The rs12917707 polymorphism at the UMOD locus and glomerular filtration rate in individuals with type 2 diabetes: evidence of heterogeneity across two different European populations.

BACKGROUND: UMOD variability has been associated at a genome-wide level of statistical significance with glomerular filtration rate (GFR) in Swedish individuals with type 2 diabetes (T2D; n = 4888). Whether this finding is extensible also to diabetic patients from other populations deserves further study. Our aim was to investigate the relationship between UMOD variability and GFR in patients with T2D from Italy. METHODS: Genotyping of the single nucleotide polymorphism (SNP) rs12917707 at the UMOD locus has been carried out in 3087 individuals from four independent Italian cohorts of patients with T2D by TaqMan allele discrimination. RESULTS: In none of the four study cohorts was rs12917707 significantly associated with GFR (P > 0.05 for all). Similar results were obtained when the four samples were pooled and analyzed together (ß = 0.83, P = 0.19). Such effect was strikingly smaller than that previously reported in Swedish patients (P for heterogeneity = 1.21 × 10-7). CONCLUSIONS: The previously reported strong association between rs12917707 and GFR in diabetic patients from Sweden is not observed in Italian diabetic patients, thus clearly pointing to a heterogeneous effect across the two different samples. This suggests that UMOD is a strong genetic determinant of kidney function in patients with T2D in some, but not all, populations.

Glucose targets for preventing diabetic kidney disease and its progression.

BACKGROUND: Diabetes is the leading cause of end-stage kidney disease (ESKD) around the world. Blood pressure lowering and glucose control are used to reduce diabetes-associated disability including kidney failure. However there is a lack of an overall evidence summary of the optimal target range for blood glucose control to prevent kidney failure. OBJECTIVES: To evaluate the benefits and harms of intensive (HbA1c < 7% or fasting glucose levels < 120 mg/dL versus standard glycaemic control (HbA1c ≥ 7% or fasting glucose levels ≥ 120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 31 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials evaluating glucose-lowering interventions in which people (aged 14 year or older) with type 1 or 2 diabetes with and without kidney disease were randomly allocated to tight glucose control or less stringent blood glucose targets. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and risks of bias, extracted data and checked the processes for accuracy. Outcomes were mortality, cardiovascular complications, doubling of serum creatinine (SCr), ESKD and proteinuria. Confidence in the evidence was assessing using GRADE. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta-analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all-cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr).For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all-cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non-fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarction, while seven adults would avoid experiencing new-onset albuminuria and two would avoid worsening albuminuria. AUTHORS' CONCLUSIONS: This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured.

A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria.

BACKGROUND: Familial Hyperparathyroidism (HPT) and Familial benign Hypocalciuric Hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. FHH has been demonstrated to be caused by inactivating mutations of calcium-sensing receptor (CaSR) gene, involved in PTH regulation as well as in renal calcium excretion. CASE PRESENTATION: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene. The hypercalcemia was present only in father, which, by contrast to the classic form of FHH showed hypercalciuria (from 300 to 600 mg/24 h in different evaluations) and a Calcium/Creatinine ratio of 0.031, instead of low or normal calciuria (<0.01 typical finding in FHH). His son showed the same mutation in CaSR gene, but no clinical signs or hypercalcemia although serum ionized calcium levels were close to the upper limit of normal values (1.30 mmol/L: normal range: 1.12-1.31 mmol/L). Sequence analysis revealed a point mutation at codon 972 of CaSR gene (chromosome 3q), located within cytoplasmic domain of the CaSR, that changes Threonine with Methionine. The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl. CONCLUSION: This is a case of a novel inactivating point mutation of CaSR gene that determines an atypical clinical presentation of FHH, characterized by hypercalcemia, hypercalciuria and inadequate normal PTH levels. Functional assay demonstrated that the 972 M variant influenced the maturation of the protein, in terms of the post-translational glycosylation. The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.

The IRS1 G972R polymorphism and glomerular filtration rate in patients with type 2 diabetes of European ancestry.

BACKGROUND: In Mexican Americans, the IRS1 G972R polymorphism (rs1801278) has been associated to such a marked reduction in glomerular filtration rate (GFR) (i.e. ß = -8.3 mL/min/1.73 m(2)) to be considered a major determinant of kidney function. METHODS: This was a cross-sectional study to investigate whether a similarly strong effect can also be observed among individuals of European ancestry. We investigated a total of 3973 White patients with type 2 diabetes. Standardized serum creatinine was measured by the modified kinetic Jaffè reaction and estimated GFR (eGFR) calculated by the modification diet renal disease (MDRD) formula; rs1801278 was genotyped by TaqMan assay. RESULTS: No significant association was observed, with R972 carriers showing only a modestly, not significant, lower eGFR level as compared with other subjects (ß = -1.82 mL/min/1.73 m(2), P = 0.086). CONCLUSIONS: Our data indicate that IRS1 G972R is not a strong determinant of GFR in diabetic patients of European ancestry as in Mexican Americans. Since we had 100% power to detect the previously reported association, the risk our finding is a false negative one is minimal.

The 9p21 coronary artery disease locus and kidney dysfunction in patients with Type 2 diabetes mellitus.

BACKGROUND: We investigated whether the coronary artery disease (CAD) locus on chromosome 9p21 (as represented by single nucleotide polymorphism rs2383206) is associated with low estimated glomerular filtration rate (eGFR) or increased urinary albumin excretion in patients with Type 2 diabetes mellitus (T2DM). METHODS: Four samples, including a total of 3167 patients, were studied. The presence of low eGFR (<60 mL/min/1.73m(2)) was estimated from serum creatinine by means of the Modification of Diet in Renal Disease Study equation. Increased urinary albumin excretion was defined as an albumin-creatinine ratio (ACR) ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women. RESULTS: No association was found between rs2383206 and low eGFR or increased ACR in each sample as well as in a pooled analysis (overall odds ratio = 1.07, 95% confidence interval 0.94-1.22, P = 0.31 and overall odds ratio = 1.00, 95% confidence interval 0.90-1.12, P = 0.95, respectively). No interaction was observed between rs2383206 and poor glycemic control [HbA1c was above the median in the pooled sample (7.7%) in modulating eGFR or ACR (P for interaction = 0.42 and 0.90, respectively)]. CONCLUSION: Variability at the 9p21 CAD locus is unlikely to play a role in modulating susceptibility to kidney dysfunction in patients with T2DM.

Para- and perirenal fat thickness is an independent predictor of chronic kidney disease, increased renal resistance index and hyperuricaemia in type-2 diabetic patients.

BACKGROUND: Many interfering factors may reduce the reliability of waist circumference (WC) measurement in estimating the risk for chronic kidney disease (CKD) associated with obesity. Therefore, we determined the independent associations of para- and perirenal ultrasonographic fat thickness with the main markers of kidney function. METHODS: A cross-sectional study was performed in 151 type-2 diabetic subjects. Para- and perirenal fat thickness was measured from the inner side of the abdominal musculature to the surface of the kidneys. CKD was defined as eGFR < 60 mL min(-1)1.73 m(-2). RESULTS: Using both univariate and multivariate regression analyses, eGFR, renal resistance index and uricaemia were best predicted by para- and perirenal fat thickness even when BMI and waist circumference were further added in the statistical model (r(2): 0.366, P = 0.001; r(2): 0.529, P = 0.005; r(2): 0.310, P = 0.026, respectively), whereas waist circumference and BMI did not contribute independently of para- and perirenal fat thickness. Albuminuria was predicted by waist circumference but not by para- and perirenal fat thickness. In subjects with waist circumference above the diagnostic values of metabolic syndrome (48M/59F), eGFR significantly and progressively declined across tertiles of para- and perirenal fat thickness (87.0 ± 27.9 vs 83.5 ± 26.0 vs 62.3 ± 30.6 mL min(-1) 1.73 m(-2), adjusted P < 0.0001) despite comparable waist circumference, and an increasing frequency of CKD was observed across tertiles of subjects with waist circumference both below and above the metabolic syndrome diagnostic values (P < 0.05). CONCLUSIONS: Para- and perirenal fat thickness is an independent predictor of kidney dysfunction in type-2 diabetes explaining an important proportion of the variance of eGFR, renal resistance index and uricaemia.

PPARγ2 P12A polymorphism and albuminuria in patients with type 2 diabetes: a meta-analysis of case-control studies.

BACKGROUND: Insulin resistance has a role in diabetic nephropathy. The A12 variant of the PPARγ2 P121A polymorphism has been firmly associated with reduced risk of insulin resistance, while its role on the risk of albuminuria in patients with type 2 diabetes is uncertain. This study investigated whether the PPARγ2 P12A polymorphism modulates the risk of albuminuria in these patients. METHODS: We tested the association between the A12 variant and albuminuria in three new case-control studies in diabetic patients from Italy (n = 841, n = 623 and n = 714 patients, respectively) and then performed a meta-analysis of all studies available to date. The nine studies we meta-analysed (six previously published and three presented here) comprised a total of 2376 cases and 4188 controls. RESULTS: In none of the three new studies was a significant association observed with odds ratio (OR) [95% confidence intervals (95% CI)] being 1.115, 0.799 and 0.849 (P = 0.603, 0.358 and 0.518, respectively). At meta-analysis, the overall OR (95% CI) for association between A12 and albuminuria was 0.694 (0.528-0.912). A significant heterogeneity of the genetic effect was observed (P = 0.026), which was totally explained by the different method of urine collection and albuminuria definition utilized across the studies. In fact, most of the effect was observed in the four studies determining albumin excretion rate rather than in those using albumin concentration in a single spot (OR, 95% CI: 0.529, 0.397-0.706, P = 0.0000164 and 0.919, 0.733-1.153, P = 0.47, respectively). CONCLUSION: The present study shows that the PPARγ2 Ala12 variant is significantly associated with a reduced risk of albuminuria among patients with type 2 diabetes.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors: a systematic review of randomized controlled trials.

BACKGROUND: A recent clinical trial showed harmful renal effects with the combined use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) in people with diabetes or vascular disease. We examined the benefits and risks of these agents in people with albuminuria and one or more cardiovascular risk factors. METHODS: MEDLINE, EMBASE and Renal Health Library were searched for trials comparing ACEI, ARB or their combination with placebo or with one another in people with albuminuria and one or more cardiovascular risk factor. RESULTS: Eighty-five trials (21,708 patients) were included. There was no significant reduction in the risk of all-cause mortality or fatal cardiac-cerebrovascular outcomes with ACEI versus placebo, ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy. There was a significant reduction in the risk of nonfatal cardiovascular events with ACEI versus placebo but not with ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy. Development of end-stage kidney disease and progression of microalbuminuria to macroalbuminuria were reduced significantly with ACEI versus placebo and ARB versus placebo but not with combined therapy with ACEI + ARB versus monotherapy. CONCLUSIONS: ACEI and ARB exert independent renal and nonfatal cardiovascular benefits while their effects on mortality and fatal cardiovascular disease are uncertain. There is a lack of evidence to support the use of combination therapy. A comparative clinical trial with ACE, ARB and its combination in people with albuminuria and a cardiovascular risk factor is warranted.

Reverse transcriptase inhibitors induce cell differentiation and enhance the immunogenic phenotype in human renal clear-cell carcinoma.

Reverse transcriptase (RT) inhibitors are emerging as a novel class of anticancer differentiating agents, active in several human tumor cell models, such as melanoma and prostate, thyroid and colon carcinoma. Indeed, much evidence suggests that they may act by inhibiting endogenous RT, a gene highly expressed in undifferentiated and transformed cells. We therefore evaluated whether endogenous RT may represent a new molecular target in the treatment of human renal clear-cell carcinoma, a neoplasm with very low sensitivity to standard pharmacological therapies. Efavirenz and nevirapine, 2 non-nucleosidic RT inhibitors commonly used in HIV patients, either induced a reversible downregulation of cell proliferation or enhanced cell differentiation in primary cultures of human renal carcinoma cells characterized by high levels of endogenous RT activity. Both agents upregulated the expression of the vitamin D receptor and calbindin 28k genes, which are constitutively expressed in renal tubular cells, and induced vitamin D signaling by enhancing the ability of tumor cells to upregulate the vitamin D-dependent gene, CYP24. Furthermore, efavirenz- and nevirapine-differentiated tumor cells exhibited an immunogenic phenotype with an increased expression of HLA-I and CD40 antigens and an enhanced ability to elicit a specific T-cell response in mixed lymphocyte/tumor-cell cultures. Indeed, renal carcinoma cells exposed to efavirenz induced a CD8(+)CCR7-CD45RA(-) effector memory T-cell phenotype, whereas untreated RCC cells induced a CD8(+)CCR7(+)CD45RA(-) central memory T-cell phenotype. These data suggest that RT inhibitors may be a novel tool in the treatment of human renal clear-cell carcinoma, potentially able to enhance the immunogenic potential of tumor cell.

Waist circumference is strongly associated with renal resistive index in normoalbuminuric patients with type 2 diabetes.

OBJECTIVE: Anthropometric parameters may play a role in modulating the risk of kidney dysfunction. The aim of this study was to evaluate whether anthropometric indices and the metabolic syndrome are associated with alterations of the renal resistive index (RI) in normoalbuminuric type 2 diabetic (T2DM) patients. METHODS: A sample of 99 consecutively recruited patients with T2DM (76 male and 23 female) was examined. The RI was assessed by duplex Doppler sonography. RESULTS: In univariate analysis, a significant association between the RI values and age (r = 0.507, p < 0.0001), gender (being higher in women, p = 0.002), systolic blood pressure (r = 0.285, p = 0.011), smoking habit (being lower in current smokers, p = 0.047), estimated glomerular filtration rate (r = -0.435, p < 0.0001), and intima-media thickness of the carotid arteries (r = 0.271, p = 0.020) was observed. As far as anthropometric parameters are concerned, a strong correlation between waist circumference (WC; r = 0.401, p < 0.0001), BMI (r = 0.337, p = 0.003) and RI values was found but only WC maintained a significant correlation after adjusting for several confounders (p = 0.001). CONCLUSIONS: In normoalbuminuric T2DM patients, the intrarenal hemodynamic abnormalities seem primarily associated with WC.

Percutaneous ultrasound-guided renal biopsy in supine antero-lateral position: a new approach for obese and non-obese patients.

BACKGROUND: Percutaneous ultrasound (US)-guided renal biopsy is the gold standard in the evaluation of renal diseases, but some patients, such as the obese, may not be eligible for this procedure. Aim of this study was to determine the feasibility, efficacy and safety of US-guided percutaneous renal biopsy in supine antero-lateral position (SALP) in high-risk patients (BMI > 30 and/or respiratory difficulty), as well as to compare the overall outcome of SALP with that of traditional prone position (PP) in low-risk patients (BMI < or = 30/no respiratory difficulty). METHODS: One hundred and ten consecutive patients scheduled for native kidney biopsy were recruited. Ninety low-risk patients were randomized following a permuted block randomization list to receive either US-guided renal biopsy in PP (Group 1) or SALP (Group 2), whereas 20 high-risk patients received US-guided renal biopsy in SALP (Group 3) and were our observational cohort study. Comfort compliance and breathing difficulty in each group were evaluated by the Visual Analogue Scale (VAS). Bleeding complications were evaluated through US renal scanning. RESULTS: Mean operating time was 7 min. Comfort compliance and breathing difficulty were significantly better for SALP in both low- and high-risk patients; there were no significant differences in pain after biopsy among the three groups. Bleeding complications were slightly higher in Group 1. Diagnostic yield was similar in all groups. CONCLUSIONS: SALP is reliable, minimally invasive, easy, highly successful, timesaving and almost free from severe side-effects. A better VAS score for breathing difficulty and comfort compliance characterizes this procedure, making it particularly suitable for obese patients.

Cigarette smoking and kidney dysfunction in diabetes mellitus.

Type 2 diabetes mellitus is one of the leading causes of end-stage renal disease in the Western world. Smoking can also be seen as a powerful agent, although often underrated, able to induce renal damage and microvascular dysfunction via several different mechanisms, which often overlap with those of diabetic disease, and in concert may eventually worsen the renal redox homeostasis. As a result of this, the association of diabetes with smoking may favor the onset and/or the progression of renal insufficiency toward renal failure, and such a conclusion is supported by an array of epidemiological and physiopathological studies. Consequently, smoking prevention and cessation programs must be strongly encouraged not only to reduce the cardiovascular risk, but also to avoid the deterioration of renal function among diabetic patients.

Nevirapine toxicity in non-HIV cancer patients.

BACKGROUND: Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor used in HIV patients and recently evaluated as a differentiating and antiproliferative agent in human malignancies. However, while NVP is a safe treatment in immunocompromised patients, NVP-containing regimens have been associated with severe immune-mediated toxicities in non-HIV individuals. METHODS AND RESULTS: We describe the toxicity profile of single-agent NVP in 6 non-HIV cancer patients treated for a median period of 7.3 months (range 1-24), reporting only a reversible grade III increase in glutamyl transpeptidase and glutamic pyruvic transaminase serum values. Interestingly, NVP treatment correlates with either a decrease in CD8+ T cell counts or a parallel increase in CD4/CD8 ratio, antithyroglobulin and antithyroid peroxidase autoantibody titers. CONCLUSIONS: These results, although obtained in a small cohort of patients, suggest that the toxicity profile of single-agent NVP may be worth testing in a phase I/II study in non-HIV cancer patients and that NVP toxicity may depend on its capacity to trigger autoimmune responses in susceptible individuals.

Retrospective Analysis of Endocrine Dysfunctions in a Population of Adult Polytransfused Patients: Correlation of GH-IGF1 Axis Alteration with Cardiac Performance.

Endocrine complications of haemochromatosis and heart failure mostly affect morbidity and mortality in polytransfused patients. This study analyzes endocrine dysfunctions and the impact of GH-IGF-1 axis alteration on cardiac performance in a population of 31 patients. A retrospective study on 31 Caucasian polytransfused outpatients, 27 adults and 4 pediatric, residing in Apulia, Italy, followed from 2005 to 2016, was conducted. Patients underwent basal and dynamic hormonal evaluation. GHRH plus arginine test was performed in 21 patients (19 adults and 2 children). Among them, 9 patients were affected by left ventricle diastolic dysfunction and/or atrial or ventricular dilatation (HD group) and 12 patients did not have cardiovascular disease (non-HD group). Twenty-nine out of 31 patients (94%) had at least one endocrinopathy. We found severe or mild GH deficit (GHD) in all HD patients versus 3 patients in the non-HD group (p=0.001). Mean IGF-1 levels were significantly lower in the HD group than in non-HD subjects (53±30 versus 122±91 µg/L, p=0.04). Our study confirms the need to perform a dynamic evaluation of the GH-IGF1 axis in polytransfused patients, especially when heart dysfunction emerges. An intervention study with GH replacement therapy in a larger randomized adult population will clarify the role of GH/IGF axis on cardiovascular outcomes in this patient population.

Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor.

INTRODUCTION: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. RESULTS: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. CONCLUSION: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.

Insulin signaling in human visceral and subcutaneous adipose tissue in vivo.

In this study, we evaluated the activation of various insulin signaling molecules in human fat in vivo and compared signaling reactions in visceral and subcutaneous fat depots. Paired abdominal omental and subcutaneous fat biopsies were obtained from nonobese subjects with normal insulin sensitivity under basal conditions and 6 and 30 min following administration of intravenous insulin. Insulin receptor phosphorylation was more intense and rapid and insulin receptor protein content was greater in omental than in subcutaneous adipose tissue (P < 0.05). Insulin-induced phosphorylation of Akt also occurred to a greater extent and earlier in omental than in subcutaneous fat (P < 0.05) in the absence of significant changes in Akt protein content. Accordingly, phosphorylation of the Akt substrate glycogen synthase kinase-3 was more responsive to insulin stimulation in omental fat. Protein content of extracellular signal-regulated kinase (ERK)-1/2 was threefold higher in omental than in subcutaneous fat (P < 0.05), and ERK phosphorylation showed an early 6-min peak in omental fat, in contrast with a more gradual increase observed in subcutaneous fat. In conclusion, the adipocyte insulin signaling system of omental fat shows greater and earlier responses to insulin than that of subcutaneous fat. These findings may contribute to explain the biological diversity of the two fat depots.

Obesity and kidney disease.

The prevalence of obesity worldwide has increased dramatically. Besides, an approximately two-fold higher rate of increase in mean BMI among the incident ESRD has been reported in the US population from 1995-2002. Chronic kidney disease (CKD) prevalence increases from 2.9% among adults with an ideal BMI to 4.5% among obese adults. The development of CKD is usually the culminating result of the interaction of multiple risk factors. Obesity represents one example of a multitoxicity state and given the background of genetic susceptibility and/or reduced nephron number, overweight may initiate renal remodeling and/or accelerate kidney failure. Obesity may be the number one preventable risk factor for CKD. Weight loss has indeed been shown to improve glomerular hemodynamics and reduce urine albumin excretion. Thus, obese patients with CKD should be counseled on the benefits of weight loss.

Reinduction of cell differentiation and 131I uptake in a poorly differentiated thyroid tumor in response to the reverse transcriptase (RT) inhibitor nevirapine.

Our recent findings have shown that the reverse transcriptase (RT) inhibitors, nevirapine and efavirenz, used for 10 years in human immunodeficiency virus (HIV) disease, act as cytostatic and differentiating agents by modulating gene expression in several human tumor cell models. In dedifferentiated thyroid cancer, they reestablish thyroid-stimulating hormone (TSH) signaling, Na/I symporter (NIS), thyroglobulin peroxidase (TPO) expression, and even radioiodine uptake (RIU). In this paper, we describe the case of a 76-year-old woman who was affected by thyroid papillary carcinoma and who underwent a total thyroidectomy and a debulking of the right laterocervical region for lymph-node metastases, vessel infiltration, and neoplastic thrombosis of the internal jugular vein, followed by 3 radioiodine treatments. At restaging, a computed tomography scan revealed that distant metastases were mostly not taking up the radioiodine at the 131I whole-body scan (WBS). An analysis of tumor cells obtained by fine-needle aspiration biopsy of a right laterocervical lymph-node revealed cell anisokaryosis, nuclear pleomorphism, and scanty colloid, as well as the undetectable expression of thyroglobulin and NIS proteins. After starting a nevirapine treatment (NT), higher thyroglobulin levels were observed and some metastases exhibited a significant increase in radioiodine uptake, which led us to again treat the patient with 131I. Five (5) months later, the 131I-WBS revealed the disappearance of RIU in some metastases and its significant reduction in other lesions, with a parallel drop in serum thyroglobulin. No new metastatic lesion was revealed by rh-TSH-stimulated 131IWBS and 18F-flourodeoxyglucose positron emission tomography scan. Cells obtained from the right laterocervical lymph-node 2 months after NT exhibited a reduced nuclear pleomorphism, an increase in colloid production, and a significant upregulation of thyroglobulin and NIS protein expression. This first in vivo molecular and morphologic evidence of cell differentiation in human cancer and low toxicity of nevirapine strongly encourage its use in dedifferentiated thyroid cancer treatment.

Cigarette smoking is associated with low glomerular filtration rate in male patients with type 2 diabetes.

OBJECTIVE: The relationship between cigarette smoking and renal dysfunction in diabetes has predominantly been documented in patients with type 1 diabetes. The aim of the present study was to explore the relationship between cigarette smoking and glomerular filtration rate (GFR) in a large cross-sectional study carried out in male subjects with type 2 diabetes. The role of metabolic syndrome in modulating this relationship was also investigated. RESEARCH DESIGN AND METHODS: One hundred fifty-eight current smokers and 158 never smokers with type 2 diabetes were consecutively recruited. Low GFR was defined as GFR <60 ml/min per 1.73 m(2). RESULTS: The proportion of patients affected by low GFR was significantly higher in current smokers (20.9 vs. 12.0%, P = 0.03). The adjusted risk (odds ratio [OR]) of low GFR in current smokers was 2.20 (95% CI 1.14-4.26, P = 0.02) and markedly higher in patients from the first tertile of disease duration (4.27 [1.26-14.40], P = 0.02). When metabolic syndrome was added to the statistical model exploring the relationship between smoking and low GFR, the risk of low GFR showed a small change, although it did not become any more significant (1.84 [0.98-3.45], P = 0.06). Current smokers showed even higher free oxygen radical test unit values (560.0 +/- 91.5 vs. 442.7 +/- 87.2, P < 0.0001). CONCLUSIONS: In a large population of male patients with type 2 diabetes, the risk of low GFR is markedly enhanced by smoking and is at least partially mediated by metabolic syndrome.

On the non-linear association between serum uric acid levels and all-cause mortality rate in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: High levels of serum uric acid (SUA) are associated with increased mortality risk in the general population. Contrasting results are available in people with diabetes. The aim of our study was to investigate the association and its functional form between SUA and all cause-mortality in patients with type 2 diabetes mellitus (T2DM). METHODS: We studied three cohorts of patients with T2DM: Gargano Mortality Study, Foggia Mortality Study, Pisa Mortality Study. All-cause mortality rate was the end point of this study. RESULTS: The most reliable relationship between SUA levels and all-cause mortality rate was quadratic, with such model being well approximated by SUA tertiles. Both tertiles 1 and 3 were at higher risk of mortality as compared to tertile 2: Hazard Ratio (HR) [95% Confidence Interval (CI)] = 1.34 (1.07-1.68) and 1.61 (1.29-1.99), respectively. In the pseudo-sample, created from the real pooled sample, the best relationship between SUA and all-cause mortality rate was quadratic. In a tree-based Recursive Partitioning and Regression Tree analysis two subgroups at increased risk of mortality were identified, namely those with SUA levels ≥7.28 mg/dl and with SUA levels <4.16 mg/dl as compared to patients with intermediate SUA levels (i.e. 4.16-7.28), thus providing further evidence on the J-shaped relationship between SUA levels and mortality rate. CONCLUSIONS: SUA was not linearly associated with all-cause mortality rate in patients with T2DM. For clinical and public health purposes such association is J-shaped.