Predictive score for vesicoureteral reflux in children with a first febrile urinary tract infection.

OBJECTIVE: To develop a simple score for predicting vesicoureteral reflux after a first febrile urinary tract infection in children. METHODS: A retrospective cohort study was conducted for a 12-year period (January 2008 to December 2019), including patients aged <72 months who underwent renal ultrasonography and voiding cystourethrography after a first febrile urinary tract infection. Patients with a history of antenatal hydronephrosis were excluded. The prediction model and score for vesicoureteral reflux were developed using multivariate logistic regression analysis. RESULTS: Out of 260 patients in total (median age 4 months, 172 boys), 41 (16%) had vesicoureteral reflux. The score was based on four independent risk factors, including age >6 months (odds ratio 2.71, 95% confidence interval 1.27-5.76), presence of sepsis (odds ratio 3.44, 95% confidence interval 1.31-9.04), white blood cell count ≥15 000/mm3 (odds ratio 1.83, 95% confidence interval 0.88-3.8) and abnormal renal ultrasonography results (odds ratio 2.08, 95% confidence interval 1-4.31). A lower probability of vesicoureteral reflux (positive likelihood ratio = 0.66; P = 0.001) was found in the low-risk group (scores 0-2), whereas a higher probability of vesicoureteral reflux (positive likelihood ratio = 2.54; P = 0.001) was found in the high-risk group (scores 3-5). The predictive ability of the model was 70%. CONCLUSIONS: The scores developed based on the patient characteristics and renal ultrasonography are useful in predicting presence of vesicoureteral reflux after a first febrile urinary tract infection in children and could guide clinicians' decisions to perform additional imaging studies.

Estimated glomerular filtration rate at dialysis initiation and subsequent decline in residual kidney function among incident hemodialysis patients.

BACKGROUND: Higher estimated glomerular filtration rate (eGFR) at dialysis initiation, known as earlier start of dialysis, is often a surrogate of poor outcomes including higher mortality. We hypothesized that earlier dialysis initiation is associated with a faster decline in residual kidney function (RKF), which is also associated with higher mortality among incident hemodialysis (HD) patients. METHODS: In a cohort of 4911 incident HD patients who initiated HD over a 5-year period (July 2001 to June 2006), we examined the trajectories of RKF, ascertained by renal urea clearance (KRU), over 2 years after HD initiation across strata of eGFR at HD initiation using case-mix adjusted linear mixed-effect models. We then investigated the association between annual change in RKF and mortality using Cox proportional hazard models. RESULTS: The median (interquartile range) baseline KRU was 2.20 (1.13-3.63) mL/min/1.73 m2. The decline of KRU was faster in patients who initiated HD at higher eGFR. The relative changes with 95% confidence intervals (CIs) in KRU at 1 year after HD initiation were -1.29 (-1.28 to -1.30), -1.17 (-1.16 to -1.18), -1.11 (-1.10 to -1.12) and -0.78 (-0.78 to -0.79) mL/min/1.73 m2 in the eGFR categories of ≥10, 8-<10, 6-<8 and <6 mL/min/1.73 m2, respectively. The faster decline of KRU at 1 year was associated with higher all-cause mortality (reference: ≥0 mL/min/1.73 m2): hazard ratios (95% CIs) for change in KRU of -1.5 to <0, -3 to less than -1.5 and less than -3 mL/min/1.73 m2 were 1.20 (1.03-1.40), 1.42 (1.17-1.72) and 1.88 (1.47-2.40), respectively. CONCLUSIONS: The faster decline of RKF happens with earlier dialysis initiation and is associated with higher all-cause mortality.

Survival Advantage of African American Dialysis Patients with End-Stage Renal Disease Causes Related to APOL1.

BACKGROUND: Observational studies show that African American (AA) dialysis patients have longer survival than European Americans. We hypothesized that apolipoprotein L1 (APOL1) genetic variation, associated with nephropathy in AAs, contributes to the survival advantage in AA dialysis patients. METHODS: We examined the association between race and mortality among 37,097 adult dialysis patients, including 54% AAs and 46% European Americans from a large dialysis organization (entry period from July 2001 to June 2006, follow-up through June 2007), within each cause of end-stage renal disease (ESRD) category associated with APOL1 renal risk variants using Cox proportional hazard models. RESULTS: AA dialysis patients had numerically lower mortality than their European American counterparts for all causes of ESRD. The mortality reduction among AAs compared to European Americans was statistically significant in patients with ESRD attributed to diabetes mellitus, hypertension, and APOL1-enriched glomerulonephritis (GN) (HR [95% CI]: 0.69 [0.66-0.72], 0.73 [0.68-0.79], and 0.89 [0.79-0.99], respectively); these are conditions in which APOL1 variants promote kidney disease. By contrast, the significant survival advantage of AA dialysis patients was not observed in patients with ESRD attributed to other kidney disease (including polycystic kidney disease, interstitial nephritis, and pyelonephritis) and other GN, which are not associated with APOL1 variants. CONCLUSIONS: These data suggest the hypothesis that the relative survival advantage of AA dialysis patients may be related to APOL1 variation. Further large population-based genetic studies are required to test this hypothesis.

Changes in pulse pressure during hemodialysis treatment and survival in maintenance dialysis patients.

BACKGROUND AND OBJECTIVES: Pulse pressure has been shown as a risk factor for mortality in patients on maintenance hemodialysis (MHD). However, the effect of change in pulse pressure during hemodialysis on survival in a large cohort of patients on MHD has not been sufficiently investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the association between time-varying Δ pulse pressure (postdialysis minus predialysis pulse pressure) and mortality in a cohort of 98,577 patients on MHD (July 2001-June 2006) using Cox proportional hazard models with restricted cubic splines. RESULTS: The average patient age was 62 years old; among the patients, 33% were black and 59% had diabetes. During 134,814 patient-years of at-risk time, 16,054 (16%) patients died, with 6827 (43%) of the deaths caused by cardiovascular causes. In the models including adjustment for either predialysis systolic BP or mean arterial BP, there was a U-shaped association between change in pulse pressure during hemodialysis and all-cause mortality. In the systolic BP plus case mix plus malnutrition-inflammation complex syndrome-adjusted model, large declines in pulse pressure (>-25 mmHg) and increases in pulse pressure >5 mmHg were associated with higher all-cause mortality (reference: ≥-5 to <5 mmHg): hazard ratios (95% confidence intervals [95% CIs]) for change pulse pressures of <-25, ≥-25 to <-15, ≥-15 to <-5, 5 to <15, 15 to <25, and ≥25 mmHg were 1.21 (95% CI, 1.14 to 1.29), 1.03 (95% CI, 0.97 to 1.10), 1.01 (95% CI, 0.96 to 1.06), 1.06 (95% CI, 1.01 to 1.11), 1.17 (95% CI, 1.11 to 1.24), and 1.15 (95% CI, 1.08 to 1.23), respectively. The U-shaped association was observed with cardiovascular death. CONCLUSIONS: Modest reductions in pulse pressure after hemodialysis are associated with the greatest survival, whereas large declines or rises in pulse pressure are related to higher mortality. Trials determining how to modify pulse pressure response to improve survival in the hemodialysis population are indicated.

Dose of hemodialysis and survival: a marginal structural model analysis.

BACKGROUND: Observational studies have consistently demonstrated the survival benefits of a greater dialysis dose in maintenance hemodialysis (MHD) patients, whereas randomized controlled trials have shown conflicting results. The possible causal impact of dialysis dose on mortality needs to be investigated using rich cohort data analyzed with novel statistical methods such as marginal structural models (MSMs) that account for time-varying confounding and exposure. METHODS: We quantified the effect of delivered dose of hemodialysis (HD) [single-pool Kt/V (spKt/V)] on mortality risk in a contemporary cohort of 68,110 patients undergoing HD 3 times weekly (7/2001- 9/2005). We compared conventional Cox proportional hazard and MSM survival analyses, accounting for time-varying confounding by applying longitudinally modeled inverse-probability-of-dialysis-dose weights to each observation. RESULTS: In conventional Cox models, baseline spKt/V showed a weak negative association with mortality, while higher time-averaged spKt/V was strongly associated with lower mortality risk. In MSM analyses, compared to a spKt/V range of 1.2 - <1.4, a spKt/V range of <1.2 was associated with a higher risk of mortality [HR (95% CI) 1.67 (1.54 - 1.80)], whereas mortality risks were significantly lower with higher spKt/V [HRs (95% CI): 0.74 (0.70-0.78), 0.63 (0.59-0.66), 0.56 (0.52-0.60), and 0.56 (0.52-0.61) for spKt/V ranges of 1.4 - <1.6, 1.6-<1.8, 1.8 - <2.0, and ≥2.0, respectively]. Thus, MSM analyses showed that the greatest survival advantage of a higher dialysis dose was observed for a spKt/V range of 1.8-<2.0, and the dialysis dose-mortality relationship was robust in almost all subgroups of patients. CONCLUSIONS: Higher HD doses were robustly associated with greater survival in MSM analyses that more fully and appropriately accounted for time-varying confounding.

Impact of age, race and ethnicity on dialysis patient survival and kidney transplantation disparities.

BACKGROUND: Prior studies show that African-American and Hispanic dialysis patients have lower mortality risk than whites. Recent age-stratified analyses suggest this survival advantage may be limited to younger age groups, but did not concurrently compare Hispanic, African-American, and white patients, nor account for differences in nutritional and inflammatory status as potential confounders. Minorities experience inequities in kidney transplantation access, but it is unknown whether these racial/ethnic disparities differ across age groups. METHODS: The associations between race/ethnicity with all-cause mortality and kidney transplantation were separately examined among 130,909 adult dialysis patients from a large national dialysis organization (entry period 2001-2006, follow-up through 2009) within 7 age categories using Cox proportional hazard models adjusted for case-mix and malnutrition and inflammatory surrogates. RESULTS: African-Americans had similar mortality versus whites in younger age groups (18-40 years), but decreased mortality in older age groups (>40 years). In contrast, Hispanics had lower mortality versus whites across all ages. In sensitivity analyses using competing risk regression to account for differential kidney transplantation rates across racial/ethnic groups, the African-American survival advantage was limited to >60-years age categories. African-Americans and Hispanics were less likely to undergo kidney transplantation from all donor types versus whites across all ages, and these disparities were even more pronounced for living donor kidney transplantation (LDKT). CONCLUSIONS: Hispanic dialysis patients have greater survival versus whites across all ages; in African-Americans, this survival advantage is limited to patients >40 years of age. Minorities are less likely to undergo kidney transplantation, particularly LDKT, across all ages.

Impact of age on survival predictability of bone turnover markers in hemodialysis patients.

BACKGROUND: Abnormalities in serum alkaline phosphatase (ALP) and intact parathyroid hormone (PTH) concentrations, as biochemical markers of bone turnover in dialysis patients, correlate with increased mortality in maintenance hemodialysis (MHD) patients. Changes in bone turnover rate vary with age. The mortality predictability of serum ALP and PTH levels in MHD patients may be different across ages. METHODS: We examined differences across four age groups (18 to <45, 45 to <65, 65 to <75 and ≥ 75 years) in the mortality predictability of serum ALP and PTH in 102 149 MHD patients using Cox models. RESULTS: Higher serum ALP levels were associated with higher mortality across all ages; however, the ALP-mortality association was much stronger in young patients (<45 years) compared with older patients. The association between higher serum PTH levels and mortality was stronger in older patients compared with the younger groups. Serum PTH levels were incrementally associated with mortality only in middle-aged and elderly patients (≥ 45 years). Compared with patients with serum PTH 150 to <300 pg/mL, the death risks were higher in patients with serum PTH 300 to <600 pg/mL [HRs (95% CI): 1.05 (1.01-1.10), 1.15 (1.10-1.21) and 1.25 (1.19-1.31) for patients 45 to <65, 65 to <75 and ≥ 75 years, respectively], and ≥ 600 pg/mL [HRs(95% CI): 1.07 (1.01-1.14), 1.31(1.21-1.42) and 1.45(1.33-1.59) for age categories 45 to <65, 65 to <75 and ≥ 75 years, respectively]. However, no significant association between higher serum PTH levels and mortality was observed in patients <45 years. CONCLUSIONS: There are important differences in mortality-predictability of serum ALP and PTH in older MHD patients compared with their younger counterparts. The effect of age needs to be considered when interpreting the prognostic implications of serum ALP and PTH levels.

Association of serum phosphorus concentration with mortality in elderly and nonelderly hemodialysis patients.

OBJECTIVE: Hypo- and hyperphosphatemia have each been associated with increased mortality in maintenance hemodialysis (MHD) patients. There has not been previous evaluation of a differential relationship between serum phosphorus level and death risk across varying age groups in MHD patients. DESIGN AND SETTINGS: In a 6-year cohort of 107,817 MHD patients treated in a large dialysis organization, we examined the association between serum phosphorus levels with all-cause and cardiovascular mortality within 5 age categories (15 to <45, 45 to <65, 65 to <70, 70 to <75, and ≥75 years old) using Cox proportional hazards models adjusted for case-mix covariates and malnutrition inflammation complex syndrome (MICS) surrogates. MAIN OUTCOME MEASURE: All-cause and cardiovascular mortality. RESULTS: The overall mean age of the cohort was 60 ± 16 years, among whom there were 45% women, 35% Blacks, and 58% diabetics. The time-averaged serum phosphorus level (mean ± SD) within each age category was 6.26 ± 1.4, 5.65 ± 1.2, 5.26 ± 1.1, 5.11 ± 1.0, and 4.88 ± 1.0 mg/dL, respectively (P for trend <.001). Hyperphosphatemia (>5.5 mg/dL) was consistently associated with increased all-cause and cardiovascular mortality risks across all age categories, including after adjustment for case-mix and MICS-related covariates. In fully adjusted models, a low serum phosphorus level (<3.5 mg/dL) was associated with increased all-cause mortality only in elderly MHD patients ≥65 years old (hazard ratio [95% confidence interval]: 1.21 [1.07-1.37], 1.13 [1.02-1.25], and 1.28 [1.2-1.37] for patients 65 to <70, 70 to <75, and ≥75 years old, respectively), but not in younger patients (<65 years old). A similar differential cardiovascular mortality risk for low serum phosphorus levels between old and young age groups was observed. CONCLUSIONS: The association between hyperphosphatemia and mortality is similar across all age groups of MHD patients, whereas hypophosphatemia is associated with increased mortality only in elderly MHD patients. Preventing very low serum phosphorus levels in elderly dialysis patients may be associated with better outcomes, which needs to be examined in future studies.

Recipient-related predictors of kidney transplantation outcomes in the elderly.

BACKGROUND: It is not clear whether in old people with end-stage renal disease kidney transplantation is superior to dialysis therapy. METHODS: We compared mortality rates between kidney transplant recipients (KTRs) and the general population across different age categories. We also examined patient and allograft survival in 15 667 elderly KTRs (65-<90 yr old, 36% female) within three age subgroups (65-<70, 70-<75, and ≥75 yr). RESULTS: The rise in the relative risk of death in older age groups was substantially less in KTRs than in the general population, that is, 1.8 and 2.0 vs. 21.4 and 76.6 in those aged 65-<75 and ≥75 yr, respectively, compared with 15- to <65-yr-old people (reference group). In 65- to <70-yr-old KTRs, obesity (BMI>30 kg/m(2) ) was associated with 19% higher risk of graft failure (HR: 1.19 [1.07-1.33], p = 0.002). Diabetes was a predictor of worse patient survival in all age groups but poorer allograft outcome in the youngest age group (65-<70 yr old) only. None of the examined risk factors affected allograft outcome in the oldest group (≥75 yr old) although there was a 49% lower trend of graft failure in very old Hispanic recipients (HR: 0.51 [0.26-1.01], p = 0.05). CONCLUSIONS: Kidney transplantation may attenuate the age-associated increase in mortality, and its superior survival gain is most prominent in the oldest recipients (≥75 yr old). The potential protective effect of kidney transplantation on longevity in the elderly deserves further investigation.

Prevention and management of dialysis catheter complications in the intensive care unit.

Dialysis dependence at hospital discharge after acute kidney injury (AKI) requiring renal replacement therapy (RRT) in the intensive care unit (ICU) is found in 10-15% of survivors. In case of severe AKI in the ICU, it is necessary to reconcile two objectives: the creation of an adequate temporary angioaccess for RRT and the preservation of the patient's vascular network in case of evolution to end-stage renal disease. A central venous catheter (CVC) is the best option for RRT in the ICU setting. Most catheter-related hazards can be prevented by following best clinical practices for insertion and handling of the CVC, and by knowing the advantages and disadvantages of the different types of catheters, the sites and techniques of insertion, the types of RRT modality for choosing the best CVC option, and the prophylactic and therapeutic measures to prevent and to manage the complications. We review here some important aspects of the CVC for the treatment of AKI in the ICU.

Glycemic control in diabetic dialysis patients and the burnt-out diabetes phenomenon.

Diabetes mellitus (DM) is the most common cause of end-stage kidney disease and a major risk of morbidity and mortality. It is not clear whether medical management of DM has any significant beneficial effect on clinical outcomes at the end-stage of diabetic nephropathy with full-blown micro- and macro-angiopathic complications. Both loss of kidney function and dialysis treatment interfere with glucose homeostasis and confound glycemic control. Given the unique nature of uremic milieu and dialysis therapy related alterations, there have been some debates about reliance on the conventional measures of glycemic control, in particular the clinical relevance of hemoglobin A1c and its recommended target range of <7 % in diabetic dialysis patients. Moreover, a so-called burnt-out diabetes phenomenon has been described, in that many diabetic dialysis patients experience frequent hypoglycemic episodes prompting cessation of their anti-diabetic therapies transiently or even permanently. By reviewing the recent literature we argue that the use of A1c for management of diabetic dialysis patients should be encouraged if appropriate target ranges specific for these patients (e.g. 6 to 8 %) are used. We also argue that "burnt-out diabetes" is a true biologic phenomenon and highly prevalent in dialysis patients with established history and end-stage diabetic nephropathy and explore the role of protein-energy wasting to this end. Similarly, the J- or U-shaped associations between A1c or blood glucose concentrations and mortality are likely biologically plausible phenomena that should be taken into consideration in the management of diabetic dialysis patients to avoid hypoglycemia and its fatal consequences in diabetic dialysis patients.

Population pharmacokinetics of mycophenolate mofetil in Thai lupus nephritis patients.

OBJECTIVE: Mycophenolic acid (MPA) has become the first-line drug therapy for proliferative lupus nephritis, a common and serious complication of systemic lupus erythematosus. Although a sufficient MPA exposure is required, a high interindividual variability in the pharmacokinetics of MPA has been observed. The knowledge of MPA pharmacokinetics in lupus nephritis patients is limited, especially in Asian patients. This study aimed to develop a population pharmacokinetic model for MPA and determine the population pharmacokinetic parameters and their interindividual variability in Thai patients with lupus nephritis. METHODS: A total of 112 MPA plasma concentrations from 14 adult lupus nephritis patients (International Society of Nephrology/Renal Pathology Society Class III/IV) receiving mycophenolate mofetil were included in this study. The data was analyzed using NONMEM. The model evaluation was performed by the bootstrap approach and visual predictive check. RESULTS: A two-compartment model with a lag time best described the data. The estimated mean apparent clearance (CL/F) was 14.5 l/h with an interindividual variability of 45.2%. The estimated mean CL/F was found to be lower than the values previously reported. The estimated mean apparent volume of the central compartment was 12.2 l with an interindividual variability of 166%. None of the covariates were found to significantly influence MPA pharmacokinetics. CONCLUSION: In this study, a population pharmacokinetic model of MPA in severe lupus nephritis patients was successfully developed. The mean pharmacokinetic parameters were estimated and a high interindividual variability of MPA in this population was observed. This provides evidence to show that individualizing dosage regimens in this population is crucial. The model developed in this study could be used to obtain initial information for MPA dose adjustments in Thai and Asian patients with lupus nephritis. Further studies are required to validate the results and clarify the influence of covariates on MMF pharmacokinetics.

Safety and immunogenicity of a 2009 influenza A (H1N1) vaccine in hemodialysis patients.

A worldwide vaccination campaign against the 2009 pandemic influenza A (H1N1) virus was launched among high-risk subjects, including hemodialysis patients. The long-term immunogenicity of an influenza vaccine has not been investigated in hemodialysis patients. This study aimed to (1) assess the long-term immunogenicity of a monovalent non-adjuvanted influenza A (H1N1) vaccine in hemodialysis patients and (2) determine the safety of this vaccine. We conducted a prospective cohort study of 44 hemodialysis patients and 149 healthy controls in 2010. All of the participants received a single dose of the monovalent non-adjuvanted 2009 influenza A (H1N1) vaccine. The level of antibodies was measured at baseline and at 4 and 24 weeks post-vaccination using a hemagglutination inhibition assay. The outcomes were the percentages of participants who achieved seroconversion and seroprotection (titer ≥ 1:40) 4 and 24 weeks after vaccination. At 4 weeks post-vaccination, seroconversion was observed in 17 (38.6%) of the hemodialysis patients and 94 (63.1%) of the controls (P=0.056), and protective titers were obtained in 22 (50%) of the hemodialysis patients and 100 (67.1%) of the controls (P=0.426). At 24 weeks post-vaccination, immunogenicity decreased in both the hemodialysis patients and the controls, but there were no significant differences between the hemodialysis patients and the controls in the seroconversion rate (27.3% versus 36.9%, P=0.526) or the seroprotection rate (38.6% versus 48.3%, P=0.996). No differences in adverse events were observed between the hemodialysis patients and the controls. In summary, the 2009 influenza A (H1N1) vaccine elicits a similar immune response in both hemodialysis patients and healthy controls, but immunity declines 24 weeks after vaccination in both groups. Hemodialysis patients should at least be vaccinated annually against the influenza virus.

Pharmacokinetics of mycophenolic acid in severe lupus nephritis.

Mycophenolic acid (MPA) is an effective treatment for active lupus nephritis despite its variable efficacy in different ethnic groups. Here we tested whether pharmacokinetic monitoring may help to optimize dosing of MPA in an Asian population. Patients with biopsy-proven class III or IV lupus nephritis (ISN/RPS category) were treated with mycophenolate mofetil or enteric-coated mycophenolate sodium. One month after initiating treatment we measured plasma MPA levels in eight samples taken over a 12-h period after drug administration. The mean area under the time-dependent curve for MPA of responding patients was significantly higher than those not responding. Successful treatment was seen in patients with areas >45 mg h/l. The dosage of the drug was not related to MPA pharmacokinetics. In the mycophenolate mofetil group, however, MPA-area under the curve was positively, and significantly, correlated with trough or 1 h after dose concentrations and associated with a therapeutic response. Thus, our study shows that MPA pharmacokinetics were positively correlated with therapeutic responses of mycophenolate, suggesting that controlling the concentrations may improve its therapeutic efficacy in lupus nephritis. As the absorption and pharmacokinetic peak of enteric-coated tablets is slower, it is important to take different formulations into account when determining optimal MPA concentrations.