Repeated Contrast Administration Is Associated With Low Risk of Postcontrast Acute Kidney Injury and Long-Term Complications in Patients With Severe Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) frequently require radiographic examinations. We investigated the impact of repeated contrast administrations on short- and long-term kidney function and mortality in kidney transplantation candidates. In a prospective study, 81 predialysis transplantation candidates underwent computed tomography angiography (CTA) and invasive coronary angiography (ICA) as part of a pretransplant cardiovascular evaluation. Postcontrast plasma creatinine (P-creatinine) changes were compared with a precontrast control period. We identified postcontrast acute kidney injury (AKI) in 10 patients (13%) after CTA and in two patients (3%) after ICA. Compared with the control period, relative changes in P-creatinine were significantly higher after CTA (p < 0.001) and ICA (p < 0.01). Diabetic kidney failure (p < 0.05) and contrast dose >0.8 mL/kg (p < 0.001) were associated with increases in P-creatinine. All cases of postcontrast AKI were reversible, and we found no differences between the progression rates of the kidney failure during 12 months before and after contrast exposure (p = 0.56). In a Cox regression analysis, creatinine changes after CTA or ICA were not associated with increased need for dialysis treatment or mortality. Contrast exposure and transient postcontrast AKI did not increase the risk of accelerated CKD progression or the time to initiation of dialysis or death.

Impact of essential hypertension and diabetes mellitus on left ventricular systolic and diastolic performance.

AIMS: To investigate left ventricular systolic and diastolic function in patients with essential hypertension and diabetes mellitus associated with hypertension by the myocardial performance index (MPI). METHODS AND RESULTS: The study included 45 patients with essential hypertension, 45 patients with diabetes mellitus and hypertension and 45 normal subjects, who underwent a complete two-dimensional and Doppler echocardiography including assessment of the isovolumetric Doppler time intervals for the estimation of the Doppler-derived MPI. The MPI was significantly higher in patients with essential hypertension and diabetes with hypertension, compared to controls (Essential hypertension=0.51+/-0.12; Diabetes=0.51+/-0.12 vs. controls 0.40+/-0.05, P=0.001). The isovolumetric contraction time was significantly prolonged in essential hypertension (56+/-26 msec vs. 40+/-17 msec, P<0.01 respectively) and among diabetes patients isovolumetric relaxation time was prolonged compared to normal subjects (100+/-20 ms vs. 87+/-16 ms, P<0.01, respectively). The index was not related to left ventricular mass, age or ejection fraction, but significantly correlated to E-wave deceleration time (rho=0.48, P<0.001). CONCLUSIONS: The MPI is increased, in both essential hypertensive patients and diabetes patients with associated hypertension, despite normal ejection fraction.

Increased urinary excretion of aquaporin 2 in patients with liver cirrhosis.

BACKGROUND AND AIM: Water retention is a major clinical problem in patients with liver cirrhosis. Recent research suggests that renal aquaporins may be pathophysiologically involved in this condition. The aim of the present cross sectional study of patients with liver cirrhosis was to determine if 24 hour urinary excretion of renal aquaporin 2 (AQP2) differed from that of healthy control subjects and if such excretion was related to the severity of liver disease and to the patient's water balance. RESULTS: Twenty four hour urinary excretion of AQP2 and free water clearance were measured in 33 stable cirrhosis patients on usual medication and in eight healthy subjects. AQP2 excretion, quantitated by immunoblotting, was eight times higher in cirrhosis patients than in controls (0.167 (0.270) U/day v 0.021 (0.017); p<0.05). Stratification according to clinical manifestations (Child- Pugh classes) revealed that it increased with the clinical severity of cirrhosis (class A 0.04 (0.04); class B 0.09 (0.16); class C 0.31 (0.35); p<0.05) but was not related to liver function, as measured by galactose elimination capacity. Excretion correlated inversely with free water clearance (rho=-0.57, p<0.01). It was higher in patients with oesophagogastric varices but not in those with ascites. Plasma vasopressin concentrations were not related to AQP2 excretion and there was no relation to dose or type of diuretic treatment. CONCLUSIONS: Urinary AQP2 excretion was increased in patients with cirrhosis. Moreover, urinary AQP2 excretion increased with severity of cirrhosis in parallel with impairment of free water clearance. This suggests a functional association between increased AQP2 excretion and increased renal reabsorption of water in cirrhosis.

Plasma cystatin C as a marker of renal function in patients with liver cirrhosis.

Cystatin C is a low molecular weight protein and the plasma level of cystatin C is mainly determined by glomerular filtration, making cystatin C an endogenous marker of glomerular filtration rate. The aim of the study was to elucidate the applicability of plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Serum cystatin C and creatinine concentrations were compared with creatinine clearance. Thirty-six patients (14 females and 22 males aged between 33 and 81 years) with liver cirrhosis with normal to severely impaired kidney function were included. Plasma cystatin C was measured by an automated particle-enhanced nephelometric immunoassay (Dade Behring Diagnostics) and plasma creatinine by an enzymatic method. Plasma levels of cystatin C and creatinine were found to increase with decreasing values of creatinine clearance. The reciprocal values of cystatin C and creatinine were compared with those for creatinine clearance revealing an r2 of 0.37 and 0.18, respectively. Comparison of the areas under the curves (AUC) of the non-parametric receiver-operating characteristic plots for plasma cystatin C (AUC=0.7364; SE=0.0929) and plasma creatinine (AUC=0.6309: SF=0.1028) revealed a significant difference between plasma cystatin C and plasma levels of creatinine (p-value=0.03). The results demonstrate that the diagnostic accuracy of plasma cystatin C was better than plasma creatinine in identifying liver cirrhotic patients with reduced glomerular filtration rate.

Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men.

Intracellular hydration may play a role in the regulation of protein and nitrogen metabolism. The hepatic removal of nitrogen by urea synthesis has a key regulatory role in nitrogen balance. The purpose of the present study was to establish the acute effects of dehydration on the hepatic kinetics of urea synthesis, quantified by functional hepatic nitrogen clearance (FHNC), in healthy volunteers. Seven healthy men were studied twice in random order. On both study days, a primed continuous infusion of alanine was given. On the day of dehydration an intravenous bolus injection of a loop diuretic (furosemide, 1 mg/kg) was superimposed. FHNC was calculated as the ratio between measured synthesis rates of urea nitrogen and blood alanine concentrations. Furosemide induced a weight loss of 1 kg. During dehydration, FHNC decreased by approx. 25% (41+/-11 to 54+/-10 litres/h; P<0.02). On both occasions individual FHNC and glucagon values were positively correlated (r(2)>0.6). In addition, dehydration more than halved the linear slope of the relationship (P<0.05). The FHNC values were correlated with the urinary excretion of both potassium and sodium (r(2)=0.68, P<0.01 and r(2)=0.62, P<0.02 respectively). Changes in the reactivity of urea synthesis to glucagon (i.e. the ratio between FHNC and glucagon concentration) was negatively correlated with an indirectly estimated change in intracellular water (r(2)=0.79, P<0.05). We conclude that acute moderate dehydration down-regulates both total urea synthesis and its sensitivity to glucagon. The latter was related to estimated intracellular water loss. Dehydration may thus have nitrogen-saving consequences with regard to the hepatic contribution to whole-body nitrogen homoeostasis. The mechanism of this effect and the relationship with sodium and potassium fluxes is not known.

Determination of free insulin-like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay.

Two fundamentally different methods are currently used for the determination of free insulin-like growth factor-I (IGF-I): ultrafiltration by centrifugation (UF) and direct immunoradiometric assay (IRMA). The aim was to evaluate a commercial IRMA (DSL, Webster, TX, USA) and to compare it with UF. In the IRMA it is recommended that samples be incubated for 2 h at 5;C. When comparing samples (n = 8) incubated for 1 and 2 h, levels increased by 27 +/- 5% (P< 0.0001). When incubating samples at 22;C instead of 5;C, levels increased by 192 +/- 32% (P< 0.0001). Addition of IGF-binding protein-1 (IGFBP-1) to normal sera (n = 6) dose-dependently decreased ultrafiltered free IGF-I only (P< 0.0007). Similarly, UF was more sensitive than IRMA to addition of IGFBP-2 (P< 0.05). In healthy subjects (n = 35) IRMA yielded 20% higher levels than UF (1.09 +/- 0.09 vs 0.91 +/- 0.12 microg/L; P< 0.0001). IRMA and UF yielded similar results in healthy subjects treated with IGF-I (n = 5) or growth hormone (n = 7) and in acromegalic patients (n = 6) before and after somatostatin analogue treatment. However, marked differences were observed in conditions with elevated IGFBP-1 and -2. In type-1 diabetics (n = 23) ultrafiltered free IGF-I was more reduced than IRMA free IGF-I (38 +/- 9 vs 76 +/- 7% of matched controls (n = 13); P< 0.0001). In patients with chronic renal failure (n = 25), IRMA free IGF-I was identical to control levels (n = 13), whereas ultrafiltered free IGF-I was decreased by 51 +/- 7% (P< 0.0001). Similarly, women with anorexia nervosa (n = 9) studied before and after weight gain showed significant changes in ultrafiltered free IGF-I only (P< 0.03). In conclusion, IRMA was not very robust with respect to variations in sample incubation and this may bias results. IRMA generally yielded higher levels than UF, in accordance with the knowledge that IRMA measures free plus readily dissociable IGF-I. IRMA was less affected than UF by added IGFBP-1 and -2, and reductions in free IGF-I were better revealed by UF than IRMA.

Nutritional status and amino acids in granulocytes and plasma in patients with chronic renal disease and varying residual renal function.

BACKGROUND: Protein metabolism changes with loss of renal function resulting in deterioration of nutritional status. Whether changes in macroscopic (anthropometry and subjective global nutritional assessment (SGNA)) and cellular (plasma and granulocyte free amino acid concentration) nutritional status with loss of residual renal function are related is not known. METHODS: Anthropometric variables, SGNA, and blood samples were measured after a night's fast in 43 patients (age 57 years, median (range 27-77), 32 males and 11 females) with chronic renal disease. A 24-hour urine sample was collected the day before the study for calculation of creatinine clearance and protein nitrogen appearance rate. The patients were stratified according to creatinine clearance (group I: >35 ml/min/1.73 m(2), group II 35-15 ml/min/1.73 m(2), group III <15 ml/min/1.73 m(2)). RESULTS: In males a significant lower body weight (p < 0.05) and upper mid-arm muscle area (p < 0.05) was found in group III compared to group I. SGNA indicated suboptimal nutritional status in 12 patients. In group I all had normal SGNA while in group II and group III, 26 and 57% respectively were malnourished. SGNA was significantly and negatively correlated to upper mid-arm muscle area (rho = -0.37, p < 0.05) and percent body fat mass (rho = -0.46, p < 0.01) and positively correlated to percent ideal body weight (rho = 0.48, p < 0.01). Nine patients with malnutrition (M) were compared with 9 well-nourished (N) patients. They were comparable with respect to creatinine clearance (M: 13 +/- 5 ml/min/1.73 m(2); N: 16 +/- 7 ml/min/1.73 m(2)), age and sex. In malnourished patients plasma concentration of nonessential amino acids was higher (23%, p < 0.05). The intracellular concentration was generally not affected except for sulfur amino acid methionine which was increased by a factor of 2.5 (p < 0.05) and taurine decreased by a factor of 1.6 (p < 0.05). CONCLUSION: Loss of renal residual function worsened both macroscopic and cellular nutritional status. SGNA correlated to objective measures of nutritional status and is clinically usable. In malnourished chronic renal patients, increased plasma concentration of nonessential amino acids was found which might indicate increased protein degradation.

Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure.

UNLABELLED: Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure. BACKGROUND: Chronic renal failure (CRF) results in major changes in the circulating growth hormone (GH)/insulin-like growth factor (IGF) system. However, there are only limited data on changes in free IGF-I in CRF. METHODS: Matched groups of nondiabetic, nondialyzed patients with CRF (N = 25) and healthy controls (N = 13) were compared. The creatinine clearance (CCr) based on a 24-hour urine collection ranged from 3 to 59 and 89 to 148 ml/min/1.73 m2 in patients and controls, respectively. Overnight fasting serum samples were analyzed for free and total IGF-I and -II, and IGF-binding protein (IGFBP)-1, -2, and -3. Additionally, intact as well as proteolyzed IGFBP-3 was determined. RESULTS: The patients had reduced serum-free IGF-I (-53%) and increased levels of total IGF-II (40%), IGFBP-1 (546%), and IGFBP-2 (270%, P < 0.05). Serum total IGF-I and free IGF-II were normal. Also, serum levels of immunoreactive IGFBP-3 were elevated (33%, P < 0.05), but this could be explained by an increased abundance of IGFBP-3 fragments, as ligand blotting showed no difference in levels of intact IGFBP-3. Accordingly, patients had an increased proteolysis of IGFBP-3 in vivo (17%) and in vitro (7%, P < 0.05). In patients, free IGF-I levels correlated positively with CCr (r2 = 0.38, P < 0.002) and inversely with IGFBP-1 (r2 = 0.69, P < 0. 0001) and IGFBP-2 (r2 = 0.41, P < 0.0007), whereas CCr was inversely correlated with levels of IGFBP-1 (r2 = 0.48, P < 0.0001) and IGFBP-2 (r2 = 0.63, P < 0.0001). CONCLUSIONS: These data strongly support the hypothesis that CRF-related growth failure and tissue catabolism are caused by an increased concentration of circulating IGFBP-1 and -2, resulting in low serum levels of free IGF-I and thus IGF-I bioactivity. In addition, low levels of free IGF-I may explain the increased secretion of GH in CRF.

The pattern of intracellular free amino acids in granulocytes from hemodialysis patients change to an oral protein supplement (granulocyte amino acids after protein in HD patients).

MATERIALS AND METHODS: The concentrations of free intracellular amino acids in granulocytes and plasma amino acids, normalized protein nitrogen appearance rate, serum insulin-like growth factors, plasma proteins, anthropometric and bioimpedance measurements were determined before and after an oral protein supplement in 19 stable patients on maintenance hemodialysis in a randomized, double-blind placebo-controlled study with crossover after 3 months. The hemodialysis patients were well-nourished with an ideal body weight of 91% after both protein supplementation and after placebo. RESULTS: After protein supplementation (7.8 g/d) the intracellular concentration of valine, isoleucine, threonine and tyrosine and the valine/glycine and tyrosine/phenylalanine ratios in the cells were significantly increased (p < 0.05). In contrast, the concentrations of plasma amino acids, serum insulin-like growth factors, and plasma proteins and body weight and anthropometric and bioimpedance measurements were unchanged. Dialysis efficiency was unchanged throughout the study. CONCLUSIONS: The present study supports the conclusion that protein supplementation to well-nourished hemodialysis patients does not improve the nutritional status measured by plasma proteins, body weight, anthropometric and bioimpedance measurements. The increase in intracellular amino acid concentrations indicates better cellular nutrition and metabolic control.

Dietary sodium affects systemic and renal hemodynamic response to NO inhibition in healthy humans.

Animal studies have indicated that increased nitric oxide (NO) synthesis plays a significant role in the renal adaptation to increased sodium intake. To investigate the role of NO during increased sodium intake in humans, we studied the effect of acute, systemic injection of NG-monomethyl-L-arginine (L-NMMA) on renal hemodynamics [glomerular filtration rate and renal plasma flow (GFR and RPF, respectively)], urinary sodium excretion (FENa), systemic hemodynamics [mean arterial blood pressure and heart rate (MAP and HR)], and plasma levels of several vasoactive hormones in 12 healthy subjects during high (250 mmol/day) and low (77 mmol/day) sodium intake in a crossover design. The sodium diets were administered for 5 days before the L-NMMA treatments, in randomized order, with a washout period of 9 days between each diet and L-NMMA treatment. GFR and RPF were measured using the renal clearance of 51Cr-labeled EDTA and 125I-labeled hippuran by the constant infusion technique in clearance periods of 30-min duration. Two baseline periods were obtained, after which L-NMMA was given (3 mg/kg over 10 min), and the effect of treatment was followed over the next five clearance periods. During high sodium intake, L-NMMA induced a more pronounced relative decrease in RPF (P = 0.0417, ANOVA), a more pronounced relative decrease in FENa (P = 0.0032, ANOVA), and a more pronounced relative increase in MAP (P = 0.0231, ANOVA). During low sodium intake, the effect of L-NMMA on FENa was abolished. During low sodium intake, L-NMMA induced a sustained drop in plasma renin (31 +/- 5 vs. 25 +/- 5 microU/ml, P < 0.001), which was not seen during high sodium intake. The data indicate that increased production of NO is an important part of the adaptation to increased dietary sodium intake in healthy humans, with respect to renal hemodynamics, sodium excretion, and the secretion of renin.

A new, fast and reliable radioimmunoassay of brain natriuretic peptide in human plasma. Reference values in healthy subjects and in patients with different diseases.

A new, fast and reliable radioimmunoassay for measurement of brain natriuretic peptide (BNP) in human plasma has been developed and its application is reported in healthy subjects and in patients with congestive heart failure, chronic renal failure, liver cirrhosis and essential hypertension. The antibody was raised in rabbits, the tracer was made by the iodogen method and polyethylene glycol was used for separation of free and bound tracer. BNP was extracted from plasma using Sep-Pak C18 cartridges. The recovery of unlabelled BNP added to plasma was 77.5 +/- 6.2% (mean +/- SD). The detection limit in plasma was 0.55 pmol l-1. No cross-reactivity existed with the natriuretic peptides ANP, CNP or urodilatin. In 124 healthy subjects the mean BNP was 1.8 +/- 1.0 pmol l-1 (SD), range 0.6-5.5. BNP increased slightly with age, was higher in women than men and had no circadian rhythm. In eight patients with congestive heart failure the median BNP level was 30.5 pmol l-1, range 3.9-65.3. In 14 patients with chronic renal failure the median BNP level was 50.5 pmol l-1, range 10.9-219.8 before dialysis, and 38.0 pmol l-1, range 9.4-180.0 immediately following dialysis. In 25 patients with liver cirrhosis the median BNP value was 7.8 pmol l-1, range 1.2-43.1. There was no difference between patients with or without ascites. In 18 medically treated patients with essential hypertension the median BNP level was 5.0 pmol l-1, range 1.2-45.5 pmol l-1.

Impaired renal haemodynamic response to amino acid infusion in essential hypertension during angiotensin converting enzyme inhibitor treatment.

OBJECTIVE: To determine whether hyperfiltration induced by amino acid infusion can be influenced by angiotensin converting enzyme (ACE) inhibition. DESIGN: We studied the acute effects of ramipril in 12 healthy control subjects and in 14 patients with essential hypertension. We studied also the effects of 2 months' treatment with ramipril inn 12 patients with essential hypertension and performed a time-control study without amino acids infusion with 12 control subjects. The glomerular filtration rate (GFR), renal plasma flow (RPF), fractional excretion of sodium (FENa) and fractional excretion of lithium (FELi) were determined during 6 clearance periods of 30 min each and amino acids infusion was administered during the last four periods. Plasma concentrations of angiotensin II, aldosterone, atrial natriuretic peptide (ANP), arginine vasopressin, insulin and glucagon were determined. RESULTS: Both the GFR and the RPF increased markedly in healthy subjects after amino acid infusion both with (GFR 7%, RPF 7%) and without ramipril (GFR 7%), RPF 8%), both P < 0.05. Ramipril administered acutely to essential hypertensives prevented the amino acid-induced increase in RPF [with ramipril 5% (NS), without ramipril 9% (P < 0.05)]. The GFR increased equally with (5%) and without (8%) ramipril (P < 0.20). ACE inhibition after 2 months' treatment of essential hypertension blunted the amino acid-induced increase both in GFR and in RPF [with ramipril GFR 5% and RPF 3% (NS), without ramipril GFR 12%, RPF 11% (P < 0.05)]. The FENa did not change in all four experiments. The FELi, insulin and glucagon increased to the same extent in the first three experiments. ANP increased (P < 0.05) in control subjects both with and without ramipril; angiotensin II and aldosterone decreased significantly in control subjects without ramipril. CONCLUSIONS: The renal haemodynamic response both after acute and after short-term ACE inhibition is attenuated in essential hypertension. Presumably, this treatment makes the arterioles at the glomeruli unresponsive to subsequent amino acid infusion. This inhibition of hyperfiltration might be an important mechanism for the renal protective effect of ACE inhibition in some renal diseases.

Development of a urodilatin-specific antibody and radioimmunoassay for urodilatin in human urine.

Urodilatin (URO) (95-126) is a renal-derived natriuretic peptide that is isolated only from human urine. This study describes the development of a URO-specific antibody and a RIA for URO in urine. At present, there is no commonly available URO-specific antibody. We produced a URO-specific antibody without cross-reactivity with atrial natriuretic peptide (ANP) analogs by immunization of rabbits with the URO (95-126) peptide and subsequent purification of the resulting URO antiserum with affinity chromatography with CNBr-activated Sepharose 4B. The urine samples were ethanol-extracted before assay. The CVs were 6.7% (intraassay) and 14.1% (interassay). This study reports the circadian urinary excretion of URO in 24 healthy subjects with seven sampling periods per 24 h.

Effect of prednisolone on amino acid-induced changes in renal haemodynamics and tubular function.

The effect of oral prednisolone treatment on renal haemodynamics, tubular function and various hormones during amino acid infusion was studied in 14 normal men. A balanced amino acid solution was infused for 120 min, before and after 4 days of prednisolone treatment (40 mg day-1). During amino acid infusion before prednisolone glomerular filtration rate, renal plasma flow, urinary sodium excretion, fractional excretion of sodium, lithium clearance, fractional excretion of lithium, serum insulin (s-insulin), plasma glucagon (p-glucagon) and s-growth hormone increased, whereas p-atrial natriuretic peptide, p-aldosterone, p-vasopressin and s-insulin-like growth factor 1 were unchanged, and potassium excretion and fractional excretion of potassium fell. After prednisolone treatment the most important differences during amino acid infusion were a significantly lower fractional excretion of sodium after 120 min (before prednisolone 26%; after prednisolone-7%; p < 0.05), a more pronounced increase in s-insulin after 120 min (before 118%; after 200%; p < 0.05) and a lower s-potassium. In conclusion, amino acid infusion increased fractional sodium excretion in healthy men, and this increase was reduced by prednisolone due to increased reabsorption in the distal tubules. It is suggested that the more pronounced the increases in plasma insulin and the decrease in serum potassium are mediators of the increased distal tubular sodium reabsorption during amino acid infusion during prednisolone treatment.

Circadian blood pressure rhythm and atrial natriuretic peptide in prednisolone-induced blood pressure elevation.

The effect of prednisolone, given as a 4-day oral treatment, on 24-h ambulatory blood pressure rhythm, vasoactive hormones and correlation between blood pressure and vasoactive hormones were studied in 11 healthy men. Blood pressure was monitored at intervals of 15 min during the day and of 30 min during the night. Plasma concentrations of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and arginine vasopressin and serum concentration of insulin were measured in the morning during basal conditions. The 24-h systolic, diastolic and mean blood pressures were significantly higher after prednisolone treatment. Waking blood pressure was not significantly changed, but sleeping systolic and mean blood pressures were significantly elevated after treatment. The nocturnal systolic blood pressure fall was less pronounced after treatment (before 22%, and after 16%, p<0.01), whereas the nocturnal, mean and diastolic dips were preserved. ANP was significantly increased by prednisolone treatment, from 10.1 to 14.6 pmol l-1, p<0.005. The changes in concentration of ANP were significantly correlated to the changes in 24-h diastolic blood pressure (r = -0.63, p<0.05), 24-h mean blood pressure (r = -0.68, p<0.05), waking diastolic blood pressure (r = 0.83, p<0.01) and waking mean blood pressure (r = -0.67, p<0.01). We found that short-term prednisolone treatment elevated the overall 24-h blood pressure, reduced systolic blood pressure fall during sleep, and increased plasma concentration of ANP, and that the increase in ANP was inversely correlated to the increase in blood pressure. We suggest that the increase in ANP is a secondary and compensatory phenomenon which at least to some extent counteracts the hypertensive and sodium retaining effect of prednisolone.