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.

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.

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.

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.

Prevalence of increased albumin excretion rate in young saudi adults.

INTRODUCTION: Albuminuria is an important risk predictor of chronic kidney disease and cardiovascular disease. In this study, we aim to evaluate the prevalence of increased urinary albumin excretion (UAE) rate amongst a subgroup of young Saudi army/navy recruits. METHODS: 2,000 Saudi military recruits were tested for microalbuminuria by dipstick and 24-hour urine collection for quantitative evaluation. RESULTS: In the whole group studied, the rate of microalbuminuria-positive dipstick testing was 10.3% (n = 206), but decreased on quantitative evaluation of 24-hour urine collection to 6.2% (n = 124). Increased UAE was independently associated with diabetes mellitus (DM), hypertension (HT), obesity, male gender and hypercholesterolemia. 55 of the 124 (44.4%) were diabetics while 14 (11.3%) were hypertensives. Around 21% of individuals with albuminuria were obese; body mass index for the whole group with albuminuria = 31.15 +/- 5.8 kg/m(2) and showed no gender difference. Increased risk of albuminuria was noted with DM (OR = 5.07 [3.5-7.4], p < 0.0001), obesity (OR = 1.59 [1.0-2.5], p = 0.042) and HT (OR = 1.8 [1.0-3.2], p = 0.046). An estimated glomerular filtration rate of approximately 77 ml/min/1.73 m(2) was present in the whole group with a significantly lower level in macroalbuminuric subjects compared to those with microalbuminuria (p = 0.03). Also, age was higher in the macroalbuminuric group (p = 0.004) with comparable prevalence of DM (47.4 vs. 45.2%, p = NS). CONCLUSIONS: This is the first description of increased UAE in a small percentage of young adult Arab subjects from Saudi Arabia detected through a selective screening process carried out on potential army recruits. It highlights the association of albuminuria in the general population with predisposing conditions such as DM, HT and obesity.

Stem cell factor in a rat model of serum nephrotoxic nephritis.

BACKGROUND: Stem cell factor (SCF) has been implicated in many disease processes characterized by tissue remodelling and fibrosis. The growth factor (SCF) was evaluated in a rat model of nephrotoxic serum nephritis (NTN), characterized by early inflammation followed by later tissue fibrosis. METHODS: NTN was induced in male Wistar Kyoto rats using rabbit anti-rat glomerular basement membrane antibodies. Animals were sacrificed at days 7, 15, 30 and 45 (n = 4-10 per group). Rats' kidneys were immunostained for ED1 as marker of inflammation, CD34, SCF, c-kit, mast cell tryptase and markers of fibrosis; collagens III and IV and alpha-SMA. Changes in SCF protein and mRNA content were evaluated by Western blotting and Northern blotting, respectively. RESULTS: In the NTN kidney, levels of immunoreactive SCF and SCF receptor (c-kit) were significantly higher in glomerular, tubular and interstitial compartments. Mast cells were barely detectable in NTN and control rat sections. Double immunostaining showed the co-localization of SCF with alpha-SMA and of the SCF receptor with CD34 and ED1 positive cells. Immunostainable SCF protein in each of the 3 compartments, glomerular, tubular and interstitial, showed a positive linear correlation with serum creatinine, proteinuria, glomerulosclerosis score and interstitial fibrosis scores. Using multivariate analysis, immunostainable tubular SCF was a predictor of glomerular sclerosis and immunostainable glomerular SCF predicted tubular atrophy. Increased SCF immunostain was not a consequence of altered transcription as there was a fall in SCF mRNA determined by Northern blotting. Western blotting of NTN kidney homogenates revealed two bands for SCF, a 43-kDa band which decreased, and a 19-kDa band which increased throughout the study. CONCLUSION: These results highlight the potential role of SCF and its receptor in the remodelling process of the NTN kidney. Upregulation of SCF may involve a translational mechanism, with the soluble SCF protein KL-S1 (19 kDa) being derived from the transmembrane SCF protein KL-1 (43 kD) by proteolytic cleavage. The immunohistochemical staining of few CD34+ cells in NTN kidneys warrants further evaluation of the nature of these cells in the context of the inflammatory as well as the fibrotic processes.

The effect of body temperature in a rat model of renal ischemia-reperfusion injury.

BACKGROUND: Renal ischemia-reperfusion injury (IRI) is an unavoidable event in renal transplantation; the effects of IRI can be seen in both the acute and long-term function of the transplanted organ. For this reason, research into the pathophysiology of ischemia-reperfusion is at the forefront of transplantation research. Animal models, particularly in the rat, provide a useful research tool in studying the intricacies of IRI and in evaluating new treatments. We describe a model of right nephrectomy and left renal clamping for 45 minutes and demonstrate the effects of temperature variation during the ischemic period. METHODS: Male Sprague-Dawley rats (under isoflurane anesthesia) underwent bilateral flank incision with removal of the right kidney and clamping of the left renal hilum for 45 minutes. The animals were divided into 3 groups (n=6): group 1 had the procedure performed on a heating mat with no temperature control facilities, group 2 used no heating mat, and group 3 used a rectal temperature-controlled homeothermic blanket system (Harvard Medical, United Kingdom). Temperature was taken every 5 minutes throughout the procedure and blood samples were taken on a daily postoperative basis via tail vein venepuncture. RESULTS: The average temperature at the end of the procedure in group 1 was 39.67 degrees C and the creatinine level at day 3 was 574+/-17.84, in group 2 the temperature was 32.6 degrees C and the creatinine level was 115+/-4.06, and in group 3 the temperature was maintained between 36.5 degrees C-37 degrees C and the serum creatinine level was 329+/-19.18. The temperature of the animal during the ischemia phase of IRI significantly affects the severity of injury. Relative hyperthermia resulted in more severe renal injury and unrecoverable acute renal failure, no source of heat led to a relative hypothermia, and reduction of renal injury. Use of the homeothermic heating blanket led to an increase in creatinine level by day 3, indicating a significant ischemic stimulus; however, by day 10 the creatinine level had returned to normal. CONCLUSION: This illustrates the importance of temperature as a variable in animal models of IRI and thus should be clearly stated in all experimental methods to ensure an appropriate ischemic stimulus and for adequate comparisons between various therapeutic interventions.

FTY720 reduces extracellular matrix expansion associated with ischemia-reperfusion induced injury.

BACKGROUND: Ischemia-reperfusion (IR) is one of the strongest nonimmune factors associated with the development of chronic allograft nephropathy (CAN). This effect is often exacerbated by immunosuppressive medications, most notably cyclosporine. Although traditionally the macrophage was thought to stimulate fibroblast activity in CAN, recent evidence supports a role for lymphocytes. FTY720 is a new immunosuppressant that promotes lymphocyte sequestration into lymph nodes and Peyer's patches. This study investigated the effect of FTY720 on renal fibrosis in the rat following an IR insult (IRI). METHODS: A rat model of IRI was used in which male Sprague-Dawley rats (under isoflurane anaesthesia) underwent bilateral flank incision with removal of the right kidney and clamping of the left renal hilum for 45 minutes. Five groups of animals were studied (n=4): nephrectomy only, IRI only, IRI+FTY720 (1 mg/kg/d), IRI+cyclosporine (15 mg/kg/d), and IRI+FTY 720 (1 mg/kg/d) and cyclosporine (15 mg/kg/d). Animals were humanely killed at 30 days. RESULTS: Serum creatinine (SCr) level was significantly reduced in the FTY720-treated animals. IRI alone produced a significant increase in SCr level compared with neprectomized animals (138 micromol/L vs 55 micromol/L; P<.05). This effect was potentiated by treatment with cyclosporine (173 micromol/L vs 55 micromol/L; P<.05). Treatment with FTY720 significantly reduced SCr level in rats following IRI alone (81 micromol/L vs 138 micromol/L; P<.01) and in rats following IRI + cyclosporine (98 micromol/L vs 173 micromol/L; P<.014). Parallel changes were seen in the levels of proteinuria. Fibrosis was assessed using Masson's trichrome (MT) staining. IRI alone produced a significant increase in MT staining compared with nephrectomized animals (0.92 vs 0.03; P<.05). This effect was potentiated by treatment with cyclosporine (1.12 vs 0.92; P=.022). Treatment with FTY720 reduced the level of MT staining in rats following IRI alone (0.34 vs 0.92; P<.05) and in rats following IRI+cyclosporine (70.34 vs 1.12; P<.05). Levels of TGF-beta1 were considerably reduced in FTY720-treated animals (compared with cyclosporine+IRI and IRI only), either alone (196+/-31 pg/mL vs 1105+/-59 pg/mL and 611+/-38; P<.05) or in conjunction with cyclosporine (423+/-26 pg/mL vs 1105+/-59 pg/mL and 611+/-38; P<.05). CONCLUSION: Our study shows that treatment with FTY720 can reduce renal fibrosis as a result of IRI, both alone and in conjunction with cyclosporine. This provides promising evidence for using FTY720 in a calcineurin-free or reduced-dose immunosuppression protocol in an effort to reduce the incidence of CAN.

Localization of matrix metalloproteinases and their inhibitors in experimental progressive kidney scarring.

The extracellular matrix (ECM) is in a continual state of turnover with homeostasis maintained by balancing synthesis and degradation rates. During progressive kidney scarring an imbalance occurs leading to ECM accumulation. Reduced matrix metalloproteinase (MMP) activity is believed to central to this imbalance. However, most of the data relating to MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinase (TIMP)) is based on homogenate studies where in situ compartmentalization is lost and thus changes in MMP activity may be artificial. To address this we have developed a sensitive, high-resolution in situ zymography technique and applied it, along with immunohistochemistry, to the 5/6th subtotal nephrectomy model of kidney scarring. ECM proteolytic activity in kidney homogenates progressively declined post-SNx against both gelatin (-82%) and collagen I (-78%) substrates. In situ zymography revealed higher activity with both substrates within the cytoplasm of normal tubular cells compared to the SNx. In contrast, there was 96% greater activity in the SNx glomeruli than normal. Immunohistochemistry confirmed a predominantly intracellular tubular location of all MMPs and TIMPs. Tubules showed reduced MMP-3 and elevated TIMP-2, whereas MMP-1 increased significantly in the glomeruli, especially in the mesangial matrix. TIMP-1 showed a fourfold increase in the remnant kidney by Western blot analysis, but could not be localized. Lowered MMP activity in homogenates results from reduced intracellular activity in the tubules, indicating that reduced MMP activity may not play a direct role in the expansion of the tubular ECM in scarring. However, elevated MMP-1 activity in the glomeruli may play a significant role in initiating glomerular remodelling.

Experimental and modeling study of C5H10O2 ethyl and methyl esters.

Due to the world's over-reliance on fossil fuels there has been a developing interest in the production of renewable biofuels such as methyl and ethyl esters derived from vegetable oils and animal fats. To increase our understanding of the combustion chemistry of esters, the oxidation of methyl butanoate and ethyl propanoate, both with a molecular formula of C5H10O2, have been studied in a series of high-temperature shock tube experiments. Ignition delay times for a series of mixtures, of varying fuel/oxygen equivalence ratios (phi = 0.25-1.5), were measured behind reflected shock waves over the temperature range 1100-1670 K, and at pressures of 1.0, and 4.0 atm. It was found that ethyl propanoate was consistently faster to ignite than methyl butanoate, particularly at lower temperatures. Detailed chemical kinetic mechanisms have been assembled and used to simulate these experiments with good agreement observed. Rate of production analyses using the detailed mechanisms shows that the faster reactivity of ethyl propanoate can be explained by a six-centered unimolecular decomposition reaction with a relatively low activation energy barrier producing propanoic acid and ethylene. The elimination reaction itself is not responsible for the increased reactivity; it is the faster reactivity of the two products, propanoic acid and ethylene that leads to this behavior.

Renal osteodystrophy: review of the disease and its treatment.

Renal osteodystrophy (ROD), which is most evident in patients on renal replacement therapy (RRT), usually begins when the kidney function starts to deteriorate. The spectrum of skeletal abnormalities seen in ROD is classified according to the state of bone turnover. In the past two decades, the prevalence of high turnover ROD has decreased while low bone turnover has become increasingly recognized. Secondary hyperparathyroidism represents a common disorder in patients with chronic kidney disease (CKD); it develops as a result of hyperphosphatemia, hypocalcemia and impaired synthesis of renal vitamin D with reduction in serum calcitriol levels. Patients with secondary hyperparathyroidism have a range of symptoms that affect their quality of life. The aim of treatment of ROD is to reduce the incidence of uremic bone disease as well as cardiovascular morbidity and mortality caused by elevated serum levels of parathormone (PTH) and calcium X phosphorus product. Treatment measures include control of phosphorus retention and prevent hyperphosphatemia, maintaining serum calcium concentrations within the normal range and prevent excess PTH secretion.

Prednisolone and azathioprine in membranous nephropathy: a 10-year follow-up study.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although its clinical course is usually benign, some patients develop chronic renal failure. Combination of corticosteroids with cytotoxic drugs and cyclosporin have been used in the treatment of the disease. Conflicting results are reported with the use ofprednisolone and azathioprine. In this study, the effect of treatment with prednisolone and azathioprine and the parameters related to a poor outcome over a follow-up period of 10 years is estimated. METHODS: 50 patients were included in this study; 33 were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg body weight/day) in gradually reduced doses for 26 +/- 9 months, whereas 17 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or end-stage renal failure (ESRF). The contribution of clinical and histological parameters in the clinical outcome was examined by univariate and multivariate analyses. RESULTS: Doubling of baseline serum creatinine was observed in 20 of 50 patients (40%), 14 from treated and 6 from the untreated group (42% vs. 35%, p=NS). ESRF developed in 10 of 50 patients (20%), 7 from treated and 3 from the untreated group (21% vs. 18%, p=NS). Most patients from both groups who reached the end-points had impaired renal function at presentation and persistent nephrotic syndrome during the follow-up period. Both parameters were identified as independent risk factors related to an unfavorable clinical outcome. No difference in the remission rate of nephrotic syndrome was observed between treated and untreated patients (51% vs. 58%, p=NS). CONCLUSION: Treatment with prednisolone and azathioprine seems to be of no long-term benefit in ameliorating the clinical course of nephrotic patients with membranous nephropathy. Thus, other therapeutic regimens including cyclophosphamide, chlorambucil or cyclosporin should be used in nephrotic IMN patients with poor prognostic features.

Transforming growth factor-beta1 SNPs: genetic and phenotypic correlations in progressive kidney insufficiency.

Associations have been described between polymorphisms of cytokine and growth factor genes and susceptibility to, or progression of, an increasing number of diseases. TGF-beta1 plays an important role in the pathogenesis of experimental and clinical glomerulosclerosis and tubulointerstitial fibrosis. In this study, single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene were investigated as possible markers for the progression of chronic kidney failure (CKF). 145 Caucasian patients with CKF were screened for four TGFbeta1 SNPs: T-509C in the promoter region; Arg25Pro and Leu10Pro in exon 1 and Thr263Ile in exon 5. There were significant differences between CKF patients and controls in allele frequencies of two of the SNPs, Leu10Pro (p = 0.038) and C-509T (p = 0.02) and in haplotype distributions (p = 0.0175), indicating an association with susceptibility to CKF. We also observed a significant association between progression of CKF and homozygosity for Arg25 (odds ratio 3.77, 95% confidence interval 1.57-9.04, p = 0.002). Homozygosity for Arg25 was also associated with severity of proteinuria at diagnosis (p = 0.038), plasma TGF-beta1 protein levels (p = 0.01), and severity of glomerulosclerosis (p = 0.04). Homozygosity for -509T was associated with severity of proteinuria at diagnosis (p = 0.0017), level of renal tubular TGF-beta1 immunostaining (p = 0.0006) and with severity of renal interstitial inflammatory cellular infiltration (p = 0.01). Tubular TGF-beta1 immunostaining was significantly higher in biopsies with inflammatory cellular infiltration compared those without inflammation (p = 0.0048). There was a significant difference in haplotype distributions between CKF patients with progressive, as opposed to non-progressive disease (p = 0.0484). TGFbeta1 SNPs may be useful prognostic indicators for the progression of CKF.

Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review.

BACKGROUND: The desert horned vipers (Cerastes cerastes and C. gasperettii) are the most familiar snakes of the great deserts of North Africa and the Middle East, including the plains of Iraq. They are responsible for many human snake bites. In Western countries, they are popular among exotic-snake keepers. AIM: To investigate mechanisms of life-threatening envenoming and treatment. DESIGN: Clinical investigation. METHODS: Clinical and laboratory studies with measurement of serum venom antigen concentrations by enzyme immunoassay. RESULTS: Two men bitten while handling captive Saharan horned vipers (Cerastes cerastes) in Europe developed extensive local swelling and life-threatening systemic envenoming, characterized by coagulopathy, increased fibrinolysis, thrombocytopenia, micro-angiopathic haemolytic anaemia and acute renal failure. The clinical picture is explicable by the presence in C. cerastes venom of several thrombin-like, Factor-X-activating, platelet-aggregating, haemorrhagic and nephrotoxic components. In one case, prophylactic use of subcutaneous epinephrine may have contributed to intracranial haemorrhage. The roles in treatment of heparin (rejected) and specific antivenom (recommended) are discussed. DISCUSSION: Cerastes cerastes is capable of life-threatening envenoming in humans. Optimal treatment of envenoming is by early administration of specific antivenom, and avoidance of ineffective and potentially-dangerous ancillary methods.

Elevated epsilon-(gamma-glutamyl)lysine in human diabetic nephropathy results from increased expression and cellular release of tissue transglutaminase.

INTRODUCTION: Diabetic nephropathy (DN) is the leading cause of chronic kidney failure, however the mechanisms underlying the characteristic expansion of the extracellular matrix (ECM) in diabetic kidneys remain controversial and unclear. In non-diabetic kidney scarring the protein crosslinking enzyme tissue transglutaminase (tTg) has been implicated in this process by the formation of increased epsilon-(gamma-glutamyl)lysine bonds between ECM components in both experimental and human disease. Studies in db+/db+ diabetic mice and in streptozotocin-treated rats have suggested a similar mechanism, although the relevance of this to human disease has not been addressed. METHODS: We have undertaken a retrospective analysis of renal biopsies from 16 DN patients with type 2 diabetes mellitus using an immunohistochemical and immunofluorescence approach, with tTg and epsilon-(gamma-glutamyl)lysine crosslink quantified by confocal microscopy. RESULTS: Immunofluorescent analysis of human biopsies (confocal microscopy) showed increases in levels of tTg (+1,266%, p < 0.001) and epsilon-(gamma-glutamyl)lysine (+486%, p < 0.001) in kidneys with DN compared to normal. Changes were predominantly in the extracellular periglomerular and peritubular areas. tTg staining correlated with epsilon-(gamma-glutamyl)lysine (r = 0.615, p < 0.01) and renal scarring (Masson's trichrome, r = 0.728, p < 0.001). Significant changes in epsilon-(gamma-glutamyl)lysine were also noted intracellularly in some (< or =5%) tubular epithelial cells. This is consistent with cells undergoing a novel transglutaminase-mediated cell death process in response to Ca2+ influx and subsequent activation of intracellular tTg. CONCLUSION: Changes in tTg and epsilon-(gamma-glutamyl)lysine occur in human DN. Cellular export of tTg may therefore be a factor in the perpetuation of DN by crosslinking and stabilisation of the ECM, while intracellular activation may lead to cell death contributing towards tubular atrophy.

Impact of cardiac transplantation on kidney function: a single- center experience.

Long-term follow-up of cardiac transplant recipients reveals a progressive decline in kidney function in a significant number of patients. This complication is one of the most important prognostic parameters for the outcome of cardiac transplantation. The risk factors implicated in the pathogenesis of renal dysfunction following cardiac transplantation are numerous, with the immunosuppressive drug cyclosporine (CsA) playing a major role. This case-control study was designed to evaluate the role of different risk factors among patients who had been transplanted at the Northern General Hospital Cardiothoracic Centre (CTC) with the possibility of identifying modifiable risk factors that mitigate the nephrotoxicity of CsA. Over a 10-year period, heart transplantation was performed in 205 patients at the CTC. Seventeen patients who experienced chronic renal failure (CRF) and were treated at the outpatient clinic of the Sheffield Kidney Institute were randomly selected from those who had >2-year graft survival and follow-up after cardiac transplantation. As controls, 15 cardiac transplant patients were randomly selected from 32 with comparable survival and follow-up after transplantation and without evidence of significant renal dysfunction (serum creatinine