Clinical Predictors and Long-term Impact of AKI on DKD Progression in Patients with T2DM

5 May, 22

Introduction

Diabetic kidney disease (DKD) being one of the most common causes of end-stage renal disease (ESRD) in patients with type-2 diabetes mellitus (T2DM), is associated with increased risk of cardiovascular disease and premature death. Considering the increasing incidence of diabetes, it is important to identify the people at high risk of progression towards DKD and to develop effective strategies to prevent and treat the disease. Several studies have demonstrated that acute kidney injury (AKI) is a determinant of renal failure events in selected patient population. Several clinical factors for AKI, including some modifiable risk factors such as serum uric acid (SUA) have also been associated with DKD in T2DM patients.

Aim

To assess the long-term impact of AKI on progression of DKD and all-cause mortality and to determine various determinants of AKI in patients with T2DM

Patient Profile

A consecutive cohort of 9,096 Chinese patients with T2DM from the Hong Kong Diabetes Register (HKDR; n=9096)

Methods

Study Design

Prospective cohort study

Definitions for Clinical Endpoints

AKI was defined as per the Kidney Disease: Improving Global Outcomes (KDIGO) criteria using serum creatinine (SCr) values as follows:
- Stage 1: Index/baseline SCr ≥1.5–2.0
- Stage 2: Index/baseline SCr ≥2.0–3.0
- Stage 3: Index/baseline SCr ≥3.0
CKD was defined as:
- Fatal and nonfatal diabetes with renal manifestations, CKD or unspecified renal failure
- Dialysis or peritoneal dialysis
- Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² during the follow-up period.
ESRD was defined as the need of dialysis, kidney transplant, or eGFR <15 mL/min/1.73 m² during the follow-up period.

Assessments

The role of SUA in pathogenesis of AKI, CKD, and ESRD was examined using a polygenic risk score (PRS) that comprised of 27 single nucleotide polymorphisms (SNPs) known to be associated with SUA in European population.

Follow-up

Median 12.3 years

Results

Mean age of the study population was 57 years; median duration of diabetes was 5 years; and 46.9% of the study population comprised of men.
Nearly 35.3% patients (n=3209) developed at least one AKI episode during a median follow-up period of 12.3 years; 12.2% (n=1,114), 7.1% (n=642), and 16% (n=1,453) had one, two, and three or more episodes of AKI, respectively.
The overall incidence rate of AKI was 29.2 [95% confidence interval (CI) 28.2–30.2] per 1,000 person-years. With respect to severity of AKI, 73.8% (n=2,367), 18% (n=579), and 8.2% (n=263) had AKI stage 1, 2, and 3, respectively.

Within 7 days 33.8% (n=1,086), 16.2% (n=521) and 13.7% (n=440) had complete recovery, partial recovery and nonrecovery, respectively.
The findings were validated in an independent cohort of 6,007 patients (age 61.2 years; 59.5% men; median duration of diabetes 10 years).
As compared with patients without AKI episodes, those with AKI were at a higher risk of developing incident CKD [hazard ratio (HR); 14.3, 95% CI; 12.69–16.11), ESRD (HR; 12.1, 95% CI; 10.74–13.62), and all-cause death (HR; 7.99, 95% CI; 7.31–8.74).
The incidence of ESRD and CKD increased with the increasing number of AKI episodes (Table 1)

Table 1: Incidence of ESRD and CKD as per the AKI episodes

AKI Episodes	ESRD Incident Rate (per 1,000 person-years)	CKD Incident Rate (per 1,000 person-years)
No episodes	7.1	42.2
1	24.4	132.7
2	32.4	159.3
3	37.3	183.6

Baseline SUA robustly and independently predicted AKI (HR; 3.58, 95% CI; 2.39–5.36, p<0.001).
A PRS comprising 27 SUA-related SNPs was associated with AKI [odds ratio (OR); 1.14, 95% CI 1.04–1.25, P=0.007) and CKD (OR; 1.15, 95% CI; 1.05–1.27, P=0.004) in both discovery and replication cohorts but not with ESRD.

Conclusions

AKI was a common finding and a powerful predictor of long-term renal complications and all-cause mortality in patients with T2DM. More severe AKI or poorer recovery from AKI, greater the risk of complication outcomes.
Elevated SUA significantly predicted DKD, mediated through increased risk of AKI.
The finding that SUA was a modifiable risk factor and PRS a nonmodifiable one may help identify the individuals at high risk to prevent AKI and its long-term impact in T2DM.

Diabetes. 2022;71:520-529.