DKD Phenotype Definitions

Not all patients with DKD will develop every form of the disease or progress to the most severe stage of ESRD. Dysfunction of the glomerular barrier, represented by albuminuria, and reduced kidney function, represented by eGFR, can develop independently. To explore the disease severity spectrum and the different disease processes represented by eGFR and albuminuria, we defined seven binary phenotypes using clinical measures of albumin-to-creatinine ratio (ACR), albumin excretion rate (AER), and eGFR (Table 1 [T2D only] and Supplementary Table 8 [T1D+T2D]). The phenotype definitions were aligned to other large-scale genetic studies of T1D DKD in SUMMIT (17) and the Diabetic Nephropathy Collaborative Research Initiative (DNCRI) (18). The definition of CKD was also aligned to that used by the CKDGen Consortium (eGFR <60 mL/min/1.73 m²), although we restricted case and control subjects to those with diabetes (13).

GWAS characteristics by DKD phenotypes in subjects with T2D and T1D

*Equivalent to the early DKD phenotype from Sandholm et al. (17).

†Not all studies were able to define microalbuminuria (due to limited information on microalbuminuric status) and thus the case and control group number is smaller than all DKD and late DKD.

‡The duration of diabetes for subjects with T1D was >15 years.

We used AER measured overnight (µg/min), during 24 h (mg/24 h), or as a spot measurement of ACR (mg/mmol) or eGFR calculated using the Modification of Diet Renal Disease Study (MDRD) formula (eGFR = 32,788 × serum creatinine (μmol/L)^−1.154 × age^−0.203 × [0.742 if female]) to classify disease stage and severity. We based the control definition on either AER or ACR, as most studies had measured either. In the studies that had measured both, two of the three measures for AER and ACR had to meet the control criteria (Table 1). We were unable to exclude albuminuric patients that presented as normoalbuminuric due to prescribed renin-angiotensin system blockers. As reduced kidney function (reflected by eGFR) and dysfunction of the glomerular filtration barrier (reflected by albuminuria) can develop independently, we did not exclude individuals with albuminuria from the control subjects for the eGFR-defined phenotypes and vice versa. In subjects with T2D, ∼46% of normoalbuminuric control subjects had an eGFR <60 mL/min/1.73 m² (1,098/2,372).

In all, we defined seven dichotomous phenotypes:

The “all DKD” phenotype, our primary phenotype, designed to capture the broadest set of DKD phenotypes.

The “microalbuminuria” phenotype (equivalent to early DKD from Sandholm et al. [17]) to identify variants that contribute to early dysfunction of the glomerular barrier.

The “late DKD” phenotype to identify variants that contribute to severe glomerular barrier dysfunction.

Two ESRD-related phenotypes focused on identification of variants associated with end-stage renal failure, comparing those with ESRD either to control subjects without any DKD (“ESRD vs. control subjects”) or to control subjects without ESRD (“ESRD vs. no ESRD”).

The “CKD” phenotype to identify variants that contribute to reduced kidney function (eGFR).

The “CKD and DKD” phenotype to identify any variants that may contribute to the development of kidney disease irrespective of glomerular barrier dysfunction or reduced kidney function.

The “eGFR” phenotype, a continuous phenotype, to identify variants that play a role in kidney function that may not be detected by the analysis of the binary DKD phenotypes. The eGFR measures were not transformed as they approximated a normal distribution (Supplementary Fig. 1).