Changes in primary glomerulonephritis in Singapore over four decades
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This review of 3,289 native kidney biopsies over the past four decades in Singapore documents the changing pattern of biopsy-proven glomerulonephritis (GN)from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative GN was the most common form of primary GN, similar to the Asian region. In the 2nd decade, the percentage of mesangial proliferative GN decreased, but membranous GN became more common, as was seen in China and Thailand. In the 3rd decade, focal segmental glomerulosclerosis (FSGS) and membranous nephropathy continued to rise, but it was only recently, in the 4th decade, that FSGS prevalence increased dramatically, although membranous nephropathy continues to increase in some Asian countries. In the last decade in Singapore, Malaysia, and Japan, prevalence of IgA nephritis has decreased but remains the most common GN. The percentage of FSGS continues to increase in many countries like in Italy, United States of America, United Kingdom, China, and Malaysia. We surmise that socioeconomic factors play significant roles in the evolution of the renal biopsy pattern.
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Predicting first-year mortality in incident dialysis patients with end-stage renal disease - the UREA5 study.

We aimed to develop a risk prediction model for first-year mortality (FYM) in incident dialysis patients with end-stage renal disease. We retrospectively examined patient comorbidities and biochemistry, prior to dialysis initiation, using a single-center, prospectively maintained database from 2005-2010, and analyzed these variables in relation to FYM. A total of 983 patients were studied. 22% had left ventricular ejection fraction (LVEF) <45%. FYM was 17%, and independent predictors included URate <500 or >600 µmol/l, LVEF <45% (higher odds ratio if <30%), Age >70 years, Arteriopathies (cerebrovascular and/or peripheral-vascular diseases), serum Albumin <30 g/l, and Alkaline phosphatase >80 U/l (p < 0.05, C-statistic 0.74), and these constitute the acronym UREA5. Using linear modeling, risk weightage/integer of 3 was assigned to LVEF <30%, 2 to age >70 years, and 1 to each remaining variable. Cumulative UREA5 scores of ≤ 1, 2, 3, 4, and ≥ 5 were associated with FYM of 6, 8, 22, 31, and 46%, respectively (p < 0.0001). Increasing UREA5 scores were strongly associated with stepwise worsening of FYM after dialysis initiation.

Glomerular filtration rates in healthy Asians without kidney disease.

AIM: The Chronic Kidney Disease Collaboration - Epidemiology (CKD-EPI) glomerular filtration rates (GFR) estimation equation is believed to estimate GFR more accurately in healthy people but this has not been validated in Asians. We studied the distribution of GFR in a multi-ethnic Asian population without CKD, and compared the performance of measures of GFR estimation, including the CKD-EPI equation, Cockroft-Gault equation, and 24-hour urine creatinine clearances. MATERIALS AND METHODS: A total of 103 healthy volunteers without a history of kidney disease, hypertension, or diabetes underwent GFR measurement using 3-sample plasma clearance of (99m) Tc-DTPA. Cockroft-Gault estimated GFR and 24-hour urine creatinine clearances were normalized to body surface area. RESULTS: The mean measured GFR was 101 ± 15.8 mL/min per 1.73 m(2) and was lowest in Indians (93 ± 12.3 mL/min per 1.73 m(2); P < 0.001). The CKD-EPI equation appears to be more accurate for healthy participants. Estimated GFR correlated with measured GFR (r = 0.57, P < 0.001), and the mean difference is 3.72 ± 14.43 mL/min per 1.73 m(2) (P < 0.001). However, estimating GFR using self-directed 24-hour urine creatinine clearances is poorer than using the CKD-EPI equation. CONCLUSIONS: GFR estimation using self-directed 24-hour urine collection for creatinine clearance is less accurate than using the CKD-EPI equation. A larger study is required to clarify GFR in healthy Asians, and the association of health outcomes of Asian kidney donors with lower GFR thresholds.

Spot urine tests in predicting 24-hour urine sodium excretion in Asian patients.

OBJECTIVE: The control of hypertension is often suboptimal, and it is frequently due to excessive sodium intake. Monitoring sodium intake is cumbersome and involves 24-hour collection of urine. We hypothesize that a spot urine test can accurately predict 24-hour urine sodium excretion in an Asian population. DESIGN: This is a prospective, observational study. We used stored urine specimens (n = 333) from the Asian Kidney Disease Study and Singapore Kidney Function Study Phase I. We measured spot urine tests and correlated these variables to the previously measured 24-hour urine sodium measurements. RESULTS: Age, gender, ethnicity, diastolic blood pressure, height, weight, body mass index, serum creatinine, spot urine sodium, spot urine chloride, and spot urine osmolality were associated with 24-hour urine sodium excretion. The final model for predicting 24-hour urine sodium less than 100 mmol included age, gender, ethnicity, weight, and spot urine sodium. CONCLUSION: Spot urine sodium can help monitor a patient's sodium intake when used in the derived 5-variable equation.

Estimating glomerular filtration rates by use of both cystatin C and standardized serum creatinine avoids ethnicity coefficients in Asian patients with chronic kidney disease.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is most accurate for estimating glomerular filtration rate (GFR) but requires an adjustment for African-American patients. Estimation equations are also improved with the use of serum cystatin C combined with standardized creatinine. Combination equations have been derived by the CKD-EPI and Chinese investigators. We investigated whether these cystatin C-based equations improve estimation adequately, so that adjustments for ethnicity are not required in a multiethnic Asian population with chronic kidney disease (CKD). METHODS: This was a cross-sectional study of 232 stable CKD patients who underwent GFR measurements using 3-sample plasma clearances of (99m)Tc-DTPA, and for whom serum cystatin C and creatinine were quantified. RESULTS: For all patients, the median biases with cystatin C equations were generally greater than with the CKD-EPI equation, and precision and root mean square error (RMSE) were not significantly better. However, the combination serum creatinine and cystatin C equation improved the precision, RMSE, and percentage of estimated GFR to within 15% and 30% of the measured GFR (57.3% vs 50.0%, 88.4% vs 82.8%, respectively). The derived ethnicity coefficients for the combination equation were all >1 (1.009-1.082) but small, suggesting that coefficients are not required. The Chinese-specific equations were more biased and performed more poorly than the CKD-EPI equation. CONCLUSIONS: The use of a cystatin C and creatinine combination equation for estimating GFR in a multiethnic Asian population with CKD does not require ethnicity coefficients because the derived coefficients are very close to each other.

Comparative outcomes of primary autogenous fistulas in elderly, multiethnic Asian hemodialysis patients.

BACKGROUND: The number of elderly (≥65 years) end-stage renal disease (ESRD) patients on hemodialysis is rapidly increasing. Vascular access outcomes remain contradictory and understudied across different elderly populations. We hypothesized age might influence primary autogenous fistula use and outcomes in a predominantly diabetic multiethnic Asian ESRD population. METHODS: Demographic and clinical factors affecting fistula patency and maturation were retrospectively compared among patients with incident ESRD aged <65 and ≥65 years at a single center. Fistula patency was estimated by Kaplan-Meier curves with log-rank test comparison. RESULTS: We analyzed 280 primary fistulas (59% radiocephalic, 33% brachiocephalic, and 8% brachiobasilic) in this cohort consisting of 31.8% aged ≥65 years, 50% Chinese, 39% Malay, 42% women, and 70% diabetic. One- and 2-year primary and secondary patency in patients aged <65 vs ≥65 years were comparable: 41.3% vs 36.7% and 28.7% vs 24.4% (P = .547) and 57.7% vs 56.8% and 47.1% vs 47.2% (P = .990). On multivariate analysis, only non-Chinese, dialysis initiation with tunneled catheters, and surgical/endovascular interventions affected fistula survival hazard ratios (HR): 0.622 (95% confidence interval [CI], 0.43-1.00), 0.549 (95% CI, 0.297-0.841), and 2.503 (95% CI, 1.695-3.697), respectively. Nonmaturation and intervention rates were also similar at 56.7% vs 61.8% and 34% vs 32.2% at 3 and 6 months and 0.31 vs 0.36 per access year, respectively (P > .05). Females and tunneled catheters were the only risk factors for nonmaturation (HR, 1.568; 95% CI, 1.148-1.608, and HR, 1.623; 95% CI, 1.400-1.881, respectively). CONCLUSIONS: A primary fistula strategy in incident elderly ESRD is feasible and does not result in inferior outcomes. Age should therefore not be a determinant for primary fistula creation.

GFR estimating equations in a multiethnic Asian population.

BACKGROUND: Clinical practice guidelines recommend using equations for estimating glomerular filtration rate (GFR) in chronic kidney disease (CKD) management and research. The MDRD (Modification of Diet in Renal Disease) Study and CKD-EPI (CKD Epidemiology Collaboration) equations originally were derived from a North American population and had an ethnic coefficient adjustment for African Americans. A Chinese coefficient for the MDRD Study equation subsequently was determined, but this has not been externally validated. We compared the accuracy of the equations, evaluated the ethnic coefficients, and assessed the equations for disease staging in a multiethnic Asian population with CKD. STUDY DESIGN: A diagnostic test study comparing the Asian coefficient (and subgroups)-modified MDRD Study and CKD-EPI equations and a cross-sectional study assessing disease staging. SETTING & PARTICIPANTS: 232 outpatients (52% men; 40.5% Chinese, 32% Malay, and 27.5% Indian/other) with stable CKD. INDEX TEST: Asian and ethnicity-based modifications of the MDRD Study and CKD-EPI equations. REFERENCE TEST: Measured GFR using 3-sample plasma clearance of technetium-99m diethylenetriaminepentaacetic acid ((99m)Tc-DTPA), calculated using the slope-intercept method, with body surface area normalization (du Bois) and Brochner-Mortensen correction. RESULTS: Overall, the CKD-EPI equation is more accurate than the MDRD Study equation throughout the GFR range, with improved bias (median difference of estimated GFR - measured GFR) and root mean square error (P <0.001). CKD-EPI versus MDRD Study equation: bias, 1.1 ± 13.8 vs -1.0 ± 15.2 mL/min/1.73 m(2); precision, 12.1 vs 12.2 mL/min/1.73 m(2). Ethnic coefficients did not improve estimates of GFR significantly. The correctness of staging was improved using the CKD-EPI equation. LIMITATIONS: All participants had CKD, but few were of European descent. The reference GFR technique was different from the original studies. CONCLUSIONS: The CKD-EPI is more accurate than the MDRD Study equation, particularly at higher GFRs. Therefore, we recommend adopting the CKD-EPI equation without ethnic adjustment for estimating GFR in multiethnic Asian patients with CKD.

Microbiology of tunnelled catheter-related infections in a multi-ethnic South-east Asian patient population.

INTRODUCTION: Clinical practice guidelines recommend empiric antibiotic therapy for suspected tunnelled haemodialysis catheter-related infections (CRI), and the choice of antibiotics should be adjusted according to the local microbiological profile and antimicrobial sensitivities. We aim to describe the microbiology, antibiotic sensitivities, and clinical outcomes of CRI with tunnelled haemodialysis catheters in a multi-ethnic South-East Asian population. METHODS: Using a prospective vascular access registry, we identified 99 patients who had catheters removed for suspected or confirmed CRI (50.5% male, mean age 56.9 years) from January 1, 2007, till May 2009. We retrospectively retrieved microbiology, mortality and echocardiography data from the hospital electronic databases. RESULTS: There were 115 removal-unique cultures that yielded 75.7% Gram-positive and 24.3% Gram-negative isolates (15 removals were polymicrobial). Organisms isolated were methicillin-resistant Staphylococcus aureus (MRSA) 28.6%, methicillin-sensitive S. aureus 26.5%, coagulase-negative staphylococci 21.4%, Pseudomonas aeruginosa 10.2%, and others. Out of 8 patients who died, 7 had MRSA. Risk factors associated with mortality were Chinese race (p = 0.03), MRSA infection (p < 0.001), and older age (p < 0.001). CONCLUSION: Gram-positive isolates accounted for most tunnelled CRI and MRSA was highly associated with death. In sick patients presenting with suspected CRI, the preferred empiric antibiotic regimen should include agents active against both MRSA and P. aeruginosa.

The clinical course of rapidly growing nontuberculous mycobacterial peritoneal dialysis infections in Asians: A case series and literature review.

INTRODUCTION: Peritoneal dialysis (PD)-related infections due to rapidly growing nontuberculous mycobacterium (RGNTM) are rare in Asians and have variable clinical outcomes. METHODS: We analysed retrospectively a series of RGNTM infections in a single-centre multi-ethnic Asian population over a 5-year period. Clinical features, treatment, risk factors and outcomes are discussed. RESULTS: Ten infections are described. They constituted 3% of all culture-positive exit site infection (ESI) and PD peritonitis. Seventy percent were due to Mycobacterium abscessus (three ESI and four peritonitis). There were two Mycobacterim fortuitum and one Mycobacterium chelonei peritonitis. No specific findings differentiated RGNTM infections from those caused by traditional organisms. Six cases had received prior antibiotics, two being topical gentamicin. Initial routine culture and alcohol acid fast bacillus were negative except for one case of M. abscessus. A confirmatory diagnosis was made a median 9 days post culture. No infection responded to routine antibiotics. Antibiotic resistance was variable but M. abscessus was universally sensitive to clarithromycin. Combined antibiotics based on sensitivity profile were successfully used in 70% of the cases. PD catheter loss was 80%. Three-month mortality was 40% (vs. 8.5% and 12% in non-RGNTM ESI and peritonitis, respectively). This may be related to the cohort high mean Charlson score of 7.5. CONCLUSION: RGNTM PD infections are commoner in Asians than previously reported. Their early diagnosis requires a high index of suspicion and appropriate treatment started promptly. They are associated with prior antibiotic use and refractory culture-negative infections, delayed diagnosis and lead to significant catheter loss and death.

Report of the Asian Forum of Chronic Kidney Disease Initiative (AFCKDI) 2007. "Current status and perspective of CKD in Asia": diversity and specificity among Asian countries.

The Japanese Society of Nephrology (JSN) sponsored the Asian Forum of CKD Initiative (AFCKDI) 2007 with the support of the International Society of Nephrology-Commission for Global Advancement in Nephrology (ISN-COMGAN), Asian Pacific Society of Nephrology (APSN), the Kidney Disease: Improving Global Outcome (KDIGO) and other national societies of nephrology in the Asian Pacific region on 27-28 May 2007 in Hamamatsu City, Japan. An international organising committee was established by leading experts of the CKD initiative. The main objective of this forum was to clarify the current status and perspectives of CKD and to promote coordination, collaboration and integration of initiatives in the Asian Pacific region. The forum received 56 papers from 16 countries; it began with the symposium "A Challenge to CKD in the world" and was followed by the ISN-COMGAN affiliated workshop "Current status and perspective of CKD in Asia". The second day was dedicated to discussion on the evaluation, surveillance and intervention in CKD in this area. At the end of the forum, we decided on the future plan as follows: (1) The AFCKDI will provide opportunities annually or biannually for every person who promotes CKD initiatives in the Asian Pacific region to join together and build consensus for action; (2) the second forum will be held in Kuala Lumpur on 4 May 2008 at the time of the 11th Asian Pacific Congress of Nephrology (APCN). Zaki Morad, President of the 11th APCN, will host the second forum; (3) the International Organising Committee (IOC) of the 1st AFCKDI will continue its function by adding other experts, including the organisers of the APCN; (4) the AFCKDI is not an organisation by itself, nor does it belong to any society, but is organised by each host national society of nephrology. The IOC will assist the domestic committee for the success of the forum and will assure the continuation of the mission; (5) in order to organise the forum and promote CKD initiatives in the Asia Pacific region, the AFCKDI will look for support by both national and international societies. The AFCKDI will keep an intimate and mutual relation with the ISN, APSN and KDIGO.

The choice of estimating equations for glomerular filtration rate significantly affects the prevalence of chronic kidney disease in a multi-ethnic population during health screening.

BACKGROUND: Patients present to the National University Hospital of Singapore and select one of several health screening packages after counselling. The prevalence of chronic kidney disease (CKD) in this population when different glomerular filtration rate (GFR) estimating equations are used has not been examined. METHODS: Demographic data and urinalyses of patients from 2000 to 2005 were extracted from laboratory computer databases and analysed. CKD was classified into stages according to the US National Kidney Foundation guidelines by eGFR (mL/min per 1.73 m(2)) using the four-variable Modification of Diet in Renal Disease equation. GFR of ethnic Chinese was also estimated using Ma's equation 8 (cGFR). Stage 1 and normal (eGFR or cGFR > 90) was discriminated by urinary microscopy or dipstick for proteinuria, albuminuria, hematuria or leukocyturia. RESULTS: There were 3979 screenings (55.9% males, 61.9% Chinese). Means: age = 47.0 +/- 12.3 years, creatinine = 80.1 +/- 26.5 micromol/L, eGFR = 89.6 +/- 19.7, cGFR = 110.8 +/- 23.8 and (eGFR + cGFR) = 102.5 +/- 24.9. By eGFR in all patients, the prevalence of CKD was 45.7%, 50.6%, 3.3%, 0.3% and 0.08% for stages normal or 1, 2, 3, 4 and 5, respectively. For Chinese patients only, eGFR and cGFR resulted in a different distribution (eGFR%/cGFR%): 24.9/50.5, 15.2/29.3, 56.8/19.7, 3/0.8, 0.2/0.2, 0/0 for stages 'Normal', 1, 2, 3, 4 and 5, respectively (P < 0.001). CONCLUSION: The prevalence of moderate to severe CKD (stage 3 to 5) in patients presenting for health screening in Singapore was 3.7%. Notably, the prevalence of mild to moderate CKD (stages 1, 2 and 3) in Chinese patients was affected significantly by the choice of GFR estimating equation.

Risk stratification of the peritoneal dialysis patient--a single-center experience.

BACKGROUND: Peritoneal dialysis (PD) patients have many risk factors that may affect their clinical outcomes. Age and diabetes status are unequally distributed in the dialysis population of Singapore. Risk stratification is a means of reducing the effects of case mix such that high-risk groups in the dialysis population can be identified. PATIENTS AND METHODS: Records for 543 patients who started on chronic dialysis during 2002 - 2005 were retrospectively studied for survival in the first year on dialysis. The age, sex, ethnicity, and diabetes status of the patients were noted. RESULTS: For patients 60 years of age and older, we observed no differences in the prevalences of diabetes, male sex, or Chinese ethnicity between patients on PD and those on hemodialysis (HD). Patients of Chinese ethnicity on PD were found to have a higher likelihood of survival in the first year as compared with patients on HD. Age, sex, and diabetes status were not associated with survival in the first year. CONCLUSIONS: In a single PD treatment center, Chinese ethnicity conferred a survival advantage in the first year on dialysis. The reasons for that finding are not clear, but they were not related to age, diabetes status, or sex.

Development of zwitterionic sulfobetaine block copolymer conjugation strategies for reduced platelet deposition in respiratory assist devices.

Respiratory assist devices, that utilize ∼2 m2 of hollow fiber membranes (HFMs) to achieve desired gas transfer rates, have been limited in their adoption due to such blood biocompatibility limitations. This study reports two techniques for the functionalization and subsequent conjugation of zwitterionic sulfobetaine (SB) block copolymers to polymethylpentene (PMP) HFM surfaces with the intention of reducing thrombus formation in respiratory assist devices. Amine or hydroxyl functionalization of PMP HFMs (PMP-A or PMP-H) was accomplished using plasma-enhanced chemical vapor deposition. The generated functional groups were conjugated to low molecular weight SB block copolymers with N-hydroxysuccinimide ester or siloxane groups (SBNHS or SBNHSi) that were synthesized using reversible addition fragmentation chain transfer polymerization. The modified HFMs (PMP-A-SBNHS or PMP-H-SBNHSi) showed 80-95% reduction in platelet deposition from whole ovine blood, stability under the fluid shear of anticipated operating conditions, and uninhibited gas exchange performance relative to non-modified HFMs (PMP-C). Additionally, the functionalization and SBNHSi conjugation technique was shown to reduce platelet deposition on polycarbonate and poly(vinyl chloride), two other materials commonly found in extracorporeal circuits. The observed thromboresistance and stability of the SB modified surfaces, without degradation of HFM gas transfer performance, indicate that this approach is promising for longer term pre-clinical testing in respiratory assist devices and may ultimately allow for the reduction of anticoagulation levels in patients being supported for extended periods. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2681-2692, 2018.

Glomerular Filtration Rates in Asians.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate (GFR) for the classification of CKD, but its accuracy was limited to North American patients with estimated GFR <60 mL/min per 1.73 m2 body surface area of European (White) or African (Black) descent. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) developed another equation for estimating GFR, derived from a population that included both participants without kidney disease and with CKD. But many ethnicities were inadequately represented. The International Society of Nephrology, Kidney Disease Improving Global Outcomes committee promulgated clinical practice guidelines, which recommended the CKD-EPI equation. Investigators in Asia subsequently assessed the performance of these GFR estimating equations-the Modification of Diet in Renal Disease study equation, the CKD-EPI equation (creatinine only), and the CKD-EPI equations (creatinine and cystatin C). In this review, we summarize the studies performed in Asia on validating or establishing new Asian ethnicity GFR estimating equations. We included both prospective and retrospective studies which used serum markers traceable to reference materials and focused the review of the performance of GFR estimation by comparisons with the GFR estimations obtained from the CKD-EPI equations.

3rd College of Physicians' lecture--translational research: From bench to bedside and from bedside to bench; incorporating a clinical research journey in IgA nephritis (1976 to 2006).

Translational research (TR) can be defined as research where a discovery made in the laboratory (bench) can be applied in the diagnosis, treatment or prevention of a disease. Examples of medical discoveries contributing to translational medicine (TM) include the isolation of insulin by Banting (Nobel Laureate, 1923), the discovery of penicillin by Alexander Fleming (Nobel Laureate, 1945) and recently the discovery of the role of bacterium Helicobacter pylori in the causation of gastritis and peptic ulcer by Marshall and Warren (Nobel Laureates, 2005). Clinical research (CR) would be a more appropriate term for the bulk of research work undertaken by doctors. CR embraces both clinical based and laboratory-based research. The terminology "bedside to bench" applies more to CR as opposed to "bench to bedside" in the case of TR. But regardless of who does it, as long as the discovery can be translated to the bedside and results in improvement in patient care it can be considered a contribution to TM. Our work spans a 30-year period, involving laboratory-based research, clinical trials and genomics of IgA nephritis (Nx). This is a series of work to elucidate the pathogensis and therapy of IgANx. Plasma beta-thromboglobulin (BTG) an in-vivo index of platelet aggregation and anti-thrombin III increase due to a constant thrombogenecity resulting from platelet degranulation formed the basis for anti-platelet and low-dose warfarin therapy. A study of the natural history of IgANx revealed 2 courses, a slowly progressive course with end-stage renal failure (ESRF) at 7.7 years and a more rapid course at 3.3 years. Triple therapy (cyclophosphamide, persantin and low-dose warfarin) delayed progression to ESRF by about 8 years and for some patients up to 20 years. Documentation of abnormal suppressor T cell function provided the basis for immune therapy. Four patterns of proteinuria were present in IgANx and it is the quality and not so much the quantity of proteinuria which determined the prognosis. Low molecular weight proteinuria was a bad prognostic marker. A controlled therapeutic trial using ACEI/ATRA showed that therapy decreases proteinuria, improves renal function and converts non-selective to selective proteinuria. Subsequent work confirmed that it was the ATRA, not the ACEI which contributed to improved renal function. Individual anti proteinuria response to ATRA varies depending on ACE gene polymorphism. We found that the II genotype of the ACE gene was renoprotective and patients with this genotype had significantly reduced incidence of ESRF compared to those with the DD genotype. Patients responsive to ATRA therapy can retard progression to ESRF by up to 32 years. Mild renal failure can be reversed with possible regression of glomerulosclerosis because of glomerular remodelling by ATRA.

Degradation Signals for Ubiquitin-Proteasome Dependent Cytosolic Protein Quality Control (CytoQC) in Yeast.

Cellular protein quality control (PQC) systems selectively target misfolded or otherwise aberrant proteins for degradation by the ubiquitin-proteasome system (UPS). How cells discern abnormal from normal proteins remains incompletely understood, but involves in part the recognition between ubiquitin E3 ligases and degradation signals (degrons) that are exposed in misfolded proteins. PQC is compartmentalized in the cell, and a great deal has been learned in recent years about ER-associated degradation (ERAD) and nuclear quality control. In contrast, a comprehensive view of cytosolic quality control (CytoQC) has yet to emerge, and will benefit from the development of a well-defined set of model substrates. In this study, we generated an isogenic "degron library" in Saccharomyces cerevisiae consisting of short sequences appended to the C-terminus of a reporter protein, Ura3 About half of these degron-containing proteins are substrates of the integral membrane E3 ligase Doa10, which also plays a pivotal role in ERAD and some nuclear protein degradation. Notably, some of our degron fusion proteins exhibit dependence on the E3 ligase Ltn1/Rkr1 for degradation, apparently by a mechanism distinct from its known role in ribosomal quality control of translationally paused proteins. Ubr1 and San1, E3 ligases involved in the recognition of some misfolded CytoQC substrates, are largely dispensable for the degradation of our degron-containing proteins. Interestingly, the Hsp70/Hsp40 chaperone/cochaperones Ssa1,2 and Ydj1, are required for the degradation of all constructs tested. Taken together, the comprehensive degron library presented here provides an important resource of isogenic substrates for testing candidate PQC components and identifying new ones.

Health economics of renal replacement therapy: perspectives from Singapore.

The prevalence of end-stage renal disease (ESRD) in Singapore is high and projected to increase sharply due to the aging population and the high prevalence of diabetes. The number of patients treated with dialysis was projected to rise from 2633 in 1999 to nearly 6000 in the year 2010. The cost of dialysis provision was estimated to increase 2.5-fold from US dollar 90 million in 1999 to US dollar 241 million in 2010. To address this, the Singapore Ministry of Health launched three initiatives in the year 2000: First, to reduce the incidence of ESRD through (1) primary prevention of diabetes, (2) community-based screening to facilitate early detection of patients with diabetes, (3) improving glycemic and blood pressure (BP) control of diabetics in the primary care setting, and (4) the establishment of dedicated Renal Retardation clinics to optimize BP control (and glycemic control for diabetics), and reduce the level of proteinuria in patients at high risk of ESRD development. Second, to increase the percentage of ESRD patients treated with continuous ambulatory peritoneal dialysis (CAPD), which is a lower-cost modality compared with hemodialysis; and third, amendments to the existing opt-out legislation for organ procurement for transplantation to increase the supply of kidneys for cadaveric renal transplant.

Dietary Protein Intake in a Multi-ethnic Asian Population of Healthy Participants and Chronic Kidney Disease Patients.

INTRODUCTION: Clinical practice guidelines recommend different levels of dietary protein intake in predialysis chronic kidney disease (CKD) patients. It is unknown how effectively these recommendations perform in a multi-ethnic Asian population, with varied cultural beliefs and diets. We assess the profi le of protein intake in a multi-ethnic Asian population, comparing healthy participants and CKD patients. MATERIALS AND METHODS: We analysed the 24-hour urine collections of the Asian Kidney Disease Study (AKDS) and the Singapore Kidney Function Study (SKFS) to estimate total protein intake (TPI; g/day). We calculated ideal body weight (IDW; kg): 22.99 × height2 (m). Standard statistical tests were applied where appropriate, and linear regression was used to assess associations of continuous variables with protein intake. RESULTS: There were 232 CKD patients and 103 healthy participants with 35.5% diabetics. The mean TPI in healthy participants was 58.89 ± 18.42 and the mean TPI in CKD patients was 53.64 ± 19.39. By US National Kidney Foundation (NKF) guidelines, 29/232 (12.5%) of CKD patients with measured glomerular filtration rate (GFR) <25 (in mL/min/1.73 m2) had a TPI-IDW of <0.6 g/kg/day. By Caring for Australasians with Renal Impairment (CARI) guidelines, 76.3% (177/232) of CKD patients had TPI-IDW >0.75g/kg/ day. By American Dietetic Association (ADA) guidelines, 34.7% (44/127) of CKD patients with GFR <50 had TPI-IDW between 0.6 to 0.8 g/kg/day. Only 1/6 non-diabetic CKD patients with GFR <20 had a protein intake of between 0.3 to 0.5 g/kg/day. A total of 21.9% (25/114) of diabetic CKD patients had protein intake between 0.8 to 0.9 g/kg/day. CONCLUSION: On average, the protein intake of most CKD patients exceeds the recommendations of guidelines. Diabetic CKD patients should aim to have higher protein intakes.