Diabetic Renal Disease Research Articles

The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases.

All national guidelines for the management of hypertension recommend angiotensin receptor blockers (ARBs) as an initial or add-on antihypertensive therapy. The eight available ARBs have variable clinical efficacy when used for control of hypertension. Additive blood pressure-lowering effects have been demonstrated when ARBs are combined with thiazide diuretics or dihydropyridine calcium channel blockers, augmenting hypertension control. Furthermore, therapeutic use of ARBs goes beyond their antihypertensive effects, with evidence-based benefits in heart failure and diabetic renal disease particularly among angiotensin-converting enzyme inhibitor-intolerant patients. On the other hand, combining renin-angiotensin system blocking agents, a formerly common practice among medical subspecialists focusing on the management of hypertension, has ceased, as there is not only no evidence of cardiovascular benefit but also modest evidence of harm, particularly with regard to renal dysfunction. ARBs are very well tolerated as monotherapy, as well as in combination with other antihypertensive medications, which improve adherence to therapy and have become a mainstay in the treatment of stage 1 and stage 2 hypertension.

Brachial-ankle pulse wave velocity in the measurement of arterial stiffness: recent evidence and clinical applications.

Arterial stiffness is a vascular measure that has been reported to predict cardiovascular events. It is important to measure arterial stiffness in order to determine current vascular status and treatment strategy. Brachial-ankle pulse wave velocity (baPWV) is a unique measure of systemic arterial stiffness that is measured by brachial and tibial arterial wave analyses. Measurement of baPWV is easy and is reproducible. For more than a decade, this measure has been used broadly in East Asian countries. Meta-analysis of cohort studies conducted in the general population with hypertension, diabetes, or end-stage renal disease, and other high-risk individuals have shown that a 1 m/s increase in baPWV is associated with 12% increase in the risk of cardiovascular events. Thus, the Japanese Circulation Society has proposed that a baPWV of 1800 cm/s is a threshold for high-risk category. For baPWV to be clinically applicable, we must confirm that circulation of the lower limbs are normal by examining brachial ankle blood pressure index. In cases of peripheral arterial disease, the reliability of baPWV measurement is attenuated. To further confirm the clinical usefulness of this measure, we need to examine the hypothesis that baPWV-guided therapy could improve prognosis in high-risk patients.

Pneumatosis cystoides intestinalis and hepatic portal venous gas on peritoneal dialysis

Pneumatosis cystoides intestinalis is a condition in which polycystic air has entered the submucosa or serosa of the intestine. A 78-year-old man was admitted to our hospital for treatment of end-stage renal disease due to diabetic nephropathy. Peritoneal dialysis was initiated on hospital Day 14. We diagnosed peritonitis and the patient was treated with vancomycin on Day 40. However, computed tomography showed hepatic portal venous gas and dilation of the small intestine with pneumatosis on Day 55, and the patient subsequently died. Autopsy revealed multiple mucosal pneumatoses, up to 1 cm in diameter, from the duodenum to jejunum, which was consistent with pneumatosis cystoides intestinalis. No cystic lesions were found in the colon. Pneumatosis cystoides intestinalis is a rare and usually benign disorder, but in patients with diabetic end-stage renal disease, it may run a malignant course, perhaps due to uremic immune incompetence.

Effects of restoring normoglycemia in type 1 diabetes on inflammatory profile and renal extracellular matrix structure after simultaneous pancreas and kidney transplantation

AimsPatients with type 1 diabetes and end-stage renal disease with simultaneous pancreas and kidney (SPK) or kidney transplants alone (KA) were recruited 9–12 years post transplantation. We investigated differences between these groups with regard to inflammatory parameters and long-term structural changes in kidneys. MethodsBlood samples were analyzed by ELISA and multiplex for chemokines, cytokines, growth factors, cell adhesion molecules and matrix metalloproteinases. Kidney graft biopsies were analyzed by electron microscopy for glomerular basement membrane thickness. Heparan- and chondroitin sulfate disaccharide structures were determined by size exclusion chromatography mass–spectrometry. ResultsThe SPK and the KA group had average glycated hemoglobin A1c (HbA1c) of 5.8% (40mmol/mol) and 8.6% (70mmol/mol) respectively. SPK recipients also had 16.2% lower body mass index (BMI) and 46.4% lower triglyceride levels compared with KA recipients, compatible with an improved metabolic profile in the SPK group. Plasminogen activator inhibitor (PAI-1), C-reactive protein (CRP) and vascular endothelial growth factor (VEGF) were lower in the SPK group. In kidney graft biopsies of the KA-patients an 81.2% increase in average glomerular basement membrane thickness was observed, accompanied by alterations in heparan sulfate proteoglycan structure. In addition to a decrease in 6-O-sulfated disaccharides, an increase in non-N-sulfated disaccharides with a corresponding slight decrease in N-sulfation was found in kidney biopsies from hyperglycemic patients. ConclusionsPatients with end stage renal disease subjected to KA transplantation showed impaired inflammatory profile, increased thickness of basement membranes and distinct changes in heparan sulfate structures compared with SPK recipients.

Components of Sustainable Health Systems: What Is Known About The Cost-Effectiveness of Clinical Care?

Evidence to ensure cost-effective purchasing of services are an important pre-requisite for ensuring financial sustainability of health systems. The Research Agenda for Health Economic Evaluation project aims to map out the economic evidence available for the treatment of the 10 highest burden conditions in the European Union and identify evidence gaps. The 10 highest burden diseases are selected by Disability Adjusted Life Years (DALYs) based on the Global Burden of Disease study for Europe (Ischemic Heart Disease, Low Back Pain, Stroke, Major Depressive Disorder, Lung Cancer, Falls, COPD, Diabetes, Other musculoskeletal, Neck pain). Clinical pathways are generated for these conditions by merging published clinical guidelines from public and professional bodies. Economic (cost-benefit and cost-effectiveness) evidence indexed by MEDLINE is stratified by treatment pathways to identify evidence gaps. Existing reviews are analysed to assess coverage of primary evidence. Results are presented for diabetes: 1,208 articles were retrieved from MEDLINE, of which 315 mapped to the treatment pathway. Most evidence was published after 2000.74 reviews were identified, of which 24 were published between 2009-13. Volume of economic studies for each treatment ranged from 0 to 39 studies. The most intensively studied were diabetic retinopathy (n=39), foot ulcers (n=34) and renal disease (n=31). Areas with no economic evidence included non-pharmacological blood pressure and dyslipidemia control. In some cases economic evidence was available, but no recent reviews of the evidence were identified (eg. islet or pancreas transplantation, diabetic neuropathy, interventions for weight loss). Economic evidence was available for the majority of treatment modalities for diabetes, however for several treatments no studies were identified. Importantly, reviews were not identified for several treatments where economic evidence was available. Lack of economic evidence prevents cost-effective commissioning, and lack of reviews of evidence may be a further barrier to translation.

Pioglitazone improves fat distribution, the adipokine profile and hepatic insulin sensitivity in non-diabetic end-stage renal disease subjects on maintenance dialysis: a randomized cross-over pilot study.

BackgroundFat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.Trial DesignThis was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.MethodsAt the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.ResultsFour months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10−3 to 0.76×10−3. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.Conclusions/LimitationsPioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.Trial RegistrationClinicalTrial.gov NCT01253928

Meckel’s Diverticulum Masquerading as an Arterio-Enteric Fistula in an Adult Patient With Simultaneous Pancreas-Kidney Transplantation

Introduction: Simultaneous pancreas-kidney (SPK) transplantation is a treatment for patients with type1 diabetes (DM) and end-stage renal disease (ESRD). Complications of SPK transplantation include peripancreatic abscess, enterocutaneous fistula, and rarely, gastrointestinal bleeding (GIB). We report a case of an adult patient with SPK transplantation who presented with massive GIB caused by Meckel’s diverticulum. Case Report: A 40-year-old male presented 3 years after SPK transplantation to an outside hospital with maroon-colored stool and dizziness. His co-morbidities included DM, ESRD, coronary artery disease, hepatitis C, nonalcoholic steatohepatitis, and cirrhosis. He was hypotensive (94/43), but otherwise, vitals were within reference range. His exam was significant for a soft abdomen with normoactive bowel sounds and mild confusion without any focal deficits or asterixis. Labs were notable for a hemoglobin of 5.9 g/dL, creatinine 1.73 mg/dL (baseline 1.1 mg/dL), BUN 64 mg/dL, and liver function tests within reference range. An esophagogastroduodenoscopy (EGD) revealed presumed Dieulafoy’s lesion, which was cauterized and clipped. Colonoscopy showed mild inflammation, but no obvious source of bleeding. Biopsies were negative for infection or inflammatory bowel disease. The patient was transferred to our center for management of persistent GIB (requiring 26 units of blood total) and worsening renal function. At our center, EGD, colonoscopy, push enteroscopy, tagged RBC scan, and provocative angiography were negative for the source of bleeding. Video capsule endoscopy showed a large amount of red blood in the small bowel without adequate identification of the source lesion. Exploratory laparotomy with intraoperative small bowel endoscopy was performed, which demonstrated a healthy appearing anastomosis with a more distal Meckel’s diverticulum full of clotted blood. The diverticulum was excised without recurrent bleeding. Discussion: The differential for lower GIB is vast, but in adult patients, Meckel’s diverticulum is a rare cause. Patients status-post SPK transplantation have additional considerations for GIB, including anastomotic site ulcer, pseudoaneurysm, arterioenteric fistula, severe graft rejection, and cytomegalovirus infection. This is a rare case of GIB secondary to Meckel’s diverticulum in patients with SPK transplantation. Clinicians should be aware of Meckel’s diverticulum as a cause of massive GIB in SPK transplant patients. A high index of suspicion and timely evaluation can improve morbidity and mortality.

Albumin antioxidant response to stress in diabetic nephropathy progression.

BackgroundA new component of the protein antioxidant capacity, designated Response Surplus (RS), was recently described. A major feature of this component is the close relationship between protein antioxidant capacity and molecular structure. Oxidative stress is associated with renal dysfunction in patients with renal failure, and plasma albumin is the target of massive oxidation in nephrotic syndrome and diabetic nephropathy. The aim of the present study was to explore the albumin redox state and the RS component of human albumin isolated from diabetic patients with progressive renal damage.Methods/Principal FindingsSerum aliquots were collected and albumin isolated from 125 diabetic patients divided into 5 groups according to their estimated glomerular filtration rate (GFR). In addition to clinical and biochemical variables, the albumin redox state, including antioxidant capacity, thiol group content, and RS component, were evaluated. The albumin antioxidant capacity and thiol group content were reciprocally related to the RS component in association with GFR reduction. The GFR decline and RS component were significantly negatively correlated (R = –0.83, p<0.0001). Age, creatinine, thiol groups, and antioxidant capacity were also significantly related to the GFR decline (R = –0.47, p<0.001; R = –0.68, p<0.0001; R = 0.44, p<0.001; and R = 0.72, p<0.0001).Conclusion/SignificanceThe response of human albumin to stress in relation to the progression of diabetic renal disease was evaluated. The findings confirm that the albumin molecular structure is closely related to its redox state, and is a key factor in the progression of diabetes nephropathy.

A New Proposal of Surgical Suture in Case of Spontaneous Renal Allograft Rupture

IntroductionSpontaneous kidney allograft rupture (KAR) is a rare but potentially life-threatening complication after kidney transplantation. It is associated with a high risk of graft loss and patient death. We report a new technique of surgical repair in case of KAR. Case ReportA 53-year-old man transplanted due to diabetic nephropathy-related end-stage renal disease experienced a spontaneous KAR 10 days after KT. Immediate laparotomy revealed the presence of a 4-cm linear kidney fracture. Dexon 2-0 wires were used for the suture, stopping each wire with Hem-o-Loks on a cylinder of oxidized cellulose gauze, with the intent of avoiding the risk of tissue fracture caused by the suture itself. Bleeding was thus controlled. The patient experienced an uneventful course and was discharged on postoperative day 26. ConclusionsAccording to the recent literature, graft nephrectomy for KAR is no longer considered the standard surgical treatment. A new approach to rupture repair has been proposed, providing good rates of graft and patient survival.

Monocyte chemoattractant protein-1 (MCP-1) g.-2518A>G polymorphism and susceptibility to type 2 diabetes (T2D) and end stage renal disease (ESRD) in the North-West Indian population of Punjab

Background: Diabetic nephropathy (DN) is a major microvascular complication that develops in nearly 20–30% of patients with type 2 diabetes (T2D) and is currently the leading cause of end stage renal disease (ESRD). Monocyte chemoattractant protein-1 (MCP-1), a potent chemokine secreted by adipocytes, has been implicated as a causal factor in the progression of vascular complications in T2D, thus MCP-1 appears to be a promising candidate for association study.Aim: The objective of the present study is to evaluate the association, if any, of g.-2518A>G polymorphism (rs1024611) in MCP-1 gene in T2D cases with and without ESRD in the population of Punjab from North-West India.Subjects and methods: A total of 571 samples from Punjab comprising 350 T2D cases (145 with ESRD and 205 without ESRD) and 221 controls were genotyped for g.-2518A>G MCP-1 polymorphism using amplification refractory mutation system- polymerase chain reaction.Results: The frequency of G allele was observed to be higher in T2D cases with ESRD (34.49%) compared to T2D cases without ESRD (24.39%) and controls (31.67%). Under the dominant model, G allele increased the risk of ESRD by 1.68-fold [p = 0.047, OR = 1.68 (1.0–2.79) at 95% CI].Conclusion: MCP-1 -2518 GG genotype and G allele may increase the risk of progression to ESRD in T2D cases.

In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone.

In patients with type 1 diabetes and end-stage renal disease (ESRD) we aimed to determine whether long-term normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, would preserve kidney graft structure and function better than live donor kidney (LDK) transplantation alone. Estimated GFR (eGFR) was calculated in SPK (n = 25) and LDK (n = 17) recipients in a stable phase 3months after transplantation and annually during follow-up. Kidney graft biopsies were obtained at follow-up for measurement of glomerular volume (light microscopy), glomerular basement membrane (GBM) and podocyte foot process widths and mesangial volume fraction (electron microscopy). SPK and LDK recipients were similar in age and diabetes duration at engraftment. Donor age was higher in the LDK group. Median follow-up time was 10.1years. Mean HbA1c levels during follow-up were 5.5 ± 0.4% (37 ± 5mmol/mol) and 8.3 ± 1.5% (68 ± 16mmol/mol) in the SPK and LDK group, respectively (p < 0.001). Compared with SPK recipients, LDK recipients had wider GBM (369 ± 109nm vs 281 ± 57nm; p = 0.008) and increased mesangial volume fraction (median 0.23 [range 0.13-0.59] vs 0.16 [0.10-0.41]; p = 0.007) at follow-up. Absolute eGFR change from baseline was -11 ± 21 and -23 ± 15mlmin(-1) 1.73m(-2) (p = 0.060), whereas eGFR slope was -1.1 (95% CI -1.7, -0.5) and -2.6 (95% CI -3.1, -2.1) mlmin(-1) 1.73m(-2) per year in the SPK and LDK group, respectively (p = 0.001). In patients with type 1 diabetes and long-term normoglycaemia after successful SPK transplantation, kidney graft ultrastructure and function were better preserved compared with LDK transplantation alone.

"Vitamin D supplementation and bone health in adults with diabetic nephropathy: the protocol for a randomized controlled trial".

BackgroundSuboptimal vitamin D status is highly prevalent in Northern communities, particularly in those patients with chronic diseases such as diabetes and chronic renal disease. Emerging literature suggests that adherence to daily vitamin D supplementation may be an important factor influencing vitamin D status and overall bone health, but compliance with therapies for bone health is a major challenge. It is unknown what level of vitamin D supplementation will ameliorate or improve suboptimal vitamin D status in patients with diabetic nephropathy or contribute to improved bone health, particularly for those living in northern climates.Methods/DesignThe study purpose was to examine two different strategies of vitamin D3 supplementation; daily dosing of 2000 IU per day verses monthly dosing of 40,000 IU per month on markers of vitamin D status, bone health and to examine whether adherence, quality of life and patient satisfaction with the supplementation strategy differs between the two vitamin D strategies in adults diagnosed with diabetic nephropathy.DiscussionThe need for RCTs assessing higher doses of vitamin D3 supplementation at varying frequencies of administration and its impact on bone health in adults with diabetes and chronic kidney disease are needed.Trial registrationClinicalTrials.gov NCT01476501.

Engaging novel cell types, protein targets and efficacy biomarkers in the treatment of diabetic nephropathy.

EDITORIAL article Front. Pharmacol., 07 August 2014Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2014.00185

Incidence of Conversion to Active Waitlist Status Among Temporarily Inactive Obese Renal Transplant Candidates

Candidates may be active or temporarily inactive (status 7) on the kidney transplant waiting list. One reason candidates may be inactive is for a "weight currently inappropriate for transplantation." We hypothesized that many of these candidates would not achieve active status. Using OPTN/UNOS data from 2006 to 2012, we used competing risks methods to determine the cumulative incidence of conversion to active status (activation), death, and delisting before conversion among 1679 obese adult kidney candidates designated as status 7 because of a weight inappropriate for transplantation. Fine and Gray competing risks regression was performed to characterize factors associated with conversion to active status in the overall study population and of transplantation among a subgroup of activated candidates. At 6 years, the cumulative incidence of activation was 49%, of death before conversion was 15%, and of delisting was 21%. Higher body mass index (BMI) was strongly associated with a decreased subhazard of activation (BMI ≥45 versus 30-34.9, sHR: 0.22; 95% CI, 0.16-0.33). Female sex, diabetic end-stage renal disease, history of a previous transplant, panel reactive antibodies less than 80%, dialysis dependence at listing, and UNOS region 5 were negatively associated with activation. Among activated candidates, the cumulative incidence of transplantation at 6 years after initial waitlisting was 61%. Our findings indicate that half of obese status 7 candidates with a weight inappropriate for transplantation will not achieve active waitlist status. BMI at listing had a strong association with conversion to active status; comorbid factors and regional variation also impact activation.

The impact of hypoxemia on nephropathy in extremely obese patients with type 2 diabetes mellitus.

Diabetes mellitus (DM) is associated with obstructive sleep apnea (OSA) and nephropathy. The hypoxemia associated with OSA may exacerbate renal deterioration in DM nephropathy. We examined the role of hypoxemia in the development of DM nephropathy in severely obese patients. This cross-sectional study examined anonymized data from 90 DM patients with extreme obesity attending a weight management service. All patients underwent a routine overnight sleep study. Respiratory parameters measured included apnea-hypopnea index (AHI), mean and minimum oxygen (O2) saturations, and time spent under 90% O2 saturation (%TST < 90%). Chronic kidney disease (CKD+) was defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m(2). Twenty (22%) patients were CKD+. These patients were 7 years older (mean age ± SD 57 ± 11 years, p = 0.003) and had greater adiposity (mean body mass index [BMI] ± SD 50.6 ± 8.7 kg/m(2), p = 0.012). No significant differences were found for median AHI and minimum O2 saturation. %TST < 90% was 4 times greater in CKD+ group (p = 0.046). Multivariate regression analysis showed that AHI (β = -0.17, 95% CI: -0.316 to -0.024) and %TST < 90% (β = -0.215, 95% CI: -0.406 to -0.023) were negatively correlated with eGFR after adjustment for age, gender, BMI, comorbidities, insulin treatment, and drugs affecting the renin-angiotensin system. No associations were found between mean and minimum O2 saturations, and eGFR. Apnea and hypopnea events as well as duration of nocturnal hypoxemia were inversely associated with renal function after adjusting for potential confounders. Given the significant burden of renal disease in diabetes, greater vigilance is required in identifying OSA in DM patients with extreme obesity.

The Outcomes of Simultaneous Pancreas Kidney Transplantation and Its Comparison With Kidney Transplantation Alone in Diabetic End Stage Renal Disease Patients.

Background: It is not established yet whether outcomes of simultaneous pancreas kidney transplantation (SPK) is similar between type I and II diabetes mellitus (DM), and whether SPK has better outcomes than living-donor (LDKT) or decreased-donor kidney transplantation (DDKT). Methods: We reviewed the clinical outcomes of 317 DM patients who received SPK, DDKT or LDKT in two centers (Seoul National University Hospital and Samsung Medical Center) between 2000 and 2012, then compared its patient survival to 227 wait-listed DM patients. Results: Among 317 DM transplant recipients, 193, 76, and 48 patients underwent LDKT, DDKT, and SPK, respectively. The mean age in the SPK group was 41.7±10.6 years, and 54.2% were male. Twenty (41.7%) patients had of type I DM. Most common complications were infection (22.9%) and hematoma (18.8%). Acute rejection occurred in 17 patients (35.4%) within 1 year after SPK. Five-year patient, kidney graft, and pancreas graft survival rate were 93.6%, 85.8%, and 88.2%, respectively. Although 1-year eGFR was higher in type I DM than in type II DM patients, the difference was not significant after adjustment for age. Adjusted relative risk (RR) for death of patients on the waiting list was 2.577 compared with transplanted groups, and especially LDKT has a significantly lower risk for death (RR, 0.312) compared to the wait-listed patients. Five-year kidney graft survival rates of SPK, LDKT, and DDKT were 86%, 94%, and 84%, respectively. Although kidney graft survival in LDKT was better than that in DDKT, there was no significant difference between LDKT and SPK. Conclusion: SPK has good outcomes for both type I and II DMESRD patients, and LDKT seemed to be the best therapeutic option for them.

Glomerulonephritis In Type 2 Diabetes Mellitus

Glomerulonephritis is also known as glomerular nephritis (GN) or glomerular disease. It is a disease of the kidney, characterized by inflammation of the glomeruli. The present study was undertaken with the objectives to explore the incidence and clinical profile of non diabetic renal disease in type 2 Diabetes Mellitus, to observe renal histology, to identify nature of glomerular disease, to identify the Prognostic factors and to observe the response to specific treatment. The Present study was conducted in June 1, 2001 to Dec 31, 2004 at Medical College Thiruvananthapuram. Twenty four patients with mean age of 51 were included in the study. Male and female ratio is 13:11. Mean duration of the patients suffering with diabetes mellitus is 8 years. Mean duration of the patients suffering with hypertension is 5 years. All patients had non nephrotic range proteinuria with a maximum of 2.8gms. Total number of patients are divided into five groups. We have observed thirteen patients with diabetes mellitus and glomerular disease with or without tubulo inerstitial nephritis. Five patients with diabetes mellitus and glomerular disease only. Four patients with diabetes mellitus only. One patient with diabetes mellitus with tubulo inerstitial nephritis. One patient with glomerular disease and tubulo inerstitial nephritis. Eleven patients were died. In the present study the relation between the variables is not statistically significant. Hence we suggest to carry out the study further with higher sample size to explore the relation well.

Coding variants in nephrin (NPHS1) and susceptibility to nephropathy in African Americans.

Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans. Exome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed. Initial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests. Coding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.

English

Lower gastrointestinal bleeding (LGIB) is a common ailment seen at emergency departments. It is a significant cause of morbidity and mortality in the elderly worldwide. The aim of this study was to determine the aetiology and management outcome of LGIB in our centre and compare it with results elsewhere. Sixty-eight consecutive patients who underwent colonoscopy for LGIB were recruited into this study. The study was carried out at the Ekiti State University Teaching Hospital (EKSUTH), Ado-Ekiti, Nigeria from January, 2010 to December, 2012. Ethical approval for the study was obtained from hospital&rsquo;s Ethics Committee and all the patients gave their individual signed consent. Relevant data were retrieved and analyzed using statistical package for social sciences (SPSS) version 15.0 (SPSS, Inc., Chicago, Illinois, USA) for statistical analysis using the t-test for quantitative variables and &chi;2 test for qualitative variables. Differences were considered to be statistically significant if P value was less than 0.05. The male: female ratio was 1.83:1. The mean age of the studied population was 56.04 &plusmn; 10.60 (age range 30 to 75). The indications for colonoscopy were; melena (11.8%), haematochezia (52.9%) and both (35.5%). Findings at colonoscopy were; haemorrhoids (35.3%), colorectal cancer (16.2%), polyps (14.7%), anal fissure (13.2%), arteriovenous malformations (5.9%) and diverticulosis (4.4%). Normal findings were reported in 10.3%. While haemorrhoids, anal fissure, colorectal cancer, polyps and diverticulosis were more prevalent in the male populations, arteriovenous malformation was more prevalent in the females. Co-morbidities found included; diabetes (14.7%), chronic liver disease (14.7%), hypertension (36.8%), diabetes and hypertension (16.2%) and renal disease (5.9%) of the studied population. These findings were found to be statistically significant (&chi;2 = 68.535, p = 0.001, &alpha; = 0.05 that is, 95% confidence interval). Haemorrhoids followed by colorectal cancer are the commonest colonoscopy findings in our environment. It is recommended that colonoscopy should be embraced for routine cancer screening and surveillance in our society. &nbsp; Key words: Colonoscopy, lower gastrointestinal bleeding, emergency departments.

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification.

Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.