Significance statement Racial and ethnic disparities in clinical trial enrollment are well described. However, whether these disparities are present in nephrology randomized clinical trials has not been previously reported. We performed a systematic review and meta-analysis of 380 randomized clinical trials involving different aspects of kidney disease published between 2000 and 2021. Our results indicate that worldwide reporting of race and ethnicity is poor and that White individuals account for most of the randomized participants with decreased enrollment of Black participants in more recent trials. However, trials conducted in the United States have representation of Black and Hispanic participants consistent with the population prevalence of disease and under-representation of Asian participants. Background Under-representation of racial and ethnic minorities in clinical trials could worsen disparities, but reporting and enrollment practices in nephrology randomized clinical trials have not been described. Methods PubMed was searched to capture randomized clinical trials for five kidney disease–related conditions published between 2000 and 2021 in ten high-impact journals. We excluded trials with <50 participants and pilot trials. Outcomes of interest were the proportion of trials reporting race and ethnicity and the proportions of enrolled participants in each race and ethnicity category. Results Among 380 trials worldwide, race was reported in just over half and ethnicity in 12%. Most enrolled participants were White, and Black individuals accounted for ≤10% of participants except in dialysis trials where they accounted for 26% of participants. However, Black participants were enrolled at high proportions relative to disease and population prevalence in US CKD, dialysis, and transplant trials representing 19% of participants in AKI, 26% in CKD, 44% in GN, 40% in dialysis, and 26% in transplant trials. Enrollment of Asian participants was low worldwide except in GN trials with marked under-representation in US CKD, dialysis, and transplant trials. Hispanic individuals represented only 13% of participants in US dialysis trials compared with 29% of US dialysis population. Conclusion More complete reporting of race and ethnicity in nephrology trials is needed. Black and Hispanic patients are well-represented in kidney disease trials in the United States. Asian patients are poorly represented in kidney trials both globally and in the United States.

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Introduction: Adiponutrin, encoded by the patatin-like phospholipase domain-containing 3 gene ( PNPLA3 ), is involved in lipid metabolism. The PNPLA3 gene rs738409 C>G single nucleotide polymorphism (SNP), particularly when homozygous, is strongly associated with non-alcoholic fatty liver disease, which has been associated with vascular disease. We hypothesized that this PNPLA3 SNP is associated with covert brain infarction (CBI). Methods: We performed a cross-sectional analysis of individuals with rs738409 genotype data in the Northern Manhattan Study MRI sub-study. The exposure was rs738409 allele frequency; noncarriers (CC genotype) served as the reference. The primary outcome was the presence of any CBI. Secondary outcomes were independently adjudicated CBI mechanism categories based on available baseline and follow-up history and imaging data: large artery atherosclerosis, cardioembolism, small vessel disease, and embolism of unknown source (EUS). Multivariable logistic regression was used to assess the relationship between SNP frequency and CBI. Principle component analysis was used to account for population-specific variations in SNP distributions. Models were adjusted for principal components, demographics, vascular risk factors, and alcohol, statin, and antiplatelet use. Results: The sample included 1,063 Northern Manhattan Study participants (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%, with 381 GC heterozygotes and 67 GG homozygotes. The prevalence of CBI was 18% (N=185): 10% (N=19) large artery atherosclerosis, 12% (N=22) cardioembolism, 16% (N=30) small vessel disease, and 62% (N=114) EUS. Individuals heterozygous for the G allele were not at greater odds of any CBI (OR 0.8; 95% CI 0.6-1.2) or any individual type of CBI, compared to CC homozygotes. The odds of any CBI were also not increased among GG homozygotes (OR 1.6; 95% CI 0.8-3.2). However, GG homozygotes were at higher odds of EUS (OR 2.3; 95% CI 1.1-4.8), but not CBI due to other mechanisms. Conclusion: Homozygosity for the PNPLA3 rs738409[G] SNP was associated with greater odds of EUS and may account for some unexplained strokes. Further study is warranted to understand the contribution of PNPLA3 variants to cerebrovascular disease.

Background: We previously showed that overall brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. Asymmetry of brain dysfunction may disrupt brain network efficiency. We hypothesized that greater left-right WMHV asymmetry was associated with functional trajectories. Methods: In the Northern Manhattan MRI study, participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences, with baseline interview and examination. Volumetric WMHV distribution across 14 brain regions (brainstem, cerebellum, and bilateral frontal, occipital, temporal, and parietal lobes, and bilateral anterior and posterior periventricular white matter) was determined separately by combining bimodal image intensity distribution and atlas based methods.. Participants had annual functional assessments with the Barthel index (BI, range 0-100) over a mean of 7.3 years. Generalized estimating equations models estimated associations of regional WMHV and regional left-right asymmetry with baseline BI and change over time, adjusted for baseline medical risk factors, sociodemographics, and cognition, and stroke and myocardial infarction during follow-up. Results: Among 1195 participants, mean age was 71 (SD 9) years, 39% were male, 67% had hypertension and 19% diabetes. Greater WMHV asymmetry in the frontal lobes (-3.53 BI points per unit greater WMHV on the right compared to left, 95% CI -0.18, -6.88) and whole brain (-7.23 BI points, 95% CI 0.07, -14.54) was associated with lower overall function. Greater WMHV asymmetry in the frontal lobes (-0.74 additional BI points per year per unit greater WMHV on the right compared to left, 95% CI 0.05, -1.54) and parietal lobes (1.11 additional BI points per year, 95% CI 0.30, 1.93) was independently associated with accelerated functional decline. Periventricular WMHV asymmetry was not associated with function. Conclusions: In this large population-based study with long-term repeated measures of function, greater regional WMHV asymmetry was associated with lower function and functional decline, especially with greater WMHV on the right. In addition to global WMHV, WHMV asymmetry may be an important predictor of long-term functional decline.

Background: Increased P-wave terminal force in lead V1 (PTFV1) of a standard 12-lead electrocardiogram (EKG), a marker of left atrial dilatation and possibly fibrosis, has been associated with stroke risk in the absence of atrial fibrillation (AF), and with subclinical infarcts in some cohorts. We hypothesized that PTFV1 would be associated with an increased prevalence of subclinical infarcts, especially cortical ones, and leukoaraiosis in a population-based, multi-ethnic cohort. Methods: PTFV1 was collected manually from baseline EKGs of participants in the population-based, prospective Northern Manhattan Study (NOMAS) who had remained clinically stroke-free and undergone brain MRI (n=1,290). MRIs were read for superficial and deep infarcts and white matter hyperintensity volume adjusted for head size (WMHV). Logistic regression models were used for the association of PTFV1 with all subclinical infarcts and with cortical infarcts, and linear regression models with logWMHV. Models were adjusted for demographics and risk factors. Results: Among the 1174 participants with PTFV1, mean age was 70 + 9 SD years at the time of MRI, 40.3% were male, and 14.4% were white, 17.6% black, and 65.8% Hispanic. Hypertension was present in 68.0%. Mean PTFV1 was 3587.35 ± 2315.62 μV-ms. MRIs were performed a mean of 6.0 + 3.4 years after EKG. Subclinical infarcts were present in 170 (15.1%) participants, and were cortical in 40 (3.6%). PTFV1 >5000 μV-ms was associated with greater WMHV even after adjusting for demographics and risk factors, including baseline AF (mean difference in logWMHV 0.14, 95% CL 0.01-0.28). There was a trend toward an association of PTFV1 with cortical (unadjusted OR per SD change logPTFV1 1.30, 95% CI 0.94-1.81) but not with all subclinical infarcts (unadjusted OR 1.00, 95% CI 0.85-1.18). Conclusion: EKG evidence of left atrial abnormality was associated with leukoaraiosis, and possibly with subclinical cortical infarcts, though the limited number of outcomes did not permit us to confirm this finding. Left atrial cardiopathy may be a source of emboli, but may also cause cerebral hypoperfusion-related injury. Further studies in large cohorts are needed to determine the relationship of PTFV1 to risk of subclinical cerebrovascular disease.