Herwig Holzer

Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients.

The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side‐effects. An enteric‐coated formulation of mycophenolate sodium (EC‐MPS; myfortic®) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC‐MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral®) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12‐month, double‐blind study. Efficacy failure (biopsy‐proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC‐MPS 25.8% vs. MMF 26.2%; 95% CI: [−8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC‐MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC‐MPS and 9.8% with MMF (p = ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC‐MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p = ns). Enteric‐coated‐MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.

Decrease in Thoracic Vertebral Bone Attenuation With Calcium-Based Phosphate Binders in Hemodialysis

We performed a posthoc analysis of a 52‐week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium‐based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. Subjects randomized to calcium salts experienced a significant reduction in trabecular bone attenuation and a trend toward reduction in cortical bone attenuation, in association with higher concentrations of serum calcium, lower concentrations of PTH, and reduced total and bone‐specific alkaline phosphatase.

Effect of cyclosporine withdrawal on Mycophenolic acid pharmacokinetics in kidney transplant recipients with deteriorating renal function: Preliminary report

Mycophenolic acid (MPA) concentrations are lower in transplant recipients receiving mycophenolate mofetil (MMF) and cyclosporine compared with MMF with tacrolimus. It is not clear whether this is due to an effect of cyclosporin or tacrolimus on MPA pharmacokinetics. To study this effect, kidney transplant recipients with deteriorating renal function (n = 5) receiving cyclosporin and steroids were given mycophenolate mofetil over 4 weeks during a run-in phase (1 g/d in week 1, 1.5 g/d in week 2, 2 g/d starting from week 3). From week 5 the cyclosporin dose was reduced, and it was completely withdrawn at week 10. Creatinine, MPA, and MPA glucuronide metabolites (MPAG, AcMPAG) were determined before (week 4) and after (week 11 and week 32) cyclosporin was withdrawn. Cyclosporin withdrawal was associated with increased MPA areas under the curve (AUCs) and predose concentrations in four of the five patients. In contrast, MPAG and AcMPAG AUCs as well as predose MPAG concentrations significantly decreased. Six months after cyclosporin withdrawal, MPA AUC and predose values tended to return to initial values, whereas metabolite concentrations remained low. Cyclosporin discontinuation caused an acute increase in MPA exposure and a concomitant reduction in metabolite concentrations. The results are consistent with the hypothesis that cyclosporin attenuates the enterohepatic recirculation of MPAG/MPA.

Bone Markers Predict Cardiovascular Events in Chronic Kidney Disease

Recent studies have indicated a link between bone metabolism and cardiovascular events in patients with chronic kidney disease (CKD). CKD is a major health problem worldwide. This study evaluates the role of noninvasive markers of bone metabolism in predicting cardiovascular morbidity (coronary artery disease, peripheral vascular disease, stroke) and mortality in patients with mild to severe forms of CKD. In a prospective cohort study, 627 patients with CKD were screened. To focus on bone metabolism, traditional risk factors for cardiovascular events were excluded, and 135 patients with CKD stages 1–5 were followed for 4 yr. Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. PTH (measured by four different assays), vitamin D 25 and 1,25, bone‐specific alkaline phosphatase (BSALP), TRACP‐5b, osteocalcin, serum collagen cross‐link molecules, RANKL, and osteoprotegerin were determined. Predictors of cardiovascular events were evaluated by multivariable logistic regression, Kaplan‐Meier survival, and Cox regression analysis. There were a total of 45 cardiovascular events (33%). Event rates were 5.6%, 29.1%, 45.2%, and 45.0% in CKD stages 1–2, 3, 4, and 5, respectively. In logistic regression, cardiovascular events were predicted only by (1) CKD stage (independent of age or sex; p < 0.001); (2) BSALP (p = 0.03); and (3) TRACP‐5b (p = 0.04). Markers of bone formation (BSALP) and resorption (TRACP‐5b) can serve as predictors of cardiovascular morbidity and mortality in CKD.

Removal of bile acids by two different extracorporeal liver support systems in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is accompanied by marked intrahepatic cholestasis leading to accumulation of cytotoxic bile acids. Extracorporeal liver support systems efficiently remove bile acids, but their effect on bile acid composition in ACLF is unknown. The aim of the present study was to compare elimination of individual plasma bile acids by albumin dialysis (Molecular Adsorbents Recirculating System, MARS) and fractionated plasma separation (Prometheus). Eight consecutive patients with ACLF underwent alternating 6-hour sessions with MARS or Prometheus in a randomized, cross-over design. Serum samples were obtained before, during, and after each treatment, and individual bile acids including cholic acid and chenodeoxycholic acid (CDCA) were measured by gas chromatography. MARS and Prometheus removed total bile acids to a similar extent (reduction ratio, 45% and 46%, respectively). Both devices cleared cholic acid more efficiently than did CDCA. The molar fraction of CDCA (fCDCA) was elevated at baseline and correlated with the degree of liver dysfunction. Prometheus but not MARS treatments further increased fCDCA. Although both devices eliminate total bile acids to a similar extent, clearance of individual bile acids is different, leading to a slight change of the bile acid profile toward hydrophobic bile acids during Prometheus treatments.

Effect of hemodialysis on the antioxidative properties of serum.

In patients with chronic renal failure undergoing regular hemodialysis (HD), oxidative stress is involved in the development of dialysis-related pathologies. The aim of the study was to measure the effect of HD treatment on the general antioxidative status of serum with special consideration of the specific oxidizability of lipids and proteins. Indicators for the oxidative/antioxidative status of plasma were monitored at the beginning and at the end of a dialysis session on the arterial and venous side of the dialyzer. A decrease in the antioxidant status was accompanied by an increased oxidizability of proteins as well as lipids during HD treatment. During the first passage of the dialyzer, the lag time of lipid oxidation decreased from 114.0+/-19.8 to 81.5+/-18.9 min, the lag time of protein oxidation decreased from 105.0+/-24.6 to 72.9+/-21.3 min and the total antioxidative status decreased from 518+/-24 to 252+/-124 microM trolox equivalents. The carbonyl content of serum proteins was high in patients with end stage renal disease (ESRD) (3.9+/-1.1 vs. 0.9+/-0.1 nmol/mg in controls) but did not change significantly during dialysis procedure. Our data demonstrate that the susceptibility of serum lipids and proteins to oxidative modification is severely increased by HD treatment.

End-stage renal failure from mushroom poisoning with Cortinarius orellanus: Report of four cases and review of the literature

Mushrooms of the ubiquitous Cortinarius species (Cs) contain nephrotoxins that can cause acute and chronic renal failure by an unknown pathomechanism. Typical is a long symptom-free interval before the onset of clinical disease. A causal form of therapy is not known. Early hemodialysis can improve the prognosis of this potentially life-threatening condition. Diagnosis of Cs poisoning can be made by detecting the responsible toxin--orellanine--in plasma or renal tissue by fluorimetry after thin-layer chromatography or by identifying the spores of left-over mushrooms as Cs. Renal histology shows nonspecific changes such as tubular dilatation and flattening of the epithelium and signs of interstitial edema followed by interstitial fibrosis. We present four cases of Cs poisoning with different outcomes and a review of the literature.

Increased susceptibility for CsA-induced hepatotoxicity in kidney graft recipients with chronic viral hepatitis C.

CsA-induced hepatotoxicity is a rare disorder in renal transplant recipients when low doses are administered and whole blood trough levels of CsA are regularly monitored. However, there is controversy about the clinical value of measuring CsA-metabolites, whose contribution to immunosuppression and toxicity is not fully understood. To assess the relation between low-dose CsA therapy and hepatotoxicity, we studied 128 renal transplant recipients attending our nephrology clinic. Eight of these patients had markedly elevated liver function tests. Three patients while receiving very low doses of oral CsA (< 3.8 mg/kg of body weight) presented marked derangements of CsA metabolism with abnormally increased CsA-metabolite levels. Parent drug levels were in the normal range. All 3 patients had chronic infection with hepatitis C virus and revealed histomorphologic evidence of hepatotoxicity. Hepatic dysfunction normalized when CsA was withdrawn or reduced by 50%. It is likely that hepatitis C virus infection interferes with CsA metabolism and/or biliary CsA-excretion and thus is responsible for CsA and/or metabolite-induced hepatotoxicity despite very low doses of CsA.

Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid.

Background. To better define subpopulations in which achieving adequate mycophenolic acid (MPA) concentrations quickly would be important, a post hoc exploratory analysis on the fixed-dose concentration-controlled database was performed, comparing high- versus low-risk renal transplant patients. Methods. Renal transplant patients were treated with mycophenolate mofetil, corticosteroids, and cyclosporine A or tacrolimus. Patients were defined as “high risk” if they had one or more of the following characteristics: delayed graft function, second or third transplantation, panel reactive antibodies >15%, four or more human leukocyte antigen mismatches, or were of black race. Results. A total of 549 patients (61%) were classified as high risk, of whom 284 were on cyclosporine A treatment and 265 on tacrolimus. In high-risk patients, the difference in rejection incidence was 14.3% in the MPA-area under the concentration (AUC) less than 30 mg hr/L vs. 7.8% in the MPA-AUC more than or equal to 30 mg hr/L groups (P=0.025) during the first month after transplantation; whereas, in low-risk patients, there were similar rejection rates (5.7% vs. 4.5%). In the subgroup of high-risk tacrolimus-treated patients, the difference in acute rejection incidence in the first month between patients with MPA-AUC0–12 less than or more than or equal to 30 mg hr/L was most pronounced: 16 of 67 patients (23.9%) vs. 18 of 173 patients (10.4%); P=0.012. Conclusions. The incidence of acute rejection is higher in high-risk patients if MPA-AUC0–12 is below 30 mg hr/L. In contrast, a difference in acute rejection incidence in low-risk patients with MPA-AUC0–12 less than or more than or equal to 30 mg hr/L was not observed. This supports the use of a higher mycophenolate mofetil starting dose in selected patient populations early after transplantation.

Determination of the glomerular filtration rate by identification of sinistrin kinetics.

A computer-based method of system identification and estimation of parameter variance for two-compartment models matched to dynamic sinistrin concentration profiles for the determination of glomerular filtration rate is described. Thereby a procedure for the judgment of the optimal sampling time horizon is presented. Since single-injection techniques are suspected of yielding systematic overestimation of the glomerular filtration rate, a method is demonstrated confirming that such a technique employing sinistrin kinetics can be used to correctly determine the glomerular filtration rate. The validation of the system parameters gained by the single-injection method is made through prediction of the concentration contour under a constant infusion regimen in the same subject on a different occasion. This was performed in healthy controls and in patients with various degrees of renal insufficiency. Upon consideration of the dependence of the clearance estimates and their variances on the protocol duration in test subjects examined from four to ten hours, an adaptive design of the protocol length is developed.