Dierik Verbeelen

Use of phosphate-binding agents is associated with a lower risk of mortality

Hyperphosphatemia has been associated with higher mortality risk in CKD 5 patients receiving dialysis. Here, we determined the association between the use of single and combined phosphate-binding agents and survival in 6797 patients of the COSMOS study: a 3-year follow-up, multicenter, open-cohort, observational prospective study carried out in 227 dialysis centers from 20 European countries. Patient phosphate-binding agent prescriptions (time-varying) and the case-mix-adjusted facility percentage of phosphate-binding agent prescriptions (instrumental variable) were used as predictors of the relative all-cause and cardiovascular mortality using Cox proportional hazard regression models. Three different multivariate models that included up to 24 variables were used for adjustments. After multivariate analysis, patients prescribed phosphate-binding agents showed a 29 and 22% lower all-cause and cardiovascular mortality risk, respectively. The survival advantage of phosphate-binding agent prescription remained statistically significant after propensity score matching analysis. A decrease of 8% in the relative risk of mortality was found for every 10% increase in the case-mix-adjusted facility prescription of phosphate-binding agents. All single and combined therapies with phosphate-binding agents, except aluminum salts, showed a beneficial association with survival. The findings made in the present association study need to be confirmed by randomized controlled trials to prove the observed beneficial effect of phosphate-binding agents on mortality.

Quantification of renal perfusion and function on a voxel‐by‐voxel basis: A feasibility study

The feasibility of a voxel‐by‐voxel deconvolution analysis of T1‐weighted DCE data in the human kidney and its potential for obtaining quantification of perfusion and filtration was investigated. Measurements were performed on 14 normal humans and 1 transplant at 1.5 T using a Turboflash sequence. Signal time‐courses were converted to tracer concentrations and deconvolved with an aorta AIF. Parametric maps of relative renal blood flow (rRBF), relative renal volume of distribution (rRVD), relative mean transit time (rMTT), and whole cortex extraction fraction (E) were obtained from the impulse response functions. For the normals average cortical rRBF, rRVD, rMTT, and E were 1.6 mL/min/mL (SD 0.8), 0.4 mL/mL (SD 0.1), 17s (SD 7), and 22.6% (SD 6.1), respectively. A gradual voxelwise rRBF increase is found from the center of two infarction zones toward the edges. Voxel IRFs showed more detail on the nefron substructure than ROI IRFs. In conclusion, quantitative voxelwise perfusion mapping based on deconvolved T1‐DCE renal data is feasible, but absolute quantification requires inflow correction. rRBF maps and quantitative values are sufficiently sensitive to detect perfusion abnormality in pathologic areas, but further research is necessary to separate perfusion from extraction and to characterize the different compartments of the nephron on the (sub)voxel level. Magn Reson Med, 2005.

Valproic Acid Attenuates Proteinuria and Kidney Injury

Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD.

Conversion from Cyclosporine to Sirolimus in Stable Renal Transplant Recipients

Background. Conversion from cyclosporine (CsA) to sirolimus (SRL) has mainly been done in clinical conditions warranting calcineurin inhibitor discontinuation. Little is known about the clinical outcome of conversion in renal transplant recipients without transplant dysfunction. Methods. This prospective, open-label, multicentric pilot study evaluates the safety and efficacy of converting patients with stable renal function from CsA to SRL. Results. Forty stable patients on CsA, mycophenolate mofetil (MMF) (1.5 g/day), and steroids (ST) were converted at 7.6±1.4 months after renal transplantation. At 1 year, graft and patient survival was 100% and the incidence of acute rejection 5%. Calculated glomerular filtration rate (GFR) increased from 54±18 to 66±16 ml/min (P<0.0001). Blood pressure remained unchanged. A gradual increase in the incidence and severity of proteinuria was observed from month 6 onwards with de novo proteinuria in 30% of the patients at 1 year. Protein excretion was below 1 g/day in 12.5%, between 1 and 3 g/day in 17.5% and above 3 g/day in 7.5% of the proteinuric cohort (P=0.0043, compared to baseline). No predictors could be identified for the development of proteinuria. All patients had a reduction in protein excretion following renin-angiotensin blockade and were continued on SRL. Conclusion. Conversion of stable renal transplant recipients from a CsA-MMF-ST to a SRL-MMF-ST regimen is safe and results in improved renal function but is associated with the development of proteinuria in 30% of the patients requiring renin-angiotensin blockade.

Comparison of Perindopril and Amlodipine in Cyclosporine-Treated Renal Allograft Recipients

The objective of this study was to compare the antihypertensive efficacy and influence on renal function of perindopril and amlodipine in cyclosporine-treated renal allograft recipients with mild to moderate hypertension. We conducted a randomized, double-blind, double-dummy crossover trial in ambulatory patients. Four phases were conducted: 2 weeks on placebo, 8 weeks of maintenance (perindopril or amlodipine), and 2 weeks of washout between treatment periods. Ten hypertensive patients with stable renal allograft function transplanted more than 6 months previously and receiving cyclosporine as part of their immunosuppressive regimen were studied. The patients were allocated to perindopril (2 or 4 mg/d) and amlodipine (5 mg/d) in a random sequence. If office diastolic pressure was greater than or equal to 90 mm Hg after 4 weeks, the dosage was doubled and continued for another 4 weeks. The main outcome measures were office and 24-hour ambulatory blood pressure changes after 8 weeks of active treatment and treatment and time effect on glomerular filtration rate and effective renal plasma flow. Perindopril and amlodipine were equally effective in lowering office blood pressure and similarly efficacious for the 24-hour period of the day. Neither drug affected glomerular filtration rate or effective renal plasma flow. Both agents demonstrated equivalent capacity (time x treatment, P = .955) to reverse renal vascular resistance (amlodipine from 0.35 +/- 0.02 to 0.30 +/- 0.02 mm Hg/mL per minute per 1.73 m2; perindopril from 0.36 +/- 0.03 to 0.32 +/- 0.01) (time effect of all treatments together, P = .043).(ABSTRACT TRUNCATED AT 250 WORDS)

COSMOS: the dialysis scenario of CKD–MBD in Europe

BACKGROUND Chronic kidney disease-mineral and bone disorders (CKD-MBD) are important complications of CKD5D patients that are associated with mortality. METHODS COSMOS is a multicentre, open cohort, prospective, observational 3-year study carried out in haemodialysis patients from 20 European countries during 2005-07. The present article describes the main characteristics of the European dialysis population, the current practice for the prevention, diagnosis and treatment of secondary hyperparathyroidism and the differences across different European regions. RESULTS The haemodialysis population in Europe is an aged population (mean age 64.8±14.2 years) with a high prevalence of diabetes (29.5%) and cardiovascular disease (76.0%), and 28.7% of patients have been on haemodialysis more than 5 years. Patients from the former Eastern countries are younger (59.3±14.3 versus 66.0±13.9), having a lower proportion of diabetics (24.1 versus 30.7%). There were relevant differences in the frequency of measurement of the main CKD-MBD biochemical parameters [Ca, P and parathyroid hormone (PTH)] and the Eastern countries showed a poorer control of these biochemical parameters (K/DOQI and K/DIGO targets). Overall, 48.0% of the haemodialysis patients received active vitamin D treatment. Calcitriol use doubled that of alfacalcidiol in the Mediterranean countries, whereas the opposite was found in the non-Mediterranean countries. The criteria followed to perform parathyroidectomy were different across Europe. In the Mediterranean countries, the level of serum PTH considered to perform parathyroidectomy was higher than in non-Mediterranean countries; as a result, in the latter, more parathyroidectomies were performed in the year previous to inclusion to COSMOS. CONCLUSIONS The COSMOS baseline results show important differences across Europe in the management of CKD-MBD.

Influence of Body Mass Index on the Association of Weight Changes with Mortality in Hemodialysis Patients

BACKGROUND AND OBJECTIVES A high body mass index (BMI) is associated with lower mortality in patients undergoing hemodialysis. Short-term weight gains and losses are also related to lower and higher mortality risk, respectively. The implications of weight gain or loss may, however, differ between obese individuals and their nonobese counterparts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS) is an observational study including 6797 European hemodialysis patients recruited between February 2005 and July 2007, with prospective data collection every 6 months for 3 years. Time-dependent Cox proportional hazard regressions assessed the effect of BMI and weight changes on mortality. Analyses were performed after patient stratification according to their starting BMI. RESULTS Among 6296 patients with complete data, 1643 died. At study entry, 42% of patients had a normal weight (BMI, 20-25 kg/m(2)), 11% were underweight, 31% were overweight, and 16% were obese (BMI ≥ 30 kg/m(2)). Weight loss or gain (<1% or >1% of body weight) was strongly associated with higher rates of mortality or survival, respectively. After stratification by BMI categories, this was true in nonobese categories and especially in underweight patients. In obese patients, however, the association between weight loss and mortality was attenuated (hazard ratio, 1.28 [95% confidence interval (CI), 0.74 to 2.14]), and no survival benefit of gaining weight was seen (hazard ratio, 0.98 [95% CI, 0.59 to 1.62]). CONCLUSIONS Assuming that these weight changes were unintentional, our study brings attention to rapid weight variations as a clinical sign of health monitoring in hemodialysis patients. In addition, a patients BMI modifies the strength of the association between weight changes with mortality.

Monitoring of Bone Mineral Content in Patients on Regular Hemodialysis

Bone mineral content (BMC) was measured at the lumbar spine region by means of dual photon absorptiometry over a 3-year period in 20 patients on regular hemodialysis (RHD). Baseline mean BMC at the start of the monitoring was significantly decreased to 82.64% of predicted value (p less than 0.05). During a 3-year follow-up mean BMC rose significantly to 90.61% (p less than 0.05). Six patients received vitamin D supplements. Analysis of the data showed that rise of BMC was similar whether vitamin D was given or not. Our data suggest that (1) RHD inhibits bone loss at the lumbar spine level that occurred mainly before active uremia treatment and (2) the increment of BMC observed in this study can be attributed to the different site of measurement, the inaccuracy of the measurements by interference with soft tissue calcifications and the dialysis conditions.

Effect of Vitamin E on Antioxidant Enzymes, Lipid Peroxidation Products and Glomerulosclerosis in the Rat Remnant Kidney

In rats with five-sixth nephrectomy (remnant kidney), glomerulosclerosis was significantly reduced by dietary administration of vitamin E (alpha-tocopherol) during 11 and 16 weeks after reduction of nephron number. The activity of catalase and the production of H2O2 in remnant kidney cortex homogenate were not influenced by the vitamin E diet; however, the activities of glutathione peroxidase and superoxide dismutase were significantly increased (up to 140 and 180%, respectively, after 16 weeks). Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentrations, was decreased in cortex homogenates and in urine. Though the extent of the effect of vitamin E on antioxidant enzyme levels and lipid peroxidation is small, the important reduction of glomerulosclerosis is in favor of dietary supplementation with vitamin E.

Divergent effects of calcium channel and angiotensin converting enzyme blockade on glomerulotubular function in cyclosporine-treated renal allograft recipients

The effects of amlodipine and perindopril on renal hemodynamics and tubular function in cyclosporine-treated hypertensive renal allograft recipients were evaluated in a randomized, double-blind crossover fashion. Ten patients were studied after a 2-week placebo run-in and, after 8 weeks of active treatment, allowing a 2-week placebo washout between treatments. At the end of each period, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured as 51Cr-EDTA and 123I-hippuran clearance, respectively, and tubular function evaluated by the lithium clearance technique was determined. Both drugs maintained GFR and ERPF and lowered mean arterial pressure (MAP, mm Hg) to a similar extent (time x treatment, P = 0.466): amlodipine from 126.9 +/- 2.5 to 115.9 +/- 2.2; perindopril from 126.9 +/- 2.5 to 117.9 +/- 3.9 (time effect of all treatments together, P = 0.003). Accordingly, renal vascular resistance (RVR, mm Hg/mL/min/1.73 m2) was equally reduced (time x treatment, P = 0.955): amlodipine from 0.36 +/- 0.03 to 0.30 +/- 0.02; perindopril from 0.36 +/- 0.03 to 0.32 +/- 0.01 (time effect all treatments together, P = 0.043). Sodium clearance and fractional excretion of sodium were not affected by either drug. Output of fluid from the proximal tubules measured as clearance of lithium (CLi, mL/min) and uric acid (CUr, mL/min) was higher after amlodipine than after perindopril (CLi 19.1 +/- 2.1 v 16.5 +/- 1.7, P =0.036 and CUr 7.0 +/- 0.6 v 5.9 +/- 0.4, P = 0.007). As a consequence, after amlodipine, distal absolute reabsorption of sodium was higher (DARNa 2.57 +/- 0.28 v 2.19 +/- 0.22 mEq/min, P = 0.027) and serum uric acid was lower (5.9 +/- 0.3 v 6.7 +/- 0.4 mg/dL, P = 0.001) in comparison with perindopril. In cyclosporine-treated renal allograft hypertensives, amlodipine and perindopril lower blood pressure equally and reduce RVR to the same extent. Overall sodium excretion is not affected by either agent. Urate clearance is higher and serum uric acid lower on amlodipine as compared with perindopril.