Vitamin K supplementation and arterial calcification in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), are prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated whether vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients. METHODS: In a 2-year, double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomized to vitamin K [menaquinone-7 (MK-7), 360 µg daily] or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aortic calcification (AAC) were used to assess arterial calcification. RESULTS: Thirty-seven participants completed Year 1, and 21 completed Year 2. At Year 2, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo {mean dp-ucMGP difference: -1380 pmol/L [95% confidence interval (CI) -2029 to -730]}. There was no significant effect of vitamin K supplementation on cfPWV [mean difference at Year 2: 1.2 m/s (95% CI -0.1 to 2.4)]. CAC Agatston score increased significantly in vitamin K supplemented participants, but was not significantly different from placebo [mean difference at Year 2: 664 (95% CI -554 to 1881)]. AAC scores increased in both groups, significantly so within the placebo group at Year 1, but with no significant between-group differences. CONCLUSIONS: Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients.

Brain swelling during dialysis: A randomized trial comparing low-flux hemodialysis with pre-dilution hemodiafiltration
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Osmotic changes in plasma are assumed to cause cerebral swelling in hemodialysis patients. We investigated the acute effect of low-flux hemodialysis (HD) (removal of small molecules) and pre-dilution hemodiafiltration (pre-HDF) (additional removal of larger molecules) on cerebral compartment volumes using quantitative magnetic resonance imaging (MRI) in chronic uremic patients. Twelve patients underwent a session of HD and pre-HDF in a randomized crossover study with equal ultrafiltration. MRI was performed immediately before and after dialysis. A linear correlation was found between changes in gray matter and plasma osmolarity (HD: r2 = 0.83; HDF: r2 = 0.73) but not between changes in white matter volume and plasma osmolarity (HD: r2 = 0.02; HDF: r2 = 0.004). Total brain volume increased by 1.8 ± 1.7% (18.7 ± 17.4 mL) (mean ± SD) during HD and 2.0 ± 0.9% (22.3 ± 10.7 mL) during pre-HDF. Gray matter volume increased: HD 3.8% (from -3.6 to 9.7) and pre-HDF 4.2% (from -2.8 to 14.3). White matter volume did not change significantly. Reduction ratio of urea (molecular weight (MW) 0.06 kDa) (HD: 68%; pre-HDF: 69.7%) and ß2-microglobulin (MW 11.7 kDa) (HD: -13.7%; pre-HDF: 67.2%) separated the treatments. This study showed that HD and pre-HDF caused equal acute cerebral swelling of the grey matter. This appeared to be driven by small solute change in plasma interacting linearly with gray matter volume regardless of additional removal of larger molecules or ultrafiltration.
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Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study).

BACKGROUND AND AIM: Little is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan. DESIGN: Randomized, double-blind, placebo-controlled, one-year intervention trial. SETTING AND PARTICIPANTS: Eighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year. INTERVENTION: Irbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients. OUTCOMES AND MEASUREMENTS: Cardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension. RESULTS: At baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on baseline parameters. CONCLUSION: Use of the ARB irbesartan as an add-on to other antihypertensive therapy did not significantly affect intradialytic hemodynamics, neither in short nor long-term, and no significant increase in hypotensive episodes was seen. TRIAL REGISTRATION: Clinicaltrials.gov NCT00791830.

Angiotensin blockade and progressive loss of kidney function in hemodialysis patients: a randomized controlled trial.

BACKGROUND: Glomerular filtration rate (GFR) declines during long-term dialysis treatment. In peritoneal dialysis, blockade of the renin-angiotensin-aldosterone system reduces GFR decline. Observational studies suggest that similar treatment may preserve kidney function in hemodialysis (HD). STUDY DESIGN: A multicenter, randomized, placebo-controlled, double-blinded trial, with 1-year follow-up. SETTING & PARTICIPANTS: Adult HD patients with urine output >300mL/24h, HD vintage less than 1 year, and cardiac ejection fraction >30%. Patients were included from 6 HD centers. INTERVENTION: Patients were randomly assigned to placebo or the angiotensin II receptor blocker irbesartan, 300mg daily. Target systolic blood pressure (BP) was 140mm Hg. OUTCOMES & MEASUREMENTS: Primary outcomes were change in GFR measured as the mean of creatinine and urea renal clearance together with urine volume. Secondary outcomes were change in albuminuria, renin-angiotensin II-aldosterone hormone plasma levels, and time to anuria. RESULTS: Of 82 patients randomly assigned (41 patients in each group), 56 completed 1 year of treatment. The placebo and irbesartan groups were comparable at baseline in terms of sex balance (26 vs 30 men), mean age (62 vs 61 years), median HD vintage (137 vs 148 days), mean HD time (10 vs 11h/wk), median urine volume (1.19 vs 1.26L/d), and mean GFR (4.8 vs 5.7mL/min/1.73m(2)). The target BP level was reached in both groups and BP did not differ significantly between groups over time. Adverse-event rates were similar. GFR declined by a mean of 1.7 (95% CI, 1.2-2.3) and 1.8 (95% CI, 1.1-2.4) mL/min/1.73m(2) per year in the placebo and irbesartan groups, respectively. Mean difference (baseline values minus value at 12 months) between groups was -0.0 (95% CI, -0.8 to 0.8). In each group, 4 patients became anuric. LIMITATIONS: GFR decline rates were lower than expected, reducing the power. CONCLUSIONS: At equal BP levels, we found that irbesartan treatment did not affect the decline in GFR or urine volume significantly during 1 year of treatment in HD patients. Irbesartan treatment was used safely in the studied population.

Renal and cardiovascular effects of irbesartan in dialysis patients--a randomized controlled trial protocol (SAFIR study).

INTRODUCTION: Cardiovascular (CV) events are a major cause of morbidity and mortality in haemodialysis (HD) patients. Hypertension, increased arterial stiffness and left ventricular (LV) hypertrophy are highly prevalent and are often poorly controlled. Volume overload is an important factor and survival could be improved by treatment strategies that preserve residual renal function (RRF), reduce blood pressure, and decrease arterial stiffness and LV hypertrophy. Angiotensin II receptor blocker (ARB) treatment can prevent CV events in patients with hypertension and heart failure. However, few data exist in patients with chronic renal failure and it is not known whether ARB treatment improves clinical outcome in HD patients. MATERIAL AND METHODS: This is a randomized, controlled and double-blinded intervention study. A total of 82 HD patients from six Danish HD centres will be treated for a year with an ARB (irbesartan) or placebo. The inclusion criteria are urine output > 300 ml/day, dialysis vintage < 1 year and LV ejection fraction > 30%. The primary outcomes are change in RRF, LV hypertrophy, arterial stiffness and intra-dialytic haemodynamics. CONCLUSION: If ARB-treatment improves RRF and intermediate CV endpoints in a group of newly started HD patients, it may improve the survival for this high risk population. FUNDING: The trial is investigator-initiated, investigator-driven and supported by the Danish Agency for Science, Technology and Innovation and several private foundations.

Endogenous markers for estimation of renal function in peritoneal dialysis patients.

OBJECTIVE: This method comparison study, conducted at the peritoneal dialysis (PD) outpatient clinic of the Department of Renal Medicine, Aarhus University Hospital, Denmark, set out to evaluate the accuracy and reproducibility of methods for estimating glomerular filtration rate (GFR) based on endogenous markers in PD patients. PATIENTS: The 12 consecutive patients included in the study were examined twice while in a stable condition. All patients finished the study. Inclusion criteria were age 18 years or older, ability to collect 24-hour urine, and urine production greater than 300 mL in 24 hours. MAIN OUTCOME MEASURES: The methods for estimating GFR using endogenous markers included the average of urinary clearances of creatinine and urea [U-Cl(crea-urea)] and two equations using the serum concentration of cystatin C [eGFR(CysC)]. The resulting GFR estimates were compared with those obtained using urinary and corrected plasma clearances of (51)Cr-EDTA [U-Cl(EDTA) and cP-Cl(EDTA)], the corrected plasma clearance being plasma clearance minus dialysate clearance. RESULTS: Compared with the U-Cl(EDTA), the U-Cl(crea-urea) GFR estimate was 12% higher [95% confidence limits (CL): 3%, 21%]. Although significantly different (p = 0.01), the latter two methods showed the best agreement. The estimates obtained using the eGFR(CysC) methods were skewed from y = x compared with the estimates obtained using other methods, indicating strong bias, probably because of extrarenal elimination. The cP-Cl(EDTA) estimate was 34% (95% CL: 26%, 42%), higher than the U-Cl(EDTA) estimate (p < 0.001). The reproducibility (coefficients of variation) differed significantly between methods: cP-Cl(EDTA), 7%; U-Cl(EDTA), 14%; U-Cl(crea-urea), 18%; and both eGFR(CysC) methods, 3%. CONCLUSIONS: In PD patients, GFR may be estimated as U-Cl(crea-urea) when complete urine collection is performed, taking into account an overestimation of approximately 12%. The available equations for eGFR(CysC) seem to be inaccurate; further development and validation is desirable. Omitting the eGFR(CysC) methods, cP-Cl(EDTA) was the most reproducible method and might be useful in certain situations.

Preserving residual renal function in dialysis patients: an update on evidence to assist clinical decision making.

It has been documented that preservation of residual renal function in dialysis patients improves quality of life as well as survival. Clinical trials on strategies to preserve residual renal function are clearly lacking. While waiting for more results from clinical trials, patients will benefit from clinicians being aware of available knowledge. The aim of this review was to offer an update on current evidence assisting doctors in clinical practice.

[Systemic capillary leak syndrome]. / Systemisk vaskulaert laekage-syndrom.

A previously healthy 51 year-old man developed various degrees of hypovolaemia 6 times between May 2003 and November 2006. The patient was thoroughly examined for causal agents without any findings (e.g. infection, allergy, tumour, angio-oedema). Each time the patient had symptoms (nausea, diarrhoea, fatigue, oedema) and biochemistry (hypoalbuminaemia, haemoconcentration, monoclonal gammopathia) which indicated systemic capillary leak syndrome.