Boon Wee Teo

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.

Hypophosphatemia during continuous hemodialysis is associated with prolonged respiratory failure in patients with acute kidney injury

BACKGROUND Hypophosphatemia is common in critically ill patients and has been associated with generalized muscle weakness, ventilatory failure and myocardial dysfunction. Continuous renal replacement therapy causes phosphate depletion, particularly with prolonged and intensive therapy. In a prospective observational cohort of critically ill patients with acute kidney injury (AKI), we examined the incidence of hypophosphatemia during dialysis, associated risk factors and its relationship with prolonged respiratory failure and 28-day mortality. METHODS This is a single-center prospective observational study. Included in the study were 321 patients with AKI on continuous dialysis as initial treatment modality. RESULTS Four per cent of the patients had a phosphate level <2 mg/dL at initiation and 27% during dialysis. Low baseline phosphate was associated with older age, female gender, parenteral nutrition, vasopressor support, low calcium, and high urea, bilirubin and creatinine, whereas hypophosphatemia during dialysis correlated with the ischemic acute tubular necrosis etiology of renal failure, intensive dose and longer therapy. Serum phosphate decline during dialysis was associated with higher incidence of prolonged respiratory failure requiring tracheostomy [odds ratio (OR) = 1.81; 95% confidence interval (CI) = 1.07-3.08], but not 28-day mortality (OR = 1.16; 95% CI = 0.76-1.77) in multivariable analysis. CONCLUSIONS Hypophosphatemia occurs frequently during dialysis, particularly with long and intensive treatment. Decline in serum phosphate levels during dialysis is associated with higher incidence of prolonged respiratory failure requiring tracheostomy, but not 28-day mortality.

GFR Estimation in Japan and China: What Accounts for the Difference?

A primary goal for staging chronic kidney disease (CKD) with glomerular filtration rate (GFR) has been to risk stratify patients for adverse outcomes.(1) A somewhat arbitrary threshold (<60 ml/min/1.73 m2) defines chronic kidney disease and another somewhat arbitrary threshold (<15 ml/min/1.73 m2) defines kidney failure. The literature based on a uniform CKD staging system supports various screening and intervention guidelines. GFR is usually estimated from serum creatinine, age, sex, and ethnicity (African American [ND1]compared to white) with the Modification of Diet in Renal Disease (MDRD) Study equation.(2) Notably, there have always been concerns with the ethnicity coefficient since it does not address non-white, non-African American ethnic groups. Several studies have sought to address this problem in order to apply GFR estimation in non-white, non-African American populations. Ma and colleagues developed a new coefficient (1.23) that estimates a 23% higher GFR in Chinese than whites (the arbitrary reference group) at the same serum creatinine level.(3) In this issue of the American Journal of Kidney Diseases, Matsuo and colleagues developed a new coefficient (0.81) that estimates a 19% lower GFR in Japanese than whites at the same serum creatinine level (4), which is similar to a previously reported Japanese coefficient (0.76).(5) To put these coefficients into perspective, a 60 year-old man with a serum creatinine of 1.4 mg/dl would have an estimated GFR of 52 ml/min/1.73 m2 if white, but 64 ml/min/1.73 m2 if Chinese and 42 ml/min/1.73 m2 if Japanese. What accounts for the difference? In order to make sense of these ethnicity coefficients, it is important to understand their biological framework. Creatinine is generated from skeletal muscle catabolism (6) and a lesser extent from dietary protein (particularly cooked meat).(7, 8) Besides glomerular filtration, creatinine is eliminated by tubular secretion and a nearly negligible fraction by intestinal excretion.(9) GFR estimating equations attempt to account for the variation in serum creatinine due to these non-GFR determinants. The MDRD Study equation models the non-GFR determinants of serum creatinine with demographic variables (age, sex, and ethnicity). One explanation is that coefficients for demographic variables model variation in muscle mass, since muscle mass declines with age consistent with the age −0.203 exponential coefficient in the MDRD Study equation, women have less muscle mass then men consistent with the female sex 0.74 coefficient, and African-American have higher muscle mass than whites, consistent with the African-American race coefficient of 1.21.(10) Thus, it is surprising that the ethnicity coefficients should be so different between Chinese and Japanese patients. If demographic coefficients are interpreted as muscle mass differences, then one would expect that Chinese compared to Japanese patients have the same difference in skeletal muscle as 33 year-old men compared to 60 year-old women. Another consideration is that one or both of the coefficients for Japanese and Chinese patients may be inaccurate due to study design differences with the MDRD Study. The Japanese coefficient is actually a “Japanese compared to white ethnicity” coefficient, but it was only developed using patients from Japan with the comparison group, whites, based on historical data. This same problem exists for the Chinese coefficient. There are several differences in the study protocols used to determine the relationship between serum creatinine and GFR in each of these ethnicity groups (Table). To compare the relationship between serum creatinine and GFR between two ethnic groups, an ideal study would use identical methods to measure serum creatinine and GFR, identical methods to identify and recruit study patients, and the same statistical approach for both groups. Both the Japanese coefficient and the Chinese coefficient studies addressed calibration differences with their serum creatinine assay compared to the MDRD Study reference laboratory.(3, 4) However, recent data suggests differences in creatinine assay calibration may still have led to inaccuracy in the Chinese coefficient.(11) Table Comparison of methods used to develop ethnicity coefficients for the Modification of Diet in Renal Disease Study equation. Another potential sources of bias is that each study used a different method to measure GFR. If there are systematic differences between methods of GFR measurement, the ethnicity coefficient will reflect these differences in addition to any true ethnic differences in the non-GFR determinants of serum creatinine. The study in Japan used inulin clearance whereas the MDRD Study used iothalamate clearance. Several investigators,(12–14) but not all,(15) have found iothalamate clearance to give higher values than a simultaneous inulin clearance and this could contribute to a Japanese coefficient 1.0.(18) A morning meal preceded the GFR measurement in the Chinese coefficient study,(19) and any dietary protein in this meal could have raised GFR(20) and contributed to a Chinese coefficient >1.0. There is not necessarily one correct approach to measuring GFR in all settings, as time, cost, and convenience are important factors. However, it is important in studies that compare groups to measure GFR the same way in each group. These studies also differed with respect to how they identified patients. The Chinese coefficient study specifically excluded patients with muscle atrophy, but muscle is the primary source of creatinine generation and this could contribute to a Chinese coefficient >1.0. Patients who were selected by physicians to undergo direct GFR measurement as part of their health care (Japanese and Chinese coefficient studies) may differ from patients who underwent GFR measurement as part of a clinical trial (the MDRD Study). It is also important to consider that Japan, China, and America all have different health care systems and possibly different referral patterns to centers where direct GFR measurement would be obtained and this could potentially affect these ethnicity coefficients. Further, these equations and ethnicity coefficients were developed using patients who had a diagnosis of CKD and may perform differently in settings where most patients are healthy and are being screened for CKD.(21–23) If study design differences had little impact on these coefficients, are the putative ethnic differences inferred for the non-GFR determinants of serum creatinine plausible? For an equation to estimate GFR per body surface area (BSA), there needs to be parity in the units on both sides of the equation, which requires the demographic coefficients to model the non-GFR determinants of serum creatinine indexed to BSA.(23) Matsuo et al suggests that the lower creatinine generation (mg/day) in Japanese compared to whites is consistent with a Japanese ethnicity coefficient that is <1.0.(4) However, a more relevant comparison would be with creatinine generation per BSA (mg/day/1.73 m2), particularly since BSA is lower in Japanese compared to whites (Table). Besides ethnic differences in muscle mass, there may be differences in other non-GFR determinants of serum creatinine. Ethnic differences in dietary protein could contribute to these ethnicity coefficients, particularly if there were practice differences with regard to protein restriction for treatment of CKD.(24, 25) There may also be ethnic differences in the tubular secretion of creatinine, a possibility that has been suggested for differences between African Americans and whites.(26) In addition to Japanese and Chinese ethnicity coefficients for the MDRD Study equation, Matsuo and colleagues developed a separate Japanese equation and Ma and colleagues developed a separate Chinese equation.(3, 4) Unlike the ethnicity coefficients used to modify the MDRD Study, these new equations optimize the serum creatinine, age, and sex coefficients to the Japanese and Chinese population. For the specific purpose of managing patients in Japan or China, one could argue that these new equations are preferred. These equations are optimized to the regional assays for serum creatinine, the regional method for measuring GFR, and the regional CKD patient population. It would be important to study these new equations with regard to their impact on risk prediction of outcomes such as mortality and end-stage renal disease. How do we improve estimation of GFR in multi-ethnic settings? The ethnicity coefficients developed in these studies (3, 4) may not be adequate for managing patients in multi-ethnic settings.(27) Additional studies of CKD patients that differ by ethnicity are needed, but these studies should use standardized serum creatinine, the same GFR measurement protocol, and the same inclusion criteria. Further work on ethnic differences with the non-GFR determinants of serum creatinine (indexed to BSA) may provide insight into the biological basis of ethnicity coefficients. Even if ethnicity coefficients are developed and well-validated in CKD populations, it would also be important to assess their validity in representative populations where screening for CKD occurs. Further work to improve estimation of GFR and its interpretation will ultimately benefit the patients we look after.

Asian chronic kidney disease best practice recommendations: Positional statements for early detection of chronic kidney disease from Asian Forum for Chronic Kidney Disease Initiatives (AFCKDI)

1. Targets

Chronic kidney disease, cardiovascular disease and mortality: A prospective cohort study in a multi-ethnic Asian population.

Background Few studies have examined the impact of chronic kidney disease (CKD) on adverse cardiovascular outcomes and deaths in Asian populations. We evaluated the associations of CKD with cardiovascular disease (CVD) and all-cause mortality in a multi-ethnic Asian population. Design Prospective cohort study of 7098 individuals who participated in two independent population-based studies involving Malay adults (n = 3148) and a multi-ethnic cohort of Chinese, Malay and Indian adults (n = 3950). Methods CKD was assessed from CKD-EPI estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Incident CVD (myocardial infarction, stroke and CVD mortality) and all-cause mortality were identified by linkage with national disease/death registries. Results Over a median follow-up of 4.3 years, 4.6% developed CVD and 6.1% died. Risks of both CVD and all-cause mortality increased with decreasing eGFR and increasing albuminuria (all p-trend <0.05). Adjusted hazard ratios (HR (95% confidence interval)) of CVD and all-cause mortality were: 1.54 (1.05–2.27) and 2.21 (1.67–2.92) comparing eGFR <45 vs ≥60; 2.81 (1.49–5.29) and 2.34 (1.28–4.28) comparing UACR ≥300 vs <30. The association between eGFR <60 and all-cause mortality was stronger among those with diabetes (p-interaction = 0.02). PAR of incident CVD was greater among those with UACR ≥300 (12.9%) and that of all-cause mortality greater among those with eGFR <45 (16.5%). Conclusions In multi-ethnic Asian adults, lower eGFR and higher albuminuria were independently associated with incident CVD and all-cause mortality. These findings extend previously reported similar associations in Western populations to Asians and emphasize the need for early detection of CKD and intervention to prevent adverse outcomes.

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.

Elevated Serum Leptin, Adiponectin and Leptin to Adiponectin Ratio Is Associated with Chronic Kidney Disease in Asian Adults

Background Adiponectin and leptin, two of the key cytokines secreted by adipocytes, have been shown to be associated with cardiovascular disease. However, the association of these adipocytokines with chronic kidney disease (CKD) is not clear. We examined the association of serum adiponectin, leptin levels and leptin to adiponectin ratio (LAR) with CKD in a population-based sample of Asian adults. Methods We conducted a case-control study (450 CKD cases and 920 controls matched for age, sex and ethnicity) involving Chinese and Indian adults aged 40–80 years who participated in the Singapore Epidemiology of Eye Diseases Study (2007–2011). CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73m2 from serum creatinine. Serum adiponectin and leptin levels were measured using commercially available ELISA. Odds ratio of CKD associated with elevated adiponectin and leptin levels were estimated using logistic regression models adjusted for age, gender, ethnicity, education, smoking, body mass index, diabetes, blood pressure, total and HDL cholesterol. Results CKD cases had higher levels of leptin (mean [SD] 9.7 [11.5] vs.16.9 [20.2] ng/mL, p<0.0001) and adiponectin (10.4 [7.4] vs. 9.2 [4.2], p = 0.001) compared to controls. In multi-variable models, compared to those in the lowest quartile, the OR (95% confidence interval) of CKD among those in the highest quartile were: 6.46 (3.84, 10.88), 1.94 (1.32–2.85) and 2.88 (1.78–4.64) for leptin, adiponectin and LAR. Similar associations were also observed when adiponectin and leptin were analyzed as continuous variables. This positive association of serum adiponectin, leptin and LAR with CKD was consistently present in subgroups of gender, ethnicity, diabetes, hypertension and overweight status (all P-interaction >0.1). Conclusions Higher levels of serum adiponectin, leptin and LAR were positively associated with CKD independent of traditional risk factors in this Asian population.

Influence of Vascular Access Type on Outcome Measures in Patients on Maintenance Hemodialysis

Background: Previous studies postulate that end-stage renal disease (ESRD) patients dialyzed with central venous catheters (CVC) have poorer outcomes compared to patients using arteriovenous fistulae (AVF) or arteriovenous grafts (AVG). Clinical practice guidelines should obviate these differences if access was not important. This study compared clinical measures of adequacy, anemia, and nutrition/inflammation in prevalent hemodialysis patients in 2003 by access type. Methods: Data from The Renal Network Data System were analyzed by univariate analysis of variance to compare Kt/V, URR, albumin, hemoglobin (Hb) and recombinant human erythropoietin (EPO) dose by access type, while adjusting for pertinent factors. Results: 12,501 patients were included. The access type distribution was AVF 36%, AVG 41%, and CVC 23%. CVC patients had lower mean URR, Kt/V, albumin concentration (p < 0.001) than other accesses. Serum Hbs were similar (p = 0.416), however EPO dose (U/kg/week) was higher in those dialyzed with CVC compared to AVF/AVG (p < 0.001). Conclusions: Despite practice guidelines, patients dialyzed via CVC have poorer outcome measures compared to other accesses. This suggests that AVF should be used and/or appropriate adjustments need to be made for those dialyzed with CVC to achieve equal outcomes. Further studies defining barriers need to be conducted.

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.

Alkalemia during continuous renal replacement therapy and mortality in critically ill patients.

Objective:Acid-base disorders are common in critically ill patients. Once continuous renal replacement therapy (CRRT) is initiated, it becomes a major determinant of acid-base status. We hypothesized that therapy-induced alkalemia and alkalosis is associated with increased mortality. Patients:The CCF-ARF Registry (1995–01) was used to identify 405 patients supported with bicarbonate based continuous hemodialysis. Proportion of days with an elevated pH to the number of days with normal pH was used to assess the association of alkalemia and the number of days with alkalemia, and mortality. Multivariable analyses were used to adjust for days with acidosis, and other relevant covariates. Main Results:Serum bicarbonate and pH levels plateau after 48 hrs of CRRT. Study subjects had on average 1.5 ± 2.9 days where pH was greater than 7.45, and .4 days where serum bicarbonate level was greater than 28 mmol/L, during a median of 9 days of CRRT. Daily dialysis dose was inversely associated with the number of days with a low serum bicarbonate level, but was not associated with increased frequency of an elevated pH or serum bicarbonate level. Increasing proportion of days with elevated pH or serum bicarbonate was not associated with increased mortality in multivariable analysis. Conclusions:Alkalemia and alkalosis occur frequently during CRRT, but they are not associated with increased mortality. Persistent acidosis and acidemia while on CRRT was a strong predictor of poor outcome.