Data driven approach to characterize rapid decline in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disease with high phenotypic variability. Furthering insights into patients' ADPKD progression could lead to earlier detection, management, and alter the course to end stage kidney disease (ESKD). We sought to identify patients with rapid decline (RD) in kidney function and to determine clinical factors associated with RD using a data-driven approach. A retrospective cohort study was performed among patients with incident ADPKD (1/1/2002-12/31/2018). Latent class mixed models were used to identify RD patients using differences in eGFR trajectories over time. Predictors of RD were selected based on agreements among feature selection methods, including logistic, regularized, and random forest modeling. The final model was built on the selected predictors and clinically relevant covariates. Among 1,744 patients with incident ADPKD, 125 (7%) were identified as RD. Feature selection included 42 clinical measurements for adaptation with multiple imputations; mean (SD) eGFR was 85.2 (47.3) and 72.9 (34.4) in the RD and non-RD groups, respectively. Multiple imputed datasets identified variables as important features to distinguish RD and non-RD groups with the final prediction model determined as a balance between area under the curve (AUC) and clinical relevance which included 6 predictors: age, sex, hypertension, cerebrovascular disease, hemoglobin, and proteinuria. Results showed 72%-sensitivity, 70%-specificity, 70%-accuracy, and 0.77-AUC in identifying RD. 5-year ESKD rates were 38% and 7% among RD and non-RD groups, respectively. Using real-world routine clinical data among patients with incident ADPKD, we observed that six variables highly predicted RD in kidney function.

Causes of Death in End-Stage Kidney Disease: Comparison between the United States Renal Data System and a Large Integrated Health Care System.

INTRODUCTION: Using a large diverse population of incident end-stage kidney disease (ESKD) patients from an integrated health system, we sought to evaluate the concordance of causes of death (CODs) between the underlying COD from the United States Renal Data System (USRDS) registry and CODs obtained from Kaiser Permanente Southern California (KPSC). METHODS: A retrospective cohort study was performed among incident ESKD patients who had mortality records and CODs reported in both KPSC and USRDS databases between January 1, 2007, and December 31, 2016. Underlying CODs reported by the KPSC were compared to the CODs reported by USRDS. Overall and subcategory-specific COD agreements were assessed using Cohen's weighted kappa statistic (95% CI). Proportions of positive and negative agreement were also determined. RESULTS: Among 4,188 ESKD patient deaths, 4,118 patients had CODs recorded in both KPSC and USRDS. The most common KPSC CODs were circulatory system diseases (35.7%), endocrine/nutritional/metabolic diseases (24.2%), genitourinary diseases (12.9%), and neoplasms (9.6%). Most common USRDS CODs were cardiac disease (46.9%), withdrawal from dialysis (12.6%), and infection (10.1%). Of 2,593 records with causes listed NOT as "Other," 453 (17.4%) had no agreement in CODs between the USRDS and the underlying, secondary, tertiary, or quaternary causes recorded by KPSC. In comparing CODs recorded within KPSC to the USRDS, Cohen's weighted kappa (95% CI) was 0.20 (0.18-0.22) with overall agreement of 36.4%. CONCLUSION: Among an incident ESKD population with mortality records, we found that there was only fair or slight agreement between CODs reported between the USRDS registry and KPSC, a large integrated health care system.

Autosomal Dominant Polycystic Kidney Disease Prevalence among a Racially Diverse United States Population, 2002 through 2018.

Among a large racially and ethnically diverse US population, the prevalence of diagnosed ADPKD between 2002 and 2018 was 42.6 per 100,000 persons.ADPKD prevalence (per 100,000) was higher in (non-Hispanic) White (63.2) and Black (73.0) patients compared with Hispanic (39.9) and Asian (48.9) patients.Given the variable penetrance of ADPKD, our findings suggest race may be a factor in the clinical presentation and diagnosis of ADPKD.

Sub-acute hyponatraemia more than chronic hyponatraemia is associated with serious falls and hip fractures.

BACKGROUND: Falls and hip fractures among older people are associated with high morbidity and mortality. Hyponatraemia may be a risk for falls/hip fractures, but the effect of hyponatraemia duration is not well understood. AIMS: To evaluate individuals with periods of sub-acute and chronic hyponatraemia on subsequent risk for serious falls and/or hip fractures. METHODS: Retrospective cohort study in the period 1 January 1998 to 14 June 2016 within an integrated health system of individuals aged ≥55 years with ≥2 outpatient serum sodium measurements. Hyponatraemia was defined as sodium <135 mEq/L with sub-acute (<30 days) and chronic (≥30 days) analysed as a time-dependent exposure. Multivariable Cox proportional-hazards modelling was used to estimate hazard ratios (HR) for serious falls/hip fractures based on sodium category. RESULTS: Among 1 062 647 individuals totalling 9 762 305 sodium measurements, 96 096 serious falls/hip fracture events occurred. Incidence (per-1000-person-years) of serious falls/hip fractures were 11.5, 27.9 and 19.8 for normonatraemia, sub-acute and chronic hyponatraemia. Any hyponatraemia duration compared to normonatraemia had a serious falls/hip fractures HR (95%CI) of 1.18 (1.15, 1.22), with sub-acute and chronic hyponatraemia having HR of 1.38 (1.33, 1.42) and 0.91 (0.87, 0.95), respectively. Examined separately, the serious falls HR was 1.37 (1.32, 1.42) and 0.92 (0.88, 0.96) in sub-acute and chronic hyponatraemia, respectively. Hip fracture HR were 1.52 (1.42, 1.62) and 1.00 (0.92, 1.08) for sub-acute and chronic hyponatraemia, respectively, compared to normonatraemia. CONCLUSIONS: Our findings suggest that early/sub-acute hyponatraemia appears more vulnerable and associated with serious falls/hip fractures. Whether hyponatraemia is a marker of frailty or a modifiable risk factor for falls remains to be determined.

Early Mortality Among Peritoneal Dialysis and Hemodialysis Patients Who Transitioned With an Optimal Outpatient Start.

INTRODUCTION: Lower early mortality observed in peritoneal dialysis (PD) compared with hemodialysis (HD) may be due to differential pre-end-stage renal disease (ESRD) care and the stable setting of transition to dialysis where PD starts are more frequently outpatient rather than during an unscheduled hospitalization. To account for these circumstances, we compared early mortality among a matched cohort of PD and HD patients who had optimal and outpatient starts. METHODS: Retrospective cohort study performed among patients with chronic kidney disease (CKD) who transitioned to ESRD from 1 January 2002 to 31 March 2015 with an optimal start in an outpatient setting. Optimal start defined as (i) HD with an arteriovenous graft or fistula or (ii) PD. Propensity score modeling factoring age, race, sex, comorbidities, estimated glomerular filtration rate (eGFR) level, and change in eGFR before ESRD was used to create a matched cohort of HD and PD. All-cause mortality was compared at 6 months, 1 year, and 2 years posttransition to ESRD. RESULTS: Among 2094 patients (1398 HD and 696 PD) who had optimal outpatient transition to ESRD, 541 HD patients were propensity score-matched to 541 PD patients (caliper distance <0.001). All-cause mortality odds ratios (OR) in PD compared with HD were 0.79 (0.39-1.63), 0.73 (0.43-1.23), and 0.88 (0.62-1.26) for 6 months, 1 year, and 2 years, respectively. Time-varying analysis accounting for modality switch (19% PD, 1.9% HD) demonstrated a mortality hazard ratio of 0.94 (0.70-1.24). CONCLUSION: Among an optimal start CKD cohort that transitioned to ESRD on an outpatient basis, we found no evidence of differences in early mortality between PD and HD.

End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population.

OBJECTIVE: To compare renal function decline, incident end-stage renal disease (ESRD), and mortality among patients with 5 common glomerular diseases in a large diverse population. PATIENTS AND METHODS: A retrospective cohort study (between January 1, 2000, and December 31, 2011) of patients with glomerulonephropathy using the electronic health record of an integrated health system was performed. Estimated glomerular filtration rate (eGFR) change, incident ESRD, and mortality were compared among patients with biopsy-proven focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MN), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), and lupus nephritis (LN). Competing risk models were used to estimate hazard ratios for different glomerulonephropathies for incident ESRD, with mortality as a competing outcome after adjusting for potential confounders. RESULTS: Of the 2350 patients with glomerulonephropathy (208 patients [9%] younger than 18 years) with a mean follow-up of 4.5±3.6 years, 497 (21%) progressed to ESRD and 195 (8%) died before ESRD. The median eGFR decline was 1.0 mL/min per 1.73 m2 per year but varied across different glomerulonephropathies (P<.001). The highest ESRD incidence (per 100 person-years) was observed in FSGS 8.72 (95% CI, 3.93-16.72) followed by IgAN (4.54; 95% CI, 1.37-11.02), LN (2.38; 95% CI, 0.37-7.82), MN (2.15; 95% CI, 0.29-7.46), and MCD (1.67; 95% CI, 0.15-6.69). Compared with MCD, hazard ratios (95% CIs) for incident ESRD were 3.43 (2.32-5.08) and 2.35 (1.46-3.81), 1.28 (0.79-2.07), and 1.02 (0.62-1.68) for FSGS, IgAN, LN, and MN, respectively. No significant association between glomerulonephropathy types and mortality was detected (P=.24). CONCLUSION: Our findings from a real-world clinical environment revealed significant differences in eGFR decline and ESRD risk among patients with 5 glomerulonephropathies. These variations in presentation and outcomes warrant different management strategies and expectations.

Use of Phosphorus Binders among Non-Dialysis Chronic Kidney Disease Patients and Mortality Outcomes.

BACKGROUND: Whether the benefits of phosphorus binders extend to those without end stage renal disease is uncertain. Among a large diverse non-dialysis chronic kidney disease (CKD) population with hyperphosphatemia, we sought to evaluate phosphorus binder use and compare mortality risk between patients prescribed and not prescribed binders. METHODS: A retrospective cohort study within an integrated health system (January 1, 1998 - December 31, 2012) among CKD patients (age ≥18) was performed. Non-dialysis CKD patients with 2 separate estimated glomerular filtrate rate (eGFR) <30 mL/min/1.73 m2 and serum phosphorus ≥5.0 mg/dL within 180 days of eGFR were included. Multivariable cox proportional hazards and inverse probability of treatment-weighted models were used to estimate mortality hazard ratios (HRs) for patients who received phosphorus binders compared to no binders. RESULTS: Among 10,165 study patients, 2,733 subjects (27%) received phosphorus binders. Compared to the no-phosphorus-binder group, the binder group had mortality HRs (95% CI) of 0.86 (0.79-0.94) and 0.86 (0.80-0.93) using traditional multivariable and inverse probability of treatment-weighted models respectively. Sensitivity analyses removing patients who were prescribed binders >180 days after index date revealed no difference in mortality between those with binders and with no binders. CONCLUSION: Our findings from a real-world clinical environment revealed that 27% of hyperphosphatemic non-dialysis CKD patients were prescribed binders. They also had lower risk of mortality compared to those not prescribed phosphorus binders. However, the lower mortality risk was not observed when we accounted for immortal time bias. Whether phosphorus binder use in CKD improves survival remains to be determined.

Plasma renin activity and risk of cardiovascular and mortality outcomes among individuals with elevated and nonelevated blood pressure.

BACKGROUND: We sought to evaluate plasma renin activity (PRA) levels and risk of mortality and cardiovascular events among individuals with elevated blood pressure [systolic blood pressure (SBP) ≥ 140 mmHg] and those with controlled blood pressure (SBP < 140 mmHg) in a large diverse population. METHODS: A retrospective cohort study between January 1, 2007, and December 31, 2013, among adults (≥ 18 years) within an integrated health system was conducted. Subjects were categorized by SBP into 2 groups: SBP < 140 mmHg and SBP ≥ 140 mmHg and then further categorized into population-based PRA tertiles within each SBP group. Cox proportional hazard modeling was used to estimate hazard ratios for cardiovascular and mortality outcomes among tertiles of PRA levels. RESULTS: Among 6,331 subjects, 32.6% had SBP ≥ 140 mmHg. Multivariable hazard ratios and 95% confidence interval for PRA tertiles T2 and T3 compared to T1 in subjects with SBP ≥ 140 mmHg were 1.42 (0.99-2.03) and 1.61 (1.12-2.33) for ischemic heart events; 1.40 (0.93-2.10) and 2.23 (1.53-3.27) for congestive heart failure; 1.10 (0.73-1.68) and 1.06 (0.68-1.66) for cerebrovascular accident; 1.23 (0.94-1.59) and 1.43 (1.10-1.86) for combined cardiovascular events; and 1.39 (0.97-1.99) and 1.35 (0.92-1.97) for all-cause mortality, respectively. Among the SBP < 140 mmHg group, there was no relationship between PRA levels and outcomes. CONCLUSION: Higher PRA levels demonstrated increased risk for ischemic heart events and congestive heart failure and a trend toward higher mortality among individuals with SBP ≥ 140 mmHg but not among those with SBP < 140 mmHg.

Comparisons of sleep apnoea rate and outcomes among patients with resistant and non-resistant hypertension.

BACKGROUND AND OBJECTIVE: We directly compared sleep apnoea (SA) rates and risk of cardiovascular and mortality outcomes among SA patients with resistant hypertension (RH) and non-RH within a large diverse hypertension population. METHODS: A retrospective cohort study between 1 January 2006 and 31 December 2010 among hypertensive adults (age ≥ 18 years) was performed within an integrated health system. Rates of SA in RH and non-RH were determined. Multivariable logistic regression analyses were used to calculate OR for SA. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) for cardiovascular and mortality outcomes between SA in RH versus SA in non-RH adjusting for age, gender, race, BMI, chronic kidney disease and other comorbidities. RESULTS: SA was identified in 33 682 (7.2%) from 470 386 hypertensive individuals. SA in RH accounted for 5806 (9.6%) compared to SA in non-RH 27 876 individuals (6.8%). Multivariable OR (95% CI) for SA was 1.16 (1.12, 1.19), 3.57 (3.47, 3.66) and 2.20 (2.15, 2.25) for RH versus non-RH, BMI ≥ 30, and males, respectively. Compared to SA in non-RH individuals, SA in RH had a multivariable adjusted HR (95% CI) of 1.24 (1.13, 1.36), 1.43 (1.28, 1.61), 0.98 (0.85, 1.12) and 1.04 (0.95, 1.14) for ischaemic heart event (IHE), congestive heart failure (CHF), stroke and mortality, respectively. CONCLUSION: We observed a modest increase in likelihood for SA among RH compared to non-RH patients. Risks for IHE and CHF were higher for SA in RH compared to SA in non-RH patients; however, there were no differences in risk for stroke and mortality.

Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension.

We sought to compare the risk of end-stage renal disease (ESRD), ischemic heart event (IHE), congestive heart failure (CHF), cerebrovascular accident (CVA), and all-cause mortality among 470,386 individuals with resistant and nonresistant hypertension (non-RH). Resistant hypertension (60,327 individuals) was subcategorized into two groups: 23,104 patients with cRH (controlled on four or more medicines) and 37,223 patients with uRH (uncontrolled on three or more medicines) in a 5-year retrospective cohort study. Cox proportional hazard modeling was used to estimate hazard ratios adjusting for age, gender, race, body mass index, chronic kidney disease (CKD), and comorbidities. Resistant hypertension (cRH and uRH), compared with non-RH, had multivariable adjusted hazard ratios (95% confidence intervals) of 1.32 (1.27-1.37), 1.24 (1.20-1.28), 1.46 (1.40-1.52), 1.14 (1.10-1.19), and 1.06 (1.03-1.08) for ESRD, IHE, CHF, CVA, and mortality, respectively. Comparison of uRH with cRH had hazard ratios of 1.25 (1.18-1.33), 1.04 (0.99-1.10), 0.94 (0.89-1.01), 1.23 (1.14-1.31), and 1.01 (0.97-1.05) for ESRD, IHE, CHF, CVA, and mortality, respectively. Men and Hispanics had a greater risk for ESRD within all three cohorts. Individuals with resistant hypertension had a greater risk for ESRD, IHE, CHF, CVA, and mortality. The risk of ESRD and CVA were 25% and 23% greater, respectively, in uRH compared with cRH, supporting the linkage between blood pressure and both outcomes.

Characteristics of resistant hypertension in a large, ethnically diverse hypertension population of an integrated health system.

OBJECTIVE: To evaluate the prevalence of and characterize resistant hypertension in a large representative population with successful hypertension management and reliable health information. PATIENT AND METHODS: We performed a cross-sectional study using clinical encounter, laboratory, and administrative information from the Kaiser Permanente Southern California health system between January 1, 2006, and December 31, 2007. From individuals older than 17 years with hypertension, resistant hypertension was identified and prevalence was determined. Multivariable logistic regression was used to calculate odds ratios (ORs), with adjustments for demographic characteristics, clinical variables, and medication use. RESULTS: Of 470,386 hypertensive individuals, 60,327 (12.8%) were identified as having resistant disease, representing 15.3% of those taking medications. Overall, 37,061 patients (7.9%) had uncontrolled hypertension while taking 3 or more medicines. The ORs (95% CIs) for resistant hypertension were greater for black race (1.68 [1.62-1.75]), older age (1.11 [1.10-1.11] for every 5-year increase), male sex (1.06 [1.03-1.10]), and obesity (1.46 [1.42-1.51]). Medication adherence rates were higher in those with resistant hypertension (93% vs 89.8%; P<.001). Chronic kidney disease (OR, 1.84; 95% CI, 1.78-1.90), diabetes mellitus (OR, 1.58; 95% CI, 1.53-1.63), and cardiovascular disease (OR, 1.34; 95% CI, 1.30-1.39) were also associated with higher risk of resistant hypertension. CONCLUSION: In a more standardized hypertension treatment environment, we observed a rate of resistant hypertension comparable with that of previous studies using more fragmented data sources. Past observations have been limited due to nonrepresentative populations, reliability of the data, heterogeneity of the treatment environments, and less than ideal control rates. This cohort, which was established using an electronic medical record-based approach, has the potential to provide a better understanding of resistant hypertension and outcomes.

Phosphorus and risk of renal failure in subjects with normal renal function.

PURPOSE: Whether higher serum phosphorus levels increase risk for kidney disease onset and progression to end-stage renal disease in those with normal renal function is largely unknown. We sought to determine whether higher serum phosphorus levels increase risk for end-stage renal disease within a large ethnically diverse population with normal kidney function. METHODS: A retrospective longitudinal cohort study was performed in the period January 1, 1998 through December 31, 2008 of adults within a vertically integrated health plan (3.4 million members). The primary objective was to determine risk of incident end-stage renal disease. Baseline and time-averaged phosphorus were used for Cox regressions analyses to calculate hazard ratios (HR) adjusting for age, sex, race, pre-existing hypertension, and diabetes. RESULTS: A total of 94,989 subjects were identified in the 11-year observation period. Mean age of the cohort was 50 years, with 61% female, 38% white, 14% black, and 25% Hispanic. Population-based phosphorus quartile ranges were 1.9-3.0 mg/dL, 3.1-3.4 mg/dL, 3.5-3.8 mg/dL, and 3.9-5.7 mg/dL. End-stage renal disease occurred in 130 (0.1%) subjects. Every 0.5-mg/dL phosphorus increase demonstrated an adjusted HR of 1.40 (95% confidence interval [CI], 1.06-1.84) and HR for mortality of 1.09 (95% CI, 1.06-1.13). Adjusted HRs were 0.64 (95% CI, 0.37-1.11), 0.83 (95% CI, 0.50-1.39), and 1.48 (95% CI, 0.96-2.28) in the 2nd, 3rd, and 4th quartile, respectively, compared with the first phosphorus quartile. Time-averaged serum phosphorus demonstrated a similar relationship across quartiles and as a continuous variable. CONCLUSION: In our large, ethnically diverse cohort of non kidney disease subjects, higher serum phosphorus levels were associated with greater risk for end-stage renal disease and mortality.

Plasma renin activity (PRA) levels and antihypertensive drug use in a large healthcare system.

BACKGROUND: Although hypertension guidelines have utility in treating uncomplicated hypertension, they often overlook the pathophysiologic basis and heterogeneity of hypertension. This may explain the relatively poor hypertension control rates. A proposed approach is to guide addition and subtraction of medications using ambulatory plasma renin activity (PRA) values. To evaluate the heterogeneity of hypertension and the medication burden associated with it, we investigated medication usage in relation to PRA among hypertensive patients within a large ethnically diverse organization. METHODS: A cross sectional data analysis was performed of hypertensive subjects with PRA measurements in the Kaiser Permanente Southern California database between 1 January 1998 and 31 October 2009. RESULTS: Among 7,887 such patients 0, 1, 2, ≥3 medication usage was 16%, 20%, 24%, 40% respectively. PRA levels ranged 1000-fold. Across PRA quartiles (Q1 to Q4) ≥3 meds were prescribed to 50%, 40%, 34%, 37%. From low to high PRA quartiles there was no usage trend for angiotensin converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (71%), but diuretics increased (52%, 53%, 57%, 68%), calcium channel blocker's (CCB) fell (56%, 53%, 51%, 42%), and ß-blockers fell (77%, 61%, 49%, 41%). Moreover, systolic BP fell (146, 142, 140, 135 mm Hg), blood urea nitrogen (BUN) rose (16, 17, 18, 20 mg/dl), serum uric acid rose (6.1, 6.3, 6.5, 6.9 mg/dl), and chronic kidney disease rose (22%, 22%, 23%, 27%). CONCLUSIONS: Polytherapy was the norm for treating hypertension. Lower PRAs were associated with higher blood pressures and more medications. Higher PRAs were associated with lower pressures and fewer medications. The results indicate that opportunities exist to simplify antihypertensive therapy by using current ambulatory PRA levels to guide drug selections and subtractions.

25-hydroxyvitamin D levels and hypertension rates.

Vitamin D deficiency has been linked to cardiovascular disease and risk factors including hypertension. The authors sought to determine prevalence rates of hypertension in adults tested for 25-hydroxyvitamin D categorized by their levels and evaluate odds ratios for hypertension at lower 25-hydroxyvitamin D levels compared with optimal levels. A cross-sectional study was conducted January 1, 2004, through December 31, 2006, of patients aged 18 years and older within a large ethnically diverse population. Diagnosis of hypertension was determined by International Statistical Classification of Diseases and Related Health Problems codes. Patients were categorized into quartiles according to 25-hydroxyvitamin D levels: ideal (≥40 ng/mL), adequate (30-39 ng/mL), deficient (15-29 ng/mL), and severely deficient (<15 ng/mL). Prevalence rates of hypertension and odds ratios were calculated for each 25-hydroxyvitamin D quartile, adjusting for age, sex, race, and renal insufficiency. A total of 2722 individuals met the inclusion criteria for the study. The overall prevalence of hypertension in the study population was 24%. Hypertension rates were 52%, 41%, 27%, and 20% in 25-hydroxyvitamin D quartiles <15 ng/mL, 15 to 29 ng/mL, 30 to 39 ng/mL, and ≥40 ng/mL, respectively (P<.001). Odds ratios (95% confidence intervals) for hypertension adjusting for age, sex, race, and renal insufficiency were 2.7 (1.4-5.2), 2.0 (1.5-2.6), and 1.3 (1.2-1.6) for 25-hydroxyvitamin D levels <15 ng/mL, 15 to 29 ng/mL, and 30 to 39 ng/mL, respectively, compared with the ≥40 ng/mL group. This study demonstrates increased rates of hypertension in individuals who tested for lower levels of 25-hydroxyvitamin D starting at levels <40 ng/mL. This retrospective analysis raises the question of whether supplementing to optimal vitamin D levels can prevent or improve hypertension.