Klaus H. Neumann

Cardiac troponin T predicts mortality in patients with end-stage renal disease

BackgroundPatients with end-stage renal disease have a high risk of premature death, mainly as the result of cardiovascular disease (CVD), which is not sufficiently explained by the conventional risk factors. We therefore prospectively investigated total mortality and cardiovascular events in 102 patients on hemodialysis and assessed the prognostic value of baseline disease status and laboratory variables including total homocysteine and cardiac troponin T. Methods and ResultsPatients were followed for 2 years or until their first event of CVD (for outcome variable cardiovascular events, n=33) or death (for outcome variable total mortality, n=28). Survival was computed by the Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of CVD events or total mortality. Cardiac troponin T emerged as the most powerful predictor of mortality, resulting in an almost 7-fold risk increase at concentrations >0.10 ng/mL (hazard ratio 6.85, 95% CI 3.04 to 15.45). Total homocysteine level greater than median was also associated with mortality (hazard ratio 2.44, 95% CI 1.10 to 5.40). These hazard ratios did not change substantially after adjustment for other risk factors. Significant predictors for CVD events were baseline diabetes, cerebrovascular disease, serum glucose, and triglycerides. After adjustment, only glucose and triglycerides remained significantly related to CVD events (hazard ratio with 95% CI 1.33 [1.12 to 1.57] and 1.14 [1.04 to 1.26], respectively, for a 1-mmol/L increase in concentration). ConclusionsWe conclude that total homocysteine and particularly cardiac troponin T are important predictors of mortality in patients with end-stage renal disease, whereas other laboratory variables and baseline disease status have less prognostic value.

B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease Results of a Randomized Controlled Trial

Background— In observational studies, hyperhomocysteinemia has been found to be a risk factor for total mortality and cardiovascular events in patients with end-stage renal disease. These patients have grossly elevated homocysteine levels that can be lowered by supplementation with folic acid and vitamin B12. We conducted a randomized clinical trial with B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality. Methods and Results— This randomized, double-blind multicenter study was conducted in 33 dialysis centers in north and east Germany between July 2002 and July 2008. We randomly assigned 650 patients with end-stage renal disease who were undergoing hemodialysis to 2 postdialysis treatments: 5 mg folic acid, 50 &mgr;g vitamin B12, and 20 mg vitamin B6 (active treatment) or 0.2 mg folic acid, 4 &mgr;g vitamin B12, and 1.0 mg vitamin B6 (placebo) given 3 times per week for an average of 2 years. The primary outcome was total mortality; the secondary outcome was fatal and nonfatal cardiovascular events. The primary outcome occurred in 102 patients (31%) receiving the active treatment and in 92 (28%) receiving placebo (hazard ratio, 1.13; 95% confidence interval, 0.85 to 1.50; P=0.51). The secondary outcome occurred in 83 patients (25%) receiving the active treatment and in 98 (30%) receiving placebo (hazard ratio, 0.80; 95% confidence interval, 0.60 to 1.07; P=0.13). Conclusions— Increased intake of folic acid, vitamin B12, and vitamin B6 did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease. Clinical Trial Registration— URL: www.anzctr.org.au. Unique identifier: ACTRN12609000911291. URL: www.cochrane-renal.org. Unique identifier: CRG010600027.

Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease

Hyperhomocysteinemia is frequently found in patients with end-stage renal disease (ESRD). Plasma total homocysteine (tHcy) concentrations may be reduced by supplementation with folic acid or combinations of folic acid, vitamin B12, and vitamin B6. Supplementation studies with vitamin B12 alone in patients with ESRD have not yet been published. In this study, we investigated the effects of intravenous injection of cyanocobalamin (1 mg/wk for 4 weeks) in ESRD patients (N = 14) with low serum cobalamin concentrations (<180 pmol/L). All patients had elevated levels of plasma tHcy, methylmalonic acid (MMA), and cystathionine before supplementation. After supplementation, plasma tHcy and MMA decreased 35% and 48%, respectively; however, cystathionine levels were unchanged. The extent of the plasma tHcy reduction tended to be influenced by the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR). Serum cobalamin increased significantly upon supplementation, whereas serum folate levels were substantially reduced by 47%. In contrast, red blood cell (RBC) folate was unchanged. This study shows that vitamin B12 supplementation effectively decreases both MMA and plasma tHcy in ESRD patients with low B12 levels. Furthermore, it illustrates the close interrelation between vitamin B12 and folate metabolism.

Washout of water‐soluble vitamins and of homocysteine during haemodialysis: Effect of high‐flux and low‐flux dialyser membranes

Aim:  Vitamin deficiencies are common in patients with end‐stage renal disease (ESRD) owing to dietary restrictions, drug–nutrient interactions, changes in metabolism, and vitamin losses during dialysis. The present study investigated the levels of serum and red blood cell (RBC) folate, plasma pyridoxal‐5′‐phosphate (PLP), serum cobalamin, blood thiamine, blood riboflavin, and plasma homocysteine (tHcy) before and after haemodialysis treatment.

Homocysteine lowering effect of different multivitamin preparations in patients with end-stage renal disease

OBJECTIVE Hyperhomocysteinemia occurs in nearly 100% of patients with end-stage renal disease (ESRD) and is associated with increased morbidity and mortality. Means to reduce elevated homocysteine concentrations is supplementation with folic acid, vitamin B6, and vitamin B12. However, doses of vitamins required for optimized treatment are subject of debate. Therefore, the effect of 2 different multivitamin preparations on the homocysteine concentrations in patients with ESRD were compared. DESIGN Patients received 3 times per week either 2 tablets of preparation A (800 microg folic acid, 6 microg vitamin B12, 10 mg vitamin B6), 2 tablets of preparation B (160 microg folic acid, no vitamin B12, 10 mg vitamin B6), or placebo for a period of 12 weeks with control of total homocysteine (tHcy) levels at baseline, and at 4, 8, and 12 weeks. SETTING The study was performed at the University Hospital of Magdeburg, Germany in patients with ESRD treated with chronic intermittent maintenance hemodialysis. RESULTS Preparation A reduced the tHcy concentration significantly by nearly 50%, whereas preparation B did not change the tHcy concentration in comparison with placebo. However, tHcy was not normalized in the majority of patients receiving preparation A. CONCLUSION The reduction of tHcy achieved by a multivitamin containing 800 microg folic acid was substantial and even higher than the reduction reported in supplementation studies using higher doses of folic acid alone. Nevertheless, hyperhomocysteinemia in ESRD patients appears relatively refractory to vitamin supplementation, in contrast with results obtained in healthy volunteers.

Vitamins are associated with survival in patients with end-stage renal disease: a 4-year prospective study.

BACKGROUND Patients with end-stage renal disease are at high risk from premature death due mainly to cardiovascular disease and infections. Established risk factors do not sufficiently explain this increased mortality. We, therefore, investigated total mortality prospectively in a single-centre study in patients on hemodialysis and assessed the prognostic value of baseline disease status, laboratory variables including emerging risk factors, and the influence of vitamin treatment. METHODS Patients (n = 102) were followed-up for 4 years or until death (n = 49). Survival was calculated by the Kaplan-Meier method. Cox-proportional hazards model was used to determine independent predictors of total mortality. RESULTS The known risk factors age, baseline clinical atherosclerotic disease, low albumin and increased cardiac troponin T were significantly associated with mortality. Patients who received multivitamins during follow-up had a significantly lower mortality risk than those not receiving this treatment (hazard ratio 0.29, 95% confidence interval 0.15-0.56). These associations remained significant after adjustment for age, cardiovascular disease, albumin and cardiac troponin T at baseline. CONCLUSIONS The present study suggests that multivitamin supplementation in patients with end-stage renal disease is closely associated with reduced mortality due to all causes. These observations have to be validated in randomized clinical intervention trials.

Komplizierter Verlauf einer nekrotisierenden Granulomatose mit pulmonaler, intestinaler und renaler Vaskulitis@@@Necrotizing Granulomatosis with Pulmonary, Intestinal and Renal Involvement

ZusammenfassungFallbeschreibung:Pulmonale, renale und okuläre Auffälligkeiten führten bei einem 45-jährigen Patienten zu der Diagnose einer ANCA-positiven Vaskulitis, die einer immunsuppressiven Therapie bedurfte. Bei Aufnahme klagte der Patient über zunehmende abdominelle Schmerzen mit Punctum maximum im Unterbauch. Die Schichtbildgebung wies intraabdominell freie Flüssigkeit sowie flüssigkeitsgefüllte dilatierte Dünndarmschlingen mit Spiegelbildung nach. Bei dem klinischen Bild eines paralytischen Ileus erfolgte eine Laparotomie. Hämorrhagisch-nekrotische Dünndarmveränderungen fielen intraoperativ auf und eine Resektion erfolgte. Die Histologie des Resektats ergab transmurale ischämische Wandnekrosen, verursacht durch eine granulomatöse Vaskulitis mittelkalibriger Darmwandarterien. Im Verlauf wurde als Ultima Ratio bei vital bedrohtem Patienten der CD20- Antikörper Rituximab verabreicht, wonach die Krankheitsaktivität kontrolliert war. Die Nierenfunktion besserte sich mittelfristig, abdominelle Beschwerden traten nicht mehr auf.Schlussfolgerung:Eine gastrointestinale Beteiligung bei nekrotisierender Vaskulitis ist eine seltene, jedoch schwerwiegende Komplikation. Die meisten Patienten sprechen auf die etablierte Therapie mit Cyclophosphamid und Glukokortikoiden an. Bei therapierefraktären Fällen stellt die Gabe von Rituximab eine erfolgversprechende Alternative dar.AbstractCase Report:In a 45 year old patient pulmonary, renal and ocular manifestations of ANCA-associated vasculitis is reported that required immunosuppressive therapy. On admission the patient complained about enduring lower abdominal pain. A CT scan revealed free intraabdominal fluid and dilated small intestine filled with fluid. Laparotomy was performed with the working diagnosis of paralytic ileus. Intraoperatively, hemorrhagic-necrotic alterations of the small intestinal wall were conspicuous and resected. Microscopic examination revealed transmural ischemic necrosis of the resected intestinal tissue with prominent granulomatous vasculitis of arteries. CD20-antibody rituximab was applied due to the life-threatening condition and as ultima ratio therapy. Subsequently the disease activity was controlled, renal function improved and abdominal discomfort subsided.Conclusion:Gastrointestinal involvement with necrotizing vasculitis is an uncommon but serious complication. Most patients respond to established therapy protocols encompassing cyclophosphamide and glucocorticoids. Administration of rituximab may be a promising alternative in refractory cases.CASE REPORT In a 45 year old patient pulmonary, renal and ocular manifestations of ANCA-associated vasculitis is reported that required immunosuppressive therapy. On admission the patient complained about enduring lower abdominal pain. A CT scan revealed free intraabdominal fluid and dilated small intestine filled with fluid. Laparotomy was performed with the working diagnosis of paralytic ileus. Intraoperatively, hemorrhagic-necrotic alterations of the small intestinal wall were conspicuous and resected. Microscopic examination revealed transmural ischemic necrosis of the resected intestinal tissue with prominent granulomatous vasculitis of arteries. CD20-antibody rituximab was applied due to the life-threatening condition and as ultima ratio therapy. Subsequently the disease activity was controlled, renal function improved and abdominal discomfort subsided. CONCLUSION Gastrointestinal involvement with necrotizing vasculitis is an uncommon but serious complication. Most patients respond to established therapy protocols encompassing cyclophosphamide and glucocorticoids. Administration of rituximab may be a promising alternative in refractory cases.