Roles of APOL1 G1 and G2 variants in sickle cell disease patients: kidney is the main target

Abstract

In African-American patients with sickle cell disease (SCD), APOL1 G1 and G2 variants are associated with increased risk of sickle cell nephropathy (SCN). To determine the role of APOL1 variants in SCD patients living in Europe, we genotyped 152 SCD patients [aged 30·4 (24·3-36·4) years], mainly of Sub-Saharan African ancestry, for APOL1 G1 and G2 and for variants of four genes with kidney tropism (GSTM1, GSTT1, GSTP1, and HMOX1). Homozygous or double-heterozygous APOL G1 and G2 genotypes were strongly associated with end stage renal disease (P = 0·003) and worse Kidney Disease: Improving Global Outcomes stages (P = 0·001). Further, these genotypes were associated in an age-dependent manner with lower estimated glomerular filtration rate (eGFR, P = 0·008), proteinuria (P = 0·009) and albuminuria (P < 0·001) but not with other SCD complications. Compared to APOL1 G1/wild type (WT), the APOL1 G2/WT genotype was associated with a lower eGFR (P = 0·04) in an age-dependent manner, suggesting that the G2/WT patients are likely to have worse kidney prognosis. Other genes variants analysed were not associated with SCN or other SCD complications. Our data indicate that APOL1 screening should be considered for the management of SCD patients, including those of non-African-American origin, as those with homozygous or double heterozygous variants are clearly at higher risk of SCN.

Hyperfiltration during early childhood precedes albuminuria in pediatric sickle cell nephropathy

“…Finally, the current study did not evaluate genetic variants associated with development of albuminuria including APOL1. Future research should consider screening for these genetic variants associated with albuminuria in their trial design and evaluate the impact of sickle cell modifying therapies or renoprotective agents on preventing albuminuria in children with these high‐risk genetic variants …”

Association Between APOL1 Genotype and Need for Kidney Replacement Therapy in Patients Without Diabetes: Does Age Matter?

“…Puerto Rico outperforms the US states and the District of Columbia ("states" hereafter) on some measures of coverage and access, 3 but substantial problems with quality of care have been documented. 4 Compared with Hispanics in the states, Hispanics in Puerto Rico receive lower quality care for chronic conditions; have worse control of diabetes, hyperlipidemia, and hypertension; and use effective medications for rheumatoid arthritis and chronic obstructive pulmonary disease less frequently. 5 In this study, we compared 1-year mortality rates and predialysis nephrology care among Hispanics in Puerto Rico and Hispanics and whites in the states who initiated maintenance hemodialysis or peritoneal dialysis between 2006 and 2015.…”

“…1 Age of KRT onset is typically younger for individuals with 2 versus 0 to 1 RRVs. [2][3][4][5] It is likely that the relationship between high-risk genotype and risk of KRT attenuates with aging, but it is unclear whether there is an age threshold when APOL1 may no longer be a strong risk factor for KRT. We performed a retrospective analysis of AASK 1,6,7 to examine whether there is an age threshold when the effect of APOL1 genotype on KRT risk attenuates among blacks with baseline CKD.…”

“…Our findings may not apply to other APOL1associated diseases (eg, HIV nephropathy) or generalize to other causes of CKD (eg, diabetes-related CKD). 3,4 We also acknowledge that our study is designed to understand a survivor bias and examine when the importance of APOL1associated KRT risk may wane with aging.…”

The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait

“…The longer HMOX1 GT-tandem repeat polymorphism in the UIC cohort was associated with lower eGFR [69]. Another smaller study of 152 SCD patients in Europe failed to delineate a relationship between the HMOX1 rs743811 variant and kidney disease [70]. However, another study of young SCD patients (median age 15 years) from Cameroon demonstrated a trend to association between HMOX1 rs743811 and macroalbuminuria, although this did not quite reach statistical significance ( p = 0.06) [62].…”