONCLUSION: In summary, the beneficial effect of PTA of TRAS on renal function is long-lasting. Therefore, PTA, usually combined with stent placement, should be first-line treatment in TRAS in all patients. Surgical revascularization is only warranted, if PTA fails.

Renin, endothelial NO synthase and endothelin gene expression in the 2kidney-1clip Goldblatt model of long-term renovascular hypertension.

OBJECTIVE: Numerous reports have shown the influence of renin, nitric oxide (NO) and the endothelin (ET) systems for regulation of blood pressure and renal function. Furthermore, interactions between these peptides have been reported. Aim of our study was to investigate the relative contribution of these compounds in long-term renovascular hypertension / renal ischemia. METHODS: Hypertension / left-sided renal ischemia was induced using the 2K1C-Goldblatt rat model. Renal renin, ET-1, ET-3 and endothelial NO synthase (eNOS) gene expression was measured by means of RNAse protection assay at different timepoints up to 10 weeks after induction of renal artery stenosis. RESULTS: Plasma renin activity and renal renin gene expression in the left kidney were increased in the clipped animals while eNOS expression was unchanged. Furthermore, an increase in ET-1 expression and a decrease of ET-3 expression was detected in early stenosis. CONCLUSIONS: While renin is obviously involved in regulation of blood pressure and renal function in unilateral renal artery stenosis, ET-1, ET-3 and endothelium derived NO do not appear to play an important role in renal adaptation processes in long-term renal artery stenosis, although ET-1 and ET-3 might be involved in short-term adaptation processes.

[Differential diagnosis and therapy of pulmorenal syndrome--the nephrologist's perspective]. / Pulmorenales Syndrom aus nephrologischer Sicht--Differentialdiagnose und -therapie.

The "pulmorenal syndrome" is a clinically defined syndrome under which one summarises disease entities with acute renal failure due to acute glomerulonephritis and alveolar lung hemorrhage. Wegener's granulomatosis, other inflammatory renal diseases and Goodpasture's syndrome are the most frequent causes of this syndrome. The physical examination and histological examination, mostly of a kidney biopsy, represent the mainstay of securing the diagnosis. The diagnosis is completed by serological testing for autoantibodies. The therapy is determined by the underlying disease. Plasmaspheresis is always performed when alveolar hemorrhage is present, and in most cases where the patient presents with the need for immediate dialysis. An immunosuppressive therapy is determined by the underlying disease.

Five-year follow-up after late conversion from calcineurin inhibitors to sirolimus in patients with chronic renal allograft dysfunction.

BACKGROUND: Chronic allograft nephropathy (CAN) is, among others, caused by nephrotoxic side effects of calcineurin inhibitors (CNI), which are to date still the mainstay of immunosuppressive therapy. Sirolimus (SIR), an immunosuppressive compound without effects on glomerular perfusion, has been used in CNI-sparing immunosuppressive protocols. We report the 5-year follow-up of a prospective, controlled conversion study from CNI to SIR in patients with moderately to severely impaired renal function. METHODS: Twelve renal transplant recipients with moderately to severely impaired renal function (estimated glomerular filtration rate of 17 to 35 mL/min according to the MDRD formula), enrolled in a prospective, controlled 1-year pilot study were followed for 5 years. RESULTS: Three renal grafts (25%) were lost during the 5-year follow-up. Graft loss was due to noncompliance in one patient and to CAN in the other two patients. These two patients returned to dialysis 43 and 59 months after conversion, corresponding to 86 and 75 months after transplantation, respectively. Six of nine patients had a stable or even better renal function compared to the baseline. The lipid profile increased initially, but then remained stable over time. CONCLUSION: Conversion of immunosuppressive therapy from CNI to SIR in patients with impaired renal function more than 1 year after transplantation is feasible and safe yielding improved renal function in the majority of patients, which was sustained at 5 years follow-up.

SDF-1 expression is elevated in chronic human renal allograft rejection.

The exact mechanism of acute and chronic allograft rejection still remains unclear. The chemokine SDF-1 as mediator of allograft rejection has been under intensive investigation in liver, cardiac and bone marrow transplantation, whereas in renal transplantation, there are no reports about SDF-1 to date. This study was performed to evaluate if SDF-1 might also play an important role in human renal graft biopsies. One hundred and ninety formalin-fixed, paraffin-embedded renal allograft biopsies were included in the analysis from patients with normal renal graft morphology (according to Banff 97 classification grade 1, n = 84), with acute interstitial rejection (Banff grade 4 type I, n = 10), with acute vascular rejection (Banff grade 4 type II, n = 21), with chronic allograft nephropathy (CAN, Banff grade 5, n = 23), and without rejection but with various other lesions (Banff grade 6, n = 42). SDF-1 was localized by immunohistochemistry. In biopsies with CAN, SDF-1 expression was significantly elevated in interstitial infiltrates and infiltrating neointimal cells of arteries compared with biopsies with normal renal graft morphology. This is the first study describing a role of SDF-1 in human renal allograft rejection. We were able to demonstrate in a large number of biopsies an upregulation of SDF-1 in patients with CAN. Whether SDF-1 has pro-inflammatory or protective properties in this setting has to be evaluated in further trials.

Increase in renal vascular resistance after intake of cyclosporin A and tacrolimus and reversal by nitroglycerin spray: a study in patients with stable renal allograft function.

PURPOSE: Acute effects of drug administration on renal arterial resistance index (RI) are still discussed controversially. In our study we investigated the immediate effects of cyclosporin A (CyA) and tacrolimus (FK-506) on renal arterial resistance indices in patients with stable graft function after renal transplantation. Additionally we studied the effects of nitroglycerin spray on resistance indices. METHODS: RI was measured by color Doppler sonography at baseline, at 1 and 2 hours after intake of medication and 30 minutes after administration of nitroglycerin spray which followed the 2-hour measurement. 34 renal transplant recipients were examined. 16 patients received CyA, 18 patients received FK-506. Whole blood levels of calcineurin inhibitors were taken at each time point. Arterial blood pressure and heart rate were measured to assess possible systemic hemodynamic effects. RESULTS: Mean RI values increased significantly in both groups 1 hour after calcineurin inhibitor intake and remained still significantly elevated after 2 hours. There was no significant increase of mean arterial blood pressure nor was there any correlation between whole blood levels of calcineurin inhibitors and mean RI. 30 minutes after administration of nitroglycerin spray, mean RI values decreased significantly to a level even below baseline. Mean arterial blood pressure also decreased after administration of nitroglycerin. CONCLUSION: Renal RI values are markedly influenced by a recent intake of calcineurin inhibitors and vasoactive substances such as nitrates. This demonstrates the necessity of keeping standardized conditions when using RI as a tool in followup investigations after renal transplantation.

Effect of ACE and AT-2 inhibitors on mortality and progression to microalbuminuria in a nested case-control study of diabetic nephropathy in diabetes mellitus type 2: results from the GENDIAN study.

INTRODUCTION: There is an established role of clinical risk factors such as arterial hypertension and smoking in causing cardiovascular morbidity and diabetic nephropathy (DNP). Genetic factors increase the risk for DNP. To examine the genetic risk, we initiated a case-control study with predefined follow-up examinations. We describe the study design and baseline characteristics under special consideration of comedication, and give preliminary results of the 4-year follow-up. METHODS: We enrolled all 477 patients with DNP receiving maintenance hemodialysis in 30 centers in Southern Germany between August 1999 and January 2000. As controls, we enrolled all 482 diabetes mellitus type 2 patients without urinary microalbuminuria in two examinations on consecutive days and without other signs of renal disease in a large diabetes clinic from September 2000 to September 2001. Follow-up examinations are performed 4 and 6 years after inclusion by questionnaire and telephone interview to determine mortality and new morbidity. Controls progressing to novel DNP at follow-up, as defined by semiquantitative dipstick urinary albumin/creatinine ratio > 30 mg/g, are defined as cases in the study's nested case control component. RESULTS: At study inclusion in cases and controls, respectively, mean age was 67.3 +/- 8.2 and 58.1 +/- 11.2 years and duration of diabetes mellitus was 15.6 +/- 9.6 (at dialysis initiation) and 11.0 +/- 8.6 years. 328 controls (of which 25 had died and 14 did not perform urinalysis) were subjected to follow-up at 4 years, at a mean of 3.5 +/- 0.8 years after inclusion. 51.2% (n = 148) of living controls remained normalbuminuric, 33.9% (n = 98) had microor macroalbuminuria, and in 14.9% (n = 43) the dipstick test was inconclusive. There was no significant difference in progression to micro- or macroalbuminuria between controls treated with ACE or AT-2 inhibitors at baseline or not. Renal function as estimated by the abbreviated MDRD formula declined from 86.8 +/- 21.0 to 82.5 +/- 22.3 ml/min/1.73 m2 (p < 0.001). The decline was significant in patients on ACE or AT-2 inhibitors at baseline and not in patients without such medication at baseline. DISCUSSION: GENDIAN is a large case-control study designed to evaluate clinical and genetic determinants of DNP and other complications of long-standing diabetes mellitus type 2. We observed an association of ACE or AT-2 inhibitor therapy with cardiovascular comorbidity and a significant decline in renal function after a 4-year follow-up.

Reverse diastolic intrarenal flow due to calcineurin inhibitor (CNI) toxicity.

Renal calcineurin inhibitor (CNI) toxicity is a frequent side effect of immunosuppression with CNIs in solid organ transplantation, leading to acute and chronic renal failure. Acute CNI toxicity is due to vasoconstriction of the vasa afferens and efferens and vacuolization of smooth muscle cells with medial hyalinosis, leading to vessel lumen narrowing. Our case had an acute renal failure 8 months after deceased donor kidney transplantation under treatment with tacrolimus, sirolimus and prednisolone. In Doppler sonography, we observed reverse diastolic intrarenal blood flow, reflecting intense vessel narrowing. There were histological signs of acute CNI toxicity. Within days of reducing the tacrolimus trough level, renal function improved markedly and Doppler sonography showed orthograde intrarenal blood flow. This is the first case of functional, Doppler sonographic evidence for CNI-induced, rapidly reversible narrowing of intrarenal vessels. This case illustrates the potential role of tacrolimus and sirolimus dosing in combination therapy to produce severe intrarenal vasoconstriction.

Pretransplant calcium levels have no predictive value for delayed graft function, long-term graft function, cardiovascular events, or graft and patient survival in renal transplantation.

BACKGROUND: Disorders of calcium homeostasis are one of the most common problems in patients with end-stage renal disease (ESRD). Elevated calcium levels increase the incidence of cardiovascular mortality in ESRD patients, and appear to be a risk factor for the occurrence of delayed graft function (DGF) after kidney transplantation. Therefore, we investigated the impact of pretransplant serum calcium levels on outcomes after kidney transplantation: DGF, acute rejection, graft function, and survival, as well as the incidence of cardiovascular events. METHODS: We studied 285 patients (96.9% of all transplanted patients) who underwent their first transplantation between 1995 and 2004. Demographic data were extracted from hospital records or were documented during follow-up; serum samples were collected at the time of transplantation. RESULTS: In our cohort the incidence of DGF was 16.5% and 35.4% of acute rejection episodes (ARE). However, pretransplant calcium levels were not related to DGF or ARE in our patient cohort. Furthermore, there was no correlation between pretransplant serum calcium level with the incidence of cardiovascular events or mortality, as well as graft function or survival. CONCLUSION: In our study population pretransplant calcium levels showed no effect on DGF, ARE rate, the occurrence of cardiovascular events or death, renal graft function, or survival. Therefore, pretransplant calcium level is not a helpful marker for risk stratification at the time of transplantation.

Effect of HMG-CoA-reductase inhibitors on survival in type 2 diabetes patients with end stage diabetic nephropathy.

INTRODUCTION: We studied the effect of HMG-CoA-reductase inhibitor (= CSE-I) treatment on mortality in a population of hemodialysis patients with diabetic nephropathy due to type 2 diabetes. Since the efficacy of CSE-I in dialysis patients is discussed controversially, we tested the hypothesis that only patients with LDL-cholesterol > 100 mg/dl benefit from CSE-I. METHODS: We enrolled all 445 prevalent chronic hemodialysis patients with end-stage diabetic nephropathy from 30 centres in Southern Germany from August 1999 to January 2000 for prospective study until December 2003. Fasting lipid profiles prior to dialysis session and a complete clinical phenotype were determined at inclusion. We formed 2 patient groups (serum LDL > vs. < or = 100 mg/dl). Only CSE-I were used as lipid lowering therapy in our cohort. 122 Patients were on CSE-I therapy during the study. All cause mortality (ACM) was the primary end point. Survival analysis was performed by Kaplan Meier and multivariate Cox regression analysis. RESULTS: Multivariate regression analysis and Kaplan Meier survival analysis showed a decrease in risk for ACM for patients on CSE-I therapy, irrespective of lipid status (multivariate hazard ratio (= HR) 0.58; p = 0.049; ACM 72.1% (no CSE-I) vs. 59.7% (+ CSE-I); mean survival 2.37 +/- 0.08 years (no CSE-I) vs. 2.77 +/- 0.12 years (+ CSE-I), p = 0.003). In patients with LDL > 100 mg/dl, statin treatment was also associated with reduced ACM: 48.0% (+ CSE-I) vs. 70.1% (no CSE-I), (multivariate HR 0.28, CI 95% 0.11 - 0.75, p = 0.01), but not in patients with LDL < or = 100 mg/dl (HR 0.84, CI 95% 0.41 - 1.72 p = 0.63). CONCLUSION: Our data indicates that hemodialysis patients with type 2 diabetic nephropathy may benefit from statin therapy irrespective of baseline LDL-cholesterol level. Patients with LDL > 100 mg/dl benefit most when treated with CSE-I.

Effect of genetic variation on therapy with angiotensin converting enzyme inhibitors or angiotensin receptor blockers in dialysis patients.

INTRODUCTION: The role of interaction of polymorphisms in the Renin-Angiotensin-System (RAS) with angiotensin converting enzyme (ACE) or angiotensin receptor (AGTR1) inhibitors (RAS inhibitors) is unknown, as is the role of such therapy in end stage renal disease (ESRD) patients. METHODS: We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective survival analysis until December 2003. Blood pressure and medication was recorded at inclusion. We determined survival specific for allelic variants of the ACE (insertion/deletion), Angiotensinogen (M235T) and AGTR1 (A1166C) genes. The effect of therapy with RAS inhibitors at study inclusion was determined for the allelic variants of each gene. The primary end point was all cause mortality (ACM). RESULTS: For all polymorphisms, and for therapy with RAS inhibitors there was no significant effect on survival in the complete collective (n = 445), though there was an insignificant trend for improved survival in patients on AGTR1 antagonists. Increased ACM risk was associated with treatment with RAS inhibitors only in patients homozygous for the wild type AGTR1 1166A allele (HR 1.65, p = 0.01). For all other polymorphisms, therapy with RAS inhibitors had no significant effect on ACM, irrespective of genotype. Similar results were obtained in patients with systolic ventricular dysfunction. CONCLUSION: Our data do not show a survival advantage for type 2 diabetes hemodialysis patients receiving RAS inhibiting therapy. In addition, our data indicate that allelic variation in RAS genes and pharmacogenetic interaction with RAS inhibition does not affect mortality risk in diabetic hemodialysis patients.

Cardiovascular risk estimates and risk factors in renal transplant recipients.

Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.