Association of toll-like receptors 2 and 6 polymorphism with clinical mastitis and production traits in Holstein cattle.

Mastitis is a costly disease of dairy cattle as it causes a loss in milk yield and milk quality in affected cows. Toll-like receptor (TLR) genes play a role in the host response to a variety of organisms including those inducing mastitis. In the present study, we investigated the polymorphism of TLR2, 4, 6 and 9 genes in Holstein cattle and their possible association with clinical mastitis (CM), milk somatic cell scores (SCS) and milk production traits. From a large commercial Holstein herd, thirty-eight blood samples were collected; 19 from cows without a previous lifetime history of mastitis (non-susceptible), and 19 from Holstein cows with at least three previous episodes of mastitis (susceptible). Genotyping of the four TLRs was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPs) with Rsa1, MSP1, Hha1, HaeIII, and Taq1 enzymes guided with DNA sequencing. Seven novel non-synonymous single-nucleotide polymorphisms (SNPs) were identified among TLR2, 4, and 6 in susceptible animals. Association was found in Taq1-TLR2 gene polymorphism with CM, fat percentage and peak yield (PY). The association of Taq1-TLR6 and PY and lactation persistency was also shown. Mutations in TLRs that were repeatedly reported in susceptible cows provide potential genetic marker assisted selection (MAS) for mastitis resistance in dairy cattle.

Characteristics of systemic lupus erythematosus in a sample of the Egyptian population: a retrospective cohort of 1109 patients from a single center.

Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can vary among different ethnic and racial groups. Objective The objective of this paper is to study the prevalence of various manifestations of SLE in a sample of the Egyptian population. Patients and methods Information in this study was derived from the medical records of SLE patients who sought medical advice at a private clinic in Cairo from January 1980 to June 2016. Results This study included 1109 SLE patients, of whom 114 (10.3%) were males and 995 were females (89.7%). Mean age of onset was 25.89 ± 10.81 years, while the median of disease duration from the onset of the disease till the last recorded visit was 26 months. The most common cumulative manifestations were arthritis (76.7%), malar rash (48.5%), leukopenia (45.7%), and photosensitivity (45.6%). A total of 33.1% of the patients had nephritis, and neuropsychiatric lupus was present in 6.4% of the patients. Secondary antiphospholipid syndrome was present in 11.5% of the patients. Antinuclear antibody and anti-double-stranded deoxyribonucleic acid were present in 1060/1094 (96.9%) and 842/1062 (79.3%) of the patients, respectively. Antiphospholipid antibodies were present in 266/636 (41.8%) of the patients, anti-Smith in 54/240 (22.5%), anti-SSA/Ro in 61/229 (20.4%), and anti-SSB/La in 32/277 (11.6%) of the patients. Male patients had a statistically higher prevalence of nephritis ( p = 0.01), whereas arthritis and alopecia were statistically higher in females ( p = 0.012 and p = 0.006, respectively). Patients with juvenile onset had a statistically higher prevalence of nephritis and seizures ( p < 0.001 and p = 0.012, respectively). Conclusions Arthritis and malar rash represented the most common clinical manifestations. Male and juvenile-onset patients had a predilection toward a more severe disease. These results are in agreement with many studies conducted in the Middle East and worldwide. On the other hand, major organ involvement was exceptionally low, which is contradictory to several reports from the Middle East and across the globe.

Management of anterior caliceal stones >15 mm.

Anterior caliceal stones represent a challenge to endourologist to select the best modality of management with the least morbidity. To study different treatment modalities of management of anterior caliceal stones >15 mm. It is an observational prospective study of patients with anterior caliceal stones more than 15 mm. Inclusion criteria were patients with isolated anterior caliceal stones, or branched anterior caliceal stones with posterior caliceal extension. Patients were evaluated using non-contrast CT preoperatively. They were divided into three groups: group 1 underwent PCNL through posterior caliceal puncture in cases with wide anterior calyx infundibulum or obtuse infundibulopelvic pelvic, group 2 underwent PCNL through anterior caliceal access in cases with narrow infundibulum or acute infundibulopelvic angel and group 3 underwent flexible ureteroscopy and laser lithotripsy. Intraoperative and postoperative findings were recorded and compared. Eighty eight patients were included in this study, Group 1 (44 patients) group 2 (28 patients), and group 3 (16 patients). Operative time was not significantly different across the three groups (68 ± 11.5, 72 ± 9 and 74 ± 11 min in group 1, 2 and 3, respectively, P = 0.053). Fluoroscopy time was significantly shorter for group 3 (2 ± 0.5 m, P = 0.0001) compared to group 1 and 2 (5.6 ± 4.6 and 4.5 ± 1.4 min), respectively. There were no significant differences in stone-free rates after initial treatment between the three groups; 84, 82, and 69 %, in groups 1, 2 and 3, respectively (P = 0.4). Postoperative hemoglobin drop was noted to be highest for group 2 and lowest for group 3 which was significantly different (1.7 ± 0.8, 2.2 ± 1.1, and 0.3 ± 0.3 g/dl, for patients in groups 1, 2 and 3 respectively, P = 0.0001). Group 2 showed the highest post-operative complication rate (21 %) in comparison to group 1 (11 %) and group 3 (6 %), however, differences were not statistically significant (P = 0.3). PCNL through posterior or anterior caliceal puncture is an excellent modality to treat anterior caliceal stones with high stone clearance rate. Despite the higher chance of bleeding with anterior caliceal puncture, it is still inevitably needed in difficult anterior caliceal stones with unfavorable anatomy. RIRS is a good alternative to PCNL with the advantage of less radiation exposure and less bleeding.

Normal radiographic and ultrasonographic appearance of the adult dromedary camel tarsus (one humped camel).

Six cadaver pelvic limbs were obtained from clinically sound dromedary camels and examined radiographically and ultrasonographically using a 7.5 MHz convex transducer. Radiographic examination was performed in dorsoplantar, lateromedial, dorsolateral-plantaromedial oblique and plantarolateral-dorsomedial oblique projections, and the bony structures and articulations of the tarsal joint were outlined. The tarsus was ultrasonographically investigated in four planes (dorsal, medial, lateral and plantar), and each plane was scrutinized in four levels (calcaneal tuber, tibial malleoli, base of calcaneus and proximal end of metatarsus) in both transverse and longitudinal views. Limbs were examined grossly, frozen at -20°C and sectioned. Radiographic and ultrasonographic findings correlated well with the gross anatomy and frozen sections. The normal appearance of bony and soft structures of the tarsus described in this study provided basic reference data for ultrasonographic and radiographic investigations of tarsal disorders in the dromedary camel.

Computed tomography and cross-sectional anatomy of the normal dromedary camel tarsus (one humped camel).

The purpose of this study was to provide a detailed computed tomographic (CT) anatomic reference for the dromedary camel tarsus. Six cadaver pelvic limbs, obtained from three clinically and radiographically sound dromedary camels, were scanned in both soft tissue and bone windows starting from the calcaneal tuber towards the proximal metatarsus. Limbs were frozen at -20°C and sectioned transversely via an electric bone saw. The CT images were evaluated and correlated with their corresponding cryosections. The resulting images provided detailed anatomic features for bones, joints and soft tissue components of the tarsus and are intended to serve as a basic reference for the CT scanning of the dromedary camel tarsal pathology.

Changes in matrix metalloproteinases and their inhibitors in kidney transplant recipients.

OBJECTIVES: Chronic allograft nephropathy remains one of the main causes of late graft loss after kidney transplant owing to multifactorial development of kidney scarring. Chronic allograft nephropathy is characterised by an excess accumulation of extracellular matrix. A key system regulating extracellular matrix homeostasis are matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. This study sought to determine if a change in the matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases system contributes to chronic allograft nephropathy-associated progressive kidney scarring. MATERIALS AND METHODS: Examination of sequential renal biopsies was done at implantation, acute rejection, and subsequent chronic allograft nephropathy. In situ localisation of matrix metalloproteinase activity was assessed with a high-resolution in situ zymography technique using gelatin and collagen 1 substrates. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were localised using immunohistochemistry. RESULTS: In situ zymography showed over a 50% reduction in matrix metalloproteinase activity against both collagen 1 and gelatin substrates in chronic allograft nephropathy biopsies. A similar loss of matrix metalloproteinase activity was seen in the glomerular and tubulointerstitial compartments. Immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were observed intracellularly in mesangial and tubular epithelial cells. Matrix metalloproteinases-1, -2, -3, and -9 were significantly reduced in acute rejection and later in chronic allograft nephropathy. However, glomerular matrix metalloproteinases 1 and 9 and tubulointerstitial matrix metalloproteinase-2 were reduced at implantation. Tissue inhibitors of matrix metalloproteinase-2 and -3 were elevated from implantation onwards. We were unable to stain reproducibly for tissue inhibitors of matrix metalloproteinase-1. CONCLUSIONS: Kidney scarring underlying chronic allograft nephropathy is associated with a reduction in matrix metalloproteinases activity that may be due to reduced expression of matrix metalloproteinases -1, -2, -3, and -9, and up-regulation of tissue inhibitors of matrix metalloproteinases -2 and -3. Some of these changes originate from implantation.

Albumin-induced epithelial mesenchymal transformation.

BACKGROUND: Progressive chronic kidney disease is often associated with albuminuria and renal fibrosis linked to the accumulation of myofibroblasts producing extracellular matrix. Renal myofibroblasts are derived from a number of cells including tubular epithelial cells (TECs) through epithelial mesenchymal transformation (EMT). This study explores the hypothesis that exposure of TECs to albumin induces EMT. METHODS: Normal rat TECs (NRK52E) were exposed in culture to de-lipidated bovine serum albumin (dBSA; 10 mg/ml) for 2, 4 and 6 days. Binding/uptake of fluoresceined albumin by PTCs was evaluated. Transformation into myofibroblasts was assessed by light and electron microscopy, immunofluorescence and Western blotting for α-smooth muscle actin (α-SMA), E-cadherin and transforming growth factor-ß1 (TGF-ß1). We also investigated the expression of fibroblast-specific protein-1 (FSP-1) and collagens I, III and IV. TGF-ß1 biological activity, mRNA and protein were measured. A neutralising anti-TGF-ß1 antibody was used to analyse the role of TGF-ß1 in albumin-induced EMT. RESULTS: Exposure of TECs to dBSA led to binding/uptake of albumin as well as fibroblastic morphological changes. Incubation of TECs with dBSA caused a reduction of TEC marker E-cadherin (ANOVA p = 0.0002) and de novo expression of fibroblast markers α-SMA and FSP-1 (ANOVA p = 0.0001) in a time-dependent manner. It also increased expression and activity of TGF-ß1. Neutralisation of TGF-ß1 significantly reduced EMT (p < 0.01). CONCLUSION: This study demonstrates that in vitro, albumin induces the transformation of TECs into cells with myofibroblast characteristics; a process that may be TGF-ß1 dependent.

Association of deprivation with worse outcomes in chronic kidney disease: findings from a hospital-based cohort in the United Kingdom.

BACKGROUND: Chronic kidney disease (CKD) prevalence and complications are known to be associated with deprivation, but there is limited understanding of the underlying reasons for inequalities. AIMS: To evaluate the association of both individual and area level socioeconomic status (SES) with heavy proteinuria at presentation, progression of CKD, end-stage renal disease (ESRD) and death. METHODS: A retrospective study of 918 CKD patients using integral multivariate logistic regression to adjust for known clinical and demographic explanatory variables. RESULTS: During 3 years of median follow-up, 34% of the study population had progression of their CKD and of these, 32% experienced rapid progression. 23% presented with heavy proteinuria (urine protein:creatinine ratio ≥300 mg/mmol), 4% developed ESRD requiring renal replacement therapy and 10% died. Area level deprivation was independently associated with heavy proteinuria, progression and rapid progression of CKD. People living in the most deprived areas were more likely to develop ESRD. Unskilled professionals were more likely to experience a higher mortality rate. CONCLUSION: Area level SES is inversely associated with both heavy proteinuria on presentation and progression as well as rapid progression of CKD. In contrast, individual level SES, unskilled professionals found to have a marginally significant association with increased risk of mortality. People living in more deprived areas presenting with CKD are likely to be at increased risk of poor outcomes and may need more active management and earlier referral.

The value of percentage free prostate specific antigen (PSA) in the detection of prostate cancer among patients with intermediate levels of total PSA (4.0-10.0 ng/mL) in Nigeria.

OBJECTIVES: To assess the value of percentage free prostate-specific antigen (%fPSA) in the detection of prostate cancer among Nigerian men with an intermediate total PSA level (4-10 ng/mL), and to show if the optimum threshold for biopsy is different from Caucasian values when the widely used (six-core, digitally directed) prostate biopsy protocol in Nigerians is applied. PATIENTS AND METHODS: The study included 105 patients aged >50 years, with a palpably benign prostate gland and intermediate levels of total PSA (4-10 ng/mL). These patients had a free PSA assay and a transrectal digitally directed six-core biopsy of the prostate. The %fPSA was calculated and the optimum threshold value for detecting prostate cancer was determined. RESULTS: The mean (SD) age of the patients was 64.4 (6.6) years and their mean (SD) total PSA level was 6.6 (1.7) ng/mL. Of these men 14 (13.3%) had cancer of the prostate detected by the prostate biopsy. The %fPSA level related directly to sensitivity values but inversely to the specificity and the positive predictive values. The best threshold of %fPSA for detecting cancer in these men was <40%, with a sensitivity of 100%, specificity of 93.4% and a positive predictive value of 70% (P < 0.05). CONCLUSIONS: In evaluating Nigerian patients with a palpably benign prostate gland and within the intermediate total PSA range, when digitally directed biopsy protocol is adopted, a %fPSA threshold of <40% will detect significant percentage of those with prostate cancer, with a minimal number of unnecessary biopsies. This value differs from that reported in western studies in which transrectal ultrasonography-directed biopsy was used.

Social deprivation and prevalence of chronic kidney disease in the UK: workload implications for primary care.

BACKGROUND: The 'inverse care law' suggests that populations with the poorest health outcomes also tend to have poorer access to high-quality care. The new general practitioner (GP) contract in the UK aimed to reduce variations in care between areas by collecting information on processes and outcomes of chronic disease management. This study investigated whether, despite reductions in inequalities, primary care in deprived areas is still at a disadvantage due to the higher prevalence of chronic diseases, using chronic kidney disease (CKD) as an example. METHODS: Initially, data from a hospital-based cohort of CKD patients were analysed to investigate the clustering of CKD patients across area-level deprivation using a geographical information system that employed kernel density estimation. Data from the Quality and Outcomes Framework were then analysed to explore the burden of CKD and associated non-communicable chronic diseases (NCD) and assess the potential impact on GPs' workload by area-level deprivation. RESULTS: There was a significant clustering of CKD patients referred to the hospital in the most deprived areas. Both the prevalence of CKD and associated conditions and caseload per GP were significantly higher in deprived areas. CONCLUSION: In the most deprived areas, there is an increased burden of major chronic disease and a higher caseload for clinicians. These reflect significant differences in workload for practices in deprived areas, which needs to be addressed.

Do changes in transglutaminase activity alter latent transforming growth factor beta activation in experimental diabetic nephropathy?

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage kidney failure worldwide. It is characterized by excessive extracellular matrix accumulation. Transforming growth factor beta 1 (TGF-ß1) is a fibrogenic cytokine playing a major role in the healing process and scarring by regulating extracellular matrix turnover, cell proliferation and epithelial mesanchymal transdifferentiation. Newly synthesized TGF-ß is released as a latent, biologically inactive complex. The cross-linking of the large latent TGF-ß to the extracellular matrix by transglutaminase 2 (TG2) is one of the key mechanisms of recruitment and activation of this cytokine. TG2 is an enzyme catalyzing an acyl transfer reaction leading to the formation of a stable ε(γ-glutamyl)-lysine cross-link between peptides. METHODS: To investigate if changes in TG activity can modulate TGF-ß1 activation, we used the mink lung cell bioassay to assess TGF-ß activity in the streptozotocin model of diabetic nephropathy treated with TG inhibitor NTU281 and in TG2 overexpressing opossum kidney (OK) proximal tubular epithelial cells. RESULTS: Application of the site-directed TG inhibitor NTU281 caused a 25% reduction in kidney levels of active TGF-ß1. Specific upregulation of TG2 in OK proximal tubular epithelial cells increased latent TGF-ß recruitment and activation by 20.7% and 19.7%, respectively, in co-cultures with latent TGF-ß binding protein producing fibroblasts. CONCLUSIONS: Regulation of TG2 directly influences the level of active TGF-ß1, and thus, TG inhibition may exert a renoprotective effect by targeting not only a direct extracellular matrix deposition but also TGF-ß1 activation and recruitment.

The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease.

BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system (RAAS) has shown to slow chronic kidney disease (CKD) progression. This is most notable at the earlier stages of diabetic and proteinuric nephropathies. Objective. Here, we observed the impact of discontinuation of angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptors blockers (ARB) in patients with advanced kidney disease. METHODS: 52 patients (21 females and 31 males) with advanced CKD (stages 4 and 5), who attended our low clearance clinic (LCC) in preparation for renal replacement therapy (RRT). Mean age was 73.3 ± 1.8 years with an estimated glomerular filtration rate (eGFR) of 16.38 ± 1 ml/min/1.73 m(2). Baseline urine protein:creatinine ratio (PCR) was 77 ± 20 mg/mmol. 46% suffered from diabetes mellitus. Patients were followed for at least 12 months before and after ACEi/ARB were stopped. RESULTS: 12 months after discontinuation of ACEi/ARB eGFR increased significantly to 26.6 ± 2.2 ml/min/ 1.73 m(2) (p = 0.0001). 61.5% of patients had more than a 25% increase in eGFR, whilst 36.5% had an increase exceeding 50%. There was a significant decline in the eGFR slope -0.39 ± 0.07 in the 12 months preceding discontinuation. The negative slope was reversed +0.48 ± 0.1 (p = 0.0001). Mean arterial blood pressure (MAP) increased from 90 ± 1.8 mmHg to 94 ± 1.3 mmHg (p = 0.02), however ≥50% of patients remained within target. Overall proteinuria was not affected (PCR before = 77 ± 20 and after = 121.6 ± 33.6 mg/mmol). CONCLUSION: Discontinuation of ACEi/ARB has undoubtedly delayed the onset of RRT in the majority of those studied. This observation may justify a rethink of our approach to the inhibition of the RAAS in patients with advanced CKD who are nearing the start of RRT.

Cardiovascular disease on hemodialysis: predictors of atherosclerosis and survival.

Cardiovascular disease (CVD) is the leading cause of mortality in hemodialysis (HD) patients. This could not be explained by the known traditional CVD risk factors. In this study, we attempted to elucidate the factors influencing atherosclerosis, as measured by carotid artery intima-media thickness (IMT), in HD patients and their impact on cardiovascular mortality. A cohort of 50 patients started on HD was selected for this study. At baseline, IMT and the presence of atheromatous plaques were assessed. Plasma homocysteine (Hcy), malondialdehyde, total antioxidant capacity, von Willebrand factor, vitamins C, E, B(6), B(12), folate, and C-reactive protein (CRP) were also measured. Patients were followed up for 2 years to determine the impact of IMT and associated markers on mortality using survival analysis as well as Cox proportional hazard. At baseline, 40% of the patients had IMT>0.8 mm. They were older, had higher CRP (P<0.001), and lower serum albumin (P=0.03). Intima-media thickness >0.8 mm was associated with high calcium (risk ratio [RR]: 6.06; confidence interval [CI]: 0.75-12.25) and CRP (RR: 10.94 [CI: 2.56-46.74]). Fifteen patients (30%) died during the 2-year follow-up; the main cause of death was CVD (42%). The relative risk mortality was high with increased IMT (RR: 120.04 [CI: 4.18-3445.9]), Index of Coexistent Disease for CVD (RR: 4.04 [CI: 1.92-8.5]), and plasma Hcy (RR: 1.08 [CI: 1.02-1.13]). Markers of inflammation and increased serum calcium were significant predictors of increased carotid artery IMT. High IMT, Index of Coexistent Disease, and Hcy were associated with a high RR of all-cause mortality among a cohort of HD patients.

Influence of obesity on progression of non-diabetic chronic kidney disease: a retrospective cohort study.

BACKGROUND: There is increasing awareness of the impact of obesity on chronic diseases including chronic kidney disease (CKD). Until recently, a limited number of epidemiologic studies have examined the association between obesity and CKD. We conducted a retrospective cohort study to evaluate whether obesity impacts on the rate of non-diabetic CKD progression. METHODS: The medical records of 125 non-diabetic CKD patients in the Sheffield Kidney Institute, Sheffield, UK, who have been followed-up for around 10 years, were reviewed. Various socio-demographic, clinical and biochemical parameters were retrospectively collected from the patients' database. Participants were categorized into normal weight, overweight and obese groups. Multivariate regression analysis was used for modelling with estimated glomerular filtration rate (eGFR) reduction per year as the dependent variable to evaluate the impact of obesity (BMI) on CKD progression. RESULTS: Patients studied were mostly CKD stage 3 with a mean GFR of 36.2 ml/min/1.73 m(2) for the control group and 44.3 ml/min/1.73 m(2) for those who were overweight or obese. Baseline diastolic and mean arterial blood pressure were significantly higher in overweight than normal weight CKD patients (p = 0.009 and p = 0.014 respectively). On follow-up, systolic, diastolic and mean arterial blood pressure were significantly higher in overweight (p = 0.03, p = 0.005 and p = 0.003, respectively) and obese (p = 0.008, p = 0.022 and p = 0.003, respectively) compared to normal weight CKD patients. Mean follow-up triglycerides level was significantly higher in obese than normal weight patients (p = 0.042). The frequency of CKD progression based on eGFR fall per year (>1 ml/min/1.73 m(2)/year) was 62.5% in overweight and 79.5% in obese compared to 44.7% in normal weight CKD patients (p = 0.007). However, no significant difference in the rate of progression (fall of eGFR ml/min/1.73 m(2)/year) was observed between the three groups. On multivariate regression analysis, adjusted for other covariates (age, BP and proteinuria), baseline BMI was an independent predictor of CKD progression (fall in eGFR, ml/min/1.73 m(2)/year) (R(2) = 0.122 and p < 0.001). Percentage changes in BMI over the observation period did not affect the rate of eGFR decline. Young age also predicted a faster CKD progression. CONCLUSIONS: Baseline BMI and young age are strongly and independently associated with faster CKD progression based on the annual rate of eGFR fall. Prospective studies to investigate the relationship between BMI and CKD and its complications are warranted.

Transglutaminase inhibition ameliorates experimental diabetic nephropathy.

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.

High prevalence of microalbuminuria in the overweight and obese population: data from a UK population screening programme.

BACKGROUND: Microalbuminuria (MA) is associated with increased risk of cardiovascular and possibly chronic kidney disease (CKD). Obesity has been linked to MA, though the prevalence of MA in overweight groups is not well documented. This population study with an overrepresentation of individuals with BMI >25 (calculated as kg/m2) investigates the prevalence of MA in different BMI categories, and the relationship between MA and BMI. METHODS: Data from two cross-sectional epidemiological studies in the City of Sheffield were combined to produce a cohort of non-diabetic, non-CKD subjects over the age of 18. The first study, Kidney Evaluation and Awareness Programme in Sheffield (KEAPS), is a general population screening programme, whilst Kidney Evaluation in Overweight Population in Sheffield (KEOPS) is a screening programme specifically for individuals with BMI >25. RESULTS: The combined database had 1,179 subjects eligible for analysis after applying exclusion criteria. The prevalence of MA in subjects with BMI <25 was 3.1% compared to 12.1% in those with BMI 25-30 and 27.2% in obese subjects with BMI >30 (p < 0.001). The prevalence of MA increased exponentially with the BMI category. BMI is a predictor of MA in logistic regression analyses in the population as a whole, males, females, younger and older age categories, and higher BMI groups (above median and upper tertile). The effect of BMI persists after adjusting for confounding variables. The relative risk for having urine albumin concentration >20 mg/l is 8.0 (95% CI 3.8-16.8, p < 0.0001) if BMI is above the 80th percentile (BMI >27.2). CONCLUSION: The prevalence of MA increases with increasing BMI in the population of Sheffield. The risk of having MA increases exponentially with BMI. The significance of the high prevalence of MA in overweight and obese individuals should be investigated longitudinally.

Cardiorenal risk prevalence in sickle cell hemoglobinopathy.

INTRODUCTION: The spectrum of kidney functional and structural alterations in sickle cell hemoglobinopathy (SCH) is broad. Also, morbidity and mortality from end organ dysfunction, especially cardiorenal dysfunction, are substantial. Consequently, screening an SCH population prospectively for surrogate markers of cardiorenal risk such as albuminuria and intima-media thickness (IMT) was the aim of this cross-sectional study. PATIENTS AND METHODS: We screened 165 patients with SCH over 4 months at the Primary Care Department, King Abdulaziz Armed Forces Hospital, Saudi Arabia. The 133 who fulfilled the inclusion criteria have been referred for further investigations. Anthropometric evaluation of body mass index (BMI) and blood pressure (BP), determination of 24-hour urine albuminuria, fasting lipids, computed atherogenic risk ratio (ARR), estimated glomerular filtration rate (eGFR), common carotid artery (CCA) IMT measurements, and hemoglobin (Hb) electrophoresis were done. RESULTS: Increased urinary albumin excretion (UAE) rate [380 (272.2-489.6) mg/day; mean and 95% confidence interval (95% CI) of mean] was detected in 24% of SCH patients (6 males and 26 females). Microalbuminuria (168.8 +/- 59.7 mg/day) was noted in the majority (63.6%) while macroalbuminuria (752.7 +/- 205.4 mg/day) was detected in a smaller percentage (36.4%). Patients with sickle cell disease (SCD) contributed about 66.6% of subjects with microalbuminuria and 100% of those with macroalbuminuria, while most individuals with sickle cell trait (89%) were normoalbuminuric (p < 0.0001). Preclinical atherosclerosis (increased CCA IMT and/or atheromatous plaques) was noticed in 68.8% of SCH individuals with increased UAE (ANOVA p = 0.003). The microalbuminuric and macroalbuminuric patients had comparable BMI, BP values and lipid profiles. However, the microalbuminuric sicklers were significantly younger (28.4 +/- 6.7 vs. 34.0 +/- 7.2 years, p = 0.04), less anemic (Hb: 9.13 +/- 2 vs. 7.47 +/- 0.8 g/dl, p = 0.015), with lesser atherosclerosis (IMT; 0.68 +/- 0.1 vs. 0.78 +/- 0.1 mm, p = 0.004) and higher eGFR (83.3 +/- 17.2 vs. 61 +/- 10.7 ml/min/1.73 m(2), p = 0.0004) compared to those with macroalbuminuria. UAE correlated positively with age (r = 0.591, p = 0.0001), systolic BP (r = 0.483, p = 0.005), IMT (r = 0.399, p = 0.024) and negatively with Hb (r = -0.409, p = 0.02), and eGFR (r = -0.620, p = 0.0001). By univariate analysis, the significant indicators of UAE in SCH patients were age (p = 0.05), BMI (p = 0.041), IMT (p = 0.018) and eGFR (p = 0.016). Also, increased risk (odds ratio) of albuminuria was noted with SCD, age, anemia, abnormal eGFR, obesity, and ARR. CONCLUSIONS: Markers of cardiorenal risk such as albuminuria and IMT are common findings in SCH patients of Arabic descent and could be useful screening tools to identify sicklers at risk for cardiovascular and renal events.

Lack of effect of IGF-I on the glomerular filtration rate in non-diabetic patients with advanced chronic kidney disease.

Recombinant human insulin-like growth factor I (rhIGF-I) acutely increases the glomerular filtration rate (GFR) in human volunteers and patients with advanced chronic kidney disease (CKD). However, on chronic administration, rhIGF-I induces tolerance to its renal effects attributed to a fall in serum IGF-binding protein 3 (IGFBP-3) enhancing its systemic clearance. Tolerance may be avoided by the use of an intermittent dosage regimen of rhIGF-I. A randomised, double-blind, placebo-controlled study was undertaken in non-diabetic patients with advanced CKD to establish whether intermittent subcutaneous injections of rhIGF-I (50 microg/kg, four days/week) could increase GFR over a 24 week period and thereby have the potential to delay the onset of renal replacement therapy. Twenty-seven patients were randomised into rhIGF-I/placebo groups using a 2:1 treatment ratio. GFR was determined by inulin clearance. RhIGF-I therapy produced a sustained increase serum total and free IGF-I elevating IGFBP-1 without decreasing IGFBP-3. Inulin clearance however, was not increased after either four weeks or over the 24 week observation period. Only 4/18 rhIGF-I treated patients compared to 6/9 placebo patients completed the study, the major reason being the requirement for dialysis. Compared with healthy volunteers, advanced CKD patients had elevated serum levels of IGFBP-1, IGFBP-2, tumour necrosis factor-alpha and asymmetric dimethylarginine, all factors proposed to mediate IGF-I resistance. In conclusion, although intermittent rhIGF-I therapy elevated serum total IGF-I and prevented any fall in serum IGFBP-3, it failed to increase GFR in non-diabetic patients with advanced CKD. The lack of efficacy was attributed to the presence of renal IGF-I resistance in CKD.