Acute renal impairment in coronavirus-associated severe acute respiratory syndrome

Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.BackgroundSevere acute respiratory syndrome (SARS) is a newly emerged infection from a novel coronavirus (SARS-CoV). Apart from fever and respiratory complications, acute renal impairment has been observed in some patients with SARS. Herein, we describe the clinical, pathologic, and laboratory features of the acute renal impairment complicating this new viral infection.MethodsWe conducted a retrospective analysis of the plasma creatinine concentration and other clinical parameters of the 536 SARS patients with normal plasma creatinine at first clinical presentation, admitted to two regional hospitals following a major outbreak in Hong Kong in March 2003. Kidney tissues from seven other patients with postmortem examinations were studied by light microscopy and electron microscopy.ResultsAmong these 536 patients with SARS, 36 (6.7%) developed acute renal impairment occurring at a median duration of 20 days (range 5–48 days) after the onset of viral infection despite a normal plasma creatinine level at first clinical presentation. The acute renal impairment reflected the different prerenal and renal factors that exerted renal insult occurring in the context of multiorgan failure. Eventually, 33 SARS patients (91.7%) with acute renal impairment died. The mortality rate was significantly higher among patients with SARS and acute renal impairment compared with those with SARS and no renal impairment (91.7% vs. 8.8%) (P < 0.0001). Renal tissues revealed predominantly acute tubular necrosis with no evidence of glomerular pathology. The adjusted relative risk of mortality associated with the development of acute renal impairment was 4.057 (P < 0.001). By multivariate analysis, acute respiratory distress syndrome and age were the most significant independent risk factors predicting the development of acute renal impairment in SARS.ConclusionAcute renal impairment is uncommon in SARS but carries a high mortality. The acute renal impairment is likely to be related to multi-organ failure rather than the kidney tropism of the virus. The development of acute renal impairment is an important negative prognostic indicator for survival with SARS

Putative tumour-suppressor gene DAB2 is frequently down regulated by promoter hypermethylation in nasopharyngeal carcinoma

<p>Abstract</p> <p>Background</p> <p>Human Disabled-2 (DAB2), is a multi-function signalling molecule that it is frequently down-regulated in human cancers. We aimed to investigate the possible tumour suppressor effect of DAB2 in nasopharyngeal carcinoma (NPC).</p> <p>Methods</p> <p>We studied the expression of DAB2 in NPC cell lines, xenografts and primary tumour samples. The status of promoter methylation was assessed by methylation specific PCR and bisulfite sequencing. The functional role of DAB2 in NPC was investigated by re-introducing DAB2 expression into NPC cell line C666-1.</p> <p>Results</p> <p>Decrease or absent of <it>DAB2 </it>transcript was observed in NPC cell lines and xenografts. Loss of DAB2 protein expression was seen in 72% (33/46) of primary NPC as demonstrated by immunohistochemistry. Aberrant <it>DAB2 </it>promoter methylation was detected in 65.2% (30/46) of primary NPC samples by methylation specific PCR. Treatment of the DAB2 negative NPC cell line C666-1 with 5-aza-2'-deoxycytidine resulted in restoration of DAB2 expression in a dose-dependent manner. Overexpression of DAB2 in NPC cell line C666-1 resulted in reduced growth rate and 35% reduction in anchorage-dependent colony formation, and inhibition of serum-induced c-Fos expression compared to vector-transfected controls. Over expression of DAB2 resulted in alterations of multiple pathways as demonstrated by expression profiling and functional network analysis, which confirmed the role of DAB2 as an adaptor molecule involved in multiple receptor-mediated signalling pathways.</p> <p>Conclusions</p> <p>We report the frequent down regulation of DAB2 in NPC and the promoter hypermethylation contributes to the loss of expression of DAB2. This is the first study demonstrating frequent DAB2 promoter hypermethylation in human cancer. Our functional studies support the putative tumour suppressor effect of DAB2 in NPC cells.</p

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases

Targeted gene sanger sequencing should remain the first-tier genetic test for children suspected to have the five common X-linked inborn errors of immunity

DATA AVAILABILITY STATEMENT : The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.The Hong Kong Society for Relief of Disabled Children and Jeffrey Modell Foundation.http://www.frontiersin.org/Immunologyam2023Paediatrics and Child Healt

Conversion from Recombinant Human Erythropoietin to Once Every 4 Weeks Darbepoetin Alfa for Treatment of Renal Anemia in CAPD Patients

BackgroundDarbepoetin alfa is a new erythropoietic protein with a three-fold longer half-life than recombinant human erythropoietin (rHuEPO), allowing for an extended dosing interval of once every 2 weeks in patients with chronic renal failure. The objective of this study was to investigate the possibility of further extending the dose interval of this erythropoietic agent to once every 4 weeks in the treatment of renal anemia in dialysis patients.MethodsA prospective study was carried out in 14 continuous ambulatory peritoneal dialysis (CAPD) patients stably maintained on subcutaneous rHuEPO with hemoglobin level of 10–13 g/dL. They were switched to subcutaneous darbepoetin alfa administered once every 4 weeks for a period of 24 weeks. The starting dose was 40 [.proportional]g. The dose of darbepoetin alfa was then adjusted to maintain a target hemoglobin level between 10 and 13 g/dL. When darbepoetin alfa was increased by 100%, the dosing interval was shortened to maintain the target hemoglobin. Evaluation was done during the last 4 weeks.ResultsOf the 14 patients recruited, 11 patients completed the study. Of these 11 patients, 9 (82%) successfully maintained the target hemoglobin with once every 4 weeks darbepoetin alfa. For those successful patients, the mean hemoglobin level during the evaluation period was 11.13 ± 2.04 g/dL (mean ± standard deviation), and the mean change in hemoglobin level from baseline was −1.03 g/dL (95% CI: −2.34, 0.27). The mean weekly darbepoetin alfa dose requirement during the evaluation period was 12.33 ± 4.80 [.proportional]g/week, and the mean change in weekly dose from baseline was +2.33 [.proportional]g/week (95% CI: −1.35, 6.02). No serious adverse event related to darbepoetin alfa occurred during the study.ConclusionDarbepoetin alfa administered once every 4 weeks effectively maintained hemoglobin level in most CAPD patients after conversion from previously stabilized rHuEPO treatment. Darbepoetin alfa is safe and well tolerated, allowing for less frequent dosing. [Hong Kong J Nephrol 2007;9(2):77–81

On-line hemodiafiltration and high-flux hemodialysis: comparison of efficiency and cost analysis

AbstractWith on-line hemodiafiltration (HDF), low molecular weight substances are predominantly cleared by diffusion while middle molecules such as ß2-microglobulin (ß2M), an amyloidogenic factor, are removed mainly by convection. The objectives of this study are to evaluate the cost-effectiveness and safety of on-line HDF with dialyzer reuse, and to compare HDF and high-flux hemodialysis (HD) with respect to ß2M removal, urea kinetics (Kt/V) and symptom relief in those patients having dialysis-related amyloidosis. Ten chronic HD patients were put on post-dilution HDF for a period of 14.2 ±7.1 months. The AK 100 ULTRA system was used for on-line preparation of substitution fluid. These patients were then switched over to high-flux HD for a period of 4.6 ±3 months. Dialyzers were reused up to 30 times to reduce the cost of HDF. All the patients were hemodynamically stable during both HDF and high-flux HD treatments. No febrile reactions were reported. The percentage reduction of ß2M during HDF was significantly higher when compared with high-flux HD (75 ±4% vs 51 ±7%, p < 0.001). After 14.2 ±7.1 months of HDF, the patients had significant reduction of both the pre-dialysis ß2M level (47.4 ±7.9 μg/mL vs 28.2 ±4.9 μg/mL, p < 0.01) and post-dialysis ß2M level (11.4 ±2.8 μg/mL vs 6.8 ±1.0 μg/mL, p < 0.01). eKt/V achieved by HDF was significantly higher than that achieved by high-flux HD (1.94 ±0.26 vs 1.75 ±0.23, p < 0.01). Those patients with dialysis arthropathy and carpal tunnel syndrome had decreased joint pain and hand numbness respectively after putting on HDF but symptoms recurred while on high-flux HD. There were no statistical significant differences in the percentage reduction of ß2M, ß2M clearance, urea clearance and eKt/V with dialyzer reuse, and no adverse patient reactions had been recorded.ConclusionOn-line HDF has been proven to be a safe and reliable treatment. The clearance of ß2M and urea are significantly increased by HDF when compared with high-flux HD, and the increase in clearance of ß2M is sustained throughout the HDF treatment period. Symptoms of dialysis-related amyloidosis are improved by HDF. Dialyzer reuse, which reduces the cost of HDF by 30%, is feasible and safe

Pneumocystis carinii Pneumonia Among Renal Transplant Recipients Despite Antibiotic Prophylaxis

Pneumocystis carinii pneumonia (PCP) is a well-known opportunistic infection in renal transplant recipients; it is associated with high mortality, mostly within the first 6 months post-transplantation. The disease has been effectively prevented by routine antibiotic prophylaxis. Recently, however, we encountered three consecutive cases of PCP; one developed the disease at 8 months and another at 11 months post-transplantation. An overall assessment of a patient's degree of immunosuppression is essential when considering the duration of PCP prophylaxis. Instead of the routine regimen of 6 months, 1-year PCP prophylaxis may be required for those who are on both tacrolimus and mycophenolate mofetil

The pharmacokinetics and bioequivalence of Gengraf and Neoral in stable renal transplant recipients

AbstractObjectiveGengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The objective of this study was to evaluate the pharmacokinetics and bioequivalence of Gengraf and Neoral in stable Chinese renal allograft recipientsMethodsIn a prospective, open-label, two-period design study, 20 renal allograft recipients receiving stable doses of Neoral were recruited. Subjects continued their Neoral regimen during period I (days 1-14). They were then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II (days 15-28). Four-hour pharmacokinetic parameters (concentration before dosing [Ctrough], maximum blood concentration [Cmax], time to maximum concentration [Tmax], and area under the blood concentration-versus-time curve [AUC0-4]) were taken on days 1, 8, 21, and 28. Biochemical parameters were also evaluated.ResultsThere was no significant difference in the pharmacokinetics of Gengraf (Ctrough, Tmax, Cmax, and AUC0-4) as compared with that of Neoral in stable renal transplant recipients. The bioequivalent capsules were interchangeable with respect to Ctrough, Cmax and AUC0-4. The 90% confidence intervals of the ratio of Ctrough, Cmax, Tmax, and AUC0-4 of Gengraf and Neoral were 0.94 to 1.21 for Ctrough, 0.97 to 1.20 for Cmax, and 0.97 to 1.20 for AUC0-4. Ctrough and C2 remained stable throughout the study without any dosage adjustments. Gengraf was well tolerated, and had a comparable safety profile as Neoral.ConclusionGengraf are bioequivalent to Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable Chinese renal allograft recipients