The effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography

BACKGROUND: Renal failure induced by radiographic contrast agents is a known complication of coronary angiography, especially among patients with chronic renal failure. Recently, treatment with N-acetylcysteine (NAC) has been shown to have a protective effect but the mechanisms are unknown. We examined the hypothesis that NAC protected against contrast-induced renal impairment through effects on nitric oxide metabolism and oxidative stress. METHODS: Patients with a serum creatinine concentration above 10(6) micromol/L undergoing coronary angiography were randomly assigned to receive either NAC 1 g (N= 24) or placebo (N= 29) twice daily 24 hours before and after angiography with 0.45% saline hydration in a double-blind study. Creatinine clearance was calculated and urinary nitric oxide and F2-isoprostane excretion were measured at baseline, 24 and 96 hours after angiography. RESULTS: Treatment with NAC significantly improved the effect of contrast media on creatinine clearance, and maximal beneficial effect was observed 24 hours after angiography. Creatinine clearance (mL/min) was 59.5 +/- 4.4, 64.7 +/- 5.8, and 58.7 + 3.9 at baseline, 24, and 96 hours after angiography in the NAC group, respectively, and 65.2 +/- 3.2, 51.5 +/- 3.7, and 53.6 +/- 3.9 in the placebo group, respectively (P < 0.0001). NAC treatment prevented the reduction in urinary nitric oxide after angiography. The urinary nitric oxide/creatinine ratio (micromol/mg) was 0.0058 +/- 0.0004, 0.0057 +/- 0.0004, and 0.0052 +/- 0.0004 at baseline, 24, and 96 hours after angiography in NAC group, respectively, and 0.0057 +/- 0.0007, 0.0031 +/- 0.0005, and 0.0039 +/- 0.0005 in the placebo group, respectively (P= 0.013). NAC had no significant effect on urinary F2-isoprostanes. CONCLUSION: NAC treatment has renoprotective effect in patients with mild chronic renal failure undergoing coronary angiography that may be mediated in part by an increase in nitric oxide production.     

Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism

BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration. METHODS: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.     

Urinary excretion of endothelin-1 (ET-1), transforming growth factor- beta1 (TGF- beta1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial.

The severity and dynamics of renal tissue damage in chronic kidney disease (CKD) may be reflected by the urinary excretion of vasoactive and growth factors released by the damaged kidney. Urinary excretion of ET-1, TGF-beta1 and VEGF(165) was evaluated in 303 children with CKD stage II-IV (GFR 48 +/- 22 ml/min/1.73 m(2)) and 81 age-matched healthy controls. Major renal disease groups were hypo-/dysplastic kidney disease (N = 183), obstructive uropathies (N = 47), glomerulopathies (N = 34), nephronophthisis (N = 19) and polycystic kidney disease (N = 20). RESULTS: The mean urinary excretion rates of each of the three putative biomarkers were significantly elevated in CKD patients compared to controls: 965 +/- 2042 vs 216 +/- 335 fmol/g creatinine for ET-1; 252 +/- 338 vs 155 +/- 158 ng/g for VEGF; 31.6 +/- 37.0 vs 10.9 +/- 9.8 ng/g for TGF-beta1 (each P < 0.0001). The excretion of ET-1 and TGF-beta1 was highest in patients with obstructive uropathies. In the patients, ET-1, TGF-beta1 and VEGF excretion rates were inversely correlated with age (r = -0.22, -0.32 and -0.17, all P < 0.005) and renal function (r = -0.21, -0.13 and -0.15; P < 0.001; < 0.05; < 0.01; respectively) VEGF and TGF-beta1 excretion rates were positively correlated both in patients and controls. CONCLUSIONS: Children with CKD exhibit significantly elevated urinary excretion of ET-1, TGF-beta1 and VEGF(165) in comparison to healthy children. Urinary excretion of these biomarkers was most enhanced in patients with obstructive uropathies. A positive correlation between urinary TGF-beta1 and VEGF(165) excretion, shown both in patients and healthy controls, indicates an interdependent nature of their generation.     

Decreased renal transplant function after parathyroidectomy.

BACKGROUND: Persistent secondary hyperparathyroidism after renal transplantation may require parathyroidectomy (PTX). Clinical experience suggests that these patients commonly develop decreased renal function thereafter. METHODS: To test this notion, we evaluated 76 transplant patients who underwent pararhyroidectomy between 1997 and 2003. RESULTS: In half the patients (47%), creatinine clearance decreased >20% (before vs after PTX, 57 +/- 21 vs 38 +/- 17 ml/min, P = 0.001). The patients with decreased creatinine clearance had higher parathyroid hormone (PTH) concentrations before and lower values after PTX compared with those who did not (594 +/- 392 vs 447 +/- 234 pg/ml before PTX, P = 0.03; 35 vs 123 pg/ml thereafter, P = 0.002). They also had lower serum calcium concentrations after PTX (2.0 vs 2.2 mmol/l, P = 0.005) and they required more calcium and vitamin D analogues. These patients also more commonly underwent total PTX with autotransplantation, compared with subtotal (75 vs 50%, P = 0.03). However, in multivariate analysis, only the delta PTH decline (%) after PTX was a significant predictor of deteriorating renal function (P = 0.005) and was correlated with the creatinine clearance decrease (R = 0.369, P = 0.001). Prospectively measured inulin and para-amino-hippuric acid (PAH) clearance decreased significantly after PTX in a subgroup of 19 patients (inulin before vs after PTX 67 vs 55 ml/min/1.73 m(2), P = 0.001; PAH 360 vs 289 ml/min/1.73 m(2), P = 0.001). Transplant biopsies revealed calcification in 70% of biopsied cases. CONCLUSION: Since PTH has a known positive regulatory effect on renal perfusion and glomerular filtration rate, we conclude that relative hypoparathyroidism after PTX is the main mechanism contributing to decreased renal function in these patients. There was no difference in 10-year-graft survival between the deteriorating and the non-deteriorating group.     

N-acetylcysteine for the prevention of kidney injury in abdominal aortic surgery: a randomized, double-blind, placebo-controlled trial

In this prospective, randomized, placebo-controlled, double-blind trial we studied the effects of IV N-acetylcysteine for prevention of renal injury in patients undergoing abdominal aortic surgery. Seventy patients without previously documented renal dysfunction were randomly allocated to receive either N-acetylcysteine (150 mg/kg mixed in 250 mL of 5% dextrose infused in 20 min, followed by an infusion of 150 mg/kg in 250 mL of 5% dextrose over 24 h) or placebo. The infusion was started after the induction of anesthesia. The primary outcome measure was renal injury as measured by the increases in urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine ratio (indicator of renal tubular injury) and urinary albumin/creatinine ratio (indicator of glomerular injury). Renal function was assessed by measuring plasma creatinine and serum cystatin C concentrations. The urinary NAG/creatinine ratio increased significantly from baseline to before crossclamp and remained increased on day 5 in both groups. The urinary albumin/creatinine ratio increased significantly from baseline to 6 h after declamping in the N-acetylcysteine group. However, the changes in the NAG/creatinine ratio and the albumin/creatinine ratio were not significantly different between the two groups. Plasma creatinine and serum cystatin C values remained unchanged during the study period in both groups. In conclusion, N-acetylcysteine did not offer any significant protection from renal injury during elective aortic operation in patients with normal preoperative renal function, and some degree of tubular injury seems to occur before aortic crossclamp.     

Radiocontrast-induced nephrotoxicity and urinary alpha-glutathione S-transferase levels: Effect of amlodipine administration

AIMS: The exact pathogenesis and prophylaxis concerning radiocontrast-induced nephrotoxicity (RCIN) was unclear. Short-acting calcium antagonists were used to prevent RCIN. This study was designed to evaluate the role of a long-acting calcium antagonist (amlodipine) administration by determining serum creatinine (SCre) levels and 24 hour urinary excretion rates of glutathione S-transferase alpha (GST-alpha) which has a selective localization only to proximal tubular epithelium. METHODS: In a prospective trial, 29 outpatients (19 M, 10 F) undergoing coronary angiography were randomized and either amlodipine 10 mg/day (n = 15) or placebo (n = 14) were administered prior to angiography and continued thereafter. All patients had normal basal renal function and none of them had any risk factor for RCIN. A low osmolar, nonionic contrast media (iopamidol 76%) was administered to all patients. Creatinine clearance (CCre), SCre and 24-hour urinary GST-alpha levels were measured before, 24 hours and 7 days after angiography. RESULTS: SCre and 24 hour urinary GST-alpha values increased on 24th hour following the angiography in both groups (p < 0.017 and 0.001, respectively). Pretreatment with amlodipine created no difference in both variables (p > 0.05). CONCLUSIONS: A reversible tubular dysfunction occurs following radiocontrast administration which was manifested by an increase in urinary GST-alpha excretion rates. Pretreatment with a long acting calcium antagonist amlodipine has no effect on the course of enzyme excretion and alteration observed in SCre.     

Lack of protection of N-acetylcysteine (NAC) in acute renal failure related to elective aortic aneurysm repair-a randomized controlled trial.

BACKGROUND: N-acetylcysteine (NAC) is an antioxidant drug largely tested in different clinical situations. Recently, NAC has been employed with variable success in the prevention of radiocontrast nephropathy. Since aortic aneurysm surgical repair is a condition that is frequently accompanied by acute renal failure (ARF), we sought to investigate whether NAC has any role in preventing ARF in this scenario. METHODS: A randomized, placebo-controlled, double-blind trial with the following inclusion criteria: elective aortic aneurysm repair in patients with stable renal function. The groups were randomly matched for age, gender, presence of diabetes and pre-existent renal failure. NAC or placebo (control) was administered p.o. for 24 h before operation and maintained i.v. for 48 h after operation. The dose of NAC was 1200 mg b.i.d. the day before surgery and 600 mg b.i.d. after. The primary endpoint was the development of ARF up to the third post-operative day, defined as an increase in SCr > or = 25% from baseline. Secondary endpoints were: ICU mortality and ICU length of stay. RESULTS: Forty-two patients (n = 18 for NAC group and n = 24 for control) were studied. The baseline SCr and calculated GFR did not differ between the groups (1.19 +/- 0.33 vs 1.37 +/- 0.49 mg/dl; and 64.6 +/- 26.22 vs 65.7 +/- 28.32 ml/min, NAC vs control, respectively, P = 0.17 and P = 0.90). Need for suprarenal aortic cross-clamping and its duration, occurrence of major bleeding, intra-operative hypotension and the post-operative peak of CPK did not differ between NAC and control groups. The overall incidence of ARF in the study was 36% (13/36), but it was not significantly different between groups (7/14, 50% in NAC vs 6/22, 27.3% in control, P = 0.16). The overall mortality was 23% (10/42) and was not different (P = 0.209) in NAC group (33.3%) when compared with control (16.7%), the same occurring with the length of ICU stay (2.93 +/- 1.53 vs 2.52 +/- 1.36 days, P = 0.40). CONCLUSION: This study suggests that the putative beneficial effects of NAC on radiocontrast nephropathy might not be applicable to other situations, such as ARF associated with elective aortic aneurysm repair.     

Ketorolac is not nephrotoxic in connection with sevoflurane anesthesia in patients undergoing breast surgery

Ketorolac, which may cause renal vasoconstriction by cyclooxygenase inhibition, is often administered to patients anesthetized with sevoflurane that is metabolized to inorganic fluoride (F(-)), another potential nephrotoxin. We assessed this possible interaction using urine N-acetyl-beta-D-glucosaminidase indexed to urinary creatinine (U-NAG/crea) as a marker of proximal tubular, beta2-microglobulin as a tubular, urine oxygen tension (P(u)O(2)) as a medullary, and erythropoietin as a marker of tubulointerstitial damage. Thirty women (ASA physical status I-II) undergoing breast surgery were included in our double-blinded study. They were allocated into two groups receiving either ketorolac 30 mg IM (Group K) or saline (Group C) at the time of premedication, at the end of, and 6 h after anesthesia maintained with sevoflurane. Urine output, U-NAG/crea, P(u)O(2,) serum creatinine, urea, and F(-) were assessed. Blood loss was larger in Group K (465 +/- 286 mL vs 240 +/- 149 mL, mean +/- SD, P < 0.05). The MAC-doses of sevoflurane were similar. U-NAG/crea increased during the first 2 h of anesthesia and serum F(-) peaked 2 h after the anesthesia without differences between the groups. There were no statistically significant changes in P(u)O(2), erythropoietin, beta2-microglobulin, serum creatinine, urea, or urine output during anesthesia or the recovery period in either group. Our results indicate that the kidneys are not affected by ketorolac administered in connection with sevoflurane anesthesia. IMPLICATIONS: The different kinetics of N-acetyl-beta-D-glucosaminidase indexed to urinary creatinine and serum inorganic fluoride during and after sevoflurane anesthesia suggest that the observed mild renal tubular function deterioration is not caused by inorganic fluoride. Administration of ketorolac IM is therefore considered safe in adequately hydrated healthy adult patients given sevoflurane anesthesia.     

Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes

Increased (intra)renal activity of the renin-angiotensin system may cause a persistent increase in renovascular resistance and intraglomerular pressure in patients with diabetes, thus contributing to the development of diabetic renal damage. The effect of chronic angiotensin II subtype 1 receptor blockade on (intra)renal hemodynamics in patients with type 2 diabetes was examined in a double-blind parallel group study. Patients were treated with 40 mg of olmesartan (n = 19) or placebo (n = 16), and renal hemodynamics were assessed before and after 12 wk of treatment using inulin and para-aminohippurate clearance techniques. Olmesartan significantly reduced 24-h ambulatory systolic and diastolic BP (both P < 0.05). In parallel, effective renal plasma flow increased significantly from 602 +/- 76 to 628 +/- 87 ml/min per 1.73 m(2), whereas filtration fraction and renovascular resistance decreased significantly (all P < 0.05). With placebo treatment, effective renal plasma flow decreased and filtration fraction increased significantly (both P < 0.05). GFR was not affected by both treatments. Active plasma renin concentration increased considerably (P < 0.05) with olmesartan therapy but remained unchanged with placebo treatment. Nitric oxide metabolism (plasma nitrate and nitrite) and asymmetric dimethylarginine blood levels were not affected by olmesartan and placebo therapy. In contrast, plasma 8-isoprostane 15(S)-8-iso-prostaglandin F(2a) concentration, a biochemical marker of oxidative stress, decreased significantly (P < 0.05) with olmesartan treatment. Chronic angiotensin II subtype 1 receptor blockade decreases (intra)renal vascular resistance and increases renal perfusion despite significant BP reduction. In addition, it significantly reduces oxidative stress. These effects of angiotensin II receptor antagonists may contribute to their beneficial long-term renal effects in patients with type 2 diabetes.     

Evaluation of kidney function in renal transplant patients receiving long-term cyclosporine

We prospectively assessed renal function in a group of 29 renal transplant patients receiving cyclosporine (CsA) in order to determine the course of their renal function over time and the relationship between different markers of glomerular function. We measured serum creatinine, DPTA, and creatinine clearances, and urinary albumin excretion. The clinical course of 24 patients (83%) permitted repeat studies over a period of 32 +/- 1 (SEM) months, and in these patients DTPA clearance, creatinine clearance, and the serum creatinine concentration did not vary with time. Five of the patients (17%) lost their grafts and returned to dialysis. On initial evaluation patients who lost their grafts had a lower DPTA clearance than those whose function was maintained (29 +/- 3 v 46 +/- 2 mL/min/1.73 m2 body surface area [BSA], respectively, P less than 0.005) and all of them had a DTPA clearance of less than 40 mL/min/1.73 m2 BSA. There was an inverse correlation between the log of the urinary albumin excretion and the DTPA clearance (n = 33, r = -0.59, P less than 0.001), a direct correlation with the serum creatinine concentration (N = 33, r = 0.89, P less than 0.0001), but no correlation with time after transplantation. Thus, despite the continued use of CsA, renal function over time was stable in patients who underwent repeated studies, as was the relationship between the DTPA clearance and the clinically used markers of transplant function, the serum creatinine concentration, and the creatinine clearance.     

Acute renal allograft rejection is associated with increased levels of vascular endothelial growth factor in the urine

AIM: The purpose of this study was to assess whether measurement of urinary vascular endothelial growth factor (VEGF) could be adopted as a new non-invasive diagnostic tool for acute rejection following renal transplantation. METHODS: Urinary concentration of VEGF was determined by an enzyme-linked immunosorbent assay technique in 215 renal allograft recipients and 80 healthy controls. RESULTS: Subjects with acute rejection (n=67) excreted urinary VEGF at a significantly higher level (28.57+/-6.21, 95% CI: 16.18-40.97 pg/mumol creatinine) than those without acute rejection. This included subjects with stable renal function and no abnormal histological findings (n=119), acute tubular necrosis (n=15), chronic allograft nephropathy (n=14) and healthy controls (n=80). Using a urinary VEGF/creatinine ratio of 3.64 pg/micromol as the cut-off point, the sensitivity and specificity for diagnosing acute rejection were 85.1 and 74.8%, respectively (P<0.001). Patients with steroid-resistant acute rejection had significantly greater urinary VEGF concentration than patients with steroid-sensitive acute rejection (42.09+/-10.00 vs 9.74+/-2.63 pg/micromol creatinine, P<0.001). Patients with graft loss after acute rejection had significantly greater urinary VEGF concentration than patients with reversible acute rejection (106.66+/-38.60 vs 19.46+/-4.13 pg/micromol creatinine, P=0.001). Using a urinary VEGF/creatinine ratio of 22.48 pg/micromol as the cut-off point, the sensitivity and specificity of the prediction to graft loss after acute rejection were 85.7% and 78.3%, respectively (P=0.001). CONCLUSION: This study demonstrates that the monitoring of urinary VEGF may be a useful non-invasive approach for the detection of acute rejection. Additionally, urinary VEGF levels were shown to predict the response to anti-rejection therapy and to predict a poor outcome after acute rejection.     

Randomized, double-blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure.

OBJECTIVE: To assess whether a ketodiet, a combination of ketoanalogs of essential amino acids (KAs) and a very low-protein diet, retards progression of chronic renal failure and maintains nutritional status. DESIGN: A prospective, randomized, double-blind, placebo-controlled trial. SETTING: Nephrology outpatient department in Northern Railways Central Hospital, New Delhi, India. PATIENTS: Thirty-four patients in predialytic stages of chronic renal failure (CRF), randomized to 2 comparable groups in terms of age, sex distribution, blood pressure control, etiology, use of angiotensin converting enzyme inhibitors, serum creatinine, glomerular filtration rate (GFR), and body mass index (BMI). INTERVENTION: Subjects randomly received either 0.6 g/kg/d protein plus placebo (n = 16) or 0.3 g/kg/d protein plus tablets of KAs (Ketosteril; Fresenius Kabi, Germany) (n = 18) for 9 months. A dietician administered the diet as well as the KAs or the placebo to the patients. OUTCOME MEASURES: Changes in GFR and renal and nutritional parameters were measured. RESULTS: Mean (+/- SD) GFR measured by the 99mTc-DTPA (99 m technetium diethylenetri-aminepenta-aceticacid) plasma sample method was unchanged in the ketodiet group: 28.1 +/- 8.8 (before) and 27.6 +/- 10.1 mL/min/1.73 m2 (after the study) (P =.72). However, it significantly decreased from 28.6 +/- 17.6 to 22.5 +/- 15.9 mL/min/1.73 m2 in the placebo group (P =.015). Serum creatinine before and after the study in the ketodiet group was 2.26 +/- 1.03 mg/dL and 2.07 +/- 0.8 mg/dL (P =.90) and in the placebo group was 2.37 +/- 0.85 and 3.52 +/- 2.9 mg/dL (P =.066), respectively. In both groups the mean BMI did not change from 25.4 +/- 4.2 to 24.5 +/- 4.2 kg/m2 (P =.46) for ketodiet and from 25.0 +/- 6.8 to 23.9 +/- 4.1 kg/m2 (P =.39) for the placebo group. Serum total proteins decreased significantly (P =.038) in the placebo group, and serum albumin showed a trend (P =.061) toward reduction, whereas both of these parameters were maintained in the ketodiet group. CONCLUSION: Over a 9-month period, very low-protein diet supplemented with ketoanalogs helped CRF patients to preserve GFR and maintain BMI. KAs were safe and efficacious in retarding the progression of renal failure and preserving the nutritional status of CRF patients.     

Ezetimibe treatment in hypercholesterolemic kidney transplant patients is safe and effective and reduces the decline of renal allograft function: a pilot study.

BACKGROUND: Ezetimibe has shown efficacy in the therapy of hypercholesterolemia in renal transplant patients. This is the first study investigating the effect of ezetimibe on renal function in kidney transplant recipients. METHODS: Fifty-six patients with statin-resistant hypercholesterolemia (total cholesterol >200 mg/dl) after renal transplantation received additional ezetimibe therapy (10 mg/day) for 12 months. A group receiving statin therapy (n=28) served as controls in this prospective study. RESULTS: Total cholesterol and LDL cholesterol concentrations decreased significantly in the ezetimibe-treated patients but remained stable in the control group (delta total cholesterol: -24+/-49 mg/dl vs 19+/-49 mg/dl, P<0.01; delta LDL: -30+/-39 mg/dl vs -3+/-31 mg/dl, P<0.01). Mean creatinine clearance remained stable in ezetimibe-treated patients but decreased significantly in control group (delta Cockcroft-Gault: 0.9+/-7.3 ml/min vs - 4.8+/-12.8 ml/min, P=0.025; delta Modification of Diet in Renal Disease: -0.4+/-6.2 ml/min/1.73 m(2) vs 4.7+/-8.8 ml/min/1.73 m(2), P=0.033). CONCLUSIONS: The data of our prospective case-control study suggest that ezetimibe appears to ameliorate the decline of renal function after renal transplantation.     

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.     

Effect of iodinated contrast agents on residual renal function in PD patients.

BACKGROUND: Residual renal function (RRF) is an important predictor of outcome in peritoneal dialysis (PD) patients. Although increasing emphasis has been placed on preserving RRF, the nephrotoxicity associated with contrast medium administration in PD patients remains a controversial issue. In the present prospective study, we evaluated the evolution of RRF 2 weeks after iodinated contrast medium administration (ICMA) in a group of stable PD patients, and compared it with that in a non-treated control group of stable PD subjects. METHODS: The study was conducted from January 2003 to October 2004. RRF was quantified by the average of 24 h urinary urea and creatinine clearance and peritoneal creatinine clearance (PcrCl) were analyzed, the levels of which were analysed prior to and 2 weeks following ICMA in 36 PD patients and also assessed at the same time points in a group of 36 PD non-ICMA control subjects, matched according to RRF characteristics. Two weeks following ICMA, the values for RRF, daily urine volume and PcrCl were assessed against those at baseline, and the evolution of RRF was compared between the two groups. In the ICMA group, this study was performed with adequate pre-hydration and a minimum dose of contrast medium. RESULTS: Compared with baseline values, RRF, daily urine volume and PcrCl were not found to be significantly different 2 weeks after ICMA (7.0+/-4.3 vs 7.2+/-4.3 ml/min/1.73 m(2), P = 0.12; 1324+/-696 vs 1360+/-755 ml/day, P = 0.5; and 41.1+/-9 vs 40.6+/-9 l/week/1.73 m(2), P = 0.6, respectively). Following ICMA, variations in RRF and daily urine volume were found to be comparable with those of the control group (0.1+/-0.5 vs 0.1+/-0.5 ml/min/1.73 m(2), P = 0.9; 36+/-440 vs 40+/-493 ml/day, P = 0.8, respectively). CONCLUSION: In this study, 2 weeks following ICMA, no accelerated decline in RRF was determined in stable PD patients with adequate pre-hydration, i.e. subjects treated under optimal circumstances compared with the control group.     

A prospective randomized study to evaluate the renoprotective action of beating heart coronary surgery in low risk patients.

OBJECTIVES: Cardiopulmonary bypass (CPB) is widely regarded as an important contributor to renal failure, a well recognized complication following coronary artery surgery (coronary artery bypass grafting (CABG)). Anecdotally off-pump coronary surgery (OPCAB) is considered renoprotective. We examine the extent of renal glomerular and tubular injury in low-risk patients undergoing either OPCAB or on-pump coronary artery bypass (ONCAB). METHODS: Forty low-risk patients with normal preoperative cardiac and renal functions awaiting elective CABG were prospectively randomized into those undergoing OPCAB (n=20) and ONCAB (n=20). Glomerular and tubular injury were measured respectively by urinary excretion of microalbumin and retinol binding protein (RBP) indexed to creatinine (Cr). Daily measurements were taken from admission to postoperative day 5. Fluid balance, serum Cr and blood urea were also monitored. RESULTS: No mortality or renal complication were observed. Both groups had similar demographic makeup, Parsonnet score, functional status and extent of coronary revascularization (2.1+/-1.0 vs. 2.5+/-0.7 grafts; P=0.08). Serum Cr and blood urea remained normal in both groups throughout the study. A significant and similar rise in urinary RBP:Cr occurred in both groups peaking on day 1 (3183+/-2534 vs. 4035+/-4079; P=0.43) before reapproximating baseline levels. These trends were also observed with urinary microalbumin:Cr (5.05+/-2.66 vs. 6.77+/-5.76; P=0.22). Group B patients had a significantly more negative fluid balance on postoperative day 2 (-183+/-1118 vs. 637+/-847 ml; P=0.03). CONCLUSIONS: Although renal complication or serum markers of kidney dysfunction were absent, sensitive indicators revealed significant and similar injury to renal tubules and glomeruli following either OPCAB or ONCAB. These results suggest that avoidance of CPB does not offer additional renoprotection to patients at low risk of perioperative renal insult during CABG.     

Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy

BACKGROUND: We reported that patients with sodium sensitive type of hypertension exhibited the lack of nocturnal fall in blood pressure with enhanced natriuresis during night. Sodium sensitivity is caused by diminished glomerular filtration capability and/or augmented tubular reabsorption of sodium, and seems tightly linked with glomerular capillary hypertension. In the present study, we investigated the relationship between glomerular filtration rate and circadian rhythms of these parameters in patients with glomerulopathy. METHODS: Twenty six patients (15 men and 11 women; aged 17 to 72 years; mean age 47 +/- 3 years), whose diagnosis was confirmed as glomerulopathy with renal biopsy, were studied during hospitalization. Ambulatory blood pressure for 24 hours was monitored, while urinary samples were collected for both daytime (6:00 a.m. to 9:00 p.m.) and nighttime (9:00 p.m. to 6:00 a.m.) to estimate circadian rhythms of urinary sodium and protein excretion rates (UNaV, UproV). Then night/day ratios of mean arterial blood pressure (MAP), UNaV, and UproV were analyzed in relation to 24-hour creatinine clearance as a marker of glomerular filtration rate. RESULTS: Serum creatinine and creatinine clearance were 1.1 +/- 0.1 mg/dL and 89 +/- 7 mL/min/1.73 m2. There were significant day-night differences in MAP (96 +/- 2 mm Hg vs. 92 +/- 2 mm Hg; P= 0.006), UNaV (6.7 +/- 0.9 mmol/hour vs. 3.6 +/- 0.3 mmol/hour; P= 0.003), and UproV (161 +/- 27 mg/hour vs. 128 +/- 28 mg/hour; P= 0.02). Creatinine clearance had significantly negative relationships with night/day ratios of MAP (r=-0.49; P= 0.01), UNaV (r=-0.43; P= 0.03,) and UproV (r=-0.41; P= 0.04). In addition, night/day ratio of MAP had significantly positive relationships with night/day ratios of UNaV (r= 0.49; P= 0.01) and UproV (r= 0.45; P= 0.02). CONCLUSION: Our results show that as renal function deteriorates in glomerulopathy the nocturnal dip in blood pressure is lost, resulting in enhanced urinary sodium and protein excretions during night. These findings are compatible with our proposal that impaired natriuresis during daytime makes nocturnal blood pressure elevated to compensate for diminished natriuresis by pressure natriuresis. We speculate that nocturnal glomerular capillary hypertension contributes, at least in part, to enhanced urinary sodium and protein excretions during night.     

Use of isotonic sodium bicarbonate to prevent radiocontrast nephropathy in patients with mild pre-existing renal impairment: a meta-analysis

Acute renal dysfunction after radiocontrast in patients with pre-existing renal impairment is not uncommon and is associated with significant morbidity and mortality. Isotonic sodium bicarbonate solution was first reported to reduce radiocontrast nephropathy in 2004. This first study was, however; limited by its small sample size and as such, the use of isotonic sodium bicarbonate to prevent radiocontrast nephropathy is still not widely used by many anaesthetists and intensivists. We meta-analysed relevant randomised controlled studies sourced from the Cochrane Controlled Trial Register (2007 issue 4), EMBASE and MEDLINE databases (1966 to April 15, 2008) without any language restriction. The use of isotonic sodium bicarbonate was associated with a significant reduction in risk of an incremental rise in serum creatinine concentration 25% above baseline (relative risk 0.22, 95% confidence interval [CI]: 0.11 to 0.44, P < 0.0001; 2 = 0%) and had a protective effect on the absolute change in serum creatinine concentration (weighted-mean-difference -9.4 micromol/l, 95% CI: -17.2 to -1.7, P = 0.02; F = 0%) and creatinine clearance (weighted-mean-difference 3.7 ml/min, 95% CI: 0.55 to 6.80, P = 0.02; F = 57.1%) after radiocontrast. The incidence of acute renal failure requiring dialysis was low (1.4%) and was not significantly different after the use of isotonic sodium bicarbonate (relative risk 0.59, 95% CI: 0.15 to 2.42, P = 0.47; F = 0%). With the limited data available, isotonic sodium bicarbonate appears to be safe and very effective in reducing radiocontrast nephropathy in patients with mild pre-existing renal impairment. A large randomised controlled study is needed to confirm whether isotonic bicarbonate can improve patient centred clinical outcomes.     

beta(2)-microglobulin kinetics in nocturnal haemodialysis.

BACKGROUND: beta(2)-Microglobulin (beta(2)m) is a major component of dialysis-related amyloidosis. The available therapeutic options do not permit normalization of the serum beta(2)m level. In a cross-over trial, we studied the kinetics of beta(2)m during two different dialytic techniques. METHODS: Ten stable, anuric end-stage renal disease patients were studied during two consecutive weeks of three conventional (CHD) and six nocturnal haemodialysis (NHD) sessions. CHD was performed for 4 h three times weekly using a polysulfone dialyser (F80, surface area of 1.8 m(2)) with a mean blood and dialysate flow rate of 401+/-91.6 and 514+/-10.9 ml/min, respectively. The NHD was done with a smaller dialyser (F40, surface area of 0.7 m(2)) and lower blood (281+/-17 ml/min) and dialysate flow rates (99+/-1.2 ml/min) for 8 h, six nights a week. RESULTS: Weekly removal of urea (51.6+/-24.6 vs 43.1+/-20.5 g) and creatinine (8501+/-5204 vs 6319+/-4134 mg) were comparable with the two modalities of dialysis but the mass of beta(2)m removed was significantly higher with NHD (127+/-48 vs 585+/-309 mg, P<0.001), with a percentage reduction in serum level of 20.5+/-5.8 vs 38.8+/-7. 1% (P<0.0001) and a Kt/V(beta2m) of 0.21+/-0.09 vs 0.56+/-0.17 (P<0. 0006). The mean post-dialysis beta(2)m (20.8+/-6.3 vs 14.0+/-3.8 mg/dl, P=0.02), Tac(beta2m) (26.2+/-5.2 vs 19.8+/-3.8 mg/dl, P=0.02) and pre-dialysis beta(2)m (beta(2)m(pre)) at the end of 1 week of therapy (24.4+/-7.6 vs 19.0+/-3.4 mg/dl, P=0.02) were lower with NHD. Long-term follow-up data were available in 13 and seven patients at the end of 1 and 2 years, respectively. Serum beta(2)m(pre) levels progressively declined from 27.2+/-11.7 mg/dl at initiation of NHD to 13.7+/-4.4 mg/dl by 9 months, and they remained stable thereafter. CONCLUSIONS: NHD provides a much higher clearance of beta(2)m than CHD, leading to a long-term decrease in the pre-dialysis concentration of beta(2)m.     

Short-term effects of fish oil treatment on urinary excretion of high- and low-molecular weight proteins in patients with IgA nephropathy

AIMS: Recently, it was shown that fish oil treatment improved renal survival in patients with IgA nephropathy. The precise mechanisms of this protective effect remained unclear. Omega-3 polyunsaturated fatty acids (PUFAs), important active substances of fish oil, are able to attenuate inflammatory responses. Thus, the renoprotective effects of fish oil may be the result of mitigation of glomerular or tubulo-interstitial inflammation. We hypothesized that such a decrease in glomerular or tubulo-interstitial inflammation could result in an improvement of glomerular permselectivity as reflected by the urinary excretion of IgG, or of tubular reabsorption capacity as reflected by the urinary excretion of low-molecular weight proteins (LMWPs), or a decrease of the excretion of the inflammatory mediators MCP-1 and TNF-alpha. METHODS: Twelve patients with a biopsy-proven IgA nephropathy, a persistent proteinuria of > 0.5 g/24 h, and an impairment of renal function (creatinine clearance 44 ml/min/1.73 m2, range 19-72) were treated with fish oil for 6 months. The daily dosage of PUFAs amounted to 3.0 g. Before start of treatment (month 0), at the end of treatment (month 6), and 6 months off treatment (month 12), renal measurements were carried out. Creatinine clearance (ECC) was measured after pretreatment with cimetidine. In timed urine samples albumin, IgG, the LMWPs beta2-microglobulin and alpha1-microglobulin, and both MCP-1 and TNF-alpha were measured. RESULTS: Six months of fish oil treatment had no effect on creatinine clearance (44 ml/min/1.73 m2 vs 42 ml/min/1.73 m2), the urinary excretion of albumin (1,594 +/- 284 vs 1,370 +/- 337 microg/min), IgG (84 +/- 16 vs 82 +/- 20 microg/min), beta2-microglobulin (medians: 1.0 vs 0.8 microg/min), alpha1-microglobulin (38 +/- 9 vs 53 +/- 15 microg/min), MCP-1 (medians: 720 vs 782 microg/min), or TNF-alpha (medians: 31 vs 27 microg/min). Mean arterial pressure gradually decreased from 102 +/- 4 to 96 +/- 4 mmHg at the end of the treatment (n.s.), however, the lowest value was observed after fish oil had been stopped for 6 months (93 +/- 3 mmHg, p < 0.05). Changes in the excretion of the urinary proteins during the 12-month study period were correlated to changes in blood pressure (r = 0.57, p < 0.01), independent of fish oil treatment. The course of the disease over the 12-month study period in our fish oil-treated patients was comparable to that of an untreated control group. CONCLUSIONS: Fish oil treatment in patients with IgA nephropathy, renal insufficiency and proteinuria did not affect the excretion of low- or high-molecular weight proteins, MCP-1 or TNF-alpha. Our data do not provide arguments for beneficial effects of fish oil treatment on glomerular permselectivity of tubulo-interstitial inflammation.