Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.

In patients with uremia, increased blood concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to the severity of atherosclerosis and to excess cardiovascular mortality. The ADMA levels and several traditional cardiovascular risk factors were assessed in 44 untreated nonsmoking patients with confirmed primary chronic renal disease at different stages of renal disease. True GFR was assessed by means of the inulin-clearance technique. For comparison, nonsmoking subjects matched with respect to age, gender, and body-mass index were examined. Mean plasma ADMA concentration was markedly higher (P < 0.0001) in all patients combined (4.2 +/- 0.9 micromol/L) than in control subjects (n = 16; age 45 +/- 10 yr; serum creatinine 1.0 +/- 0.1 mg/dl; ADMA 1.4 +/- 0.7 micromol/L). However, mean ADMA levels were similar in patients with normal renal function (n = 16; age 41 +/- 9 yr; serum creatinine 1.1 +/- 0.1 mg/dl; GFR 120 +/- 14 ml x min(-1) x 1.73 m2; ADMA 4.0 +/- 0.7 micromol/L), in patients with moderate renal failure (n = 15; 47 +/- 7 yr; 1.8 +/- 0.3 mg/dl; 65 +/- 10 ml x min(-1) x 1.73 m2; 3.8 +/- 0.6 micromol/L) and in patients with advanced renal failure (n = 13; 46 +/- 9 yr; 4.2 +/- 0.9 mg/dl; 25 +/- 4 ml x min(-1) x 1.73 m2; 4.7 +/- 1.2 micromol/L). Furthermore, ADMA levels were increased to the same extent in normotensive (n = 17; 4.0 +/- 0.8 micromol/L) and in hypertensive (n = 27; 4.2 +/- 0.9 micromol/L) patients. In contrast to ADMA, mean total plasma homocysteine concentration were similar in control subjects (10.6 +/- 2.9 micromol/L) and in patients with normal GFR (11.0 +/- 2.9 micromol/L), but were significantly higher in patients with moderate renal failure (17.7 +/- 4.1 micromol/L) and particularly in patients with advanced renal failure (28.2 +/- 10.6 micromol/L). Finally, mean total serum cholesterol concentrations were comparable in the control group and in the three groups of patients with renal disease. In contrast to several traditional cardiovascular risk factors, markedly increased blood concentrations of ADMA, a putative biochemical marker of atherosclerosis, are present even in nonsmoking patients without diabetes with incipient primary renal disease. Thus, the early increase of ADMA levels may be of relevance for the excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with renal disease.     

Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0+/-0.5 versus 1.0+/-0.1 micromol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31+/-0.70 versus 3.95+/-0.52 micromol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD.     

Subpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition

Increased blood concentrations of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to high blood pressure and to cardiovascular mortality. We evaluated the effects of a subpressor ADMA dose on NO production, renal hemodynamics, sodium handling and active renin and noradrenalin plasma concentrations in 12 healthy subjects (age 26 +/- 1 year) using a double-blind placebo-controlled study design. Infusion of ADMA caused a significant decrease in plasma cyclic guanosine monophosphate (cGMP) levels, i.e. the second messenger of NO (from 6.1 +/- 0.4 to 4.3 +/- 0.3 pmol/l; p < 0.05). In parallel, effective renal plasma flow (ERPF) decreased while renovascular resistance (RVR) increased significantly (ERPF from 667 +/- 9 to 603 +/- 10 ml/min/1.73 m2; RVR from 79 +/- 2 to 91 +/- 2 ml/min/mm Hg; both p < 0.05 vs. baseline). Infusion of placebo did not cause significant changes in plasma cGMP levels, ERPF and RVR (cGMP from 5.7 +/- 0.5 to 5.9 +/- 0.6 pmol/l; ERPF from 665 +/- 12 to 662 +/- 11 ml/min/1.73 m2; RVR from 79 +/- 2 to 78 +/- 2 ml/min/mm Hg; all non-significant). Moreover, urinary sodium excretion was significantly lower with infusion of ADMA as compared with placebo infusion (128 +/- 8 vs. 152 +/- 7 micromol/min; p < 0.05). In contrast, blood pressure, active renin and noradrenalin plasma concentrations did not change significantly with either infusion protocol. Acute infusion of a subpressor ADMA dose modulates several aspects of renal function in humans without affecting the activity of the renin-angiotensin and sympathetic system. Whether chronic (intrarenal) NO synthase inhibition in individuals with increased ADMA blood levels may cause persistent renal vasoconstriction and sodium retention must be evaluated.     

Simultaneous hemodialysis during coronary angiography fails to prevent radiocontrast-induced nephropathy in chronic renal failure

BACKGROUND: Radiocontrast medium- (RM) associated nephrotoxicity continues to be a common cause of acute renal failure and may lead in patients with pre-existing chronic renal insufficiency even to end-stage renal failure requiring chronic dialysis. Since extracorporeal removal of RM after RM administration has been shown to be effective but does not prevent radiocontrast-induced nephropathy, the effect of a simultaneous dialysis during RM administration on renal function is not clear. METHODS: In a prospective, randomized and controlled trial, we studied the effect of a 4-hour online dialysis during RM (iomeprol) application in patients with advanced chronic renal failure (serum creatinine > or = 3 mg/dl) undergoing coronary angiography. All patients received hydration with saline before and after standardized coronary angiography and were randomized to receive a simultaneous high-flux hemodialysis (7 patients, HD group) or to control group (10 patients). 24-hour creatinine clearance (CrCl) was measured in all patients before, 1 week and 8 weeks after coronary angiography. The clinical follow-up comprised 8 weeks after RM application. RM plasma levels were measured in both groups 15, 30, 60 minutes, 2, 4, 12, 24, 48 and 72 hours after application by high-pressure liquid chromatography. RESULTS: At baseline, CrCl (19 +/- 10 vs 17 +/- 7 ml/min), percentage of diabetics (57 vs 70%) and dose of RM (77 +/- 27 vs 86 +/- 21 ml) were similar in both groups. Pharmacokinetics: Total clearance of iomeprol was significantly higher (54 +/- 15 vs 20 +/- 12 ml/min, p < 0.001) and the area under curve (AUC) was significantly lower (23 +/- 10 g x h/l vs 94 +/- 57 g x h/l, p < 0.001) in the HD group compared to control group. RM peak plasma levels 15 min after application were not different in both groups (3.0 +/- 1.1 vs 4.2 +/- 1.7 mmol/l, NS), however, significantly lower 60 min (1.6 +/- 0.4 vs 3.7 +/- 1.5 mmol/l, p < 0.01) and 240 min (0.7 +/- 0.3 vs 2.3 +/- 0.7 p < 0.001) after angiography. Clinical results: CrCl showed no difference 1 week (24 +/- 11 vs 19 +/- 9 ml/min, ns) and 8 weeks (24 +/- 5 vs 20 +/- 9 ml/min, NS) after angiography from baseline or between the groups. In each group, 2 patients developed end-stage renal disease and requested permanent dialysis during the 8-week follow-up. CONCLUSION: Simultaneous dialysis reduces AUC of iomeprol significantly, however, does not influence plasma peak concentration after angiography. Renal function and incidence of end-stage renal failure were not influenced by online-dialysis.     

The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.     

Effect of simvastatin on plasma asymmetric dimethylarginine concentration in patients with chronic kidney disease

BACKGROUND: The endogenous inhibitor of nitric oxide (NO) synthase, asymmetric dimethylarginine (ADMA), is a strong cardiovascular (CV) risk marker in patients with chronic renal insufficiency. Statins have pleiotropic effects and are currently considered as potential ADMA-lowering agents. METHODS: We investigated the effect of simvastatin on plasma ADMA levels in 35 patients with chronic kidney disease (CKD) by performing a secondary analysis of a randomized double-blind placebo-controlled trial where patients were randomized to receive simvastatin or placebo for 6 months. RESULTS: Plasma ADMA was higher in CKD patients (0.84 +/- 0.14 micromol/L) than in healthy subjects (0.69 +/- 0.10 micromol/L) (p<0.001). In CKD patients, ADMA at baseline was related directly with triglycerides (r=0.42, p=0.01) and inversely with HDL cholesterol (r=-0.37, p=0.03) and creatinine clearance (p=0.03). As expected, simvastatin caused significant reductions in total cholesterol, LDL cholesterol and triglycerides, as well as in C-reactive protein (CRP; -28%, p=0.001) and IL-6 (-20%, p=0.05) but failed to decrease plasma ADMA both in crude and adjusted analyses. CONCLUSIONS: Simvastatin does not modify plasma ADMA. Because raised ADMA is known to prevent the favorable effect of statins on myocardial blood flow, cointerventions aimed at lowering or antagonizing ADMA may either prompt or potentiate the cardiovascular protective effect of simvastatin.     

Serum creatinine is a poor marker of GFR in nephrotic syndrome.

BACKGROUND: In daily clinical practice creatinine clearance is used as marker of glomerular filtration rate (GFR). As a result of the tubular secretion process endogenous creatinine clearance (ECC) overestimates glomerular filtration rate, particularly in patients with impaired renal function. It has been suggested that the tubular handling of creatinine is altered in patients with a nephrotic syndrome. METHODS: Inulin clearance (GFR) and creatinine clearance (ECC) have been simultaneously measured in a cohort of 42 patients with proteinuria and 45 healthy controls. The clearance of creatinine by tubular secretion (TScreat) can be estimated by ECC-GFR. TScreat was calculated in both groups. Regression analysis was performed to identify factors that independently influence tubular creatinine secretion. RESULTS: The mean age (+/-SD) of the patients was 41+/-13 years, serum albumin 26+/-9 g/l, median (IQR) proteinuria 4.5 (3.6-8.2) g/10 mmol creatinine, serum creatinine 103 (84-143) micromol/l, ECC 85 (69-118) ml/min/1.73 m2, and GFR 54 (36-83) ml/min/1.73 m2. Median TScreat amounted to 29 (21-36) ml/min/1.73 m2. In the healthy controls serum creatinine was 75 (70-81) micromol/l, ECC 118 (109-125) ml/min/1.73 m2, GFR 106 (102-115) ml/min/1.73 m2, and TScreat 11 (3.5-19) ml/min/1.73 m2. By regression analysis serum albumin was identified as an independent predictor of tubular creatinine secretion. We divided the patients in two subgroups based on serum albumin levels. TScreat was 24 (14-29) ml/min/1.73 m2 in patients with serum albumin levels >25.8 g/l, and 36 (28-54) ml/min/1.73 m2 in patients with serum albumin levels <25.8 g/l (P<0.01). CONCLUSION: Serum albumin levels influence tubular creatinine secretion. As a result, the endogenous creatinine clearance as well as estimated GFR using a modified MDRD equation more pronouncedly overestimate glomerular filtration rate in nephrotic syndrome.     

Renal and hemodialysis clearances of endogenous natriuretic peptide. A clinical and experimental study

The purpose of the present study was to assess the plasma levels of atrial natriuretic peptide (ANP) in chronically uremic patients not submitted to dialysis and to determine the predialysis plasma concentration of ANP, the effect of ultrafiltration on plasma levels of ANP (hemodialysis, (HD), and the HD clearance of ANP in a population of adult patients treated with maintenance HD. The mean plasma ANP concentration (pg/ml) in HD was 370.2 +/- 35.5 pg/ml (mean +/- SEM) before HD and decreased to 165.3 +/- 15.2 after HD (p less than 0.01). Both values were significantly higher than in controls (28 +/- 2; n = 39). The changes in plasma ANP levels correlated inversely with those in plasma protein concentration (r = -0.53; p less than 0.03; y = 48.6 +/- 0.8 x). ANP clearance across the cuprophan membrane averaged 13 +/- 6.4 ml/mn. Resting plasma ANP values in the 16 uremic patients ranged between 16 and 277 pg/ml (124 +/- 11 pg/ml). These levels were significantly higher than those observed in controls (p less than 0.01). In these patients there was a highly significant correlation between serum creatinine and plasma ANP concentrations (p less than 0.01; r = 0.75; y = 0.2x + 3). Furthermore we report the results of the determination of the renal clearance of ANP in normal dogs. In all dogs a fall in plasma ANP concentration was recorded between the aorta (28.6 +/- 4.5 pg/ml) and the renal vein (14.2 +/- 2.7 pg/ml). The renal extraction ratio averaged 51.3 +/- 3.7%. Mean ANP renal clearance was 38.2 +/- 5.2 ml/mn.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dialysis adequacy and homocyst(e)ine concentrations in peritoneal dialysis patients.

INTRODUCTION: Determinants of hyperhomocysteinaemia in peritoneal dialysis patients have been recently reported but there is still conflicting data on the influence of dialysis adequacy on homocysteine (Hcy). METHODS: We studied 46 consecutive new continuous ambulatory peritoneal dialysis (CAPD) patients to determine the variation of Hcy before and 1 and 6 months after dialysis. The variation in Hcy was analysed with respect to dialysis adequacy, factors known to influence its metabolism, and Hcy peritoneal clearance. RESULTS: Hcy was 31.9+/-9 micromol/l before dialysis. It was significantly higher before dialysis than 1 month after the onset of PD (31.9+/-9 micromol/l vs 23.2+/-6.9 micromol/l, P < 0.0005). Weekly PD Hcy clearance was 14.3+/-5.4 1. There was no relationship between pre-dialysis Hcy and 1 month post-dialysis Hcy (r=0.176, P=0.15). There was a strong relationship between PD Hcy clearance and both PD creatinine clearance (r=0.502, P<0.005) and Kt/V (r=0.42, P<0.005). There was no relationship between Hcy and PD creatinine clearance (r= -0.221, P=0.11). In contrast, the decrease in tHcy at 1 month was related to PD Hcy clearance (r=0.487, P<0.01), to PD creatinine clearance (r= 0.349, P<0.02) and to Kt/V (r=0.32, P<0.02). Multivariate analysis confirmed the relationship between the decrease in Hcy and dialysis adequacy. Eleven patients (24%) experienced arteriosclerotic complications. Fasting Hcy concentrations in this population were significantly higher before and 1 month-post-dialysis than in patients without cardiovascular complications. CONCLUSIONS: We observed a significant and prolonged reduction in Hcy concentrations by peritoneal dialysis in end-stage renal disease patients. The decrease in Hcy concentration was positively related to dialysis adequacy. This study suggests the possibility that dialysis adequacy may influence arteriosclerotic outcomes through an Hcy-lowering effect.     

Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial.

OBJECTIVE: Renal dysfunction following cardiac surgery is more apparent in high-risk patients with pre-existing renal dysfunction, diabetes and impaired left-ventricular function, and following complicated procedures involving prolonged cardiopulmonary bypass (CPB). The aim of this prospectively randomised double-blinded placebo-controlled study was to evaluate reno-protective effect of low-dose furosemide infusion in this high-risk group. METHODS: Patients with preoperative serum creatinine >130 micromol/l (1.4 mg/dl), left-ventricular ejection fraction <50%, congestive heart failure, diabetes, or procedures involving prolonged CPB were randomised to receive either saline at 2 ml/h (n=21), or furosemide at 4 mg/h (n=21). Infusion was commenced after induction of anaesthesia and continued for 12h postoperatively. Renal dysfunction was defined as >50% increase in serum creatinine postoperatively, or >130 micromol/l (1.4 mg/dl), or requirement for haemodialysis, or all of these. In patients with preoperative serum creatinine >130 micromol/l, >50% increase over preoperative levels was used to define postoperative renal dysfunction. RESULTS: Following cardiac surgery, patients receiving furosemide had a higher urine output (3.4+/-1.2 ml/kg/h in furosemide group and 1.2+/-0.5 ml/kg/h in placebo group; p<0.001), higher postoperative fluid requirement (4631+/-1359 ml in furosemide group and 3714+/-807 ml in placebo group, p=0.011), and lower urinary-creatinine (2+/-1.3 micromol/l in furosemide group and 5.9+/-2.5 micromol/l in placebo group p<0.001). Both groups had significant increase in retinol binding protein/creatinine ratio (7.2+/-6 to 3152+/-1411 in furosemide group; 4.9+/-2.1 to 2809+/-1125 in placebo group; p<0.001) and peak serum creatinine (98+/-33 to 177+/-123 micromol/l in furosemide group; 96+/-20 to 143+/-87 micromol/l in placebo group; p<0.001), and a significant decrease in peak creatinine-clearance (64.3+/-29.4 to 39.1+/-16.6 ml/min in furosemide group; 65.5+/-38.6 to 41.8+/-17.8 ml/min in placebo group; p<0.001) following cardiac surgery, implying significant renal injury following cardiac surgery. Peak creatinine levels (177+/-123 micromol/l in furosemide group and 143+/-87 micromol/l in placebo group; p=0.35) and peak creatinine-clearance (39.1+/-16.6 ml/min in furosemide group and 41.8+/-17.8 ml/min in placebo group; p=0.61) were similar in the two groups. Importantly, there was no difference in incidence of renal dysfunction between the furosemide group (9/21) and the control group (8/21) (relative risk 1.1, 95% confidence interval 0.6-2.2; p=0.99). CONCLUSIONS: Our randomised trial did not demonstrate any benefit of furosemide-infusion postoperatively in high-risk cardiac surgical patients. Although urinary output increased with furosemide, there was no decrease in renal injury, and no decrease in incidence of renal dysfunction.     

Leptin in CAPD patients: serum concentrations and peritoneal loss.

BACKGROUND: To determine whether serum leptin concentrations in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are influenced by peritoneal loss of leptin and to compare serum leptin levels of normal subjects with those of patients receiving renal replacement therapy such as haemodialysis (HD), CAPD, or kidney transplantation. SUBJECTS AND METHODS: Eighty-four individuals were investigated: six females and 14 males on standard CAPD; 13 females and 13 males on chronic HD; 10 female and eight male kidney transplant recipients, and 10 female and 10 male subjects as controls. Morning serum, 8-h and 24-h samples of peritoneal fluid concentrated to 6-20-fold by Centricon 3 (cutoff 3000 daltons), and 24-h urinary concentrations of leptin were measured with commercial RIA (Linco Research, Inc., USA). Venous blood and peritoneal fluid samples of albumin, beta2-microglobulin, glucose, urea, and creatinine were determined by standard laboratory techniques. Serum insulin levels were measured by radioimmunoassay. RESULTS: Patients (men and women) on CAPD and after kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/BMI ratios than control subjects. These increased values did not reach statistical significance in HD patients. Serum leptin concentrations were correlated very significantly with BMI in all cases (r=0.380, P<0.001). Moreover, in CAPD patients (r=0.630, P<0.007) and in HD patients (r=0.668, P<0.005), but not in kidney transplant recipients or control subjects, significant correlations were observed between serum leptin and insulin concentrations. Residual renal function (RRF) in the range 0-12.8 ml/min and serum beta2-microglobulin levels in the range 7.9-47.1 mg/l did not influence serum leptin levels in CAPD and HD patients. As expected, leptin was detected in the peritoneal fluid of CAPD patients. Twenty-four-hour peritoneal loss (30.95+/-21.05 ng/min) and 24-h peritoneal clearance (0.01+/-0.01 ml/kg/min) of leptin account for only 3.9% of estimated whole-body leptin production rate and 0.7% of leptin clearance from plasma respectively. Twenty-four-hour urinary losses of leptin in CAPD patients were negligible, accounting for 5.6+/-1.8% (range 0.3-15.2%) of total (peritoneal and urinary) loss of this hormone. CONCLUSIONS: These findings suggest that serum leptin levels are not affected by continuous peritoneal loss of leptin during CAPD and that insulin resistance and hyperinsulinaemia contribute to elevated serum leptin concentrations in CAPD and HD patients. The aetiology of increased serum leptin levels in kidney transplant recipients is probably different from that in dialysis patients.     

Changes in renal function in patients with familial amyloid polyneuropathy treated with orthotopic liver transplantation.

BACKGROUND: Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease caused by a point mutation in the gene encoding transthyretin, which is secreted by the liver. Orthotopic liver transplantation (OLT) has been proposed to prevent disease progression. Little is known about long-term changes in renal function and lesions after OLT. METHODS: The renal function of 33 patients with FAP was evaluated (proteinuria, serum creatinine, creatinine clearance) before OLT and over a period of at least 5 years afterwards. A pre-transplantation renal biopsy was performed in 14 patients and a follow-up biopsy in eight patients. RESULTS: Before transplantation, mean serum creatinine concentration was 86 micromol/l (47-126 micromol/l) and creatinine clearance was 71.9+/-31.6 ml/min/1.73 m(2). Proteinuria was detected in 54% of patients (0.3-4 g/day). Pre-transplant renal biopsies (n = 14) revealed glomerular, tubular and vascular amyloid deposits in 90, 58 and 66% of patients, respectively. Eleven patients (33%) died after OLT. Death occurred most frequently in patients having weight losses >7 kg (P<0.05). After transplantation, 25 patients (76%) suffered acute renal failure but only one required dialysis. One month after transplantation, the mean serum creatinine concentration was 134.1+/-73 micromol/l and remained constant during follow-up. Eight patients underwent a second renal biopsy 2 years after transplantation. No significant changes in deposits or renal toxicity due to calcineurin inhibitors were detected. CONCLUSION: Although liver transplantation in FAP does not affect existing renal amyloid deposits, it prevents the progression of renal disease.     

Glomerular filtration rate estimated from the uptake phase of 99mTc-DTPA renography in chronic renal failure.

BACKGROUND: The purpose of the study was to compare the estimation of glomerular filtration rate (GFR) from 99mTc-DTPA renography with that estimated from the renal clearance of 51Cr-EDTA, creatinine and urea. METHODS: Fifty patients with reduced renal function (serum creatinine between 150 and 600 micromol/l) were enrolled in the study. GFR was estimated from the uptake phase of 99mTc-DTPA renography (GFR(DTPA)). The renal clearance of 51Cr-EDTA (GFR(EDTA)) was used as the reference method. Creatinine clearance (C(Cr)), urea clearance (C(Ur)) and the mean of urea and creatinine clearance (C(Cr+Ur)/2) were also calculated from urine collected during a period of 24 h. Limits of agreement were used for method comparison. RESULTS: The limit of agreement between GFR(DTPA) and GFR(EDTA) was 2 +/- 17 ml/min. The mean difference did not deviate significantly from zero. The other clearance techniques had larger limits of agreement and a mean difference significantly different from zero. Furthermore, C(Ur) and C(Cr+Ur)/2 had systematic deviations of the differences, indicating that C(Ur) and C(Cr+Ur)/2 are poor estimates of GFR. CONCLUSION: The limit of agreement between GFR(DTPA) and GFR(EDTA) are acceptable and, therefore, GFR estimated from 99mTc-DTPA renography is acceptable for clinical use in patients with reduced renal function. Furthermore, the method is simple and less time consuming compared with renal clearance techniques.     

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.     

Plasma concentration and peritoneal clearance of oxalate in patients on continuous ambulatory peritoneal dialysis (CAPD)

Accumulation of oxalate, resulting in high plasma levels, is a common finding in end-stage renal disease. We investigated plasma concentration and peritoneal clearance of oxalate in 14 patients on continuous ambulatory peritoneal dialysis. The plasma oxalate levels in these patients (30.2 +/- 11.2 mumol/l) were as high as those in hemodialysis patients before dialysis (31.9 +/- 11.1 mumol/l). There was a significant correlation between plasma oxalate and urea nitrogen appearance (UNA). Dietary protein seems to be an important oxalate source in these patients, because the UNA reflects protein intake in stable patients. The mean peritoneal oxalate clearance was 6.64 +/- 1.56 l/day, close to the creatinine clearance. These results suggest that the plasma oxalate levels in CAPD patients may be sufficiently high to induce calcium oxalate deposition, and that methods of increasing oxalate removal and reducing oxalate burden are necessary for CAPD patients.     

Abnormalities of glucose metabolism in patients with early renal failure

Abnormalities of glucose metabolism and hyperinsulinemia have been demonstrated in patients with end-stage renal disease and may contribute to the development of atherosclerotic complications in these patients. In the present study, we investigated the stage of renal failure in which abnormalities of glucose metabolism develop and whether these abnormalities were associated with an increased prevalence of cardiovascular events in patients with early renal failure. In 321 untreated essential hypertensive patients, we assessed renal function by measuring 24-h creatinine clearance, urinary protein excretion, and microalbuminuria; we assessed cardiovascular status by clinical and laboratory tests; and we measured plasma glucose, insulin, and C-peptide levels at fasting and after a 75-g oral glucose load. To evaluate insulin sensitivity, a hyperinsulinemic-euglycemic clamp was performed in a subgroup of 104 patients. Patients with creatinine clearance < 30 ml.min(-1).1.73 m(-2), severe hypertension, BMI < 30 kg/m(2), and diabetes or family history of diabetes were excluded. Hypertensive patients were found to be hyperinsulinemic when compared with 92 matched normotensive subjects. Early renal failure (creatinine clearance < 90 ml.min(-1).1.73 m(-2)) caused by hypertensive nephrosclerosis was detected in 116 of 321 patients. Analysis of patients with varying degrees of renal function impairment demonstrated increased plasma glucose and insulin response to oral glucose load, decreased fasting glucose-to-insulin ratio, and reduced sensitivity to insulin only in those patients with creatinine clearance < 50 ml.min(-1).1.73 m(-2). Parameters of glucose metabolism were not correlated with creatinine clearance and microalbuminuria. Prevalence of atherosclerotic cardiovascular events was significantly related to reduction of creatinine clearance, but parameters of glucose metabolism were comparable in patients with and without evidence of atherosclerotic damage. Thus, in patients with hypertensive nephrosclerosis and early impairment of glomerular filtration, alterations of glucose metabolism become evident only when creatinine clearance is < 50 ml.min(-1).1.73 m(-2) and are not related to microalbuminuria and cardiovascular complications.     

Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients.

BACKGROUND AND METHODS: In order to examine the clinical outcome of IgA nephropathy (IgAN) superimposed on diabetic glomerulosclerosis in type 2 patients we studied 36 Chinese patients (26 men, 10 women), who were recruited for renal biopsy when they had proteinuria of more than 1 g/day. Twenty-seven had isolated diabetic glomerulosclerosis and nine had IgAN superimposed on diabetic glomerulosclerosis (combined). Renal function was assessed by serial serum creatinine, 24-h urine protein and creatinine measurements. Patient survival rate, incidence of end-stage renal disease (ESRD), blood pressure, and glycaemic control status were determined. RESULTS: The age at the time of renal biopsy was younger for the combined group when compared with the diabetic glomerulosclerosis group (44+/-3.6 vs 58+/-2.1 years, P=0.006). The duration of diabetes was, however, similar for the two groups (8.0+/-2.3 vs 6.7+/-1.2 years, P=NS). After a mean follow-up of 31.6+/-15.3 months, 15 patients (one in the combined group and 14 in the diabetic glomerulosclerosis group) developed ESRD. Nine patients (all in the diabetic glomerulosclerosis group) died during follow-up. With similar glycaemic and blood pressure control, the two groups had comparable rate of decline of creatinine clearance (CrCl) (-0.73+/-0.26 vs -0.73+/- 0.18 ml/min/1.73 m(2)/month, P=NS), final serum creatinine (363+/-134 vs 426+/-52 micromol/l, P=NS) and proteinuria levels (4.3+/-0.9 vs 4.4+/-0.6 g/day, P=NS), as well as CrCl (44.1+/-19.0 vs 33.4+/-6.9 ml/min/ 1.73 m(2), P=NS). CONCLUSION: It is concluded that the superimposed IgAN does not significantly alter the medium-term clinical outcome of patients with diabetic glomerulosclerosis.     

Continuous renal replacement therapy: does technique influence azotemic control?

BACKGROUND AND OBJECTIVES: Different techniques of continuous renal replacement therapy (CRRT) might have different effects on azotemic control. Accordingly, we tested whether continuous veno-venous hemodiafiltration (CVVHDF) or continuous veno-venous hemofiltration (CVVH) would achieve better control of serum creatinine and plasma urea levels. DESIGN: Retrospective controlled study. SETTING: Two tertiary Intensive Care Units. PATIENTS: Critically ill patients with acute renal failure (ARF) treated with CVVHDF (n = 49) or CVVH (n = 50). Interventions: Retrieval of daily morning urea and creatinine values before and after the initiation of CRRT for up to 2 weeks of treatment. MEASUREMENTS AND RESULTS: Before treatment, serum urea and creatinine concentrations were significantly lower in the CVVH group than in CVVHDF group (urea: 31.0 +/- 15.0 mmol/L for CVVHDF and 24.7 +/- 16.1 mmol/L for CVVH, p = 0.01, creatinine: 547 +/- 308 micromol/L vs. 326 +/- 250 micromol/L, p < 0.0001). These differences were still significant after 48 h of treatment (urea: 20.1 +/- 8.3 mmol/L vs. 14.1 +/- 6.1 mmol/L; p = 0.0003, creatinine: 360 +/- 189pmol/L vs. 215 +/- 118 micromol/L; p < 0.0001). Throughout the duration of therapy, mean urea levels (22.3 +/- 9.0 mmol/L for CVVHDF vs. 16.7 +/- 7.8 mmol/L for CVVH, p < 0.0001) and mean creatinine levels (302 +/- 167 vs. 211 +/- 103 micromol/L, p < 0.0001) were better controlled in the CVVH group. CONCLUSIONS: CRRT strategies based on different techniques might have a significantly different impact on azotemic control.     

Assessing residual renal function and efficiency of hemodialysis--an application for urographic contrast media

BACKGROUND: In patients on hemodialysis with end-stage renal disease there is an increasing interest in measuring both residual renal function (RRF) and quantity and quality of dialysis because insufficient dialysis gives higher mortality. For that purpose we have measured clearances of two urographic iodine (I) contrast media (CM) with different molecular masses (iohexol 821 u and iodixanol 1, 550 u). These CM are filtered through glomeruli and dialysis membranes and have higher molecular masses than urea and creatinine and might represent the dialyzability of the hypothetic uremic toxins with a molecular mass of 300-5,000 u. METHODS: Thirteen patients (8 of them were anuric) immediately after hemodialysis received 15 ml iohexol (300 mg I/ml i.v.) and 2 weeks later in the same way 15 ml iodixanol (320 mg I/ml). Nine other patients (2 anuric) received CM after only one dialysis; 8 got iohexol and 1 got iodixanol. After the CM injections the iodine concentrations were measured with X-ray fluorescence in blood and, when available, urine during the following 2 days including both the start and end of the next dialysis. Eighteen patients after two dialysis sessions, 2 weeks apart, received 10 ml iohexol i.v., and a single blood sample was taken at the start of the next dialysis 2 days later to determine RRF alone. RESULTS: In the 10 anuric patients the extrarenal clearances (mean +/- SD) were 2.5 +/- 1.1 and 2.7 +/- 1.1 ml/min/1.73 m(2) for iohexol and iodixanol, respectively. In patients with RRF good correlations were demonstrated between body clearance, based on two blood samples, and renal clearance of CM. Good correlations (r(2) = 0.853 for iohexol, r(2) = 0.933 for iodixanol) were noted between two-sample and single-sample body clearances. Repeated single sample iohexol clearances gave a coefficient of variation of 15%. During dialysis the clearances of iohexol and iodixanol were, respectively, 69 +/- 16 and 58 +/- 11 ml/min/1.73 m(2) when calculated from a single-pool model (hemodialysis clearance of CM from plasma). A median increase (rebound) of CM concentrations in plasma 45 min dialysis was 8% for iodixanol and 18% for iohexol. When the CM concentration 45 min after dialysis was used, the clearance values were by 8-10% lower and represented the hemodialysis clearance of CM from the extracellular compartments. The dialysis eliminations of iohexol and iodixanol were similar to that of urea, measured as percentage reduction of serum levels during dialysis. CONCLUSIONS: A single injection of CM at the end of dialysis followed by a single blood sample at the start of the next dialysis gives total body clearance, i.e., an estimation of the RRF. An additional blood sample at the end of the next dialysis gives dialysis efficiency.