Optimal current frequency for the detection of changes in extracellular water in patients on hemodialysis by measurement of total body electrical resistance.

BACKGROUND & AIMS: Measurement of total body electrical resistance (TBER) to an alternating current is useful to monitor extracellular water (ECW) in patients on hemodialysis (HD). Which current frequency is preferable is subject of ongoing debate. The aim of this study was to quantify the implications of TBER measurements at current frequencies ranging from 0 to 1000 kHz for ECW monitoring in patients on HD. METHODS: Bioimpedance spectroscopy measurements were performed in 39 patients on HD using the Body Composition Monitor (BCM, Fresenius Medical Care). TBER data at 5, 50, 200, 500, and 1000 kHz were compared with the extrapolated TBER at 0 kHz (TBER0) assessed by Cole-Cole analysis. Sensitivity of each TBER configuration was evaluated at individual level, by assessment of the smallest ultrafiltration (UF) volume that induced a significant change in TBER, i.e. a change in TBER ≥ 2.7%. RESULTS: TBER precision was very high for all frequencies, with coefficients of variation of 0.25%-0.28%. Baseline TBER decreased with increasing current frequency. TBER was 2.9% lower at 5 kHz (P < 0.001), 11.6% lower at 50 kHz, and up to 22.0% lower at 1000 kHz. This pattern is attributed to a progressive increase in intracellular current conduction at higher frequencies. Sensitivity to volume changes induced by UF also decreased with increasing current frequency. At 0 and 5 kHz, an UF volume ≤ 0.5 L was sufficient to induce a significant increase in TBER in 87% of patients. This decreased to 69% at higher frequencies. CONCLUSION: ECW monitoring by TBER requires measurement at 5 kHz or less to ensure optimal performance.

Sensitivity of total body electrical resistance measurements in detecting extracellular volume expansion induced by infusion of NaCl 0.9.

BACKGROUND: Fluid balance management in hospitalized patients is hampered by the limited sensitivity of currently available tools. The aim of this study was to assess the sensitivity of total body electrical resistance (TBER) measurements for the detection of extracellular volume (ECV) expansion. METHODS: TBER and plasma resistivity (ρplasma) were measured during a 4-h infusion of NaCl 0.9% at a rate of 500 mL/h in 23 patients undergoing a diagnostic saline infusion test for primary hyperaldosteronism. Extracellular fluid gain (EFG) was defined as infusion volume minus urinary volume. RESULTS: Infusion of 2.0 L NaCl 0.9% was associated with a mean diuresis of 1.1 ± 0.5 L, an EFG of 0.9 ± 0.5 L, a decrease in ρplasma of 1.1 ± 0.7 Ω·cm or 1.7 ± 1.0% (P < 0.001), and a decline in TBER of 23.2 ± 10.9 Ω or 4.6 ± 2.2% (P < 0.001). At group level, infusion of 80 mL saline was sufficient to induce a statistically significant decline in mean TBER. At personal level, the decline in TBER was significant on 76% of occasions after an EFG of 0.5-0.75 L, and on all occasions after an EFG of 1.0 L or greater. CONCLUSION: Raw TBER data are very informative for the detection of ECV expansion induced by the infusion of NaCl 0.9%, with a sensitivity at a personal level that is relevant for clinical practice.

Assessment of Plasma Resistivity as a Surrogate for Extracellular Fluid Resistivity: Analytical Performance and Impact of Fluid Composition.

Bio-electrical impedance analysis (BIA) is frequently used to assess body composition in man. Its accuracy in patients is limited, possibly because the employed algorithms are based on the assumption that total body electrical resistance (TBER) is exclusively related to body water volume, and that variation in fluid composition and its effect on fluid resistivity can be ignored. This may introduce substantial calculation errors. The aim of this study was to develop an objective method to assess plasma resistivity (ρplasma) based on measurements by a conductivity probe, as a surrogate for extracellular fluid resistivity (ρe). Sample measurements were standardized at body temperature. Analytical variation was 0.6% within runs and 0.9% between runs. The critical difference, i.e. the smallest difference needed to consider changes within individuals significant, was 1.8% for measurements within runs and 4.3% for measurements between runs. The normal range was defined by a mean ± SD of 66.9 ± 1.8 Ω cm. Multiple regression demonstrated that ρplasma was inversely related to plasma sodium and chloride concentrations, and positively related to total protein (overall R2 = 0.92, p < 0.001). In conclusion, ρplasma measurements were sufficiently robust to be useful as a tool to examine and improve the validity of BIA in clinical settings.

Low-pressure pneumoperitoneum during laparoscopic donor nephrectomy to optimize live donors' comfort.

Nowadays, laparoscopic donor nephrectomy (LDN) has become the gold standard to procure live donor kidneys. As the relationship between donor and recipient loosens, it becomes of even greater importance to optimize safety and comfort of the surgical procedure. Low-pressure pneumoperitoneum has been shown to reduce pain scores after laparoscopic cholecystectomy. Live kidney donors may also benefit from the use of low pressure during LDN. To evaluate feasibility and efficacy to reduce post-operative pain, we performed a randomized blinded study. Twenty donors were randomly assigned to standard (14 mmHg) or low (7 mmHg) pressure during LDN. One conversion from low to standard pressure was indicated by protocol due to lack of progression. Intention-to-treat analysis showed that low pressure resulted in a significantly longer skin-to-skin time (149 ± 86 vs. 111 ± 19 min), higher urine output during pneumoperitoneum (23 ± 35 vs. 11 ± 20 mL/h), lower cumulative overall pain score after 72 h (9.4 ± 3.2 vs. 13.5 ± 4.5), lower deep intra-abdominal pain score (11 ± 3.3 vs. 7.5 ± 3.1), and a lower cumulative overall referred pain score (1.8 ± 1.9 vs. 4.2 ± 3). Donor serum creatinine levels, complications, and quality of life dimensions were not significantly different. Our data show that low-pressure pneumoperitoneum during LDN is feasible and may contribute to increase live donors' comfort during the early post-operative phase.

Poor early graft function impairs long-term outcome in living donor kidney transplantation.

BACKGROUND: Poor early graft function (EGF) after living donor kidney transplantation (LDKT) has been found to decrease rejection-free graft survival rates. However, its influence on long-term graft survival remains inconclusive. METHODS: Data were collected on 472 adult LDKTs performed between July 1996 and February 2010. Poor EGF was defined as the occurrence of delayed or slow graft function. Slow function was defined as serum creatinine above 3.0 mg/dL at postoperative day 5 without dialysis. RESULTS: The incidence of slow and delayed graft function was 9.3 and 4.4%, respectively. Recipient overweight, pretransplant dialysis and warm ischemia were identified as risk factors for the occurrence of poor EGF. The rejection-free survival was worse for poor EGF as compared to immediate graft function with an adjusted hazard ratio (HR) of 6.189 (95% CI 4.075-9.399; p < 0.001). Long-term graft survival was impaired in the poor EGF group with an adjusted HR of 4.206 (95% CI 1.839-9.621; p = 0.001). CONCLUSIONS: Poor EGF occurs in 13.7% of living donor kidney allograft recipients. Both, rejection-free and long-term graft survivals are significantly lower in patients with poor EGF as compared to patients with immediate graft function. These results underline the clinical relevance of poor EGF as phenomenon after LDKT.

Deleterious influence of prolonged warm ischemia in living donor kidney transplantation.

BACKGROUND: Recent studies investigating early graft function (EGF) after living donor kidney transplantation (LDKT) identified prolonged warm ischemia time (WIT) as a risk factor for the occurrence of poor EGF. The latter is associated with long-term graft loss; therefore the question arises whether prolonged WIT affects long-term outcomes in LDKT. METHODS: Data were collected on 472 consecutive adult LDKTs. Patients were divided according to the total WIT into 3 groups with short (<30 minutes), intermediate (30-45 minutes), or prolonged (>45 minutes) WIT. RESULTS: Of all patients, 193 (40.9%) experienced short, 249 (52.8%) intermediate, and 30 (6.4%) prolonged WIT. Prolonged WIT was a significant risk factor for the occurrence of poor EGF with an adjusted odds ratio of 4.252 (95% confidence interval [CI), 1.914 -9.447). Long-term graft survival was impaired in patients with prolonged WIT, with an adjusted hazard ratio of 3.163 (95% CI, 1.202-8.321). Multivariate analysis revealed determinants of prolonged WIT, including laparoscopic procurement, recipient overweight, right donor kidney, and multiple renal arteries. CONCLUSION: Prolonged WIT impairs long-term graft survival in LDKT. This finding underlines the need to develop strategies to avoid the occurrence of prolonged WIT in LDKT.

Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers?

In patients with proteinuric renal diseases the rate of progression of renal insufficiency is determined by the level of blood pressure and proteinuria. It has been demonstrated that strict blood pressure control with angiotensin converting enzyme (ACE)-inhibitors or beta-blockers, aimed at reaching values below 130/80 mm Hg, attenuates the deterioration of renal function. In general, the beneficial effects of these drugs are reflected in a parallel lowering of proteinuria. Calcium channel blockers are effective antihypertensive drugs, however, their safety in patients with proteinuric renal diseases and renal insufficiency may be questioned because of reported untoward effects on urinary protein excretion. The present review discusses the potential benefits and risks of calcium channel blockers (CCBs) in the treatment of patients with renal diseases. To this end we have evaluated the effects of these drugs in animal models of progressive renal injury. In these animal models adverse effects of CCBs have been reported which are attributed to an impairment of autoregulation. In patients with proteinuria, the dihydropyridine CCBs do not lower proteinuria despite a reduction of blood pressure. Studies on the effects on the course of renal function are limited, however, the available data do suggest that this class of CCBs may be less advantageous than other antihypertensive drugs, thus arguing against the use of these agents as first-line drugs in patients with proteinuric renal diseases. Information on the effects of the non-dihydropyridine CCBs is limited to a small number of studies in patients with diabetic renal disease. Although the data suggest that these classes of CCBs might be more beneficial, more studies are needed, particularly in patients with non-diabetic renal diseases, before founded conclusions can be reached.

Effects of low-dose nifedipine on urinary protein excretion rate in patients with renal disease.

BACKGROUND: The observation that proteinuria is an important determinant of the progression of renal disease has prompted numerous studies on the effects of antihypertensive agents on protein excretion. Reports on the proteinuric effects of calcium-channel blockers are quite controversial. It has been suggested that the short-acting dihydropyridine calcium-channel blocker nifedipine increases protein excretion by interference with tubular protein reabsorption. METHODS: In a randomized controlled trial 10 patients with renal disease and proteinuria were treated with a dose of 10 mg nifedipine o.d. (slow release formulation) for 1 week. The acute effects on renal and systemic haemodynamics and on urinary albumin, IgG, and beta2-microglobulin excretion were investigated during a clearance study in the supine position after the first dose. After 1 week of treatment urinary protein excretion rates were measured in 24-h urine samples collected in the ambulatory patient in consecutive fractions of 4-8 h during normal daily activities. RESULTS: After the first dose nifedipine lowered mean arterial blood pressure in the supine position by 7+/-1 mmHg (<0.01), attenuated proximal tubular sodium reabsorption (fractional excretion of sodium 3.48+/-0.49 vs 2.62+/-0.35% during control, P<0.02), but did not affect proximal tubular protein reabsorption (fractional urinary excretion of beta2-microglobulin 0.97+/-0.30 vs 0.98+/-0.32% during control, NS). The decrease in blood pressure was not accompanied by decreases in urinary albumin or IgG excretion rates. The selectivity index as well as GFR, RPF, and FF did not change. Continued treatment for 1 week with nifedipine did not influence 24-h protein excretion. However, we observed a rise of proteinuria during daily activities in the first 4 h after drug intake compared to the start of the study with the patients in supine position. During control measurements there was a slight increase in proteinuria. During nifedipine the increase in proteinuria was more marked and correlated with the selectivity index. CONCLUSIONS: (1) Nifedipine 10 mg orally did not impair tubular protein reabsorption. (2) Nifedipine had no immediate antiproteinuric effect despite the observed blood pressure reduction. (3) Nifedipine increased proteinuria in ambulatory urine collections. This latter observation might explain the seemingly different effects of dihydropyridine calcium-channel blockers as reported in previous studies.

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function.

1. The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function. 2. After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0 +/- 3.0, 11.1 +/- 3.0, 8.7 +/- 3.7 and 6.7 +/- 2.1 l h-1 (means +/- s.d.) in patients with creatinine clearances (CLcr) of > 100, 41-100, 21-40, and 8-20 ml min-1, respectively. .3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CLcr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CLcr < 40 ml min-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups. 4. This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.

Oedema formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention?

OBJECTIVE: To determine whether the common side effect of ankle oedema with arteriolar vasodilators such as the calcium entry blocker (CEB) nifedipine and the potassium channel opener (PCO) diazoxide is the direct result of peripheral vasodilation or merely a consequence of renal sodium retention. DESIGN: In 12 healthy sitting volunteers we studied for 3 h the effects of 20 mg nifedipine, 150 mg diazoxide intravenously, 25 mg captopril and placebo on oedema formation and sodium excretion. CONCLUSIONS: Foot swelling was determined with a new accurate device (coefficient of variation 0.30%), which uses Archimedes principle to measure water displacement induced by immersion of the foot. Blood pressures were recorded with a Hawksley random-zero sphygmomanometer. RESULTS: All of the active drugs decreased diastolic blood pressure (captopril by 9 +/- 2%, nifedipine by 4 +/- 3% and diazoxide by 2 +/- 2%, compared with an increase of 5 +/- 2% with placebo). Foot volume increased acutely after administration of nifedipine (by 2.6 +/- 0.4%), whereas it remained stable with placebo and the other drugs. Administration of captopril and nifedipine induced increases of fractional sodium excretion (by 20 +/- 9% and 40 +/- 20%, respectively) in contrast to the decreases with placebo and diazoxide (by 13 +/- 11% and 24 +/- 10%, respectively). Only administration of nifedipine induced significant, albeit small, increases in haemoglobin and serum albumin levels. CONCLUSIONS: Administration of nifedipine increased foot volume and natriuresis simultaneously, thereby supporting the hypothesis that development of ankle oedema with CEB is a local phenomenon at the site of vasodilation. The absence of a similar increase in foot volume with diazoxide administration should be interpreted with caution because of the rather minor effect of this dose of diazoxide on blood pressure. However, it could be indicative of a different mechanism of oedema formation with PCO.

Exogenous aldosterone antagonizes distal tubular effects of calcium entry blocker felodipine.

Calcium entry blockers, such as felodipine, increase natriuresis without increasing kaliuresis. Since these drugs acutely increase plasma renin activity without a concomitant change of aldosterone, inhibition of such stimulated aldosterone release might explain the absence of kaliuresis. In a randomized crossover study in 12 male volunteers, we compared the effects of simultaneously administered exogenous aldosterone and felodipine with the effects of either felodipine or aldosterone alone. Felodipine infusion decreased blood pressure, increased renal plasma flow, and induced natriuresis without kaliuresis. Aldosterone alone reduced sodium excretion and increased potassium excretion without influencing hemodynamics. Addition of aldosterone to felodipine attenuated its natriuretic effect and induced a kaliuresis, which clearly exceeded the rise of potassium excretion during aldosterone alone [delta% fractional excretion of K+ +42 +/- 12 with felodipine+aldosterone and +7 +/- 8% with aldosterone alone; means +/- SE, P < 0.02]. Our data suggest that felodipine-mediated inhibition of stimulated aldosterone release is essential for the absence of kaliuresis with felodipine. In addition, the pronounced kaliuresis with aldosterone during felodipine is in keeping with increased distal sodium delivery due to a proximal tubular action of felodipine.

Angiotensin converting enzyme inhibition does not prevent the natriuretic effect of felodipine.

The mechanism of natriuresis with calcium entry blockers such as felodipine is largely unexplained. As these drugs prevent sodium retention following exogenous angiotensin II, the natriuretic effect of felodipine might be due to a similar interaction with endogenous angiotensin II. In such a case, angiotensin converting enzyme inhibition with ramipril should prevent natriuresis with felodipine. We tested this hypothesis in a randomized, double-blind, crossover study in 12 male volunteers by comparing intravenous felodipine after 1 week of oral ramipril with felodipine after placebo and with solvent after ramipril. Ramipril pretreatment reduced ACE activity to 11 +/- 1%, lowered the blood pressure, and increased renal blood flow. However, ramipril pretreatment did not prevent the pronounced increase in natriuresis and diuresis with felodipine. Fractional sodium excretion only tended to increase less during felodipine after ramipril than during felodipine after placebo (absolute changes of + 1.2 +/- 0.2 and + 1.7 +/- 0.2%, respectively; p = 0.07). Ramipril did not influence the felodipine-mediated blood pressure reduction and renal vasodilation. In conclusion, ACE inhibition has no significant effect on the natriuretic and hemodynamic effects of felodipine, suggesting that mechanisms other than interaction with endogenous angiotensin II are involved in these effects of calcium entry blockers.

Angiotensin-converting enzyme inhibition and the combination of a beta blocker and a diuretic are equally effective in lowering proteinuria in patients with glomerulonephritis.

In this study we compared the antihypertensive and antiproteinuric efficacies of an angiotensin-converting enzyme inhibitor and of conventional treatment consisting of a beta blocker and a diuretic in 13 patients with biopsy-proven glomerulonephritis and a proteinuria of more than 2 g/24 h. Ten of these 13 patients were normotensive. None had diabetes mellitus. In a randomized cross-over design with two treatment periods of 6 weeks, each preceded by a washout period of 4 weeks, patients were treated with benazepril (20 mg o.d.) and the combination of metoprolol (200 mg o.d.) and chlorthalidone (25 mg o.d.). At the end of the treatment periods with benazepril or metoprolol/chlorthalidone mean arterial pressure was lowered to a similar degree by 7.4 (mean, 95% confidence interval 2.0-12.7) and 9.7 (5.7-13.7) mmHg respectively. Both treatment modalities caused similar reductions in proteinuria, being 3.4 g/24 h (mean, 95% confidence interval 2.1-4.8) on benazepril and 3.2 (1.2-5.1) g/24 h on metoprolol/chlorthalidone. Glomerular filtration rate and renal plasma flow were slightly less during metoprolol/chlorthalidone treatment. Subgroup analysis of normotensive patients gave similar results. In conclusion, in these patients with glomerular disease angiotensin-converting enzyme inhibition was not more effective than the conventional treatment with the combination of a beta blocker and a diuretic in reducing blood pressure and proteinuria. Both treatments reduced proteinuria not only in hypertensive, but also in normotensive patients.

Effects of nitrendipine and cilazapril on renal hemodynamics and albuminuria in hypertensive patients with chronic renal failure.

In 11 hypertensive patients with chronic renal failure we studied the short-term effects of the calcium antagonist nitrendipine, the angiotensin-converting enzyme inhibitor cilazapril, and the combination of both drugs on blood pressure, renal hemodynamics, and proteinuria in a randomized, double-blind, placebo-controlled way. After one week of treatment, blood pressure at 2-5 h after drug administration amounted to 159 +/- 5/101 +/- 3 mm Hg (means +/- SEM) during placebo. Nitrendipine, cilazapril, and the combination lowered mean arterial pressure by 1.4 +/- 1.6 (NS), 6.0 +/- 1.7 (p less than 0.10), and 10.3 +/- 2.1% (p less than 0.01), respectively. Glomerular filtration rate did not change. As compared to placebo, renal blood flow increased and renal vascular resistance decreased significantly during the combination. Filtration fraction amounted to 22.7 +/- 1.2% during placebo and was 22.0 +/- 1.4 (NS), 20.4 +/- 1.2 (p less than 0.01), and 20.5 +/- 1.4% (p less than 0.05) during nitrendipine, cilazapril, and the combination, respectively. During nitrendipine, albuminuria was slightly higher than during placebo: 0.86 +/- 0.39 vs. 0.58 +/- 0.25 mg/min (NS). During cilazapril alone and during the combination of both drugs, albuminuria was lower as compared to nitrendipine: 0.38 +/- 0.14 mg/min (p less than 0.01) and 0.44 +/- 0.18 mg/min (p less than 0.01), respectively. The data suggest that the combination of nitrendipine and cilazapril is an effective treatment in renal hypertension. In addition, cilazapril alone as well as the combination with nitrendipine reduced albuminuria, possibly by decreasing filtration fraction and/or reduction of blood pressure.

Antihypertensive effects of nitrendipine and cilazapril alone, and in combination in hypertensive patients with chronic renal failure.

1. It has been reported that calcium antagonists lower blood pressure more effectively in salt replete hypertensive patients with a low plasma renin activity (PRA), whereas angiotensin converting enzyme (ACE) inhibitors are more effective in salt depleted patients with a high level of PRA. An inverse relationship between the antihypertensive effects of these two groups of drugs might therefore be expected. 2. Since salt retention and inappropriately high levels of PRA are said to contribute to hypertension in patients with chronic renal failure (CRF), an additive antihypertensive effect with both drugs might also be expected in such patients. 3. To test these hypotheses, we investigated the acute and chronic antihypertensive effects of the calcium antagonist nitrendipine and the new ACE inhibitor cilazapril, given alone, and in combination, in a double-blind, randomized, placebo controlled study of 11 hypertensive patients with chronic renal failure who had a mean pretreatment blood pressure of 149 +/- 3/96 +/- 2 mm Hg. Patients received nitrendipine 10 mg, cilazapril 1.25 or 2.5 mg depending on creatinine clearance, or placebo once daily orally. Nitrendipine and cilazapril were also combined at the same doses. 4. Nitrendipine and cilazapril were equally effective, with a maximal acute reduction of mean arterial pressure (MAP) of 5.3 +/- 1.8% and 8.0 +/- 1.9%, and after 1 week of treatment 5.0 +/- 2.4% and 8.1 +/- 1.8%, respectively. In individual patients no inverse relationship between the blood pressure responses to the two drugs was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dihydropyridine calcium antagonists on rabbit renal Na,K-ATPase activity in vitro.

Dihydropyridines are reported to have a stimulatory effect on vascular smooth muscle Na,K-ATPase activity in vitro. We studied the effects of the dihydropyridine calcium antagonists nimodipine, nitrendipine, nisoldipine, niludipine, nifedipine and felodipine (10(-5) M) on purified Na,K-ATPase isolated from rabbit kidney outer medulla. We were unable to detect an effect of the drugs on the enzyme activity, either under optimal or suboptimal substrate conditions. Likewise, Na,K-ATPase activity, partly inhibited by the addition of ouabain (10(-6) M), Ca2+ (10(-3) M) or arachidonic acid (4 x 10(-5) M), was not influenced by the dihydropyridines. The absence of a stimulatory effect of dihydropyridines on renal Na,K-ATPase is in agreement with the known diuretic and natriuretic effects of the drugs in normotensive and hypertensive men.