Reduced Creatinine Clearance Research Articles

Renal Dendritic Cells Stimulate IL-10 Production and Attenuate Nephrotoxic Nephritis

The role of renal dendritic cells (DCs) in glomerulonephritis is unknown. This question was addressed in nephrotoxic nephritis, a murine model of human necrotizing glomerulonephritis, which is dependent on CD4(+) Th1 cells and macrophages. DCs in nephritic kidneys showed signs of activation, accumulated in the tubulo-interstitium, and infiltrated the periglomerular space surrounding inflamed glomeruli. In ex vivo coculture experiments with antigen-specific CD4(+) T cells, DCs stimulated the secretion of IL-10, which is known to attenuate nephrotoxic nephritis, and the Th1 cytokine IFNgamma. Endogenous renal CD4(+) T cells produced both of these cytokines as well, but those from nephritic mice secreted increased amounts of IL-10. Renal DCs were found to express ICOS-L, an inducer of IL-10. To evaluate the in vivo role of renal DCs in disease, CD11c(+) DCs were depleted on days 4 and 10 after the induction of nephritis by injecting CD11c-DTR/GFP mice with diphtheria toxin. Sparing DCs until day 4 did not affect the autologous phase of nephritis. The number of renal DCs was reduced by 70% to 80%, the number of renal macrophages was unchanged, and periglomerular infiltrates were eliminated. On days 11 to 14, we observed aggravated tubulointerstitial and glomerular damage, reduced creatinine clearance, and increased proteinuria. These findings demonstrate that renal DCs exert a renoprotective effect in nephrotoxic nephritis, possibly by expressing ICOS-L and/or by inducing IL-10 in infiltrating CD4(+) Th1 cells.

Development of hepatorenal syndrome in bile duct ligated rats

To evaluate in bile duct ligated rats whether there were progressive alterations of renal function without changes in histopathology. Male Wistar rats were submitted to sham-surgery or bile duct ligation (BDL) and divided according to the post-procedure time (2, 4 and 6-wk). To determine renal function parameters, rats were placed in metabolic cages and, at the end of the experiment, blood and urine samples were obtained. Histology and hydroxyproline content were analyzed in liver and renal tissue. Rats with 2 wk of BDL increased free water clearance (P = 0.02), reduced urinary osmolality (P = 0.03) and serum creatinine (P = 0.01) in comparison to the sham group. In contrast, rats at 6 wk of BDL showed features of HRS, including significant increase in serum creatinine and reductions in creatinine clearance, water excretion and urinary sodium concentration. Rats with 4 wk of BDL exhibited an intermediate stage of renal dysfunction. Progressive hepatic fibrosis according to post-procedure time was confirmed by histology. The increased levels of liver hydroxyproline contrasted with the absence of structural changes in the kidney, as assessed by histology and unchanged hydroxyproline content in renal tissue. Our data show that BDL produced progressive renal dysfunction without structural changes in the kidney, characterizing HRS. The present model will be useful to understand the pathophysiology of HRS.

Lowering the Threshold for Defining Microalbuminuria: Effects of a Lifestyle-metformin Intervention in Obese "Normoalbuminuric" Non-diabetic Subjects

We investigated whether levels of albuminuria (urinary albumin excretion (UAE)) below those conventionally accepted as microalbuminuria (<30 mg/day) are sensitive to correction of obesity and obesity-related risk factors. The effects of a 12-month lifestyle modification-metformin program were evaluated in otherwise healthy overweight/obese "normoalbuminuric" subjects: group I with UAE of <10 mg/day (n = 23) and group II with UAE of 10-29 mg/day (n = 18). The subjects of group II were older and heavier, and had higher blood pressure (BP) and lower high-density lipoprotein (HDL) levels, than those of group I. Creatinine clearances were also higher in group II (148 +/- 14 ml/min) than in group I (108 +/- 9 ml/min). Although the intervention induced comparable reductions in obesity, BP, lipids and insulin levels in both groups, UAE was significantly reduced in group II (9.1 +/- 1.8 mg/24 h; 60% reduction; P < 0.001), and non-significantly in group I (0.75 +/- 0.5 mg/day; 12% reduction; P > 0.1). Additionally, greater reduction in creatinine clearance was observed in subjects with higher UAE rates. After the intervention, both groups achieved similar UAE rates (5.7 +/- 0.9 and 5.2 +/- 1.0 mg/day; P > 0.10). Basal UAE was related to the subjects' creatinine clearance (r = 0.38; P = 0.04). For both groups together, intervention-induced changes in UAE rates were not significantly related to BP, age, or body weight. However, for group II subjects, BP and UAE reduction were positively associated (r = 0.44; P = 0.03). UAE of 10-29 mg/day (hyperalbuminuria), below the conventionally used limit to define microalbuminuria, is already associated with a more adverse cardiovascular risk profile, and is exquisitely sensitive to interventions that reduce obesity, BP, and insulin resistance.

Protective Effects of Morroniside Isolated from Corni Fructus against Renal Damage in Streptozotocin-Induced Diabetic Rats

In our previous study, we reported the renoprotective effect of Hachimi-jio-gan, a Chinese traditional prescription consisting of eight medicinal plants, and also reported the effect of Corni Fructus (Cornus officinalis SIEB. et ZUCC.), a component of Hachimi-jio-gan, on diabetic nephropathy using diabetic rats. In this study, we investigated the effects of morroniside isolated from Corni Fructus on renal damage in streptozotocin-treated diabetic rats. Oral administration of morroniside at a dose of 20 or 100 mg/kg body weight/d for 20 d to diabetic rats resulted in significant decreases in increasing serum glucose and urinary protein levels. Moreover, the decreased levels of serum albumin and total protein in diabetic rats were significantly increased by morroniside administration at a dose of 100 mg/kg body weight/d. In addition, morroniside significantly reduced the elevated serum urea nitrogen level and showed a tendency to reduce creatinine clearance. Morroniside also significantly reduced the enhanced levels of serum glycosylated protein, and serum and renal thiobarbituric acid-reactive substances. Protein expressions related to the advanced glycation endproduct (AGE) level and actions, oxidative stress such as N(epsilon)-(carboxyethyl)lysine, as well as receptors for AGE and heme oxygenase-1 were increased in diabetic rats, but the levels were also significantly decreased by the administration of morroniside. This suggests that morroniside exhibits protective effects against diabetic renal damage by inhibiting hyperglycemia and oxidative stress. These results indicate that morroniside is one component partly responsible for the protective effects of Corni Fructus and Hachimi-jio-gan against diabetic renal damage.

Drugs and the kidney: more than a question of dose

Drugs and the kidney: more than a question of dose

Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia

Hydrochlorothiazide (HCTZ) is used to manage hypertension and heart failure; however, its side effects include mild hypokalemia, metabolic abnormalities, and volume depletion, which might have deleterious effects on renal and endothelial function. We studied whether HCTZ cause renal injury and/or altered vasoreactivity and if these changes are hypokalemia-dependent. Rats were given a normal diet or a diet moderately low in potassium K+ with or without HCTZ. Animals fed either a low K+ diet alone or HCTZ developed mild hypokalemia. There was no significant difference in systolic blood pressure in the different treatment groups. All three groups with hypokalemia had mild proteinuria; low K(+)-HCTZ rats had reduced creatinine clearance. HCTZ-treated rats displayed hypomagnesemia, hypertriglyceridemia, hyperglycemia, insulin resistance, and hyperaldosteronism. No renal injury was observed in the groups without HCTZ; however, increased kidney weight, glomerular ischemia, medullary injury, and cortical oxidative stress were seen with HCTZ treatment. Endothelium-dependent vasorelaxation was reduced in all hypokalemic groups and correlated with reduced serum K+, serum, and urine nitric oxide. Our results show that HCTZ is associated with greater renal injury for the same degree of hypokalemia as the low K+ diet, suggesting that factors such as chronic ischemia and hyperaldosteronism due to volume depletion may be responsible agents. We also found impaired endothelium-dependent vasorelaxation was linked to mild hypokalemia.

Safety Profile of Intravenous Bisphosphonates

Because of their proven efficacy, intravenous bisphosphonates play an important role in reducing the risk of skeletal-related events including pathologic fractures, spinal cord compression, and palliative radiotherapy to bone in patients with malignant bone lesions. Overall, intravenous bisphosphonates have an acceptable safety profile and are commonly associated with transient and manageable flu-like symptoms after initial infusions. In addition, bisphosphonates have dose- and infusion rate-dependent effects on renal function that can be proactively managed in patients with reduced creatinine clearance rates by following recommended dosing guidelines. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in patients with advanced cancer receiving complex chemotherapeutic treatment regimens and supportive care with bisphosphonates. ONJ prevention and management recommendations have been developed that may reduce the risk of ONJ and the impact of ONJ on quality of life. Moreover, bisphosphonate therapy has resulted in considerable clinical benefits in patients with malignant bone disease; therefore, the potential for adverse events such as ONJ must be placed into context with these meaningful benefits.

Two-Stage Pharmacokinetic & Efficacy Study of Lenalidomide Alone or Combined with Recombinant Erythropoietin (EPO) in Lower Risk MDS EPO-Failures [PK-002

Background: Lenalidomide (LEN) is a myelosuppressive immunomodulatory drug that has erythropoietic activity in lower risk MDS patients who failed treatment with rhu-EPO (N Eng J Med 2005; 352:549). We previously reported that LEN acts to relieve suppression of the EPO-receptor signal in MDS erythroid precursors, suggesting that the erythropoietic activity of LEN might be improved by combined treatment with rhu-EPO. To evaluate the potential benefit of the combination and the relationship between LEN pharmacokinetics (PK) and treatment-related cytopenias, we performed a PK and efficacy study using a two step design.Methods: Eligible patients had transfusion-dependent, Low/Int-1 IPSS MDS and documented prior treatment with rhu-EPO (≥40,000 U/wk x 6, or darbepoetin equivalent). In the first phase of the study, patients received LEN monotherapy at a dose of 10mg/d [n=25] or 15 mg/d [n=15]. Single dose [n=12] and steady state [n=24] fasting PK were evaluated on days −7 and +14, respectively in subjects receiving the 10mg LEN dosage. After 16 weeks of monotherapy, erythroid non-responders (NR) and minor (MiE) responders (IWG 2000) were offered Combined Treatment in which epoetin alpha (EPO) was added at a weekly dose of 40,000 units sc for a minimum of 8 weeks. Bone marrow (BM) aspirate & biopsy were repeated within 72H of the first grade 4 cytopenia nadir.Results: Demographics of the 39 patients treated to date include: median age, 73 years; IPSS categories, Low [n=17] and Int-1 [n=22]; deletion 5q, n=7. Among 33 patients that completed 16 weeks of monotherapy, 11 (33%) were erythroid responders [10 mg, 7/22 (32%); 15 mg, 4/11 (36%)] with 9 major [del(5q), n=6] and 2 MiE. Sixteen patients proceeded to the Combination Phase with 4 (25%) achieving an erythroid response (2 major, 2 MiE) [10 mg, 1/10; 15 mg, 3/6]. PK analyses showed no evidence of drug accumulation after 14 days of treatment. LEN AUC was highest in patients with reduced creatinine clearance (CLcr, 30–49 mL/min, n=2: 955±49; vs. CLcr ≥50 mL/min, n=22: 558±166). There was no significant difference in steady state AUC or Cmax in patients experiencing a ≥50% vs. <50% decrease in ANC or platelet count during the first 28 days of treatment. However, mean AUC inversely correlated with the interval to ≥50% reduction in platelet count (ANOVA, P = 0.04). Neutropenia [overall, 28/39 (72%); 10mg, 20/25 (80); 15mg, 8/14 (57%)] and thrombocytopenia [overall, 23/39 (59%); 10mg, 17/25 (68%); 15mg, 6/14 (43%)] were the most common ≥grade 3 adverse events (CTC v.3.0), which were accompanied by no significant change in BM cellularity or myeloid:erythroid ratio in non-del5q patients (n=10; P=0.566).Conclusions: Inter-patient variation in systemic LEN exposure is influenced by renal function and may impact interval to development of dose-limiting cytopenias. LEN has erythropoietic activity in primary EPO-non-responders, which may be improved with the addition of EPO. The clinical benefit of the LEN+EPO combination will be investigated in a phase III intergroup study, E2905, in patients who failed primary EPO treatment or have a poor cytokine response profile.

Insulinbedarf bei Typ-1-Diabetikern mit nachlassender Nierenfunktion: Human-Insulin versus Analog-Insulin

Insulin clearance and the degree of insulin resistance change in type 1 diabetes in patients with reduced kidney function and make it more difficult to achieve good metabolic control. For some years different analogue insulins have become available. Their pharmacological characteristics in renal failure have not as yet been investigated in detail. The aim of the present retrospective study was to determine the insulin dosage in relation to kidney function in patients with type 1 diabetes treated with human or analogue insulin. Insulin dosage of 68 patients treated with human insulin and 74 patients treated with analogue insulin was related to the creatinine clearance (calculated with the Cockcroft-Gault formula). In addition, diabetes-related laboratory parameters, the prevalence of hypertension and the kind of antihypertensive therapy were analysed in both groups. Patients with type 1 diabetes treated with human or analogue insulin have different insulin demands if their renal function is decreased. In analogue-treated patients, insulin dosage significantly decreased with reduced creatinine clearance (r = 0,257; p = 0,026) in contrast to human insulin treated patients who did not show such a decrease (r = 0,159; p = 0,165). There were no significant differences between treatment groups with respect to demographic data, metabolic control or antihypertensive therapy. Linear regression analysis revealed kidney function as a significant factor influencing insulin dosage in the analogue group, while the corresponding factors in the human insulin group were metabolic control and age. The results indicate that insulin clearance and/or the metabolic activity of human and analogue insulin differ if renal function is reduced. This may be due to different pharmacokinetic or pharmacodynamic characteristics of these insulins in renal failure, a finding which needs further investigation.

Clinicopathology of maternal scleroderma

Women with scleroderma who become pregnant have an increased incidence of perinatal loss, premature birth, and growth restriction [1]. Placental abnormalities, including acute atherosis, infarcts, and other manifestations of reduced placental blood flow, are found in many cases of collagen vascular disease [2]. A 27-year-old woman (gravida 1) with scleroderma was admitted to hospital at 31 weeks of gestation with uterine contractions and intrauterine growth restriction (IUGR). Scleroderma was diagnosed 2 years previously and she was treated with penicillamine (250 mg per day). Antitopoisomerase I (anti-Scl-70) and anti-nuclear antibodies were positive. Doppler examination revealed IUGR and increased resistance index in the umbilical artery (pulsatility index (PI), 1.24). At 37 weeks of gestation she underwent a cesarean delivery; the 1860 g female infant developed necrotic enterocolitis after 4 days. Three days postpartum the patient developed elevated blood pressure (170/100 mm Hg), mild proteinuria (280 mg/ 24 h), with normal serum creatinine level and liver function tests, but reduced creatinine clearance (70 mL/min). Renal crisis episode and pre-eclampsia were included in the differential diagnosis. In order to control hypertension, an angiotensin-converting enzyme (ACE) inhibitor was used. On discharge from hospital the patient had normal blood pressure and normal renal function. At histopathology examination the placenta weighed 395 g and measured 16×9×4 cm. The umbilical cord presented eccentric insertion and was 38 cm in length and 1.2 cm in diameter. It contained 3 vessels. More than 5 placental infarcts were identified (measuring 1–3 cm). Histological examination of multiple sections (15) showed old placental infarcts and changes consistent with placental mesenchymal dysplasia (PMD, Fig. 1a), decidual vasculopathy (Fig. 1b), foci of decreased vascularity, foci of chorioangiosis, stromal fibrosis of villi, and extensive fibrinoid deposition on the villi. Focal

Cisplatin-induced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: Role of augmented renal alpha-adrenergic responsiveness

The pathogenesis of cisplatin-induced renal failure is related to reduced renal blood flow due to severe tubular damage and enhanced renovascular resistance. It is also known that α 1-adrenoceptors, the major subtype of α-adrenoceptors in renal vasculature play the pivotal role in regulating renal hemodynamics. With this background, we have hypothesized that the altered renal hemodynamics and enhanced renovascular resistance in cisplatin-induced renal failure might be caused by the altered α-adrenergic responsiveness with a possible involvement of α 1-adrenoceptors in the renal vasculature. In a unique experimental approach with anesthetized rats, this study has therefore examined if there is any shift in the renovascular responsiveness to renal nerve stimulation and a series of α-adrenergic agonists in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats with cisplatin-induced renal failure in comparison with their body weight-matched normal controls. Thirty-two male rats of both WKY ( n=16) and SHR ( n=16) origin with body weight 236±7.9 g received cisplatin (5 mg/kg i.p.). The renal failure was confirmed in terms of significantly reduced renal blood flow, reduced creatinine clearance, increased fractional excretion of sodium, increased kidney index (all P<0.05) and tubular damage. After 7 days of cisplatin, the overnight fasted rats were anesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and renal vasoconstrictor experiments were done. The changes in the vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by electrical renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine and methoxamine. It was observed that in the cisplatin-treated renal failure WKY and SHR rats there were significant (all P<0.05) reductions in the renal blood flow along with significantly ( P<0.05) higher renal adrenergic responsiveness as compared with their non-renal failure controls. The data showed that in the renal failure WKY and SHR rats, the altered renal hemodynamics might be caused by an augmented renal adrenergic responsiveness. The results obtained further led us to suggest that the augmented renal adrenergic responsiveness in the cisplatin-induced renal failure rats were possibly mediated by the α 1-adrenoceptors.

Indikationen zur Parathyreoidektomie

The standard of care for primary hyperparathyroidism is surgical removal of all hyperfunctional parathyroid tissue. In experienced hands, parathyroidectomy is successful in 95-99% of cases with a very low complication rate. Surgery is indicated for all patients with symptomatic primary hyperparathyroidism. Asymptomatic individuals should also be surgically treated when patients are younger than 50 years, have severe hypercalcemia, markedly reduced creatinine clearance and/or profound osteopenia (according to the NIH Consensus Conference 2002). A precise preoperative localisation of parathyroid adenomas using cervical ultrasound and Sestamibi scintigraphy enables to elect the minimally invasive parathyroidectomy in most of the cases. Nowadays, the former routine of open bilateral cervical exploration is indicated only if preoperative localisation was not successful and hyperplasia of all four parathyroid glands is anticipated.

Mesangial immune complex glomerulonephritis due to complement factor D deficiency

Complement factor D is a serine protease essential for the activation of the alternative pathway and is expressed in the kidney, adipocytes, and macrophages. Factor D is found at relatively high levels in glomeruli suggesting that this component of the complement cascade could influence renal pathophysiology. In this study, we utilize mice with a targeted deletion of the activating complement factor D gene and compare these results to mice with targeted deletion of the inhibitory complement factor H gene. Eight-month-old mice with a deleted factor D gene spontaneously develop albuminuria and have reduced creatinine clearance due to mesangial immune complex glomerulonephritis. These mesangial deposits contain C3 and IgM. In contrast to the mesangial location of the immune deposits in the factor D-deficient mice, age-matched factor H-deficient mice develop immune deposits along the glomerular capillary wall. Our observations suggest that complement factor D or alternative pathway activation is needed to prevent spontaneous accumulation of C3 and IgM deposits within the mesangium. Our studies show that the complement factor D gene knockout mice are a novel model of spontaneous mesangial immune complex glomerulonephritis.

Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function

Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there are conflicting views on whether NSAIDs are associated with adverse renal effects. The primary objective of this review was to determine the effects of NSAIDs on postoperative renal function in adults with normal preoperative renal function. Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Handsearching of conference abstracts published in major anaesthetic journals was also performed. Date of most recent search: May 2006 The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of postoperative pain, with relevant postoperative renal outcome measures, in adult surgical patients with normal renal function. The data were extracted independently by two authors. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium and need for dialysis. Weighted mean differences for continuous outcomes and relative risk (RR) and risk difference (RD) for dichotomous outcomes were estimated with 95% confidence intervals (CI). Twenty-three trials (1459 patients) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 mL/min (95%CI 5 to 28) and potassium output by 38 mmol/day (95%CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 umol/L, 95%CI -3 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenac, ketorolac, indomethacin, ketoprofen or etodolac. No cases of postoperative renal failure requiring dialysis were described. The trials were not heterogeneous for the primary outcome. NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.

Poor Prognosis for Patients with Chronic Kidney Disease Despite ICD Therapy for the Primary Prevention of Sudden Death

Chronic kidney disease (CKD) has been independently associated with increased cardiovascular mortality. Little is known about the benefit of implantable cardioverter defibrillator (ICD) therapy for prevention of sudden death in this large, high-risk population. We sought to evaluate the impact of CKD on survival in patients who received an ICD for primary prevention of sudden death. In this retrospective study of patients who underwent ICD implantation for primary prevention of sudden death, patients were stratified by CKD, defined as serum creatinine > or = 2 mg/dL or dialysis use. Primary endpoint was mortality. CKD was identified in 35 of 229 patients (15.3%). There were 33 deaths during a follow-up period of 18.0 +/- 15.2 months: 17 of 35 CKD patients and 16 of 194 patients without CKD (48.6% vs 8.2%, P < 0.00001 by log-rank). One-year survival for patients with and without CKD was 61.2% and 96.3%, respectively. Cox regression analysis controlling for age, sex, comorbidities, ejection fraction, and medications proved CKD to be the strongest independent predictor of death (hazard ratio 10.5; 95% confidence interval 4.8-23.1; P = 0.0001). This risk was dependant on severity of CKD; a 10 mL/min reduction in creatinine clearance was associated with a 55% increase in hazard of death (P < 0.0001). In patients receiving an ICD for primary prevention of sudden death, CKD significantly reduced long-term survival. This poor prognosis may limit the impact of primary prevention ICD therapy in this patient population.

High Plasma Norepinephrine Levels Associated with .BETA.2-Adrenoceptor Polymorphisms Predict Future Renal Damage in Nonobese Normotensive Individuals

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and beta2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. beta2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as > or =mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of beta2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the beta2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.

Subtle renal dysfunction after radiocontrast administration in prospective renal donors: Does N-acetylcysteine have a role in its prevention?

<b>Background: </b> Radiographic contrast media (RCM) can cause a reduction in the renal function by multiple mechanisms; reactive oxygen species is one of them. Whether the reduction can be prevented by the administration of antioxidants is still debatable. <i> N</i> -acetylcysteine (NAC) has shown some benefit in patients with renal dysfunction in the prevention of radiocontrast-induced nephropathy (RCIN). <b> Materials and</b> <b> Methods</b> : We prospectively studied 95 healthy kidney donors, who were undergoing intravenous urography (IVU) followed by digital subtraction renal angiography (DSRA) with ionic, high-osmolar contrast agent for pretransplant evaluation. Patients were randomly assigned either to receive the <i> N</i> -acetylcysteine 600 mg orally twice daily (acetylcysteine group) or placebo (control group) on the day before and that of RCM administration in addition to the intravenous 0.45% saline (1 ml/kg body weight per hour) on the day and following day of the procedure. Serum creatinine, urinary enzymes <i> N</i>-acetyl β glucosaminidase (NAG), γ glutamyl-1-transferase (GGT), alanine amino peptidase (AAP), fractional excretion of sodium (FeNa) and 24-h urinary creatinine clearance were performed before and 48 h after the procedure. The levels of urinary enzymes measured after 96 h of DSRA were available in only 57 donors. Radiocontrast-induced nephropathy was defined as an increase in the baseline serum creatinine of at least 0.5 mg/dl within 48 h after injection of radiocontrast media (RCM). <b> Results: </b> Increase in the urinary enzymes (NAG, GGT and AAP) and reduction in creatinine clearance was observed in both groups after receiving the contrast media. However, the number of patients with significant increase in enzymuria (at least >50% increase above the baseline value) and mean drop in creatinine clearance was statistically not different between the acetylcysteine and control groups. <b> Conclusion:</b> Renal damage in the form of reduction in creatinine clearance and increase in urinary enzymes has been observed after administration of radiocontrast. However, clinically significant RCM-induced acute kidney injury is uncommon in patients with normal renal function. Prophylactic oral administration of the antioxidant <i> N</i> -acetylcysteine at a dose of 600 mg twice daily before and on the day of contrast administration is probably not required in patients with normal renal function.

Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis

Objective. Amyloid A protein quantification in fat tissue is a new immunochemical method for detecting AA amyloidosis, a rare but serious disease. The objective was to assess diagnostic performance in clinical AA amyloidosis.Methods. Abdominal subcutaneous fat tissue of patients with AA amyloidosis was studied at the start of an international clinical trial with eprodisate (NC-503; 1,3-propanedisulfonate; Kiacta™), an antiamyloid compound. All patients had renal findings, i.e. proteinuria (≥1 g/day) or reduced creatinine clearance (20 – 60 ml/min). Controls were patients with other types of amyloidosis and arthritic patients without amyloidosis. Amyloid A protein was quantified by ELISA using monoclonal antihuman serum amyloid A antibodies. Congo red stained slides were scored by light microscopy in a semiquantitative way (0 to 4+).Results. Ample fat tissue (>50 mg) was available for analysis in 154 of 183 patients with AA amyloidosis and in 354 controls. The sensitivity of amyloid A protein quantification for detection of AA amyloidosis (>11.6 ng/mg fat tissue) was 84% (95% CI: 77 – 89%) and specificity 99% (95% CI: 98 – 100%). Amyloid A protein quantification and semiquantitative Congo red scoring were concordant. Men had lower amyloid A protein values than women (p < 0.0001) and patients with familial Mediterranean fever had lower values than patients with arthritis (p < 0.001) or other inflammatory diseases (p < 0.01).Conclusions. Amyloid A protein quantification in fat tissue is a sensitive and specific method for detection of clinical AA amyloidosis. Advantages are independence from staining quality and observer experience, direct confirmation of amyloid AA type, and potential for quantitative monitoring of tissue amyloid over time.Trial registration: ClinicalTrials.gov identifier: NCT00035334.

Creatinine Clearance but Not Serum Creatinine Alone Predicts Long-Term Postoperative Survival after Lower Extremity Revascularization

Background: Renal insufficiency is a well-described risk factor for perioperative morbidity and shortened survival after major vascular procedures. Due to the potential inaccuracy of serum creatinine levels alone in measuring kidney function, our aim was to determine whether estimated creatinine clearance more consistently predicted long-term survival. Methods: A retrospective review of one institution’s vascular registry was performed. Logistic regression analysis was conducted to determine independent predictors of 1-, 2- and 3-year postoperative mortality. Creatinine clearance was estimated as [140 – age (years)] × weight (kg)/72 × serum creatinine (mg/dl), multiplied by 0.85 for women. Results: A total of 252 consecutive patients underwent infrainguinal bypass procedures between August 1999 and May 2000. Demographics included average age 68 years, 65% male, 74% diabetic, 12% dialysis-dependent, 23% history of congestive heart failure, 12% history of stroke and 20% serum creatinine >2 mg/dl. One-year mortality was 16% (n = 40), 2-year mortality was 25% (n = 64), and 3-year mortality was 35% (n = 88). There was no difference in serum creatinine values between survivors and non-survivors at 1 year (1.8 vs. 1.9, p = 0.80), 2 years (1.8 vs. 2.0, p = 0.62) or 3 years (1.8 vs. 2.0, p = 0.24), and creatinine >2 mg/dl did not predict long-term adverse outcomes. In contrast, reduced creatinine clearance (≤60 ml/min) was an independent predictor of mortality regardless of dialysis status (1 year: OR = 2.53, p = 0.014; 2 years: OR = 2.46, p = 0.004; 3 years: OR = 2.45, p = 0.001), and creatinine clearance was higher for survivors versus non-survivors at all 3 time points (1 year: 70.2 vs. 49.5, p = 0.003; 2 years: 72.3 vs. 51.2, p < 0.0001; 3 years: 74.7 vs. 52.6, p < 0.0001). Other independent predictors of mortality included a history of stroke (1 year: OR = 3.28, p = 0.008; 2 years: OR = 2.55, p = 0.025; 3 years: OR = 2.35, p = 0.038) and congestive heart failure (1 year: OR = 2.86, p = 0.006; 2 years: OR = 2.54, p = 0.005; 3 years: OR = 2.13, p = 0.017). Conclusions: Independent of dialysis status, a decreased creatinine clearance, but not elevated serum creatinine alone, is an independent predictor of mortality after lower extremity arterial reconstruction. Determination of creatinine clearance should replace serum creatinine in the preoperative risk evaluations of patients undergoing major vascular surgical procedures.

Annual change in bone mineral density in predialysis patients with chronic renal failure: significance of a decrease in serum 1,25-dihydroxy-vitamin D

Bone disease occurs in the predialysis phase of chronic renal failure (CRF). The aim of this study was to examine how a decrease in renal function affects annual bone mineral density (BMD) changes in predialysis CRF patients and to examine the factors that affect BMD. The BMD of the distal radius in 53 predialysis CRF patients (age, 61.3 +/- 10.8 years; serum creatinine 2.7 +/- 1.2 mg/dl) was measured by peripheral quantitative computed tomography (pQCT) twice with a 1-year interval. The total BMD of the radius significantly decreased over a year (P < 0.001), and both trabecular and cortical BMD showed a significant decrease. Significant positive correlations with BMD changes were found for estimated creatinine clearance (r = 0.375, P < 0.01) and baseline serum 1,25(OH)(2)D (r = 0.434, P < 0.005), indicating that BMD decreased to a greater extent with larger reductions in creatinine clearance and serum 1,25(OH)(2)D. Of several bone metabolic markers examined, baseline serum osteocalcin was significantly positively correlated with annual BMD changes (r = -0.276, P < 0.05). Multiple regression analysis showed that baseline serum 1,25(OH)(2)D (beta = 0.434) was a significant predictor of decreases in total and trabecular BMD (R (2) = 0.188, P < 0.01; and R (2) = 0.207, P < 0.01), independent of other confounding factors. These results indicate that BMD decreases as renal function deteriorates in predialysis CRF patients, and that osteocalcin is a clinically useful marker associated with the decrease in BMD. The serum 1,25(OH)(2)D level is the principal factor affecting BMD of the radius, suggesting that supplementation with an active form of vitamin D is of importance for predialysis CRF patients.