Effect of oral cyclosporin on renal function in Crohn's disease

Twenty-one patients with Crohn's disease were followed prospectively for 24 weeks to examine the effect of a low-dose cyclosporin regime on renal function (initial dose 5 mg/kg reduced by 1 mg/kg every two months to a maintenance of 2 mg/kg). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by radioisotope clearance at 0,6 and 24 weeks. GFR and ERPF fell significantly (mean GFR at baseline: 120.9 ml/min/1.73 m²; at six weeks: 100.9 ml/min/1.73 m²; mean ERPF at baseline: 497.3 ml/min/1.73 m²; at six weeks: 398.5 ml/min/1.73 m²). Following dose reduction, the ERPF remained lower than baseline (mean 408.6 ml/min/1.73 m²), and there was a trend towards the GFR remaining low (mean 111.8 ml/min/1.73 m²). Serum creatinine rose significantly (median pretreatment 72 mol/liter; median at four weeks 86 mol/liter) but returned to baseline after dose reduction. Plasma cyclosporin levels and serum creatinine did not help predict the extent of changes in renal function. At low doses, cyclosporin causes changes in renal hemodynamics that may not be reversed by dose reduction.     

Effect of inhibition of angiotensin converting enzyme on hypertension following kidney transplantation

The activation of the renin angiotensin system is thought to be an important factor contributing to hypertension following kidney transplantation (TX). We studied 21 hypertensive renal transplant recipients, without evidence of acute graft rejection or transplant artery stenosis, 6 to 60 months post-TX. The acute responses of mean arterial pressure (MAP) and renal hemodynamics (ERPF: effective renal plasma flow, 131I-Hippuran clearance) and function (GFR: glomerular filtration rate, creatinine clearance; UNaV: urinary sodium excretion rate) to converting enzyme inhibition (CEI) by captopril were assessed. CEI induced a decrease in MAP (118 +/- 2 to 110 +/- 2 mmHg), renal resistance (RR: 0.27 +/- 0.02 to 0.21 +/- 0.01) and filtration fraction (FF: 0.31 +/- 0.02 to 0.23 +/- 0.01). ERPF (307 +/- 24 to 333 +/- 18 ml/min/1.73 m2) and GFR (88 +/- 5 to 78 +/- 5 ml/min/1.73 m2) were not significantly changed. UNaV increased by 53 +/- 24 mumol/min. Changes in MAP (r = -0.66), ERPF (r = 0.74) and FF (r = -0.88) were significantly correlated with the log of control plasma renin activity (PRA). In 10 patients with an increase of ERPF (range: + 30 to + 70%) and no change in GFR, the activated renin system could originate from the recipient's own kidneys. In the remaining 11 patients, CEI was associated with no increase in ERPF (change: + 2 to - 27%) and a fall in GFR, a response suggesting a possible intrarenal vascular damage. These results indicate that RAS participates in the regulation of systemic and renal vascular tone, with a possible predominant effect on efferent glomerular arteriole.     

Renal function after autologous bone marrow transplantation in children: a long-term prospective study

We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean GFR before BMT was close to normal in both groups. Mean GFR decreased from 124 [CI 114,134] ml/min/1.73 m(2) before BMT to 99 [CI 82,115] ml/min/1.73 m(2) 6 months after BMT in the + TBI group (P < 0.001). There was no significant change in the -TBI group. Mean ERPF before BMT was high: 1110 [95% CI 830,1390] ml/min/1.73 m(2) in the + TBI group and 910 [CI 570,1250] ml/min/1.73 m(2) in the - TBI group. Six months after BMT, there was a tendency to a decrease in ERPF in the +TBI group, to 760 [CI 580,940] ml/min/1.73 m(2) (P = 0.064). After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR <70 ml/min/1.73 m(2)). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.     

Renal function and structure in subacute hepatic failure

BACKGROUND AND AIMS: Subacute hepatic failure (SHF) is a fatal complicaton of acute viral hepatitis. Renal failure has been implicated as the main cause of death in this disease. However, renal functional and structural evaluation in such patients have not been performed. The present prospective study evaluated the renal functional and structural abnormalities in patients with subacute hepatic failure. METHODS: Fourteen consecutive patients with SHF, 11 with acute liver failure (ALF) and 15 with cirrhosis of the liver (Child's B or C) were included in the present study. All 40 patients had liver disease caused by hepatitis viruses. The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) estimations were measured in all patients by the use of technetium-99m diethylenetriaminepentaacetic acid and [131I]-labeled ortho-iodohippuric acid, respectively. Ante-mortem or post-mortem liver biopsies were performed in all patients. In three patients with SHF, post-mortem kidney biopsies were also performed. RESULTS: Thirty six percent (5/14) of patients with SHF, 18% (2/11) of patients with ALF and 20% (3/15) of patients with cirrhosis had renal failure. Seven patients with SHF, seven with ALF and nine with cirrhosis died. All the patients with renal failure in each of the three groups were among the deceased patients. Glomerular function was markedly affected among patients with SHF, which was shown by significantly higher (P < 0.05) proteinuria levels (0.367 +/- 0.38 g/24 h) compared to levels in patients with ALF (0.178 +/- 0.11 g/24 h) and cirrhosis (0.212 +/- 0.133 g/24 h). The GFR in SHF (56 +/- 27 mL/min per 1.73 m2) and cirrhotic patients (58 +/- 36 mL/min per 1.73 m2) was significantly lower compared to those in ALF patients (102 +/- 51 mL/min per 1.73 m2; P < 0.05). A significantly higher proportion (P < 0.05) of patients with SHF and cirrhosis (64 and 73%, respectively) had a GFR below 80 mL/min per 1.73 m2 compared to patients with ALF (18%). The GFR value among the deceased SHF patients (46 +/- 26 mL/min per 1.73 m2) was significantly lower (P < 0.05) than those SHF patients who survived (65 +/- 25 mL/min per 1.73 m2). However, similar features could not be documented among patients with ALF or cirrhosis. Subtle structural changes in the glomerulus were also noted in patients with SHF. These included mesangial proliferation and thickening, basal membrane thickening and increased cellularity with interstitial edema. The ERPF was markedly reduced (P = 0.058) among patients with SHF (347 +/- 131 mL/min per 1.73 m2) and cirrhosis (395 +/- 137 mL/min per 1.73 m2) in comparison to ERPF documented among patients with ALF (436 +/- 217 mL/min per 1.73 m2). Such a reduction in renal tubular blood flow, along with histologic documentation of hyaline presence, bile and grannular cast in the tubule, indicated a possible tubular dysfunction in patients with SHF. CONCLUSION: It is concluded that glomerular and tubular dysfunction with subtle structural abnormalities does occur in patients with SHF. These are similar to renal changes in cirrhosis and may have similar pathogenetic mechanisms that require further evaluation.     

The effect of fenoldopam on renal haemodynamics and natriuresis in chronic renal failure

The effect of oral administration of fenoldopam, a dopamine-1 receptor agonist, on blood pressure, renal haemodynamics and natriuresis was studied in 12 patients with chronic renal insufficiency. In addition, the effect of administering a low intravenous dose of fenoldopam on top of the oral dose was compared with the effect of the same intravenous dose given immediately before oral fenoldopam. Oral administration of fenoldopam (50 mg t.i.d. for 3 +/- 1 days followed by 100 mg t.i.d. for 8 +/- 1 days) induced a significant fall in blood pressure (median MAP from 107 to 101 mm Hg). Compared to baseline values, body weight, effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and fractional sodium excretion remained unchanged. Infusion of fenoldopam (0.05-0.1 micrograms/kg/min) on day 1 led to a significant fall in blood pressure (median mean arterial pressure from 107.0 to 98.5 mm Hg), and a significant rise in effective renal plasma flow (median ERPF from 132 to 146 ml/min/1.73 m2). Median fractional sodium excretion increased significantly from 2.1 to 3.3%. GFR, filtration fraction and plasma aldosterone concentration did not change. No relationship was found between the fenoldopam-induced changes in ERPF and natriuresis, nor between baseline GFR or ERPF and fenoldopam-induced urinary sodium loss. Infusion of fenoldopam while patients were on oral fenoldopam had no effect on blood pressure, ERPF or GFR. However, again natriuresis was induced, which did not differ significantly from the fenoldopam-induced natriuresis on day 1. We conclude that oral fenoldopam has a moderate blood pressure lowering effect in patients with chronic renal insufficiency, but exerts no effect on ERPF or GFR. Secondly, a fenoldopam-induced natriuresis does not appear to be related to changes in ERPF or aldosterone secretion.     

Cyclophosphamide-containing regimen (TCD) is superior to melphalan-containing regimen (MPT) in elderly multiple myeloma patients with renal impairment

Renal impairment (RI) is a frequent complication with higher incidence of infections and an important prognostic factor for survival. Melphalan clearance is renal function dependent whereas cyclophosphamide is renal function independent. We investigated which combination regimen should be selected between melphalan-combining regimen (MPT) or cyclophosphamide-combining regimen (TCD) in elderly multiple myeloma (MM) patients with RI. Between 2005 and 2009, 157 newly diagnosed MM patients with RI were included comparing MPT with TCD therapy as initial treatment. Seventy-four patients were given MPT regimen, and 83 patients were given TCD regimen. Baseline characteristics were similar between the MPT and TCD groups. Analysis of different cutoff levels between 25% and 75% quartiles using log-rank test determined that glomerular filtration rate (GFR), 40 ml/min/1.73 m(2) as the cutoff point, yielded the highest difference in event-free survival (EFS) and overall survival (OS). The MPT subgroup with low GFR (GFR <40 ml/min/1.73 m(2)) had poorer response rates than others. The incidence of neutropenia and infection with febrile neutropenia were higher in the MPT subgroup with low GFR than the others (p = 0.016, p < 0.001). Furthermore, mortality due to the infection was higher in the MPT subgroup with low GFR than the others (p < 0.001). EFS was lower in the MPT subgroup with low GFR than the others (p < 0.001). OS was lower in the MPT subgroup with low GFR than the others (p < 0.001). In newly diagnosed elderly MM patients with RI, TCD regimen would be an effective and tolerable treatment option due to the combination of cyclophosphamide independent to renal function and dexamethasone effective for RI.     

Renal changes on hyperglycemia and angiotensin-converting enzyme in type 1 diabetes

Hyperglycemia causes capillary vasodilation and high glomerular capillary hydraulic pressure, which lead to glomerulosclerosis and hypertension in type 1 diabetic subjects. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene can modulate risk of nephropathy due to hyperglycemia, and the II genotype (producing low plasma ACE concentrations and probably reduced renal angiotensin II generation and kinin inactivation) may protect against diabetic nephropathy. We tested the possible interaction between ACE I/D polymorphism and uncontrolled type 1 diabetes by measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) during normoglycemia ( approximately 5 mmol/L) and hyperglycemia ( approximately 15 mmol/L) in 9 normoalbuminuric, normotensive type 1 diabetic subjects with the II genotype and 18 matched controls with the ID or DD genotype. Baseline GFR (145+/-22 mL/min per 1.73 m2) and ERPF (636+/-69 mL/min per 1.73 m2) of II subjects declined by 8+/-10% and 10+/-9%, respectively, during hyperglycemia; whereas baseline GFR (138+/-16 mL/min per 1.73 m2) and ERPF (607+/-93 mL/min per 1.73 m2) increased by 4+/-7% and 6+/-11%, respectively, in ID and DD subjects (II versus ID or DD subjects: P=0.0007 and P=0.0005, for GFR and ERPF, respectively). The changes in renal hemodynamics of subjects carrying 1 or 2 D alleles were compatible, with a mainly preglomerular vasodilation induced by hyperglycemia, proportional to plasma ACE concentration (P=0.024); this was not observed in subjects with the II genotype. Thus, type 1 diabetic individuals with the II genotype are resistant to glomerular changes induced by hyperglycemia, providing a basis for their reduced risk of nephropathy.     

Systemic and renal effect of nicotine in non-smokers: influence of vitamin C

OBJECTIVES: To investigate whether the administration of the anti-oxidant vitamin C could prevent the systemic and renal effects of nicotine in healthy non-smoker volunteers. METHODS: The acute effects of oral, 4 mg, nicotine gum (n = 10), intravenous vitamin C (12 mmol, n = 8) or both (n=9) on mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and urinary cyclic guanosine monophosphate (cGMP) were assessed in non-smokers. RESULTS: In subjects receiving nicotine, MAP (+8 +/- 4 mmHg, P<0.0001) and HR (+13 +/- 8 beats/min, P < 0.001) increased whereas ERPF (-65 +/- 69 ml/min per 1.73 m2, P < 0.01), GFR (-14.5 +/- 16.8 ml/min per 1.73 m2, P < 0.01) and cGMP (-180 +/- 173 pmol/min, P < 0.01) decreased as compared to baseline values. The concomitant administration of nicotine and vitamin C caused similar haemodynamic changes; however, cGMP remained unchanged. In subjects receiving only vitamin C, there were no significant changes in MAP, heart rate, ERPF, GFR and cGMP. CONCLUSIONS: The present findings indicate that vitamin C was unable to prevent the renal vasoconstriction, but it prevented the fall in cGMP provoked by nicotine in non-smokers. This suggests that nicotine induces a degradation of nitric oxide mediated by oxygen-derived free radicals which may be prevented by vitamin C administration. The nicotine-induced renal vasoconstriction may be related to other mechanism(s).     

Renal functional reserve is impaired in patients with systemic sclerosis without clinical signs of kidney involvement

OBJECTIVE: To evaluate the functional response of the kidney to an amino acid challenge (the so called renal functional reserve (RFR)) in patients with systemic sclerosis (SSc) with no clinical sign of renal involvement. METHODS: Before and after an intravenous amino acid load (Freamine III Baxter, 8.5% solution, 4.16 ml/min for two hours), glomerular filtration rate (GFR, as creatinine clearance), effective renal plasma flow (ERPF, as para-aminohyppurate clearance), and calculated total renal vascular resistance (TRVR) were measured in 21 patients with SSc with apparently normal renal function and 10 normal controls. RESULTS: In basal conditions, patients had lower ERPF (403.5 (SD 43.8) v 496.4 (SD 71.3) ml/min, p<0.0002) and higher TRVR (10 822 (SD 2044) v 8874 (SD 1639) dyne/sxcm(-5), p<0.014) than controls. The RFR, evaluated as the percentage increase of GFR after the amino acid load, was significantly reduced in patients with SSc (SSc +1.9 (SD18.6)%, controls +34.8 (SD 13.9)%; p<0.0002). However, the response of patients was not uniform. Multiple regression analysis showed that the RFR was inversely dependent on the patients' mean arterial pressure at admission and basal GFR (R(2)=65%, p<0.0001). CONCLUSIONS: Most patients with SSc cannot increase renal filtration under the challenge of a protein overload. This defective renal response to the amino acid load test sustains the concept of the prevalence of vasoconstrictor over vasodilating factors in the kidney of these patients.     

Advancing age and acute infection influence the kinetics of ceftazidime

The pharmacokinetics of ceftazidime were studied after single intravenous injections of 2 g in 10 healthy, elderly male volunteers (63-76 years old). None of the subjects were on concurrent drug treatment and all had normal age-correlated glomerular filtration rate. Mean values for major pharmacokinetic variables were: terminal half-life 2.63 h, area under the serum concentration curve 417.6 h mg/l, total clearance 74.6 ml/(min 1.73 m2), renal clearance 53.6 ml/(min 1.73 m2), urinary recovery/12 h 71.7% of dose and apparent volume of distribution (Vss) 15.0 l/1.73 m2. Data were compared with our earlier findings in studies of young male volunteers and elderly, acutely ill male patients. Advanced age was accompanied by a reduction in clearance of ceftazidime, while no significant age-related changes in distribution were noted. Acute infection was associated with increased Vss and enhanced renal clearance; alterations possibly caused by fever-induced changes in vascular permeability and renal blood-flow.     

Performance of the revised ‘175’ Modification of Diet in Renal Disease equation in patients with type 2 diabetes

AIMS/HYPOTHESIS: Estimation of GFR (eGFR) is recommended for the assessment of kidney function in all patients with diabetes. We studied performance of the traditional '186' Modification of Diet in Renal Disease (MDRD) equation, and the 2005 revised '175' MDRD equation in patients with type 2 diabetes. METHODS: Two hundred and ninety-three mainly normoalbuminuric (267/293) patients were recruited. Patients were classified as having mild renal impairment (group 1, GFR <90 ml min(-1) 1.73 m(-2)) or normal renal function (group 2, GFR >or=90 ml min(-1) 1.73 m(-2)). eGFR was calculated by the traditional 186 MDRD equation using traditional creatinine values and the revised 175 MDRD equation using isotope dilution mass spectrometry-standardised creatinine values. Isotopic GFR was measured by the four-sample plasma clearance of (51)Cr-EDTA. RESULTS: For patients in group 1, mean +/- SD isotopic (51)Cr-EDTA GFR (iGFR) was 83.8 +/- 4.3 ml min(-1) 1.73 m(-2), and eGFR was 73.2 +/- 11.9 and 75.8 +/- 13.7 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -10.6 with the 186 MDRD and -7.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. In group 2, iGFR was 119.4 +/- 20.2 ml min(-1) 1.73 m(-2), and eGFR was 92.3 +/- 18.6 and 97.5 +/- 21.6 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -27.1 with the 186 MDRD equation and -21.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. CONCLUSIONS/INTERPRETATION: In patients newly diagnosed with type 2 diabetes, the revised 175 MDRD equation was less biased than the traditional 186 MDRD equation. Despite a continued tendency to underestimate isotopically measured GFR, use of standardised creatinine values is a positive step towards improved estimation of GFR.     

Validity of creatinine clearance from serum creatinine in subjects over 80 years old

In clinical practice, the Cockcroft and Gault formula (CG) is used to evaluate creatinine clearance from serum creatinine in the elderly. Its validity in a very old nondebilitated population over 80 years of age has not been investigated. In our study, we compared the calculated creatinine clearance with the glomerular filtration rate (GFR) measured using the clearance of 99m-diethyleenetriamine pentaacetic acid (99m Tc TDPA), isotopic method which avoids urinary collection in 25 patients over 80 years old. The CG clearance largely underestimates the isotopic GFR: mean calculated creatinine clearance is 37.6 ± 9.8 ml/min/1.73 m2 and the mean isotope GFR is 57.8 ± 15 ml/min/1.73 m2. The mean underestimation is the same in the subgroup of 11 patients with plasma creatininemia below 100 μmol/l and in the subgroup of 14 patients with creatininemia over 100 μmol/1.     

Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction: are the equations for estimating renal function better?

BACKGROUND: The Cockcroft-Gault formula (CGF) is used to estimate the glomerular filtration rate (GFR) based on serum creatinine (Cr) levels, age and sex. A new formula developed by the Modification of Diet in Renal Disease (MDRD) Study Group, based on the patient's Cr levels, age, sex, race and serum urea nitrogen and serum albumin levels, has shown to be more accurate. However, the best formula to identify patients with advanced liver disease (ALD) and moderate renal dysfunction (GFR 60 mL/min/1.73 m2 or less) is not known. The aim of the present study was to compare calculations of GFR, using published formulas (excluding those requiring urine collections) with standard radionuclide measurement of GFR in patients with ALD. METHODS: Fifty-seven consecutive subjects (40% women) with a mean age of 50 years (range 16 to 67 years) underwent 99m-technetium-diethylenetriamine pentaacetic acid (99mTc-DTPA) (single injection) radionuclide measurement of GFR. To calculate GFR, three formulas were used: the reciprocal of Cr multiplied by 100 (100/Cr), the CGF and the MDRD formulas. Pearson's correlation coefficient (r) and Bland-Altman analyses of agreement were used to analyze the association between 99mTc-DTPA clearance and the three equations for GFR. RESULTS: The mean 99mTc-DTPA clearance was 83 mL/min/1.73 m2 (range 28 mL/min/1.73 m2 to 173 mL/min/1.73 m2). Mean calculated GFRs by 100/Cr, the CGF and the MDRD formula were 106 mL/min/1.73 m2, 98 mL/min/1.73 m2 and 86 mL/min/1.73 m2, respectively. Regression analysis showed good correlation between radionuclide GFR and calculated GFR with r(100/Cr)=0.74, r(CGF)=0.80, r(MDRD)=0.87, all at P > or = 0.0001. The MDRD formula provided the least bias. The Bland-Altman plot showed best agreement between GFR calculated by the MDRD formula and 99mTc-DTPA clearance, with only 3 mL/min/1.73 m2 overestimation. There was higher variability between radionuclide GFR and calculated GFR by the CGF and by 100/Cr. Although there was no difference in precision, GFR calculated by the MDRD formula had the best overall accuracy. The sensitivity and specificity for detection of moderate renal dysfunction by the MDRD formulas were 73% and 87%, respectively. CONCLUSIONS: Among the Cr-based GFR formulas, the MDRD formula showed a larger proportion of agreement with radionuclide GFR in patients with ALD. In clinical practice, the MDRD is the best formula for detection of moderate renal dysfunction among those with ALD.     

The relationship between renal functions and thrombolysis in myocardial infarction frame count in patients with slow coronary flow

We investigated the relationship between renal function and coronary thrombolysis in myocardial infarction frame count (TFC) in patients with slow coronary flow (SCF). The patient group was composed of 34 patients with SCF. The control group was made up of 34 well-matched individuals who have normal SCF in their coronary arteries. The coronary flow rates of all subjects were documented by TFC. Glomerular filtration rate (GFR) and corrected GFR (cGFR) were calculated by creatinine clearance according to the Cockcroft-Gault formula. There is no difference in the gender or age of the groups. Blood urea nitrogen and creatinine were significantly higher in the SCF group compared the control group (blood urea nitrogen: 17 ± 6 mg/dL vs. 14 ± 4 mg/dL, p=0.04 and creatine: 0.9 ± 0.1mg/dL vs. 0.7 ± 0.1mg/dL, p=0.01). GFR and cGFR were significantly different between the groups (GFR: 92 ± 28 mL/min vs. 112 ± 27 mL/min, p=0.004 and cGFR: 77 ± 22 mL/min/1.73 m(2)vs. 96 ± 24 mL/min/1.73 m(2), p=0.007). There was a negative correlation between GFR/cGFR and TFC in all coronary arteries. This study shows that impaired renal function is associated with SCF. Patients with SCF have worse renal function compared with patients without SCF.     

The impact of renal function on the long-term clinical course of patients who underwent percutaneous coronary intervention.

OBJECTIVES: To determine the impact of the level of kidney function on the extended (>5 years) long-term clinical course of patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Chronic kidney disease (CKD) has been significantly associated with an increased in-hospital and 1-year mortality following PCI. METHODS: In this single-centre retrospective study, glomerular filtration rate (GFR) at baseline was estimated in 371 patients not on dialysis, who underwent successful PCI between mid-1995 and mid-1999. Baseline demographic and angiographic characteristics, and long-term major adverse cardiac events and symptoms were compared for patients with GFR > or =60 ml/min/1.73 m(2) (normal or mildly impaired renal function) and GFR > or = 60 ml/ min/1.73 m(2) (CKD). The independent effect of GFR, modelled both as a categorical and a continuous variable, on long-term clinical outcomes was also investigated using multivariate Cox regression analysis. RESULTS: Nine-year all-cause and cardiac mortality rates were significantly higher in the CKD group (45.9% vs. 10.6%, P < 0.0001 and 35.4% vs. 7.1%, P < 0.0001 respectively), while there was no difference in the repeat revascularization (P = 0.27) and nonfatal Q-wave myocardial infarction (P = 0.74) rates. Multivariate analysis demonstrated an independent impact of the level of GFR on long-term mortality; adjusted 9-year all-cause and cardiac mortality increased by approximately 16% and 11%, respectively for a decrease of GFR from 120 to 60 ml/min/1.73 m(2) and by approximately 14% and 9%, respectively for a decrease of GFR from 60 to 30 ml/min/1.73 m(2). CONCLUSIONS: The level of renal function is a strong determinant of long-term all-cause and cardiac mortality after successful PCI.     

Renal function in the obese Zucker rat

The hyperphagic, genetically obese Zucker rat (fa/fa) exhibits both a greater kidney size and a progressive, premature glomerular sclerosis. In the present study, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and renal tubular function were evaluated during study 1 in lean Zucker (FA/-), fa/fa, and lean Sprague-Dawley (S-D) rats. The GFR as measured by renal inulin clearance (ClIN) was not significantly different (P greater than 0.05) between S-D (1.36 +/- 0.18 ml/min) vs FA/- (1.36 +/- 0.33 ml/min) and FA/- vs fa/fa (1.25 +/- 0.42 ml/min). The ERPF as measured by renal p-aminohippurate (PAH) clearance (ClPAH) also was not significantly different between S-D (3.98 +/- 0.80 ml/min) vs Fa/- (3.71 +/- 0.81 ml/min) and Fa/- vs fa/fa (3.34 +/- 1.60 ml/min). There was a significant difference (P less than 0.05) in the renal tubular transport maximum (Tm) of PAH between S-D (2.23 +/- 0.40 mg/min) and Fa/- (1.64 +/- 0.63 mg/min) groups but not between Fa/- and fa/fa (1.29 +/- 0.61 mg/min) groups, indicating a strain effect in organic anionic renal transport. The Fa/- vs fa/fa comparisons were significant when GFR, ERPF and Tm were corrected for total body or kidney weight. In a second group of animals (study 2), GFR (as reflected by creatinine clearance [Clcr]) and histologic studies were performed in Fa/- and fa/fa rats. Clcr values were significantly higher in the fa/fa (2.10 +/- 0.44 ml/min) vs Fa/- (1.68 +/- 0.17 ml/min). Histologic studies in group 2 demonstrated no remarkable differences between Fa/- and fa/fa rats. These results suggest wide interanimal variation in obesity associated changes in renal function and possibly pathology in the fa/fa rat.     

Influence of renal function on the usefulness of N-terminal pro-B-type natriuretic peptide as a prognostic cardiac risk marker in patients undergoing noncardiac vascular surgery

N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is related to stress-induced myocardial ischemia and/or volume overload, both common in patients with renal dysfunction. This might compromise the prognostic usefulness of NT-pro-BNP in patients with renal impairment before vascular surgery. We assessed the prognostic value of NT-pro-BNP in the entire strata of renal function. In 356 patients (median age 69 years, 77% men), cardiac history, glomerular filtration rate (GFR, ml/min/1.73 m(2)), and NT-pro-BNP level (pg/ml) were assessed preoperatively. Troponin T and electrocardiography were assessed postoperatively on days 1, 3, 7, and 30. The end point was the composite of cardiovascular death, Q-wave myocardial infarction, and troponin T release. Multivariate analysis was used to evaluate the interaction between GFR, NT-pro-BNP and their association with postoperative outcome. Median GFR was 78 ml/min/1.73 m(2) and the median concentration of NT-pro-BNP was 197 pg/ml. The end point was reached in 64 patients (18%); cardiac death occurred in 7 (2.0%), Q-wave myocardial infarction in 34 (9.6%), and non-Q-wave myocardial infarction in 23 (6.5%). After adjustment for confounders, NT-pro-BNP levels and GFR remained significantly associated with the end point (p = 0.005). The prognostic value of NT-pro-BNP was most pronounced in patients with GFR > or =90 (odds ratio [OR] 1.18, 95% confidence interval [CI] 0.80 to 1.76) compared with patients with GFR 60 to 89 (OR 1.04, 95% CI 1.002 to 1.07), and with GFR 30 to 59 (OR 1.12, 95% CI 1.03 to 1.21). In patients with GFR <30 ml/min/1.73 m(2), NT-pro-BNP levels have no prognostic value (OR 1.00, 95% CI 0.99 to 1.01). In conclusion, the discriminative value of NT-pro-BNP is most pronounced in patients with GFR > or =90 ml/min/1.73 m(2) and has no prognostic value in patients with GFR <30 ml/min/1.73 m(2).     

Preservation of glomerular filtration rate in human heart failure by activation of the renin-angiotensin system

When renal perfusion pressure is reduced in experimentally induced low-output states, glomerular filtration rate is preserved by angiotensin II-mediated efferent arteriolar vasoconstriction, but available evidence in man suggests that angiotensin II supports renal function only to the extent that it preserves systemic blood pressure. We performed simultaneous assessments of cardiac and renal function in 56 patients with severe chronic heart failure before and after 1 to 3 months of converting-enzyme inhibition. Among the 29 patients with a pretreatment renal perfusion pressure under 70 mm Hg, patients with preserved renal function (creatinine clearance greater than 50 ml/min/1.73 m2) had markedly elevated values for plasma renin activity (11.8 +/- 3.8 ng/ml/hr) and showed a significant decline in creatinine clearance after converting-enzyme inhibition (61.1 +/- 3.0 to 45.9 +/- 5.3 ml/min/1.73 m2; p less than .05). In contrast, although similar with respect to all pretreatment demographic, hemodynamic, and clinical variables, patients with a creatinine clearance under 50 ml/min/1.73 m2 had low values for plasma renin activity (3.4 +/- 0.8 ng/ml/hr) and, despite similar drug-induced decreases in systemic blood pressure, showed no change in creatinine clearance after therapy with captopril or enalapril (32.6 +/- 2.5 to 41.4 +/- 3.8 ml/min/1.73 m2). Changes in creatinine clearance varied linearly and inversely with pretreatment values for plasma renin activity (r = - .64, p less than .001); converting-enzyme inhibition effectively abolished the pretreatment difference in renal function seen in the high- and low-renin subgroups. In the 27 patients with a renal perfusion pressure of 70 mm Hg or greater, creatinine clearance did not vary significantly with plasma renin activity and was not altered by therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular and renal profile of acute peripheral dopamine1-receptor agonism with fenoldopam

Whether the dopaminergic system may be involved in essential hypertension is of pathogenetic as well as therapeutic interest. Therefore, we investigated in eight hypertensive and 12 normal subjects cardiovascular, endocrine, and renal responses to fenoldopam, which has been characterized experimentally as an agonist of peripheral postsynaptic dopamine1 receptors. A single oral dose of fenoldopam, 100 mg, changed blood pressure (BP) in hypertensive subjects (from 163/103 to 147/76 mm Hg; p less than 0.01 for systolic and p less than 0.001 for diastolic BP) and normal subjects (from 121/81 to 123/65 mm Hg; p less than 0.001 for diastolic BP); percentage decreases in diastolic BP averaged -20 +/- 6 and -16 +/- 7%, respectively. Fenoldopam-induced effects on other variables were similar in the two groups. Heart rate rose (p less than 0.001) on average from 69 to 92 beats/min in hypertensive and from 64 to 84 beats/min in normal subjects. Effective renal plasma flow increased (from 552 to 765 and 634 to 937 ml/min/1.73 m2; p less than 0.01), while glomerular filtration rate tended to decrease (from 121 to 99 ml/min/1.73 m2 in the hypertensive and from 119 to 97 ml/min/1.73 m2; p less than 0.001 in the normal group). Fractional sodium clearance was elevated (from 2.8 to 5.2 and 1.7 to 3.8%; p less than 0.01), as was free water clearance (from -1.7 to 0.6 and -1.7 to 0.1 ml/min/1.73 m2; p less than 0.01). Potassium clearance was largely unchanged. Plasma renin activity increased about twofold (p less than 0.01 in normal subjects), and plasma aldosterone by 40% (NS). Plasma norepinephrine levels increased twofold to 2.5-fold (p less than 0.001), and urinary norepinephrine excretion fivefold to 10-fold (p less than 0.01). Fenoldopam-induced changes were not significantly modified by intravenous and/or oral pretreatment with the dopamine-receptor antagonist metoclopramide or the cyclooxygenase inhibitor indomethacin. These findings suggest that in humans, fenoldopam may acutely override the dopaminergic antagonism of metoclopramide given in clinical dosage and that its cardiovascular and renal effects are not prostaglandin-mediated. Although acute sympathetic stimulation may be partially antagonistic, the concomitant BP-lowering, renal vasodilating, and natriuretic actions of fenoldopam represent a desirable profile of a potential antihypertensive agent.     

Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.

The relationship between renal insufficiency and amino-terminal pro-brain natriuretic peptide (NT-proBNP) levels remains unclear. We examined this relationship in the context of patients who presented to the emergency department of an urban tertiary care medical center with dyspnea. Even in the presence of renal insufficiency, NT-proBNP remained a valuable tool for the diagnosis of acute congestive heart failure and it provides important prognostic information. OBJECTIVES: We sought to examine the interaction between renal function and amino-terminal pro-brain natriuretic peptide (NT-proBNP) levels. BACKGROUND: The effects of renal insufficiency on NT-proBNP among patients with and without acute congestive heart failure (CHF) are controversial. We examined the effects of kidney disease on NT-proBNP-based CHF diagnosis and prognosis. METHODS: A total of 599 dyspneic patients with glomerular filtration rates (GFRs) as low as 14.8 ml/min were analyzed. We used multivariate logistic regression to examine covariates associated with NT-proBNP results and linear regression analysis to analyze associations between NT-proBNP and GFR. Receiver-operating characteristic analysis determined the sensitivity and specificity of NT-proBNP for CHF diagnosis. We also assessed 60-day mortality rates as a function of NT-proBNP concentration. RESULTS: Glomerular filtration rates ranged from 15 ml/min/1.73 m2 to 252 ml/min/1.73 m2. Renal insufficiency was associated with risk factors for CHF, and patients with renal insufficiency were more likely to have CHF (all p < 0.003). Worse renal function was accompanied by cardiac structural and functional abnormalities on echocardiography. We found that NT-proBNP and GFR were inversely and independently related (p < 0.001) and that NT-proBNP values of > 450 pg/ml for patients ages <50 years and >900 pg/ml for patients > or =50 years had a sensitivity of 85% and a specificity of 88% for diagnosing acute CHF among subjects with GFR > or =60 ml/min/1.73 m2. Using a cut point of 1,200 pg/ml for subjects with GFR <60 ml/min/1.73 m2, we found sensitivity and specificity to be 89% and 72%, respectively. We found that NT-proBNP was the strongest overall independent risk factor for 60-day mortality (hazard ratio 1.57; 95% confidence interval 1.2 to 2.0; p = 0.0004) and remained so even in those with GFR <60 ml/min/1.73 m2 (hazard ratio 1.61; 95% confidence interval 1.14 to 2.26; p = 0.006). CONCLUSIONS: The use of NT-proBNP testing is valuable for the evaluation of the dyspneic patient with suspected CHF, irrespective of renal function.