Implication of Trends in Timing of Dialysis Initiation for Incidence of End-stage Kidney Disease.

Importance: In the last 2 decades, there have been notable changes in the level of estimated glomerular filtration rate (eGFR) at which patients initiate long-term dialysis in the US and around the world. How changes over time in the likelihood of dialysis initiation at any given eGFR level in at-risk patients are associated with the population burden of end-stage kidney disease (ESKD) has not been not well defined. Objective: To examine temporal trends in long-term dialysis initiation by level of eGFR and to quantify how these patterns are associated with the number of patients with ESKD. Design, Setting, and Participants: Retrospective cohort study analyzing data obtained from a large, integrated health care delivery system in Northern California from 2001 to 2018 in successive 3-year intervals. Included individuals, ranging in number from as few as 983 122 (2001-2003) to as many as 1 844 317 (2016-2018), were adult members with 1 or more outpatient serum creatinine levels determined in the prior year. Main Outcomes and Measures: One-year risk of initiating long-term dialysis stratified by eGFR levels. Multivariable logistic regression was performed to assess temporal trends in each 3-year cohort with adjustment for age, sex, race, and diabetes status. The potential change in dialysis initiation in the final cohort (2016-2018) was estimated using the relative difference between the standardized risks in the initial cohort (2001-2003) and the final cohort. Results: In the initial 3-year cohort, the mean (SD) age was 55.4 (16.3) years, 55.0% were women, and the prevalence of diabetes was 14.9%. These characteristics, as well as the distribution of index eGFR, were stable across the study period. The likelihood of receiving dialysis at eGFR levels of 10 to 24 mL/min/1.73 m2 generally increased over time. For example, the 1-year odds of initiating dialysis increased for every 3-year interval by 5.2% (adjusted odds ratio, 1.052; 95% CI, 1.004-1.102) among adults with an index eGFR of 20 to 24 mL/min/1.73 m2, by 6.6% (adjusted odds ratio, 1.066; 95% CI, 1.007-1.130) among adults with an eGFR of 16 to 17 mL/min/1.73 m2, and by 5.3% (adjusted odds ratio, 1.053; 95% CI, 1.008-1.100) among adults with an eGFR of 10 to 13 mL/min/1.73 m2, adjusting for age, sex, race, and diabetes. The incidence of new cases of ESKD was estimated to have potentially been 16% (95% CI, 13%-18%) lower if there were no changes in system-level practice patterns or other factors besides timing of initiating long-term dialysis from the initial 3-year interval (2001-2003) to the final interval (2016-2018) assessed in this study. Conclusions and Relevance: The present results underscore the importance the timing of initiating long-term dialysis has on the size of the population of individuals with ESKD.

Research-based versus clinical serum creatinine measurements and the association of acute kidney injury with subsequent kidney function: findings from the Chronic Renal Insufficiency Cohort study.

BACKGROUND: Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. METHODS: We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. RESULTS: During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73 m2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73 m2/year), which was not impacted by source of serum creatinine. CONCLUSIONS: AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria.

Renin-Angiotensin System Blockade after Acute Kidney Injury (AKI) and Risk of Recurrent AKI.

BACKGROUND AND OBJECTIVES: How to best medically manage patients who survived hospitalized AKI is unclear. Use of renin-angiotensin system blockers in this setting may increase risk of recurrent AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a cohort study of 10,242 members of an integrated health care delivery system in Northern California who experienced AKI and survived a hospitalization between January 1, 2006 and December 31, 2013. All study participants did not have prior heart failure or use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) up to 5 years prior. New receipt and time-updated exposure of ACE-Is/ARBs was identified on the basis of dispensed prescriptions found in outpatient health plan pharmacy databases. The main outcome of interest was subsequent episode of hospitalized AKI after discharge from an initial index hospitalization complicated by AKI. Recurrent AKI episode was defined using acute changes in serum creatinine concentrations. Marginal structural models were used to adjust for baseline and potential time-dependent confounders. RESULTS: Forty-seven percent of the study population had a documented eGFR<60 ml/min per 1.73 m2 or documented proteinuria before hospitalization. With a median of 3 (interquartile range, 1-5) years of follow-up, 1853 (18%) patients initiated use of ACE-Is/ARBs and 2124 (21%) patients experienced recurrent AKI. Crude rate of recurrent AKI was 6.1 (95% confidence interval [95% CI], 5.9 to 6.4) per 100 person-years off ACE-Is/ARBs and 5.7 (95% CI, 4.9 to 6.5) per 100 person-years on ACE-Is/ARBs. In marginal structural causal inference models that adjusted for baseline and potential time-dependent confounders, exposure to ACE-I/ARB use was not associated with higher incidence of recurrent AKI (adjusted odds ratio, 0.71; 95% CI, 0.45 to 1.12). CONCLUSIONS: In this study of AKI survivors without heart failure, new use of ACE-I/ARB therapy was not independently associated with increased risk of recurrent hospitalized AKI.

Elevated BP after AKI.

The connection between AKI and BP elevation is unclear. We conducted a retrospective cohort study to evaluate whether AKI in the hospital is independently associated with BP elevation during the first 2 years after discharge among previously normotensive adults. We studied adult members of Kaiser Permanente Northern California, a large integrated health care delivery system, who were hospitalized between 2008 and 2011, had available preadmission serum creatinine and BP measures, and were not known to be hypertensive or have BP>140/90 mmHg. Among 43,611 eligible patients, 2451 experienced AKI defined using observed changes in serum creatinine concentration measured during hospitalization. Survivors of AKI were more likely than those without AKI to have elevated BP--defined as documented BP>140/90 mmHg measured during an ambulatory, nonemergency department visit--during follow-up (46.1% versus 41.2% at 730 days; P<0.001). This difference was evident within the first 180 days (30.6% versus 23.1%; P<0.001). In multivariable models, AKI was independently associated with a 22% (95% confidence interval, 12% to 33%) increase in the odds of developing elevated BP during follow-up, with higher adjusted odds with more severe AKI. Results were similar in sensitivity analyses when elevated BP was defined as having at least two BP readings of >140/90 mmHg or those with evidence of CKD were excluded. We conclude that AKI is an independent risk factor for subsequent development of elevated BP. Preventing AKI during a hospitalization may have clinical and public health benefits beyond the immediate hospitalization.

Relationship of urine dopamine with phosphorus homeostasis in humans: the heart and soul study.

BACKGROUND: Urine dopamine (DA) is produced in the proximal tubule and has been found to increase in response to dietary phosphorus intake, and to contribute to greater urinary phosphorus excretion in animal models. Whether urine DA is associated with phosphorus homeostasis in humans is uncertain. METHODS: This was a cross-sectional study of 884 outpatients. DA was measured from 24-hour urine collections. We examined cross-sectional associations between urine DA and serum phosphorus, 24-hour urine phosphorus (as an indicator of dietary phosphorus absorption), fractional excretion of phosphorus (FEphos), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). Models were adjusted for age, sex, race, eGFR, albuminuria, hypertension, heart failure, tobacco use, body mass index, and diuretic use. RESULTS: Mean age was 66.6 ± 11 years and mean eGFR was 71 ± 21.3 ml/min/1.73 m(2). The mean urine DA was 193 ± 86 µg/day, mean serum phosphorus was 3.6 ± 0.6 mg/dl, mean daily urine phosphorus excretion was 671 ± 312 mg/day, and mean FEphos was 17 ± 9%. In adjusted models, each standard deviation higher DA was associated with 78.4 mg/day higher urine phosphorus and 0.9% lower FEphos (p < 0.05 for both). There was no statistically significant association between urine DA, serum phosphorus, FGF-23 or PTH in adjusted models. CONCLUSIONS: Higher dietary phosphorus absorption is associated with higher urine DA in humans, consistent with animal models. However, higher urine DA is not associated with FGF-23 or PTH, suggesting that known mechanisms of renal tubular handling of phosphorus may not be involved in the renal dopamine-phosphorus regulatory pathway in humans.

Proteinuria and reduced glomerular filtration rate as risk factors for acute kidney injury.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is a major public health concern, and preexisting kidney disease may be one of the most important risk factors. We review recent epidemiologic evidence supporting baseline proteinuria and reduced glomerular filtration rate as risk factors for AKI. RECENT FINDINGS: In 2008, a case-control study of over 600 000 patients in an integrated healthcare system in California first quantified a graded association between reduced baseline estimated glomerular filtration rate (eGFR) and risk of dialysis-requiring AKI; it also showed proteinuria as an independent predictor for AKI. In 2010, a cohort study consisting of 1235 adults undergoing coronary artery bypass graft in Taiwan demonstrated that mild and heavy degrees of proteinuria detected by dipstick were associated with increasingly higher odds ratio of postoperative AKI, independent of chronic kidney disease stage. A US cohort study in 2010 of over 11 000 patients determined that elevated urine albumin-to-creatinine ratio (UACR) was an independent risk factor for hospitalizations with AKI; this association started with the submicroalbuminuric range (UACR 11-29 mg/g) and increased stepwise along severity of albuminuria, after adjustment for eGFR. A cohort study in 2010 of over 900 000 adults in Alberta demonstrated increased rates of hospital admissions with AKI for patients with mild and moderate dipstick proteinuria across all values of eGFR. SUMMARY: The presence of baseline proteinuria and reduced baseline eGFR are powerful independent predictors for AKI and should be taken into account in clinical practice to identify high-risk patients for receipt of aggressive preventive measures to reduce risk of AKI.

Nonrecovery of kidney function and death after acute on chronic renal failure.

BACKGROUND AND OBJECTIVES: Relatively little is known about clinical outcomes, especially long-term outcomes, among patients who have chronic kidney disease (CKD) and experience superimposed acute renal failure (ARF; acute on chronic renal failure). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tracked 39,805 members of an integrated health care delivery system in northern California who were hospitalized during 1996 through 2003 and had prehospitalization estimated GFR (eGFR) <45 ml/min per 1.73 m(2). Superimposed ARF was defined as having both a peak inpatient serum creatinine greater than the last outpatient serum creatinine by > or =50% and receipt of acute dialysis. RESULTS: Overall, 26% of CKD patients who suffered superimposed ARF died during the index hospitalization. There was a high risk for developing ESRD within 30 d of hospital discharge that varied with preadmission renal function, being 42% among hospital survivors with baseline eGFR 30-44 ml/min per 1.73 m(2) and 63% among hospital survivors with baseline eGFR 15-29 ml/min per 1.73 m(2). Compared with patients who had CKD and did not experience superimposed ARF, those who did had a 30% higher long-term risk for death or ESRD. CONCLUSIONS: In a large, community-based cohort of patients with CKD, an episode of superimposed dialysis-requiring ARF was associated with very high risk for nonrecovery of renal function. Dialysis-requiring ARF also seemed to be an independent risk factor for long-term risk for death or ESRD.

Risk factors for end-stage renal disease: 25-year follow-up.

BACKGROUND: Few cohort studies have focused on risk factors for end-stage renal disease (ESRD). This investigation evaluated the prognostic value of several potential novel risk factors for ESRD after considering established risk factors. METHODS: We studied 177 570 individuals from a large integrated health care delivery system in northern California who volunteered for health checkups between June 1, 1964, and August 31, 1973. Initiation of ESRD treatment was ascertained using US Renal Data System registry data through December 31, 2000. RESULTS: A total of 842 cases of ESRD were observed during 5 275 957 person-years of follow-up. This comprehensive evaluation confirmed the importance of established risk factors, including the following: male sex, older age, proteinuria, diabetes mellitus, lower educational attainment, and African American race, as well as higher blood pressure, body mass index, and serum creatinine level. The 2 most potent risk factors were proteinuria and excess weight. For proteinuria, the adjusted hazard ratios (HRs) were 7.90 (95% confidence interval [CI], 5.35-11.67) for 3 to 4+ on urine dipstick, 3.59 (2.82-4.57) for 1 to 2+ on urine dipstick, and 2.37 (1.79-3.14) for trace vs negative on urine dipstick. For excess weight, the HRs were 4.39 (95% CI, 3.38-5.70) for class 2 to class 3 obesity, 3.11 (2.51-3.84) for class 1 obesity, and 1.65 (1.39-1.97) for overweight vs normal weight. Furthermore, several independent novel risk factors for ESRD were identified, including lower hemoglobin level (1.33 [1.08-1.63] for lowest vs highest quartile), higher serum uric acid level (2.14 [1.65-2.77] for highest vs lowest quartile), self-reported history of nocturia (1.36 [1.17-1.58]), and family history of kidney disease (HR, 1.40 [95% CI, 1.02-1.90]). CONCLUSIONS: We confirmed the importance of established ESRD risk factors in this large cohort with broad sex and racial/ethnic representation. Lower hemoglobin level, higher serum uric acid level, self-reported history of nocturia, and family history of kidney disease are independent risk factors for ESRD.

Higher serum creatinine concentrations in black patients with chronic kidney disease: beyond nutritional status and body composition.

BACKGROUND AND OBJECTIVES: Serum creatinine concentrations tend to be higher in black than white individuals and people of other races or ethnicities. These differences have been assumed to be largely related to race-related differences in body composition, especially muscle mass. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a diverse population of hemodialysis patients, we compared mean serum creatinine concentrations in black versus nonblack patients, adjusting for case mix (age, gender, diabetes, and dialysis vintage), body size (height, weight), laboratory parameters of nutritional status (albumin, predialysis blood urea nitrogen, transferrin, phosphorus, glucose), dialysis dosage (urea reduction ratio), and parameters of bioelectrical impedance (resistance and reactance), proxies for body composition. RESULTS: Adjusted mean serum creatinine concentrations were significantly higher in black versus nonblack patients (11.7 versus 10.0 mg/dl; P < 0.0001). Black patients were roughly four-fold more likely to have a serum creatinine concentration >10 mg/dl and six-fold more likely to have a serum creatinine concentration >15 mg/dl. Higher serum creatinine concentrations were associated with a lower relative risk for death (0.93; 95% confidence interval 0.88 to 0.98 per mg/dl); the association was slightly more pronounced among nonblack patients. CONCLUSIONS: Serum creatinine concentrations are significantly higher in black compared with nonblack hemodialysis patients; these differences are not readily explained by differences in nutritional status or body composition.

Body mass index and risk for end-stage renal disease.

BACKGROUND: Although interest in the relationship between obesity and kidney disease is increasing, few epidemiologic studies have examined whether excess weight is an independent risk factor for end-stage renal disease (ESRD). OBJECTIVE: To determine the association between increased body mass index (BMI) and risk for ESRD. DESIGN: Historical (nonconcurrent) cohort study. SETTING: A large integrated health care delivery system in northern California. PARTICIPANTS: 320,252 adult members of Kaiser Permanente who volunteered for screening health checkups between 1964 and 1985 and who had height and weight measured. MEASUREMENTS: The authors ascertained ESRD cases by matching data with the U.S. Renal Data System registry through 2000. RESULTS: A total of 1471 cases of ESRD occurred during 8,347,955 person-years of follow-up. Higher BMI was a risk factor for ESRD in multivariable models that adjusted for age, sex, race, education level, smoking status, history of myocardial infarction, serum cholesterol level, urinalysis proteinuria, urinalysis hematuria, and serum creatinine level. Compared with persons who had normal weight (BMI, 18.5 to 24.9 kg/m2), the adjusted relative risk for ESRD was 1.87 (95% CI, 1.64 to 2.14) for those who were overweight (BMI, 25.0 to 29.9 kg/m2), 3.57 (CI, 3.05 to 4.18) for those with class I obesity (BMI, 30.0 to 34.9 kg/m2), 6.12 (CI, 4.97 to 7.54) for those with class II obesity (BMI, 35.0 to 39.9 kg/m2), and 7.07 (CI, 5.37 to 9.31) for those with extreme obesity (BMI > or = 40 kg/m2). Higher baseline BMI remained an independent predictor for ESRD after additional adjustments for baseline blood pressure level and presence or absence of diabetes mellitus. LIMITATIONS: Primary analyses were based on single measurements of exposures. CONCLUSIONS: High BMI is a common, strong, and potentially modifiable risk factor for ESRD.

Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease.

BACKGROUND: Many cases of end-stage renal disease (ESRD) are ascribed to hypertension. However, because renal disease itself can raise blood pressure, some investigators argue that ESRD seen in patients with hypertension is due to underlying primary renal disease. Previous cohort studies of the relationship between blood pressure and ESRD did not uniformly screen out baseline kidney disease. METHODS: We conducted a historical cohort study among members of Kaiser Permanente of Northern California, a large integrated health care delivery system. The ESRD cases were ascertained by matching with the US Renal Data System registry. RESULTS: A total of 316 675 adult Kaiser members participated in the Multiphasic Health Checkups from 1964 to 1985. All subjects had estimated glomerular filtration rates of 60 mL /min per 1.73 m(2) or higher and negative dipstick urinalysis results for proteinuria or hematuria. During 8 210 431 person-years of follow-up, 1149 cases of ESRD occurred. Compared with subjects with a blood pressure less than 120/80 mm Hg, the adjusted relative risks for developing ESRD were 1.62 (95% confidence interval [CI], 1.27-2.07) for blood pressures of 120 to 129/80 to 84 mm Hg, 1.98 (95% CI, 1.55-2.52) for blood pressures of 130 to 139/85 to 89 mm Hg, 2.59 (95% CI, 2.07-3.25) for blood pressures of 140 to 159/90 to 99 mm Hg, 3.86 (95% CI, 3.00-4.96) for blood pressures of 160 to 179/100 to 109 mm Hg, 3.88 (95% CI, 2.82-5.34) for blood pressures of 180 to 209/110 to 119 mm Hg, and 4.25 (95% CI, 2.63-6.86) for blood pressures of 210/120 mm Hg or higher. Similar associations between blood pressure level and ESRD risk were seen in all subgroup analyses. CONCLUSIONS: Even relatively modest elevation in blood pressure is an independent risk factor for ESRD. The observed relationship does not appear to be due to confounding by clinically evident baseline kidney disease.

Factors associated with future amputation among patients undergoing hemodialysis: results from the Dialysis Morbidity and Mortality Study Waves 3 and 4.

BACKGROUND: Amputation is more common in hemodialysis patients than in the general population, but risk factors for amputation in this population have not been studied extensively. METHODS: We used the US Renal Data System Dialysis Morbidity and Mortality Study Waves 3 and 4 in combination with Medicare discharge data to identify factors associated with lower-extremity amputation (excluding toe amputations) in hemodialysis patients. We used stepwise multivariable logistic regression analysis to identify variables most strongly associated with amputation within 2 years of the study start date. RESULTS: Male sex, diabetes, previous diagnosis of peripheral vascular disease (PVD), mean systolic blood pressure, and elevated serum phosphorus level were associated with the outcome of amputation within 2 years of the study start date. Among patients without diabetes, a previous diagnosis of cardiac disease, longer time from initiation of dialysis therapy (vintage), and previous hospitalization for limb ischemia were associated with increased risk for future amputation. CONCLUSION: The importance of preventing amputation in this population cannot be overemphasized. The strength of the association of amputation with PVD makes a strong case for screening all dialysis patients for this disease. The association of amputation with serum phosphorus level reported here should be explored further because this may offer an avenue for future intervention to reduce amputation rates.

Elevations of serum phosphorus and potassium in mild to moderate chronic renal insufficiency.

BACKGROUND: Reduced renal function is associated with a variety of biochemical abnormalities. However, the extent of these changes and their magnitude in relation to renal function is not well defined, especially among individuals with mild to moderate chronic renal insufficiency (CRI). METHODS: We analysed the Third National Health and Nutrition Examination Survey (NHANES III; 1988-1994) data for 14722 adults aged >/=17 years with measurements of serum creatinine and all electrolytes including ionized calcium. General linear models were used to determine the relationship between mean concentrations of electrolytes and different levels of Cockcroft-Gault creatinine clearance (CrCl). Sample weights were used to produce weighted regression parameters. RESULTS: Changes in mean serum phosphorus and potassium concentration were evident at relatively modest reductions in CrCl (around 50 to 60 ml/min). Changes in the anion gap and mean levels of ionized calcium and bicarbonate were not apparent until CRI was advanced (CrCl 80 ml/min, those with CrCl 60-50, 50-40, 40-30, 30-20 and