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Rationale and Objective
Patients with a high-risk Apolipoprotein L1 (APOL1) genotype are more likely to develop chronic kidney disease and end-state kidney disease (ESKD). However, it is unclear whether this increased risk is entirely due to the eventual development of proteinuria.
Study Design
Retrospective observational study of the AASK and CRIC cohorts.
Exposures and Predictors
Self-identified race (Black/non-Black) and presence of high-risk APOL1 genotype. The primary model was adjusted for age, gender, estimated glomerular filtration rate, and urine protein to creatinine ratio.
Outcomes
Time to ESKD defined as years to dialysis or transplantation. 
Analytical Approach
We used Cox proportional hazard models to study how proteinuria mediates the association between APOL1 and ESKD. We modeled proteinuria at baseline and as a time varying covariate. 
Results
A high-risk APOL1 genotype was associated with a significantly higher risk of ESKD, even for patients with minimal proteinuria (HR: 1.87; 95% CI [1.23. 2.84]). The association was not significant among patients with high proteinuria (HR: 1.22, 95% CI [0.93, 1.61]). When modeling proteinuria as a time varying covariate, a high-risk APOL1 genotype was associated with higher ESKD risk even among patients who never developed proteinuria (HR: 2.04, 95% CI: [1.10, 3.77]). Compared to non-Black patients, Black patients without the high-risk genotype did not have higher risk of ESKD (HR: 0.96, 95% CI: [0.85, 1.10]).
Limitations
Two datasets were combined to increase statistical power. Limited generalizability beyond the study cohorts. Residual confounding common to observational studies.
Conclusions
A high-risk APOL1 genotype is significantly associated with increased ESKD risk, especially among patients without baseline proteinuria. Although our results suggest that the risk is partially mediated through proteinuria, higher ESKD risk was present even among patients who never developed proteinuria. Providers should consider screening for the high-risk APOL1 genotype, especially among Black patients without proteinuria in populations with CKD.


APOL1 Genotype, Proteinuria, and the Risk of Kidney Failure: A Secondary Analysis of the AASK and CRIC Studies

Rationale and Objective:  Acute declines in glomerular filtration rate (GFR) occur commonly during intensive BP lowering.  Our objective was to determine the relation between acute declines in estimated GFR and patient outcomes.
Study Design, Setting, and Participants:  Participants from four randomized controlled trials of intensive BP lowering with CKD (MDRD, AASK, SPRINT, and ACCORD).
Exposure:  Acute declines in estimated GFR (defined as a >15% versus <15% decline in eGFR between baseline and month 4).
Outcomes:  Risk of kidney replacement therapy (KRT, primary outcome).   KRT was defined as need for dialysis or transplant except in the ACCORD trial, where the trial-defined kidney outcome of a composite occurrence of serum creatinine >3.3 mg/dl, kidney failure, or KRT was used.  
Approach:  Multivariable Cox models.
Results:   We included 4,465 individuals randomly assigned to intensive versus usual BP control who had a total of 350 kidney outcomes and 304 deaths over median follow-up of 21 and 24 months, respectively.  Approximately 15% of participants exhibited an acute decline in eGFR; 11.0% in the usual and 17.7% in the intensive BP treatment arm.  In adjusted models, compared to a ?15% decline in the usual BP arm, a ?15% decline in the intensive BP control arm was associated with lower risk of the kidney outcome (0.73; 95% CI 0.56-0.96).  In contrast, a >15% decline in eGFR was associated with higher risk of the kidney outcome in both the usual (HR 2.48; 95% CI 1.81-3.40) and intensive BP treatment arms (HR 2.04; 95% 1.48-2.81) compared with a ?15% decline in the usual BP arm. 
Limitations:  Observational study, residual confounding.
Conclusions:  Declines in eGFR >15% in both the usual and intensive BP treatment arms were associated with higher risk of kidney outcomes in comparison with a ?15% decline in the usual BP arm and may be a harbinger of adverse outcomes.


Acute Declines in Estimated GFR in Blood Pressure Target Trials and Risk of Adverse Outcomes

Background. Creatinine-based equations are the most used to estimate glomerular filtration rate (eGFR). The Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI), the re-expressed Lund-Malmö Revised (r-LMR) and the European
Kidney Function Consortium (EKFC) equations are the most validated. The EKFC and r-LMR equations have been
suggested to have better performances in young adults, but this is debated.
Methods. We collected data (GFR) measured by clearance of an exogenous marker (reference method), serum creatinine,
age and sex from 2366 young adults (aged between 18 and 25 years) both from Europe and the USA.
Results. In the European cohorts (n = 1892), the bias (in mL/min/1.73 m²) was systematically better for the EKFC and
r-LMR equations compared with the CKD-EPI equation [2.28, 95% confidence interval (1.59; 2.91), –2.50 (–3.85; –1.76), 17.41
(16.49; 18.47), respectively]. The percentage of estimated GFR within 30% of measured GFR (P30) was also better for EKFC
and r-LMR equations compared with the CKD-EPI equation [84.4% (82.8; 86.0), 87.2% (85.7; 88.7) and 65.4% (63.3; 67.6),
respectively]. In the US cohorts (n = 474), the bias for the EKFC and r-LMR equations was better than for the CKD-EPI
equation in the non-Black population [0.97 (–1.69; 3.06), –2.62 (–5.14; –1.43) and 7.74 (5.97; 9.63), respectively], whereas the
bias was similar in Black US individuals. P30 results were not different between the three equations in US cohorts.
Analyses in sub-populations confirmed these results, except in individuals with high GFR levels (GFR ≥120 mL/min/1.73
m²) for whom the CKD-EPI equation might have a lower bias.
Conclusions. We demonstrated that both the EKFC and r-LMR creatinine-based equations have a better performance
than the CKD-EPI equation in a young population. The only exception might be in patients with hyperfiltration.

Estimating glomerular filtration in young people

Background:  The effect of intensive blood pressure (BP) lowering on the risk of kidney replacement therapy (KRT) remains unclear in patients with advanced kidney disease who were not well-represented in trials evaluating intensive BP control.   
Methods:  We pooled individual-level data from seven trials that included patients with eGFR<60 mL/min/1.73 m2 to examine the effect of intensive BP lowering on the risk of KRT, or when not possible, trial-defined kidney outcomes.  We performed pre-specified subgroup analyses to evaluate the effect of intensive BP control by baseline albuminuria and eGFR (CKD stage 4-5 versus 3).  
Results:  We included 5823 trial participants, of whom 526 developed the kidney outcome and 382 died.  Overall, intensive (versus usual) BP control was associated with a lower risk of the kidney outcome (HR 0.87 [95% CI 0.74-1.04]) and death (HR 0.87 [95% CI 0.71-1.06]) in unadjusted analysis which did not achieve statistical significance.  However, there was heterogeneity in the effect of the intervention on the kidney outcome by baseline GFR (pinteraction=0.05).  By intention to treat, intensive (versus usual) BP control was associated with lower risk of the primary kidney outcome in those with CKD GFR stage 4-5 (HR 0.80 [95% CI 0.65-0.98]) but not in CKD GFR stage 3 (HR 1.08 [95% CI 0.79-1.48]).  There was no interaction between intensive BP control and severity of albuminuria for kidney outcomes (p=0.32).  
Conclusion:  In patients with CKD, intensive BP control was associated with a reduction in the risk of kidney outcomes, especially in the setting of stage 4-5 disease.  These findings suggest the safety of and need to conduct future trials of BP targets focused on populations with advanced kidney disease.


Intensive blood pressure control in patients with chronic kidney disease and risk for adverse outcomes

The new creatinine-based European Kidney Function Consortium (EKFC) is used to estimate glomerular filtration rate (GFR). This equation has been developed and validated mainly in European subjects. This equation is based on rescaled creatinine, with the rescaling factor (Q-value) defined as the median normal value of serum creatinine in a given population. The validation was limited in Black and non-Black Americans. In this cross-sectional analysis, we included 12,854 participants from 9 studies with measured GFR by clearance of an exogenous marker (reference method), serum creatinine, age, sex, and self-reported race available. Two strategies were considered with population specific Q-values in Black and non-Black men and women (EKFCPS) or a race-free Q value (EKFCRF). In the whole population, only the EKFCPS equation showed no statistical bias (0.14 95%CI[-0.07;0.35] mL/min/1.73m²), and the statistical bias of the EKFCRF (0.74 95%CI[0.51;0.94] mL/min/1.73m²) was closer to zero than that of the CKD-EPI2021 equation (1.22 95%CI[0.99;1.47]) mL/min/1.73m²]. The percentage of estimated GFR within 30% of measured GFR was similar for CKD-EPI2021 (79.2% [78.5%-79.9%]) and EKFCRF (80.1% [79.4%-80.7%]), but improved with the EKFCPS equation (81.1% [80.5%-81.8%]). The EKFC-equation can be used to estimate GFR in the USA incorporating either self-reported race or unknown race at the patient’s discretion per hospital registration records.

Performance of the European Kidney Function Consortium (EKFC) creatinine-based equation in American cohorts

Estimating glomerular filtration rate (GFR) is important in daily practice to assess kidney function and adapting the best clinical care of patients with and without chronic kidney disease. The new creatinine-based European Kidney Function Consortium (EKFC) equation is used to estimate GFR. This equation was developed and validated mainly in European individuals and based on a rescaled creatinine, with the rescaling factor (Q-value) defined as the median normal value of serum creatinine in a given population. The validation was limited in Non-Black Americans and absent in Black Americans. Here, our cross-sectional analysis included 12,854 participants from nine studies encompassing large numbers of both non-Black and Black Americans with measured GFR by clearance of an exogenous marker (reference method), serum creatinine, age, sex, and self-reported race available. Two strategies were considered with population-specific Q-values in Black and non-Black men and women (EKFCPS) or a race-free Q-value (EKFCRF). In the whole population, only the EKFCPS equation showed no statistical median bias (0.14, 95% confidence interval [-0.07; 0.35] mL/min/1.73m2), and the bias for the EKFCRF (0.74, [0.51; 0.94] mL/min/1.73m2) was closer to zero than that for the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI2021) equation (1.22, [0.99; 1.47]) mL/min/1.73m2]. The percentage of estimated GFR within 30% of measured GFR was similar for CKD-EPI2021 (79.2% [78.5%; 79.9%]) and EKFCRF (80.1% [79.4%; 80.7%]), but improved for the EKFCPS equation (81.1% [80.5%; 81.8%]). Thus, our EKFC equations can be used to estimate GFR in the United States incorporating either self-reported race or unknown race at the patient's discretion per hospital registration records.

Performance of the European Kidney Function Consortium (EKFC) creatinine-based equation in United States cohorts.

Background: Differences in performance of estimating glomerular filtration rate (eGFR) equations 
have been attributed to the mathematical form of the equations and to differences between patient 
demographics and measurement methods. We evaluated differences in serum creatinine (SCr) and 
eGFR in cohorts matching for age, sex, BMI and measured GFR (mGFR).
Methods: White North Americans from Minnesota (n=1093) and the Chronic Renal Insufficiency 
Cohort (CRIC) (n=1548), and White subjects from the European Kidney Function Consortium (EKFC)
cohort (n=7727), were matched for demographic patient characteristics (equal sex, age±3 years, 
BMI±2.5kg/m²) and renal function (measured GFR±3mL/min/1.73m²). SCr was measured with 
isotope dilution mass spectrometry (IDMS) traceable assays in Minnesota and EKFC and with nonstandardized SCr-assays recalculated to IDMS in CRIC. Minnesota and CRIC shared the common 
method to measure GFR (renal clearance of iothalamate) while EKFC used a variety of exogenous 
markers and methods, all with recognized sufficient accuracy. We compared the SCr-levels and eGFRpredictions (for CKD-EPI and EKFC-equations) of patients fulfilling these matching criteria.
Results: For 305 matched individuals, mean SCr was not different between Minnesota and EKFC
0.83±0.20 vs 0.86±0.23, females and 1.06±0.23 vs 1.12±0.37, males (p>0.05), but significantly 
different from CRIC (1.13±0.23 (p<0.0001), females and 1.42±0.31 (p<0.0001), males). CKD-EPIequations performed better than the EKFC-equation in the CRIC-cohort, while the opposite was true 
in the Minnesota and EKFC-cohort.
Conclusion: Significant differences in SCr-concentrations between Minnesota/EKFC versus CRIC were 
observed in subjects with the same level of mGFR and equal demographic characteristics and can be 
explained by the difference in SCr-calibration. 

Standardization of serum creatinine is essential for accurate use of unbiased estimating GFR equations. Evidence from three cohorts matched on renal function.

Title	PMID	PMCID	Public Release Type	Publication Year	DOI	Study Acronym	Request ID(s)	Public Release Origin
APOL1 Genotype, Proteinuria, and the Risk of Kidney Failure: A Secondary Analysis of the AASK and CRIC Studies	36479469		Journal	2022	10.1016/j.xkme.2022.100563	AASK Trial, AASK Cohort, CRIC	22088, 22550	Secondary Research
Acute Declines in Estimated GFR in Blood Pressure Target Trials and Risk of Adverse Outcomes	37269972		Journal	2023	10.1053/j.ajkd.2023.03.013	AASK Trial, MDRD, AASK Cohort	4528	Secondary Research
Estimating glomerular filtration in young people	39314869		Journal	2024	10.1093/ckj/sfae261	AASK Trial, AASK Cohort, CRIC	23401	Contributing Study
Intensive blood pressure control in patients with chronic kidney disease and risk for adverse outcomes			Journal	2023		AASK Trial, MDRD, AASK Cohort	4528	Secondary Research
Performance of the European Kidney Function Consortium (EKFC) creatinine-based equation in American cohorts	38101514		Journal	2023	10.1016/j.kint.2023.11.024	MDRD, DCCT/EDIC, AASK Trial, PERL, CRISP, ALTOLD, CRIC, AASK Cohort	23649	Secondary Research
Performance of the European Kidney Function Consortium (EKFC) creatinine-based equation in United States cohorts.	38101514		Journal	2024	10.1016/j.kint.2023.11.024	AASK Trial, AASK Cohort, CRIC	23401	Contributing Study
Standardization of serum creatinine is essential for accurate use of unbiased estimating GFR equations. Evidence from three cohorts matched on renal function.	36381377	PMC9664577	Journal	2022	10.1093/ckj/sfac182	AASK Trial, CRIC, AASK Cohort	23401	Secondary Research
The retention of rhythmic components in blood pressure: a novel prognostic indicator in chronic kidney disease			Conference Presentation	2022		AASK Trial, AASK Cohort	22857	Secondary Research

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