Long-Term Effects of High-Protein Diets on Renal Function.

Chronic kidney disease (CKD) has a prevalence of approximately 13% and is most frequently caused by diabetes and hypertension. In population studies, CKD etiology is often uncertain. Some experimental and observational human studies have suggested that high-protein intake may increase CKD progression and even cause CKD in healthy people. The protein source may be important. Daily red meat consumption over years may increase CKD risk, whereas white meat and dairy proteins appear to have no such effect, and fruit and vegetable proteins may be renal protective. Few randomized trials exist with an observation time greater than 6 months, and most of these were conducted in patients with preexisting diseases that dispose to CKD. Results conflict and do not allow any conclusion about kidney-damaging effects of long-term, high-protein intake. Until additional data become available, present knowledge seems to substantiate a concern. Screening for CKD should be considered before and during long-term, high-protein intake.

Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease.

Low-birth-weight individuals have a higher risk of hypertension and end-stage renal disease (ESRD). Here we investigated whether low birth weight was associated with earlier onset of ESRD in patients with autosomal dominant polycystic kidney disease (ADPKD). In collaboration with all Danish departments of nephrology, 307 of 357 patients with ADPKD and ESRD born and living in Denmark were recruited. We were able to analyze complete data of 284 patients obtained from both hospital medical files and midwife protocols in the Danish State Archives. Multivariable linear regression adjusted for birth weight, adult height, mean arterial pressure, gender, birth decade, and type of antihypertensive treatment showed that for every kilogram increase in birth weight, the age at onset of ESRD significantly increased by 1.7 years. Male gender and increased mean arterial pressure were both associated with earlier onset of ESRD. Patients treated with renin-angiotensin system blockade or calcium channel blockers during follow-up had significantly later onset of ESRD by 4.3 years and 2.1 years, respectively. Treatment with beta-blockade or a diuretic was not associated with the age at onset of ESRD. Thus, low birth weight may contribute to considerable phenotypic variability in the progression of renal disease between individuals with ADPKD.

Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney disease and end-stage renal disease.

BACKGROUND: With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31 December 2008. METHODS: Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular, cerebrovascular, infection, other and unknown. RESULTS: Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios (HR) 0.65, P=0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P=0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval, the prevalence of cancer increased by 35% (P=0.0002) while the cancer incidence was stable. CONCLUSIONS: In Danish patients with ADPKD and ESRD, there was a significant reduction in cardiovascular and cerebrovascular deaths from 1993 to 2008. The prevalence of cancer increased without significant change in cancer incidence or deaths from cancer.

Ambulatory arterial stiffness index in chronic kidney disease stage 2-5. Reproducibility and relationship with pulse wave parameters and kidney function.

BACKGROUND: Arterial stiffness contributes to the increased cardiovascular risk in patients with chronic kidney disease (CKD). Reproducible and easily obtainable indices of arterial stiffness are needed in order to monitor therapeutic strategies. The ambulatory arterial stiffness index (AASI) has been proposed as such a marker. The present study investigated the day-to-day reproducibility of AASI in CKD stage 2-5 and its relationship with other markers of arterial stiffness as well as with kidney function. METHODS: Eighty-three patients (29% female, median age 62 years) were studied by 24 h ambulatory blood pressure monitoring (ABPM), aortic pulse wave velocity (aPWV), augmentation index (AIx) and estimated glomerular filtration rate (eGFR) at a median interval of 7 days. Individual AASIs were calculated from 24 h ABPMs as 1 minus the regression slope of diastolic blood pressure over systolic blood pressure. RESULTS: Mean AASI, aPWV, AIx and 24 h pulse pressure (PP) were similar on repeated measurements. The intraclass correlation coefficients were between 72% and 78% for AASI calculated by three different methods, 87% for aPWV, 88% for AIx, and 96% for 24 h PP. The correlation coefficients between AASI and aPWV were from 0.48 to 0.53; with AIx it was between 0.19 and 0.34. After adjustment for covariates none of the arterial stiffness indices were significantly correlated to eGFR. CONCLUSIONS: In patients with CKD stage 2-5 AASI had a moderate, but acceptable reproducibility. The correlation between AASI and aPWV was good whilst the correlation between AASI and AIx was considerably lower. There was no significant correlation between AASI and eGFR.

Estimating glomerular filtration rate using the new CKD-EPI equation and other equations in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: No studies have compared the performance of equations for estimating glomerular filtration rate (GFR) in patients with autosomal dominant polycystic kidney disease (ADPKD), where the declining GFR typically is followed for many years or even decades. This was the purpose of the present investigation. METHODS: 101 ADPKD patients with chronic kidney disease stages 1-5 were recruited and GFR was measured with the (51)Cr-EDTA clearance method, and estimated with the Modification of Diet in Renal Disease Study (MDRD) equation with 4 variables, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault equation adjusted for body surface area and the MDRD equation with cystatin C. Performance was evaluated by mean bias, precision and accuracy. RESULTS: The MDRD equation with cystatin C had 97% of GFR estimates within 30% of measured GFR (accuracy). Both the CKD-EPI and Cockcroft-Gault equations had an accuracy of 90% whereas the MDRD equation had an accuracy of 83%. This difference of accuracy was especially marked with GFR >60 ml/min/1.73 m(2). CONCLUSION: For estimating GFR in ADPKD patients the MDRD equation with cystatin C incorporated had the best performance. The CKD-EPI or the Cockcroft-Gault equations showed better performance compared to the 4-variable MDRD equation.

Feasibility of combined treatment with enalapril and candesartan in advanced chronic kidney disease.

BACKGROUND: Dual blockade of the renin-angiotensin system (RAS) has been claimed to have a specific renal protective effect in chronic kidney disease (CKD). The present short-term study reports on the feasibility of dual blockade in a consecutive group of patients with CKD stage 3-5. METHODS: Forty-seven CKD patients, mean age 59 years, with mean estimated glomerular filtration rate (GFR) 26 ml/min/1.73 m(2) (range 13-49) and blood pressure (BP) 133/78 mmHg, were block randomized in an open study to 16 weeks of monotherapy with increasing doses of RAS blockade aiming at enalapril 20 mg o.d. or candesartan 16 mg o.d. Thereafter, the complementary drug was added in incremental doses over a period of 5 weeks aiming at combined enalapril 20 mg and candesartan 16 mg for 3 weeks. Seventy-five percent of the patients were known to be RAS blockade tolerant. Blood samples and BP were measured every 2-3 weeks. Doses of study medication were reduced in case of hyperkalemia >5.5 mmol/l, a sustained rise in p-creatinine >30% or symptomatic hypotension. RESULTS: Twenty-one patients (45%) did not tolerate dual blockade in aimed dosages due to unacceptable p-creatinine increase (n = 12, including two study withdrawals), hypotension (n = 6), general discomfort (n = 2) or unmanageable hyperkalemia (n = 1). Hyperkalemia >5.5 mmol/l was seen in seven patients (15%). The reduced-dose group had baseline lower eGFR and diastolic BP. CONCLUSIONS: Forty-five percent of CKD stage 3-5 patients did not tolerate dual RAS blockade with 20 mg enalapril and 16 mg candesartan daily, primarily due to loss of renal function or hypotension. Hyperkalemia could be managed in most patients. Caution is recommended when giving this treatment to patients with advanced CKD.

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin-angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.

Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) with normal renal function have endothelial dysfunction and decreased nitric oxide synthase activity in subcutaneous resistance vessels. We investigated asymmetric dimethylarginine (ADMA) as a marker of an inhibitor of nitric oxide synthase and the lipid peroxidation product 13-hydroxyoctadecadienoic acid (HODE) as a marker of oxidative stress in patients with early ADPKD. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Patients with early ADPKD (n = 27) and age-matched volunteers (n = 30) from a single academic medical center. FACTOR: Patients with ADPKD versus controls. OUTCOMES & MEASUREMENT: Plasma (P) levels, urinary (U) excretion, and urinary clearance (C) of ADMA and HODE. Because of multiple comparisons, P for significance is considered less than 0.0167. RESULTS: Patients with ADPKD had significantly increased P(ADMA) levels (604 +/- 131 versus 391 +/- 67 nmol/L; P < 0.01) and U(ADMA) excretion (22 +/- 4 versus 15.2 +/- 3 nmol/micromol creatinine; P = 0.01), decreased C(ADMA) (25 +/- 3 versus 33 +/- 4 mL/min; P = 0.01), increased P(HODE) levels (316 +/- 64 versus 230 +/- 38 nmol/L; P < 0.01) and U(HODE) excretion (467 +/- 67 versus 316 +/- 40 nmol/micromol creatinine; P < 0.01), and decreased plasma nitrite plus nitrate (P(NOx)) levels (21 +/- 5 versus 32 +/- 6 micromol/L; P < 0.01) and U(NOx) excretion (59 +/- 7 versus 138 +/- 27 micromol/micromol creatinine; P < 0.01). LIMITATIONS: Small sample size, cross-sectional nature of study, and limited number of markers of oxidative stress. CONCLUSIONS: P(ADMA) and P(HODE) levels are increased in patients with early ADPKD. Increased P(ADMA) level is related to decreased C(ADMA) and is accompanied by oxidative stress.

Longitudinal observations on circadian blood pressure variation in chronic kidney disease stages 3-5.

BACKGROUND: It has been suggested that status as a 'non-dipper' determined from 24-h blood pressure (BP) recordings is associated with increased risk of end-organ damage but little is known about the consistency of dipper status in renal patients. The present post hoc analysis evaluated dipper/non-dipper status prospectively in a study on dosage of enalapril in progressive chronic kidney disease (CKD) stages 3-5. METHODS: In 34 patients, 24-h ambulatory BP (A&D TM2421) was measured at baseline and every 4 months for 1 year or until the need for renal replacement therapy. For each BP recording patients were classified as dippers or non-dippers based on the presence or absence of a nighttime reduction in both systolic and diastolic BP > 10%. Antihypertensive treatment aimed at an office BP < 120/80 mmHg. GFR was measured by the plasma clearance of (51)Cr-EDTA and albuminuria was determined from 24-h collections. RESULTS: A total of 125 24-h BP recordings were made. Ten patients were constant dippers and five were constant non-dippers throughout the study whereas nineteen patients changed dipping status apparently at random. When analysing pairs of sequential recordings in the individual patient, non-dipper and dipper status remained unaltered in 25 (27%) and 32 (35%) of comparisons, respectively, whereas it was inconsistent in 34 (38%) of cases. No correlation between dipper status and GFR, decline in renal function, degree of albuminuria or BP level could be demonstrated. CONCLUSIONS: The consistency of circadian BP variation seems to be poor in CKD stages 3-5 and single measurements of 24-h ambulatory BP are therefore probably inadequate for the evaluation of dipping status.

Reproducibility of pulse-wave analysis and pulse-wave velocity determination in chronic kidney disease.

BACKGROUND: Indices of central arterial stiffness, derived by use of applanation tonometry, have shown to be strong independent predictors of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). The objective of this study was to evaluate the intra- and inter-observer and day-to-day reproducibility of pulse-wave analysis (PWA) and pulse-wave velocity (PWV) in pre-dialysis patients with CKD stages 3-5 using applanation tonometry with the SphygmoCor software and hardware. METHODS: Double recordings of the radial pressure waveform and the aortic and brachial PWV were performed under standardized conditions in 19 CKD patients with a mean GFR 25.3 ml/min/1.73 m(2) (range 9.9-42.2) by two trained observers and repeated by one of the observers within a week. RESULTS: The mean inter-observer and day-to-day differences (+/-2 SD) for the augmentation index (AIx) were 0.9 +/- 15.8% and 2.6 +/- 11.2%, for subendocardial viability ratio (SEVR) -0.9 +/- 15.5% and -0.4 +/- 24.7%, for aortic pulse pressure (PP) 1.4 +/- 13.3 mmHg and 0.3 +/- 20.9 mmHg and for aortic PWV 0.3 +/- 3.2 m/s and -0.7 +/- 1.9 m/s, respectively. Intra-observer differences were calculated for each of three sets of double measurements and showed good reproducibility as well. Calculations on sample size needed in a clinical trial showed a limited number of patients needed in a clinical study over time. CONCLUSIONS: PWA and PWV based on applanation tonometry using the SphygmoCor software and hardware are highly reproducible in pre-dialysis patients with CKD with the day-to-day variation being in accordance with the intra- and inter-observer variation. Thus, applanation tonometry using the SphygmoCor system is a simple, non-invasive method to assess central haemodynamics in clinical trials in patients with pre-dialysis CKD with only a limited number of patients needed to detect significant differences.

Pulse wave reflection is amplified in normotensive patients with autosomal-dominant polycystic kidney disease and normal renal function.

BACKGROUND: In young ADPKD patients, we have previously found an impaired endothelium-dependent relaxation in small resistance vessels but a normal flow-mediated dilatation of the brachial artery. The present study investigated arterial stiffness in early ADPKD by pulse-wave analysis (PWA) and measurement of pulse-wave velocity (PWV). METHODS: 18 young normotensive ADPKD patients with normal renal function and 18 controls were studied by applanation tonometry with the SphygmoCor equipment. Parameters included an estimate of aortic blood pressure, augmentation index (AIx), AIx standardized to heart rate 75 (AIx(HR75)) and PWV. Glomerular filtration rate (GFR) was measured by the 51Cr-EDTA plasma clearance method. Statistical comparisons were made with t tests and multiple linear regression analysis. RESULTS: GFR was the same in the two groups. Brachial diastolic blood pressure was slightly but significantly higher in ADPKD patients than in controls (81 +/- 9 vs. 73 +/- 9 mm Hg, p < 0.05). No significant difference was present in brachial systolic blood pressure. AIx was significantly higher in ADPKD than in controls: 21.6 +/- 11.3 vs. 11.4 +/- 11.2%, p < 0.02. AIx(HR75) and estimated aortic systolic and diastolic blood pressure was likewise significantly higher in ADPKD than in controls. Multiple linear regression analysis showed AIx and AIx(HR75) to be independently correlated to group (ADPKD/control), p < 0.02 and p < 0.05, respectively. No difference was found between PWV in the two groups. CONCLUSION: Reflection of the pulse wave was amplified in young normotensive ADPKD patients, demonstrating early pathology in the arterial system.

The expression and activity of renal nitric oxide synthase and circulating nitric oxide in polycystic kidney disease rats.

Nitric oxide (NO) influences tubular fluid and electrolyte transport, and hence possibly also fluid accumulation in renal cysts. The expression and activity of intrarenal constitutive NO synthase (cNOS) [neuronal NOS, nNOS and endothelial NOS, eNOS] and inducible NOS (iNOS) and plasma nitrite/nitrate (PNOx) concentration were assessed in homozygous Han:SPRD polycystic kidney disease (PKD) rats (cy/cy), heterozygous Han:SPRD PKD rats (cy/+), homozygous normal Han:SPRD littermates (+/+) and Sprague Dawley rats (sd). The results showed: 1) nNOS expression was decreased in proximal tubules and thick ascending limbs of the loop of Henle in cy/cy and cy/+ rats compared to +/+ and sd rats (p<0.05). nNOS was weakly expressed in the epithelium of small cysts and unexpressed in epithelium of large cysts. 2) iNOS expression was increased in proximal tubular epithelial cells in cy/+ rats compared to +/+ rats and sd rats (p<0.01). iNOS expression in cyst epithelium was decreased in cy/+ rats (p<0.05) and absent in cy/cy rats. 3) eNOS expression was similar in the endothelium of intrarenal arteries in all groups. 4) The activity of renal cNOS was decreased in cy/cy and cy/+ rats; the activity of iNOS was decreased only in cy/cy rats, with no significant difference among the other three groups. 5) PNOx concentration was higher in cy/cy rats than in the other three groups, and correlated positively with plasma creatinine and urea. In conclusion, NOS expression and activity decreased as cysts developed, suggesting that NO downregulation is involved in the pathogenesis of PKD.

Nephrectomy and peritoneal dialysis eliminates circulating renin and controls uraemia in the rat.

OBJECTIVE: The aim of the present study was to develop a rat model for in vivo studies of the local effects of the renin-angiotensin system (RAS) following elimination of circulating renin. METHODS: Sprague Dawley rats were bilaterally nephrectomised and had a peritoneal dialysis catheter implanted. The rats were maintained on dialysis continuously for 48 hours, using Dianeal PD4 3.86% glucose dialysis solution. The peritoneal catheter and an automated system for dialysate exchange were made in our laboratory. A sham nephrectomised control group of rats was also dialysed. RESULTS: Nephrectomised and sham-operated rats remained active and in good general condition during peritoneal dialysis. At 48 hours, in nephrectomised, dialysed rats, peritoneal urea clearance was 4.14+/-0.52 ml/hour, plasma urea was 40.0+/-7.7 mmol/L, plasma creatinine was 0.423+/- 0.070 mmol/L and plasma renin was below the limit of detection. CONCLUSIONS: In conclusion, it was possible to sustain bilaterally-nephrectomised rats on continuous peritoneal dialysis for 48 hours, pending elimination of renin from the circulation. The nephrectomised dialysed rat model should be useful for investigation of the physiological effects of the circulating versus the local RAS.

[Microalbuminuria is associated with a fourfold increased risk of ischemic heart disease among hypertensive patients]. / Mikroalbuminuri er associeret med firedobbelt risiko for iskaemisk hjertesygdom blandt hypertensive.

INTRODUCTION: The urinary excretion of albumin is positively correlated to the presence of ischaemic heart disease and atherosclerotic risk factors in subjects with arterial hypertension. The aim of this population-based, follow-up study of hypertensive patients was to assess the predictive impact of a slightly elevated urinary excretion of albumin, i.e. microalbuminuria, on ischaemic heart disease. MATERIAL AND METHODS: In 1983-1984, blood pressure, the albumin/creatinine concentration ratio in a morning urine sample, total and HDL cholesterol in plasma, body mass index, and smoking habits were measured in a population of 2085 men and women aged 30-60 years. Exclusion criteria were ischaemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated hypertension or borderline hypertension (a systolic blood pressure above 140 mmHg and/or a diastolic blood pressure above 90 mmHg) were found in 204 of the participants, who were followed up until 1993 with respect to the development of ischaemic heart disease through the Danish Hospital Register and Death Certificate Register. RESULTS: Over 1978 person-years, 18 participants (9%) developed ischaemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile in the hypertensive population under study (1.07 mg/mmol), was the strongest predictor of ischaemic heart disease with a relative risk (95% confidence interval) of 4.2 (1.5-11.9) (p = 0.006). When adjusted for all other variables, including age and sex, the relative risk was 3.5 (1.0-12.1) (p = 0.05). DISCUSSION: Microalbuminuria is associated with a fourfold increased risk of ischaemic heart disease in subjects with untreated hypertension or borderline hypertension. Urinary excretion of albumin should perhaps be monitored regularly in the hypertension clinic, and rigorous control of blood pressure and other modifiable atherosclerotic risk factors is to be recommended in hypertensive patients with microalbuminuria.

Bradykinin antagonist counteracts the acute effect of both angiotensin-converting enzyme inhibition and of angiotensin receptor blockade on the lower limit of autoregulation of cerebral blood flow.

The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination of enalaprilat and Hoe 140, and a combination of candesartan and Hoe 140. In the control group, the lower limit of CBF autoregulation was 54±9 mm Hg (mean±s.d.), with enalaprilat it was 46±6, with candesartan 39±8, with Hoe 140 53±6, with enalaprilat/Hoe 140 52±6, and with candesartan/Hoe 140 50±7. Both enalaprilat and candesartan lowered the lower limit of autoregulation of CBF significantly. The bradykinin antagonist abolished not only the effect of the ACE inhibitor but surprisingly also the effect of the ARB on the lower limit of CBF autoregulation, the latter suggesting an effect on intravascular bradykinin.

[Secondary prevention of stroke with effective antihypertensive treatment]. / Sekundær prævention af apopleksi med effektiv antihypertensiv behandling.

In this meta-analysis, four of five placebo-controlled studies showed that antihypertensive treatment prevented stroke recurrence, most markedly in a study with a combination of an angiotensin-converting enzyme inhibitor and a diuretic. Studies with beta-blockers were not included. Two head-to-head comparisons of a calcium antagonist and an angiotensin receptor antagonist showed no clear difference. Danish studies show that approximately 60% of patients with stroke are hypertensive one year after discharge from hospital. Antihypertensive treatment should be started or intensified in such patients.

Eplerenone attenuates pulse wave reflection in chronic kidney disease stage 3-4--a randomized controlled study.

BACKGROUND: Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity associated with increased arterial stiffness. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. It was hypothesized that aldosterone receptor inhibition with eplerenone could reduce arterial stiffness in CKD stage 3-4. STUDY DESIGN: The design was randomized, open, parallel group. Measurements of arterial stiffness markers were undertaken at weeks 1 and 24. INTERVENTION: 24 weeks of add-on treatment with 25-50 mg eplerenone or standard medication. OUTCOMES: Primary outcome parameter was carotid-femoral pulse wave velocity (cfPWV). Secondary outcomes were augmentation index (AIx), ambulatory arterial stiffness index (AASI) and urinary albumin excretion. RESULTS: Fifty-four CKD patients (mean eGFR 36 mL/min/1.73 m(2), SD 11) were randomized. Forty-six patients completed the trial. The mean difference in cfPWV changes between groups was 0.1 m/s (95%CI: -1.0, 1.3), P = 0.8. The mean difference in AIx changes between groups was 4.4% (0.1, 8.6), P = 0.04. AASI was unchanged in both groups. The ratio of change in urinary albumin excretion in the eplerenone group compared to the control was 0.61 (0.37, 1.01), P = 0.05. Four patients were withdrawn from the eplerenone group including three because of possible side effects; one was withdrawn from the control group. Mild hyperkalemia was seen on three occasions and was easily managed. LIMITATIONS: The full planned number of patients was not attained. The duration of the trial may have been too short to obtain full effect of eplerenone on the arteries. CONCLUSIONS: Add-on treatment with eplerenone in CKD stage 3-4 did not significantly reduce cfPWV. There may be beneficial vascular effects leading to attenuated pulse wave reflection. Treatment was well-tolerated. TRIAL REGISTRATION: ClinicalTrials.govNCT01100203.