Haplotypes of vitamin D receptor modulate the circulating levels of lead in exposed subjects

Genetic factors influence whole blood lead (Pb-B) concentrations in lead exposed subjects. This study aimed at examining the combined effects (haplotype analysis) of three polymorphisms (BsmI, ApaI and FokI) in vitamin D receptor (VDR) gene on Pb-B and on the concentrations of lead in plasma (Pb-P), which is more relevant to lead toxicity, in 150 environmentally exposed subjects. Genotypes were determined by RFLP, and Pb-P and Pb-B were determined by inductively coupled plasma mass spectrometry and by graphite furnace atomic absorption spectrometry, respectively. Subjects with the bb (BsmI polymorphism) or ff (FokI polymorphism) genotypes have lower B-Pb than subjects in the other genotype groups. Subjects with the aa (ApaI polymorphism) or ff genotypes have lower P-Pb than subjects in the other genotype groups. Lower Pb-P, Pb-B, and %Pb-P/Pb-B levels were found in subjects with the haplotype combining the a, b, and f alleles for the ApaI, BsmI, and FokI polymorphisms, respectively, compared with the other haplotype groups, thus suggesting that VDR haplotypes modulate the circulating levels of lead in exposed subjects.

Association Among Microalbuminuria and Oxidative Stress Biomarkers in Patients With Type 2 Diabetes

Aim: Hyperglycemia in diabetes mellitus (DM) may be one of the most important factors responsible for the development of oxidative stress, which promotes the main complications in DM patients. Therefore, this study evaluated if the hyperglycemia could be related to oxidative stress biomarkers, lipid profile, and renal function in type 2 diabetes patients without clinic complications. Methods: Plasmatic malondialdehyde (MDA), serum protein carbonyl (PCO), serum creatinine levels, microalbuminuria, glycated hemoglobin, and lipid profile were analyzed in 37 type 2 diabetic patients and 25 subjects with no diabetes. Results: Serum creatinine levels were within the reference values, but microalbuminuria presented increased levels in all the patients compared with controls (P G 0.05) and above of the reference values. The MDA, PCO, low- density lipoprotein, and triglyceride levels showed positive correlation with microalbuminuria levels. Moreover, glycated hemoglobin presented positive correlation with MDA, PCO, and microalbuminuria levels. Conclusions: The hyperglycemia could be responsible for the increase of the microalbuminuria levels and for the oxidation process in lipids and proteins in DM patients. Therefore, we suggested that the microvascular lesion is a direct consequence from hyperglycemia and an indirect one from the increased oxidative stress. Malondialdehyde and protein carbonyl levels could be suggested as additional biochemical evaluation to verify tissue damage in type 2 DM patients.

Use of methotrexate in older patients - A risk-benefit assessment

Methotrexate is eliminated almost entirely by the kidneys. The risk of methotrexate toxicity is therefore increased in patients with poor renal function, most likely as a result of drug accumulation. Declining renal function with age may thus be an important predictor of toxicity to methotrexate. Up to 60% of all patients who receive methotrexate for rheumatoid arthritis (RA) discontinue taking it because of adverse effects, most of which occur during the first year of therapy. Gastrointestinal complications are the most common adverse effects of methotrexate, but hepatotoxicity, haematological toxicity, pulmonary toxicity, lymphoproliferative disorders and exacerbation of rheumatic nodules have all been reported, Decreased renal function as a result of disease and/or aging appears to be an important determinant of hepatic, lymphoproli ferative and haematological toxicity, Concomitant use of low doses of folic acid has been recommended as an approach to limiting toxicity. Interactions between methotrexate and several nonsteroidal anti-inflammatory drugs have been reported, but they may not be clinically significant. However, caution is advised in the use of such combinations in patients with reduced renal function. More serious toxicities (e.g. pancytopenia) may result when other inhibitors of folate utilisation [e.g. cotrimoxazole (trimethoprim-sulfamethoxazole)] or inhibitors of renal tubular secretion (e.g. probenecid) are combined with methotrexate. Before starting low dose methotrexate therapy in patients with RA, a full blood count, liver function tests, renal function tests and chest radiography should be performed. Blood counts and liver function tests should be repeated at regular intervals. Therapeutic drug monitoring of methotrexate has also been suggested as a means of limiting toxicity. Patients with RA usually respond very favourably to low dose methotrexate therapy, and the probability of patients continuing their treatment beyond 5 years is greater than for other slow-acting antirheumatic drugs. Thus, given its sustained clinical utility and relatively predictable toxicity profile, low dose methotrexate is a useful addition to the therapy of RA.

Conversion to Sirolimus in Kidney-Pancreas and Pancreas Transplantation

Reports on the use of sirolimus (SRL) in pancreas transplantation are still limited. The aim of this study was to evaluate the outcome of SRL conversion in pancreas transplant patients. Among 247 patients undergoing simultaneous kidney-pancreas or solitary pancreas transplantation, 33 (13%) were converted to SRL. The reasons for conversion were calcineurin inhibitors (CNI) nephrotoxicity (n = 24; 73%), severe neurotoxicity owing to CNI (n = 1; 3%), severe and/or recurrent acute rejection episodes (n = 7; 21.%), gastrointestinal (GI) side effects of mycophenolate mofetil (MMF; n = 5; 15%), and hyperglycemia (n = 4; 12%). Before conversion, all patients were maintained on a CNI, MMF, and low-dose steroids. They were gradually converted to SRL associated with either CNI or MMF withdrawal. Sixty-three percent (n = 15) of patients who were converted owing to CNI nephrotoxicity, showed stable or improved renal function. At 12 months after conversion, serum creatinine levels were significantly decreased in this group (2.2 +/- 0.5 vs 1.6 +/- 0.3 mg/dL; P = .001) and C-peptide values increased (2.9 +/- 1.1.1 vs 3.1 +/- 1.3 nmol/L; P = .01.8). The only patient with leucoencephalopathy showed improved neurologic status after SRL conversion. All patients converted to SRL because of GI side effects of MMF showed improvements, and none of those converted because of hyperglycemia experienced improvement. There were no episodes of acute rejection after conversion. We concluded that conversion to SRL in pancreas transplantation should be considered an important alternative strategy, particularly for CNI nephrotoxicity and neurotoxicity, and in cases of severe diarrhea due to MMF.

Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women

We aimed to investigate whether creatine supplementation affects the measured glomerular filtration rate in postmenopausal women (age, 58 +/- 3 years). Subjects were randomly assigned to receive either creatine (20 g(.)day(-1) for 1 week and 5 g(.)day(-1) thereafter) or a placebo. Kidney function was assessed at baseline and after 12 weeks. [(51)Cr] EDTA clearance remained unchanged (CR-PRE: 86.16 +/- 14.36 mL(.)min(-1) per 1.73 m(2), POST: 87.25 +/- 17.60 mL(.)min(-1) per 1.73 m(2); PL-PRE: 85.15 +/- 8.54 mL(.)min(-1) per 1.73 m(2), POST: 87.18 +/- 9.64 mL(.)min(-1) per 1.73 m(2); p = 0.81). Thus, we concluded that creatine supplementation does not affect glomerular filtration rate in postmenopausal women.

Collapsing glomerulopathy associated with proliferative lupus nephritis: reversible acute kidney injury

Collapsing glomerulopathy is a rare form of glomerular injury, characterized by segmental or global collapse of the glomerular capillaries, wrinkling and retraction of the glomerular basement membrane, and marked hypertrophy and hyperplasia of podocytes. Prognosis is usually poor, with most cases developing end-stage renal disease, in spite of treatment. The association of collapsing glomerulopathy and systemic lupus erythematosus is very unusual. In this report, we describe the first case of a simultaneous diagnosis of collapsing glomerulopathy and diffuse proliferative lupus nephritis. The case presented with acute kidney injury and nephrotic syndrome and evolved with partial remission of nephrotic syndrome and recovery of renal function after aggressive treatment with intravenous cyclophosphamide and methylprednisolone. Lupus (2011) 20, 98-101.

Association of the MCP-1-2518 A/G Polymorphism and No Association of Its Receptor CCR2-64 V/I Polymorphism with Lupus Nephritis

Objective. To evaluate whether the A/G polymorphism at position 2518 in the regulatory region of the monocyte chemoattractant protein-1 (MCP-1) or the V/I polymorphism at position 64 of the receptor. CCR2, are associated with lupus nephritis (LN) or any clinical characteristics of the disease or with renal survival in a patient population. Methods. We selected 197 patients with lupus nephritis and 220 matched healthy controls for study. MCP-1 and CCR2 genotyping was performed by polymerase chain reaction. Clinical and laboratory data were compiled from patients` charts over followup that ranged from 6 months to 10 years. Results. The GIG genotype of MCP-1 was more common in LN patients (p = 0.019), while the A allele was associated with healthy controls (p = 0.007) as was the V allele of CCR2 (p = 0.046) compared to LN patients. Clinical index measures [SLE Disease Activity Index (SLEDAI)], immunological markers, renal histology, renal function at enrollment, and renal survival were not influenced by these polymorphisms. A less aggressive renal disease, measured by renal SLEDAI index, was associated with the V allele of the CCR2 gene polymorphism. Conclusion. These findings support that MCP-1 2518 GIG is associated with LN but there was no association of this genotype with renal function or renal survival. When studying CCR2 64 V/I polymorphism we showed a positive association of the V allele with healthy controls but no association of the genotype with LN patients. (First Release March 152010; J Rheumatol 2010;37:776-82; doi:10.3899/jrheum.090681)

Fetal cystoscopy for severe lower urinary tract obstruction-initial experience of a single center

Objective To report the experience with fetal cystoscopy and laser fulguration of posterior urethral values (PUV) for severe lower urinary tract obstruction (LUTO). Methods Between July 2006 and December 2008, fetal cystoscopy was offered to 23 patients whose fetuses presented with severe LUTO. favorable urinary analysis and gestational age <26 weeks. Fetal urinary biochemistry was evaluated before and after cystoscopy. All infants were followed 6-12 months after birth. Abnormal renal function was defined when serum creatinine higher than 50 mu mol/L (2 Standard Deviation) or the necessity of dialysis or renal transplantation. Autopsy was always performed whenever fetal or neonatal deaths occurred. Results Eleven patients decided to undergo fetal therapy and 12 elected to continue with expectant observation. There was no difference between both groups in gestation age at diagnosis and referral examinations. Urethral atresia was diagnosed in 4/11 (36.4%) fetuses by fetal cystoscopy. At 26 weeks, fetuses that were managed expectantly presented with worse urinary biochemistry results (p < 0.05). Survival rates and percentage of infants with normal renal function were significantly higher in the cystoscopic group than in the expectant group (P < 0.05). Conclusions Percutaneous fetal cystoscopy is feasible using a thinner special cannula for prenatal diagnosis and therapy of LUTO. Prenatal laser ablation of the PUV under cystoscopy may prevent renal function deterioration improving postnatal outcome. Copyright (C) 2009 John Wiley & Sons, Ltd.

A novel WT1 heterozygous nonsense mutation (p.K248X) causing a mild and slightly progressive nephropathy in a 46,XY patient with Denys-Drash syndrome

WT1 mutations have been described in a variety of syndromes, including Denys-Drash syndrome (DDS), which is characterized by predisposition to Wilms` tumor, genital abnormalities and development of early nephropathy. The most frequent WT1 defects in DDS are missense mutations located in exons 8-9. Our aim is to report a novel WT1 mutation in a 46,XY patient with a DDS variant, who presented a mild nephropathy with a late onset diagnosed during adolescence. He had ambiguous genitalia at birth. At 4 months of age he underwent nephrectomy (Wilms` tumor) followed by chemotherapy. Ambiguous genitalia were corrected and bilateral gonadectomy was performed. Sequencing of WT1 identified a novel heterozygous mutation (c.742A > T) in exon 4 that generates a premature stop codon (p.K248X). Interestingly, this patient has an unusual DDS nephropathy progression, which reinforces that patients carrying WT1 mutations should have the renal function carefully monitored due to the possibility of late-onset nephropathy.

Obstetric Outcome in Pregnant Women on Long-term Dialysis: A Case Series

Background: Although still uncommon, pregnancy frequency in women on maintenance hemodialysis therapy has increased in the past 20 years. Most published reports suggest that intensified hemodialysis regimens result in better pregnancy outcomes. The small number of patients investigated in all reported series is the main limitation of the available studies. Study Design: Retrospective case series. Setting & Participants: Data for all pregnancies that occurred in 1988-2008 in women undergoing maintenance hemodialysis (52 pregnancies) at the Sao Paulo University Medical School (Sao Paulo, Brazil). Outcomes & Measurements: We analyzed maternal and fetal outcomes of 52 pregnancies, as well as their relationship with various clinical, laboratory, and hemodialysis parameters, such as pre-eclampsia, pregnancy before or after dialysis therapy, hemodialysis dose, polyhydramnios, anemia, and predialysis serum urea level. In addition, logistic regression models for a composite adverse fetal outcome (perinatal death or extremely premature delivery) and linear regression models for birth weight were built. Results: 87% overall rate of successful delivery, with a mean gestational age of 32.7 +/- 3.1 weeks. Pre-eclampsia was associated with a poor prognosis compared with pregnancies without pre-eclampsia: a successful delivery rate of 60% versus 92.9% (P = 0.02), extremely premature delivery rate of 77.8% versus 3.3% (P = 0.001), lower gestational age (P = 0.001), and birth weight (P = 0.001). Patients with an adverse composite fetal outcome had a higher frequency of pre-eclampsia (P = 0.001), lower frequency of polyhydramnios (P = 0.03), lower third-trimester hematocrit (P = 0.03), and higher predialysis serum urea level (P = 0.03). The same results were seen for birth weight. Limitations: Retrospective data analysis. The absence of creatinine clearance measurements did not allow evaluation of the impact of residual renal function on fetal outcome. Conclusions: Outcomes of pregnancy in women undergoing hemodialysis often are good. Preeclampsia, third-trimester hematocrit, polyhydramnios, and predialysis serum urea level are important variables associated with fetal outcome and birth weight. Am J Kidney Dis 56:77-85. (C) 2010 by the National Kidney Foundation, Inc.Inc

Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1

Crajoinas RO, Oricchio FT, Pessoa TD, Pacheco BP, Lessa LM, Malnic G, Girardi AC. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol 301: F355-F363, 2011. First published May 18, 2011; doi: 10.1152/ajprenal.00729.2010.-Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 mu g.kg(-1).min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.

Prednisone monotherapy induced remission in a group of patients with membranous lupus nephritis

The treatment of membranous lupus nephritis (MLN) is still controversial in the literature. We conducted a retrospective analysis of patients in two medical centers of Sao Paulo-Brazil in order to evaluate the clinical response in patients submitted to either a regimen with prednisone alone or to a double immunosuppressive regimen (prednisone plus cyclophosphamide or prednisone plus azathioprine). Methods: MLN female patients were enrolled in this retrospective study conducted from February 1999 to June 2007. Data were collected from the patients` medical charts. Race distribution was similar in both groups: Caucasian (72.3%) and Afro-Latin-American (27.7%). The prednisone regimen consisted of 1 mg/kg/day for 8 weeks and tapering until 0.1 mg/kg/day (n = 29). The double immunosuppressive treatment consisted of the same doses of prednisone plus monthly intravenous cyclophosphamide or azathioprine for 6 months (n = 24). Criteria for remission (complete and partial) and renal function loss as well as flare criteria followed those used in the literature. Results: There was no difference between the prednisone group and the double immunosuppressive group regarding age (33.2 +/- 9.4 vs. 29.1 +/- 9.1 y), estimated GFR (76.5 +/- 26.6 vs. 74.1 +/- 39.6 ml/min/1.73 m(2)), serum albumin (2.8 +/- 0.7 vs. 2.6 +/- 0.3 g/dl), positive ANA (87.5 vs. 90.0%), positive anti-dsDNA (47.6 vs. 44.0%), renal SLEDAI indices (6.6 +/- 2.6 vs. 7.0 +/- 3.1), follow-up time (71 +/- 46 vs. 62 +/- 45 months), as well as proteinuria (3.1 +/- 1.9 vs. 4.8 +/- 2.4 g/day) and number of non-nephrotic patients (6 in the prednisone group vs. 3 in the double immunosuppressive group). The prednisone group presented higher C3 values (85.2 +/- 31.5 vs. 62.3 +/- 41.6 U/ml, p = 0.04). Clinical and laboratory characteristics at 6 months and at last follow-up did not reveal any differences between treatment regimens. Renal survival after an 8-year follow-up did not differ in both groups (prednisone group 86.2% vs. double immunosuppressive group 75%), and patients in both groups showed a high rate of renal flares (prednisone group 51.7% vs. double immunosuppressive group 62.5%). Univariate analysis showed that only patient age predicted flares (r = -0.048, p = 0.04). Borderline significance was obtained for proteinuria analysis (p = 0.07). Adverse effects did not differ between the groups. Conclusions: A regimen of corticosteroids in MLN induced a high remission rate after 6 months. Both treatment regimens showed a high flare rate and age was the only predictive parameter (r = -0.048, p = 0.04). Renal survival after 8 years did not differ between the groups.

Ultrasound evaluation of prognosis in fetuses with posterior urethral valves

Purpose: The aim of this study was to evaluate the ability of prenatal ultrasound markers to predict postnatal renal prognosis in fetuses with posterior urethral valves. Methods: Medical files on fetuses with prenatal diagnosis of posterior urethral valves from 2000 to 2006 were reviewed retrospectively. Data from prenatal follow-up included gestational age at diagnosis, ultrasound renal parenchyma evaluation, and presence and time of oligohydramnios onset. Prenatal parameters studied were correlated to postnatal renal function. Results: Thirty-one male fetuses were included. Six pregnancies were terminated. Of the remaining 25 pregnancies that were continued, 4 children had abnormal creatine and 21 normal creatinine levels at follow-up. Presence and time of oligohydramnios onset did not differ between groups (P = .43). Ultrasound detected bilateral renal abnormalities in 3 fetuses (75%) with altered renal function, and 10 fetuses (55%) with normal creatinine, at follow-up. Conclusions: None of the ultrasound parameters evaluated were able to reliably predict postnatal renal function. (C) 2011 Elsevier Inc. All rights reserved.

Mild chronic kidney dysfunction and treatment strategies for stable coronary artery disease

Objective: Our objective was to evaluate the association of chronic kidney dysfunction in patients with multi-vessel chronic coronary artery disease, preserved left ventricular function, and the possible interaction between received treatment and cardiovascular events. Methods: The glomerular filtration rate was determined at baseline on 611 patients who were randomized into three treatment groups: medical treatment, percutaneous coronary intervention, and coronary artery bypass surgery. Incidence of myocardial infarction, angina requiring a new revascularization procedure, and death were analyzed during 5 years in each group. Results: Of 611 patients, 112 (18%) were classified as having normal renal function, 349 (57%) were classified as having mild dysfunction, and 150 (25%) were classified as having moderate dysfunction. There were significant differences among the cumulative overall mortality curves among the three renal function groups. Death was observed more frequently in the moderate dysfunction group than the other two groups (P < .001). Interestingly, in patients with mild chronic kidney dysfunction, we observed that coronary artery bypass treatment presented a statistically higher percentage of event-free survival and lower percentage of mortality than did percutaneous coronary intervention or medical treatment Conclusions: Our results confirm that coronary artery disease accompanied by chronic kidney dysfunction has a worse prognosis, regardless of the therapeutic strategy for coronary artery disease, when renal function is at least mildly impaired. Additionally, our data suggest that the different treatment strategies available for stable coronary artery disease may have differential beneficial effects according to the range of glomerular filtration rate strata.

Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation

Fanelli C, Fernandes BH, Machado FG, Okabe C, Malheiros DM, Fujihara CK, Zatz R. Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation. Am J Physiol Renal Physiol 301: F580-F587, 2011. First published June 8, 2011; doi:10.1152/ajprenal.00042.2011.-We recently standardized a model (L(Lact)) of severe chronic kidney disease based on impaired nephrogenesis by suppression of angiotensin II activity during lactation (Machado FG, Poppi EP, Fanelli C, Malheiros DM, Zatz R, Fujihara CK. Am J Physiol Renal Physiol 294: F1345-F1353, 2008). In this new study of the L(Lact) model, we sought to gain further insight into renal injury mechanisms associated with this model and to verify whether the renoprotection obtained with the association of the angiotensin II receptor blocker losartan (L) and hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, would provide similar renoprotection. Twenty Munich-Wistar dams, each nursing six pups, were divided into control, untreated, and L(Lact) groups, given losartan (L; 250 mg.kg(-1).day(-1)) until weaning. The male LLact offspring remained untreated until 7 mo of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (L(Lact)Pre), and followed no further. The remaining rats were then divided among groups L(Lact) + V, untreated; L(Lact) + L, given L (50 mg.kg(-1).day(-1)) now as a therapy; L(Lact) + H, given H (6 mg.kg(-1).day(-1)); and L(Lact) + LH, given L and H. All parameters were reassessed 3 mo later in these groups and in age-matched controls. At this time, L(Lact) rats exhibited hypertension, severe albuminuria, glomerular damage, marked interstitial expansion/inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. L monotherapy normalized albuminuria and prevented hypertension and the progression of renal injury, inflammation, and myofibroblast infiltration. In contrast to the remnant model, the LH combination promoted only slight additional renoprotection, perhaps because of a limited tendency to retain sodium in L(Lact) rats.