Normal Creatinine Clearance Research Articles

Diastolic Heart Failure Versus Diastolic Dysfunction: Difference in Renal Function

Despite the common finding of diastolic dysfunction with a preserved ejection fraction on routine echocardiography in elderly patients, it is unknown why some patients with isolated diastolic dysfunction are asymptomatic whereas others develop diastolic heart failure (ie, signs and symptoms of congestive heart failure). We hypothesized that renal insufficiency is more common in those patients with diastolic heart failure than those with diastolic dysfunction; it is intrinsic renal insufficiency that determines whether diastolic dysfunction becomes symptomatic. We reviewed 686 consecutive transthoracic echocardiograms (TTEs). Patient age, race, weight, and cardiovascular risk factors (hypertension, diabetes, and coronary artery disease) were recorded. We used the Framingham Criteria for Congestive Heart Failure to determine the presence of diastolic heart failure by symptoms, exam findings, and radiological studies. Average creatinine clearance (CrCl), calculated by both total body weight and lean body mass, and estimated glomerular filtration rate (eGFR) were calculated for each group. Of the 686 TTEs reviewed, 18 patients fulfilled the criteria for diastolic heart failure and 118 patients had asymptomatic diastolic dysfunction. There was no difference in age, race, or gender nor was there any difference in the echocardiographic variables of diastolic function or left ventricular hypertrophy between groups. Multiple regression analysis showed only lower CrCl (44 ± 36 mL/min vs 76 ± 42 mL/min, total body weight, P = 0.0015; and 31 ± 24 mL/min vs 51 ± 27 mL/min, lean body mass, P = 0.0012) and eGFR (44 ± 33 mL/min/M² vs 69 ± 28 mL/min/M², P = 0.0003) were associated with diastolic heart failure. There was no significant difference in the presence of hypertension, diabetes, and coronary artery disease between groups. The results of this study support the hypothesis that patients with normal left ventricular ejection fractions but diastolic dysfunction develop congestive heart failure because of underlying renal insufficiency. A larger, prospective study is needed to confirm this hypothesis.

Inhibition of the renal renin‐angiotensin system and renoprotection by pitavastatin in type 1 diabetes

1. The aim of the present study was to investigate whether or not pitavastatin ameliorates diabetic nephropathy and if inhibition of the rennin-angiotensin-aldosterone system (RAAS) is associated with any renoprotective effects. Pitavastatin (10mg/ kg/day) and/or spironolactone (100mg/kg/day) were given by gavage for 3weeks to uninephrectomized rats with streptozotocin-induced diabetes. 2. Pitavastatin or spironolactone significantly reduced proteinuria and collagen deposition, and normalized creatinine clearance, serum creatinine levels and blood urea nitrogen concentrations. 3. Reverse transcription polymerase chain reaction analysis showed that the renal expression of collagenI, transforming growth factor-β and monocyte chemoattractant-1 were increased in diabetic rats and reduced by the pitavastatin and/or spironolactone treatment. 4. These agents also decreased angiotensin converting enzyme expression and aldosterone concentrations in the renal homogenate, but had no effect on blood glucose, haemoglobinA(1c) , and plasma total cholesterol, Na(+) , K(+) , aldosterone and NOx levels, or on systolic blood pressure measured by the tail-cuff method. Interestingly, cotreatment with pitavastatin and spironolactone did not result in additional normalization. 5. These results suggest that pitavastatin shows renoprotective effects against diabetic nephropathy mediated in part by inhibition of the renal RAAS, including the suppression of angiotensin-converting enzyme expression and aldosterone production.

Effect of nephrotic syndrome on homocysteine metabolism

Proteinuria and hyperhomocysteinaemia are independently associated with increased risk of atherosclerosis and cardiovascular disease. The available data on plasma homocysteine (Hcy) level in patients with nephrotic syndrome (NS) are contradictory with increased, decreased and unchanged values reported by different investigators. The majority of Hcy in the plasma is bound to albumin whose urinary losses and diminished plasma concentration are the defining features of NS. The present study was designed to explore the effect of NS on plasma concentration and urinary excretion of Hcy and hepatic expression of methylenetetrahydrofolate reductase (MTHFR) and cystathionine-β-synthase (CBS), the key enzymes in re-methylation and trans-sulphuration of Hcy, respectively. Sprague-Dawley rats were rendered nephrotic by IP injection of puromycin aminonucleoside. Urine and plasma were used for measurement of Hcy, and the liver was processed for assessment of MTHFR and CBS protein expression. Compared with the controls, nephrotic rats showed heavy proteinuria, hypoalbuminaemia, hypercholesterolaemia, normal plasma creatinine and creatinine clearance, reduced plasma Hcy, increased urinary Hcy, and downregulation of CBS but not MTHFR expression. Plasma Hcy correlated directly with plasma albumin and inversely with urinary protein excretion. The urinary Hcy excretion correlated directly with urine protein excretion. NS results in significant reduction in plasma total Hcy concentration which is due to the reduction in albumin-bound Hcy as opposed to the free Hcy fraction. This is coupled with increased urinary excretion of albumin-bound Hcy. In addition, NS results in down-regulation of CBS which can curtail conversion of Hcy to cysteine and reduce production of H(2)S which is an important endogenous signalling molecule.

Aminoglycoside Pharmacokinetic Parameters in Neurocritical Care Patients Undergoing Induced Hypothermia

To determine the effects of mild-to-moderate induced hypothermia-a neuroprotectant and/or therapeutic strategy for the management of intracranial hypertension in neurologically injured patients-on the pharmacokinetics of aminoglycoside therapy. Pharmacokinetic analysis. Critical care unit at a university-affiliated hospital. Three patients, aged 22, 24, and 47 years, who received tobramycin and had documented tobramycin levels while undergoing induced hypothermia for more than 24 hours for intracranial hypertension. For each of the three patients, predicted pharmacokinetic parameters (volume of distribution, first-order elimination rate constant, half-life, and renal drug clearance) based on population data were compared with their actual pharmacokinetic parameters that were calculated based on observed tobramycin serum levels. All three patients had a normal creatinine clearance, estimated according to established methods. When pharmacokinetic parameters were calculated after the first tobramycin dose using a one-compartment method, all patients had a slower first-order elimination rate and a larger volume of distribution compared with predicted population estimates. These findings suggest that induced hypothermia may result in impaired elimination of aminoglycosides. Caution should be exercised when attempting to use predicted pharmacokinetic parameters to dose aminoglycosides in this patient population, and first-dose pharmacokinetics should be considered to optimize the dose and dosing interval early in the course of therapy. Further investigation of this phenomenon with greater numbers of patients are needed to confirm these findings and to determine optimal dosing strategies of aminoglycosides in patients undergoing induced hypothermia.

The effect of creatinine clearance on the short-term outcome of neuropathic diabetic foot ulcers

Reduced creatinine clearance is related to an increased risk for diabetic foot ulcer development. Wound healing has been reported to be worse in diabetic patients with impaired kidney functions than general diabetic population. This study aimed to investigate the effect of creatinine clearance on the short-term outcome of neuropathic diabetic foot ulcers. Data from 147 neuropathic diabetic foot ulcer episodes were included in this observational study. Patients were admitted to Dokuz Eylul University Hospital between January 2003 and June 2008. Patients were excluded if they had limb ischemia. Diabetic nephropathy was investigated by 24 h urinary albumin excretion and serum creatinine levels. Creatinine clearance was calculated according to Cockcroft–Gault formula. Foot ulcers were followed up for 6 months to determine the outcome. Our short-term follow-up revealed that neuropathic diabetic ulcers healed worse in patients with decreased creatinine clearance than in those who had normal creatinine clearance. Amputation rates were also found to be higher. Our results suggest that creatinine clearance is an important factor affecting wound healing in patients with neuropathic diabetic foot ulcers.

Effect of Once-Yearly Zoledronic Acid Five Milligrams on Fracture Risk and Change in Femoral Neck Bone Mineral Density

The HORIZON-PFT (Health Outcomes and Reduced Incidence with Zoledronic Acid Once-Yearly–Pivotal Fracture Trial) was a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. The results demonstrated that a once-yearly intravenous infusion of zoledronic acid (ZOL) 5 mg over a period of 3 years significantly reduced the risk of vertebral, hip, and other fractures. Several risk factors for fracture in postmenopausal women have been identified. Some investigators have suggested that ZOL may be more effective across individual categories of risk factors, and that there may be an interaction between these factors and treatment. This study investigated the possible association of individual baseline risk factors with greater treatment efficacy during ZOL 5 mg treatment in patients from HORIZON-PFT. The study subjects received a single intravenous infusion of ZOL 5 mg (treatment group, [n = 2822]) or placebo (control group, [n = 2853]) at baseline, 12 and 24 months. The primary study outcomes were new vertebral fracture and hip fracture. Secondary outcomes included nonvertebral fracture and change in femoral neck bone mineral density (BMD). Evaluated baseline risk factors were age, BMD, race and geographic region, body mass index (BMI), renal impairment (creatinine clearance), concomitant osteoporosis medications, and previous bisphosphonate therapy. The data were adjusted using logistic regression analysis. ZOL treatment was associated with greater reduction in the risk of vertebral fracture (significant treatment-factor interactions) in younger women (<70 years) (P = 0.05), women who were overweight or obese (BMI >30 gm/cm2) (P = 0.02), and those with normal creatinine clearance (P = 0.04). Treatment-factor interactions were not significant for hip or nonvertebral fracture or for change in BMD. These findings show that once-a-year therapy with ZOL for postmenopausal osteoporosis is more effective in preventing vertebral fracture in younger women, and those with higher BMI or normal renal function.

Derivatization of Methylamine and Ethylamine Followed by LC and Fluorescence Detection for Measurement of Urinary Clearance

Monomethylamine (MMA) and ethylamine (EtA) accumulate in uremia. However, the urinary clearances of these compounds in normal humans and those with chronic kidney disease (CKD) have not been studied. In this work, an LC based fluorescence assay for MMA and EtA was developed. In applying the method, we found that some previous assays of urinary levels of MMA and EtA lead to overestimations. Normal subjects with average creatinine clearance of 82 ± 21 mL min−1 demonstrate clearances for the two aliphatic amines less than the creatinine clearance, and in the range of urinary urea clearance. CKD subjects with an average creatinine clearance of 37 ± 12 mL min−1 had modestly but significantly elevated serum levels of MMA and EtA above normals. Their fractional clearances were increased markedly compared to normals, mitigating the rise in their plasma levels. These findings imply enhanced secretion and/or reduced reabsorption of the amines with CKD.

Lenalidomide on alternative days is effective in myelodysplastic syndrome with 5q‐ deletion

Lenalidomide is the treatment of choice in low-risk patients with myelodysplastic syndrome (MDS) and 5q- deletion, at the standard dose of 10 mg for 21 d of every 28-d cycle (Giagounidis et al, 2008). The main response criteria is to achieve blood transfusion independence and recent data reported a response rate of more than 60% in this subset of patients (Jädersten & Hellström-Linderberg, 2009). Nevertheless this effective treatment frequently induce severe (World Health Organization grade III–IV) neutropenia (55% of treated patients) and thrombocytopenia (44% of patients) at least during the initial 2–3 months. Another problem to be considered is the high cost of this standard therapy, as recently highlighted (Stone, 2009). One way to reduce toxicity has been reported by lowering the standard dose from 10 to 5 mg/d for 21 d (Giagounidis et al, 2008), but this schedule did not substantially affect the cost, because of the tablets’ unit price. On this particular issue we would like to report our pivotal experience in six patients treated with lenalidomide at 10 mg on alternative days for 21 d every 28 d. Our intent was to maintain the same efficacy, reduce treatment-related toxicity and also lower the cost of treatment. Moreover, there are no published data to date about the target plasma concentration of lenalidomide required to effectively inhibit the del 5q clone (Kelaidi et al, 2008). Patients signed an informed consent before starting this modified drug schedule. Their characteristics and response to lenalidomide are summarized in Table I. All six patients were blood transfusion-dependent (Haemoglobin level ranging from 70 to 85 g/l) after failing erythropoietin (EPO). Blood values included also mild leucopenia (range white blood cell count ranged from 2 to 4 × 109/l) and a normal/slightly high platelet count (range 280 to 450 × 109/l). All patients started lenalidomide with a normal creatinine clearance (90–125 ml/min) and no serological abnormal value, apart from an elevated ferritin level (range 520–1900 μg/l). No other treatment except EPO and red cells support was previously given to the patients. After receiving lenalidomide at 10 mg/d on alternative days for 21 d every 28 d, all six patients achieved transfusion independence within 3 months (three patients) and within 4 months (three patients) from starting the treatment, respectively. At the time of this report the last haemoglobin level of the patients ranged from 110 to 143 g/l after a median time of treatment of 11 months (range 6–14 months) (Table I). Five out of 6 patients were evaluated for cytogenetic response (CyR): 2/5 patients achieved a complete cytogenetic response (CCyR) after 7 and 6 months of treatment, respectively, while 3/5 patients obtained a partial CyR (with residual 5q- mitosis ranging from 20% to 25%) after 7, 8 and 9 months of treatment, respectively. CyR was confirmed in all patients at last follow-up. Regarding drug-related toxicity, only 1/6 (17%) patients experienced a grade 3 thrombocytopenia, while 2/6 (33%) patients had grade 3 neutropenia, which needed a short course of granulocyte colony-stimulating factor treatment. None of the patients had fever or infection and no further dose reduction was applied. To our knowledge, this is the first report suggesting that 10 mg lenalidomide on alternative days is as effective and possibly less toxic than standard 10 mg/d dose in 5q- syndrome patients. Although the achievement of transfusion independence may appear delayed compared to the standard 10 mg/d schedule, the reduction of haematological toxicity may be an important aspect in this patient population. In addition, with respect to the more conventional dose reduction schedule of 5 mg/d, our scheme has the advantage of lowering the cost of treatment by 50% in a subset of patients in which cost-effectiveness of new generation drugs as compared to best supportive care is still controversial (Goss et al, 2006; Greemberg et al, 2008). Despite the limited series of patients treated and the short follow-up, we believe that the rate of response together with the reduced toxicity and the good economic impact of the adjusted dose, strongly suggest that this schedule should be explored in a larger cohort of patients with 5q- MDS.

Induction Immunosuppression with Anti-CD25 Monoclonal Antibody (Basiliximab) Allows Delayed Initiation and Uptitration of Calcineurin Inhibitor Post Cardiac Transplant

Background:The role of anti-CDmonoclonal antibodies in induction immunosuppression for cardiac transplantation remains unclear. This study sought to determine if basiliximab allows delayed commencement, slower uptitration and reduced nephrotoxicity or allograft rejection with cyclosporin. Methods: We performed retrospective analysis of cardiac transplant patients on cyclosporin, mycophenolate mofetil, and corticosteroids and compared the results depending on whether they received basiliximab post transplant. Data was collected for 21 days post transplant. Exclusion criteria: <18 yrs old, alternative immunosuppression, multi-organ transplant. Results: 39 patients studied (basiliximab: 22; nonbasiliximab: 17). More patients in the non-basiliximab group were ex-smokers (71% vs. 32%, p= 0.025) and type 2 diabetics (35% vs. 4.5%, p= 0.03) but had similar demographics for stroke, hypertension, mechanical support and indication for transplant. No patients received OKT3 or antithymocyte globulin. Time to cyclosporin initiation (mean± 1SD) was 0.12± 0.35 days for non-basiliximab versus 1.50± 2.54 days for basiliximab (p= 0.003). Therapeutic cyclosporin levels (250–300mg/L) were reached later in the basiliximab arm (11.1± 3.7 days) versus (17.1± 7.4 days) (p= 0.003). There was a trend to decreased Grade 3 rejection on day 14 in the basiliximab arm (p= 0.09). There were no significant differences in average creatinine clearance between the groups within the initial 21 days (p= 0.71). Conclusion: Post cardiac transplant, basiliximab allowed delayed initiation and time to therapeutic trough levels of cyclosporin with a trend to decreased severe rejection on day 14. Nephrotoxicity was not reduced. A larger study group is needed to evaluate basiliximab’s effect on rejection rate and renal function.

Renal Dysfunction in Thalassemia.

Abstract 2008Poster Board I-1030 BACKGROUND:Renal function is generally thought to be normal in patients with thalassemia, but it has not been studied in detail. There are recent reports of renal tubular defects in both thalassemia intermedia and major. The cause is unclear, but both iron toxicity and iron chelation therapy have been suggested. The study of renal function in thalassemia is timely, because the new oral iron chelator, deferasirox, may increase creatinine concentration and cause proteinuria. Pre-existing, thalassemia-related renal function abnormalities could be a risk factor for deferasirox-related nephropathy. Therefore, it is critical to know how thalassemia affects the kidney. We aimed to determine the prevalence of renal function abnormalities in patients with thalassemia before deferasirox was widely clinically available and to evaluate associations between renal abnormalities and genetic factors, environmental factors, and transfusion regimens. METHODS:We studied patients who participated in the Low Bone Mass Cross-sectional Observational Study (LBMCOS) of the NIH Thalassemia Clinical Research Network. We included all LBMCOS patients (≥6 years of age) with a creatinine clearance (CCr) and calcium to creatinine ratio (Ca:Cr) measured by 24-hour urine collection. We only included patients whose urinary creatinine excretion rate was appropriate for age and gender, indicating a complete urine collection. Notably, none of these patients was treated with deferasirox; nearly all were treated with deferoxamine. We used multivariable models to determine significant predictors of CCr and Ca:Cr. Potential predictors included age, gender, diagnosis, transfusion status, serum transferrin receptor concentration, serum ferritin, and the presence of a variety of clinical complications. RESULTS:This cohort included 216 patients [51.4% female, mean age 12.6 years (range 6.1 – 75.4)]. 188 had beta thalassemia, 14 had Hb H disease or Hb H-Constant Spring, 13 had Hb E-beta-thalassemia, and 1 had homozygous alpha thalassemia major. 180 subjects were regularly transfused (≥8/yr) and 36 were not. Among all patients, 7.8% had a low CCr, 71.3% had a normal CCr, and 20.8% had a high CCr (adjusted for age, gender and body surface area). Regularly transfused patients had significantly lower mean CCr than those not regularly transfused [143.8 ± 54.3 (mean ± SD) mL/min/1.73 m2 vs. 173.4 ± 65; P=0.004]. Among all patients, 71.3% had a normal Ca:Cr, whereas 28.7% had a high Ca:Cr. Regularly transfused patients had significantly higher mean Ca:Cr than those not regularly transfused (0.18 ± 0.10 vs. 0.10 ± 0.08; P<0.0001). Multivariable models showed that the only significant predictors of CCr were regular transfusion status [Odds Ratio (OR) 0.39, 0.17-0.88] and serum transferrin receptor concentration (OR 1.03, 1.01-1.05). Likewise, the only significant predictors of Ca:Cr were regular transfusion status (OR 3.72, 1.24-11.2) and serum transferrin receptor concentration (OR 0.98, 0.95-0.99). CONCLUSIONS:Renal hyperfiltration is common in thalassemia patients, especially those who are not regularly transfused. Hyperfiltration could be the consequence of chronic anemia. Regularly transfused thalassemia patients have a lower CCr and are more likely to have hypercalciuria than patients who are not regularly transfused. This transfusion-related effect could represent iron-mediated tubular and glomerular injury. Awareness of underlying renal dysfunction in thalassemia patients could inform decisions about the use and monitoring of potentially nephrotoxic agents, such as deferasirox. Further studies are needed to better understand renal function in patients with thalassemia. Disclosures:No relevant conflicts of interest to declare.

Decreased renal uptake of 99mTc-DMSA in patients with tubular proteinuria

Although technetium-99m-dimercaptosuccinic acid ((99m)Tc-DMSA) renal scans are widely used to evaluate renal tubular mass function, the mechanism by which renal uptake of DMSA occurs is still the subject of debate. Patients with various proximal tubular disorders show markedly decreased renal DMSA uptake, even when there is normal creatinine clearance. We measured the renal uptake of (99m)Tc-DMSA 3 h after its injection in 13 patients with Dent disease or Lowe syndrome, both of which are typical proximal tubular disorders with defective megalin and cubilin-mediated endocytosis. Serial images of three patients were also obtained at 0.5, 1, 2 and 3 h post-injection. The correlations between renal uptake of (99m)Tc-DMSA and creatinine clearance and the degrees of acidemia and tubular proteinuria were then evaluated. The renal uptake of (99m)Tc-DMSA was markedly decreased in all patients, and the decreased uptake was detected in all serial images. In contrast, bladder radioactivity was higher than normal in all of the serial images when compared to renal radioactivity. Additionally, the uptake of (99m)Tc-DMSA was inversely proportional to the amount of urine beta(2)-microglobulin. These results strongly suggest that DMSA is filtered in the glomeruli and subsequently undergoes megalin- and cubilin-mediated endocytosis in the proximal tubules.

Effect of Once-Yearly Zoledronic Acid Five Milligrams on Fracture Risk and Change in Femoral Neck Bone Mineral Density

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment. We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months. Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications. Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index >or= 25 kg/m(2) (P = 0.02). There were no significant treatment-factor interactions for hip or nonvertebral fracture or for change in BMD. ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

The level of uric acid and its role at early stages of essential hypertension

Aim: correlation of uric acid (UA) level on serum blood and urine with indicators of not specific inflammation and clinical characteristic in essential hypertension (EH) patients. Methods: 67 patients with EH (48 men) 30-65 years age (442) with stage 1 EH (n=37) and 2 (n=30) with moderate or high cardiovascular (CV) risk. The control group - 14 healthy peoples: (6 men) 45,52,1 years age with normal blood pressure (BP). The normal level of С-reactive protein (CRP) is less 3 mg/l. The normal level of UA in blood is 202,3-416,5 mkmol/l, and in urine is 1,48-4,43 mmol/24 hour. The estimates of creatinine clearance by the Cockroft-Gault formula. Results: the patients with EH have bigger level CRP, UA in blood and urine than healthy peoples with normal BP. Higher levels UA in blood and urine have patients even with early stages EH and moderate CV risk. The bigger level of UA in blood has EH patients with obesity and dyslipidaemia. The level of UA in blood and urine is higher at EH patients with hyperfiltration vs patients with normal creatinine clearance. Conclusion: the patients with early stage of EH have higher level of UA in blood and urine than healthy peoples with normal BP. The level of UA in blood and urine is correlated with dyslipidaemia. Key words: essential hypertension, uric acid, non specific inflammation

Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study

OBJECTIVEMetformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes.RESEARCH DESIGN AND METHODSThe Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance.RESULTSA total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56).CONCLUSIONSThe SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes.

Recommended dose of arbekacin, an aminoglycoside against methicillin-resistantStaphylococcus aureus, does not achieve desired serum concentration in critically ill patients with lowered creatinine clearance

To define the pharmacokinetics of arbekacin (ABK), an aminoglycoside, in patients with acutely lowered renal function. We measured the serum concentrations of ABK, using fluorescence polarization immunoassay, in 10 critically ill patients (patient group) and six healthy volunteers (control group). Data were analysed with a two-compartment model and parameters were estimated by the Bayesian method. The Mann-Whitney U-test or chi-squared test was used as appropriate (P < 0.05). Creatinine clearance (CCR), measured or estimated using Cockcroft and Gault's formula of the patient group (CCR: 58 +/- 13 mL/min), was significantly lower than that of the control group (CCR: 99 +/- 8 mL/min). However, despite the low CCR, even the maintenance ABK dosage for normal CCR did not elevate the highest serum level (C(max)) to the effective range in the patient group. Although the ABK clearance (CL) did not differ between the groups, the patients' distribution volume (V(d)) increased significantly compared with the control. The transfer rate constant from central to peripheral compartment (k(12)) in the patient group was much higher than that in the control. In critically ill patients with lowered CCR, the ABK dose for normal CCR subjects does not elevate its serum concentration to effective levels because of augmented V(d) caused by increased k(12). The present results hypothesize that adjustment of antibiotic dosing according to CCR further lowers C(max) in critically ill patients with reduced CCR.

Risk of development of chronic kidney disease in patients with type 2 diabetes having metabolic syndrome.

To measure the relation of creatinine clearance in type-2 diabetic patients with different components of metabolic syndrome and to quantify the relationship of frequency of incident CKD with increasing number of metabolic syndrome components while controlling for age, gender and duration of diabetes. Cross-sectional descriptive study. Diabetes Clinic, Fauji Foundation Hospital, Rawalpindi, from January to August 2006. Patients having type-2 Diabetes for more than 5 years were enrolled. Information regarding age, gender, duration of diabetes , type of diabetes, treatment taking, complete fasting lipid profile, fasting blood glucose, Body Mass Index (BMI), 24 hours urinary proteins and creatinine clearance, co-existent risk factors like hypertension and ischemic heart disease was taken. Patients were divided into groups having one to all five metabolic syndrome traits. Progressive increase in the metabolic syndrome traits was compared with decline in creatinine clearance. Pearson correlation test and multiple logistic regression were applied to determine correlation with significance at 'r' and 'p' < 0.05. Out of 104 evaluated female and male patients, 70% had hypertension, ischemic heart disease and a family history of diabetes. While 20% had normal creatinine clearance, 37% had a creatinine clearance between 60-90 ml/min, 19% had a creatinine clearance of 30-59 ml/min, 18% had a creatinine clearance of less than 30 ml/min and 10% were already in stage 5 CKD. The decline in renal function was more severe in subjects evaluated who had a higher number of features of the metabolic syndrome. Age was the only significant determinant of development of CKD (p=0.05). The renal function progressively declined with 3 or more features of the metabolic syndrome.

Sirolimus (Rapamycin) Induced Proteinuria in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplant

Proteinuria and renal dysfunction have been reported in patients receiving sirolimus after renal (1) or islet cell transplants (2). We report the case of a 28-year-old man undergoing allogeneic hematopoietic stem cell transplantation who suffered acute kidney injury with nephrotic range proteinuria after initiation of sirolimus. This patient with anaplastic large cell lymphoma in complete remission by positron emission tomography scan was admitted for an allogeneic hematopoietic stem cell transplant from a molecularly human leukocyte antigen-matched unrelated female donor. Four months before admission, the patient had a creatinine clearance (24 hr urine collection) of 106 mL/min and 1 month before admission had a clearance of 115 mL/min. During those outpatient visits, the patient had no protein detected by urinalysis. As part of his treatment for lymphoma, the patient received 4 monthly treatments with cisplatin and cytarabine. The last dose of cisplatin was administered 30 days before admission. Graft-versus-host disease prophylaxis consisted of sirolimus (12 mg load followed by 4 mg orally per day) and tacrolimus (0.3 mg/kg intravenous continuous infusion). At the time graft-versus-host disease prophylaxis was initiated, the patient had been on the following antibiotics in the hospital: piperacillin/ tazobactam, amikacin, and micafungin for 4 days; voriconazole for 2 days and vancomycin for 1 day. Eight days after initiation of sirolimus, blood urea nitrogen rose from 9 to 29 mg/dL and creatinine from 0.8 to 1.5 mg/dL. The tacrolimus level initially was 1.8 ng/mL, peaked at 8.6 ng/mL, but was 3.6 ng/mL during the time of acute kidney injury. The sirolimus level was initially 2.1 ng/mL, and 4.3 ng/mL during the time of acute kidney injury. The urine was cloudy and foamy and contained a jelly-like substance. Urinalysis showed 3+ protein and few white cells, and a random urine protein-to-creatinine ratio was 17. Triglycerides increased from 148 to 327 mg/dL. Albumin fell from 4.6 to 3.0 g/dL. After addition of sulfosalicylic acid the urine precipitated proteinaceous casts within seconds. Urine protein electrophoresis displayed a nonselective pattern with all fractions elevated. The creatinine peaked at 3.6 mg/dL. Sirolimus was discontinued, while tacrolimus prophylaxis was maintained. The blood urea nitrogen and creatinine improved over 3 to 4 days. The urinary protein-to-creatinine ratio declined from 17 to less than 0.5 over 2 days. Currently, patient is maintained on tacrolimus without any proteinuria and a creatinine of 0.9 mg/dL. Sirolimus has been associated with high-range proteinuria when used as replacement therapy for calcineurin inhibitors in chronic allograft nephropathy (3). Urinary protein loss presumably results from reduced tubular protein reabsorption (1). A specific pattern of renal injury has also been noted in rat models with increased intratubular cast formation, increased tubular epithelial cell proliferation, and protein endocytosis, causing massive proteinuria (4). Renal transplant patients treated with sirolimus have rarely developed intratubular casts indistinguishable from myeloma cast nephropathy. Histologically, these casts have been composed of renal tubular epithelial cells (1). Alternatively, there is speculation that sirolimus induced proteinuria is related to collapsing focal segmental glomerulosclerosis associated with vascular endothelial growth factor over-expression in podocytes (5). Senior et al. (2) have reported sirolimus related proteinuria in a nontransplanted kidney before. There was resolution of proteinuria from the native kidneys when sirolimus was discontinued in some patients with islet cell transplant. We present another case of sirolimus-related renal dysfunction and proteinuria but in a patient undergoing allogeneic hematopoietic stem cell transplantation. There was no evidence of underlying kidney disease in this patient given normal creatinine clearance and absence of proteinuria before administration of sirolimus. This patient did receive other medications that could be nephrotoxic, including tacrolimus, cisplatin, and several antibiotics. Though these medications could have contributed to the patient’s renal toxicity, the time course and dosages were not consistent with their being the primary cause of his nephrotic syndrome and acute onset of kidney injury. Because the tacrolimus levels were in the lower range of normal during the kidney insult, and because renal function recovered after cessation of sirolimus while the tacrolimus was maintained, this drug was not considered a major contributor. Similar reports of sirolimus-induced proteinuria have occurred only in renal transplant cases where the diagnosis often has been confounded by graft rejection or recurrence of the primary kidney disease. This case demonstrates a direct toxic effect of sirolimus on a nontransplanted kidney without prior tubular or glomerular disease. Kenar D. Jhaveri Division of Nephrology and Hypertension New York Presbyterian Hospital at Weill Cornell Medical Center New York, NY Jonathan H. Schatz Medical Oncology-Department Memorial Sloan-Kettering Cancer Center New York, NY James W. Young Division of Bone Marrow Transplantation Memorial Sloan-Kettering Cancer Center New York, NY Carlos Flombaum Division of Nephrology Memorial Sloan-Kettering Cancer Center New York, NY

Hantavirus infection with acute kidney failure

Hantavirus infection was confirmed by history, symptoms and biochemical changes, as well as immunofluorescence test in 29 patients (24 men, 5 women; mean age 36.9 +/- 11.5 years) with nontraumatic renal failure (ANF), retrospectively in 15 patients. Cardinal symptoms were acute onset (n = 29), fever (n = 27), pain in the flanks, abdomen or head (n = 27), reduced glomerular filtration rate (n = 29), proteinuria (n = 25) and thrombocytopenia (n = 16). Normal renal function was restored in all patients. Follow-up examination of 15 patients 6-7 years after the acute illness revealed normal blood pressure, normal serum creatinine, absent proteinuria and normal inulin clearance in all, thus confirming the favourable prognosis of the infection in Western Europe. Nonetheless, because Hantavirus infection is by no means rare, it should be included in the differential diagnosis of acute renal failure.

Angiotensin II infusion improves renal function in experimental hyperdynamic sepsis

In a model of hyperdynamic sepsis we found a large increase in renal blood flow (RBF) that was paradoxically accompanied by renal failure, which we hypothesized may be caused by decreased glomerular filtration rate due to efferent arteriolar vasodilatation. We therefore investigated the effect in sepsis of infusion of angiotensin II (Ang II), a preferential efferent arteriolar vasoconstrictor. In 6 conscious ewes, with flow probes around the aorta and renal, mesenteric, coronary and iliac arteries, intravenous live E. Coli. induced hyperdynamic sepsis (hypotension and increased cardiac output). RBF increased (292 ± 61 to 397 ± 74 mL/min P&lt;0.01), but oliguria developed and creatinine clearance decreased (88.7 ± 19.6 to 47.7 ± 21.0 mL/min, P&lt;0.01). Ang II restored arterial pressure and RBF, increased urine output 6 to 8 fold and doubled creatinine clearance. Importantly, Ang II had no adverse affects on vital organ blood flows or biochemical variables. In experimental hyperdynamic sepsis, Ang II restored arterial pressure, increased urine output and normalized creatinine clearance. This beneficial effect of Ang II supports the notion that sepsis‐induced acute renal failure is due to efferent arteriolar vasodilatation and a subsequent loss of glomerular filtration pressure. Ang II may be a safe and effective treatment to normalize arterial pressure and renal function in sepsis. Funded by NHMRC, Australia.

Analysis of the upper urinary tract function in multiple sclerosis patients

The objective of this study was to analyse the upper urinary tract (UT) function in a group of consecutive multiple sclerosis (MS) patients, who had not previously been treated by urologist. Ninety-two MS patients suffering from lower UT dysfunction were included in the study. The group of patients consisted of 69 women and 23 men. The average Expanded Disability Status Scale (EDSS) score in our group was 4.29 (0-8.5). Functional examination of the kidneys using assessment of creatinine clearance and morphological examination of the kidneys using ultrasound was performed in all patients. Analysis of the upper UT function is presented. The average serum creatinine clearance in our group was 132.84 ml/min/1.73 m(2) (46.8-510). Lower levels than normal were found in three patients (3.3%). Abnormal ultrasound findings were recorded in five patients (5.4%). The creatinine clearance was correlated with the clinical subtype of MS, the severity expressed by EDSS, the urodynamic parameters, the duration of the disease, the duration of the symptoms of lower UT and the EDSS score. We did not find a statistically significant correlation for any of these parameters. Our results suggest that impairment of the upper UT function is exceptional in MS patients.