Study Calls for Reevaluation of Proteinuria Treatment Target in IgA Nephropathy

Anne-Laure Faucon, MD, PhD

Credit: Karolinska Institute

Findings from a recent study suggest the current risk-based proteinuria treatment target in IgA nephropathy (IgAN) may be overlooking patients with a lower urine albumin-to-creatinine ratio (uACR), a population currently considered to be at low risk of chronic kidney disease (CKD) progression.¹

Results showed a substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, further highlighting an incremental association between proteinuria and the risk of poor kidney outcome and suggesting any reduction in uACR is associated with better outcomes.¹

Currently, Kidney Disease Improving Global Outcomes (KDIGO) cites proteinuria reduction to < 1 g/d as a “reasonable treatment target” that serves as a surrogate marker of improved kidney outcomes in patients with IgAN.² However, the long-term health outcomes of patients with proteinuria < 1 g/d have not been explored.¹

“Identifying the optimal target of proteinuria in patients with IgAN is of importance for risk stratification, as well as tailoring monitoring and treatment strategies,” Anne-Laure Faucon, MD, PhD, a post-doctoral researcher in the department of medical epidemiology and biostatistics at Karolinska Institutet in Sweden, and colleagues wrote.¹

To explore long-term kidney outcomes in patients with low-grade proteinuria, investigators enrolled patients with biopsy-proven IgAN from the Swedish Renal Registry, a nationwide registry of patients receiving nephrology specialist care in Sweden that collects clinical and biological data of CKD patients with an incident estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73m². The study population consisted of adult patients with non-dialysis CKD due to primary IgAN registered in the Swedish Renal Registry between January 1, 2005, and December 31, 2021.¹

Investigators divided patients into 2 cohorts, the first of which included all patients with primary IgAN and ≥ 1 uACR measurement, calculated as urinary albumin concentration divided by urinary creatinine concentration and expressed in g/g. For the second cohort, the study population was restricted to patients with a second recorded visit within 12±6 months that included an uACR measurement.¹

The primary study outcome was major adverse kidney events (MAKE), a composite of kidney replacement therapy (KRT) and experiencing a >30% decline in eGFR from baseline. Secondary outcomes included the single components of MAKE. Patients were followed until kidney event, death, or the end of follow-up on December 31, 2021.¹

In total, investigators identified 1269 patients with primary IgAN. Their median age was 53 years, 74% were men, and the mean eGFR was 33±20 mL/min/1.73m². Investigators noted 38% of patients had uACR >1 g/g, 10.5% had uACR 0.3 to 0.5 g/g, and 20.4% had uACR 0.5 to 1.0 g/g.¹

During a median follow-up of 5.5 (Interquartile range [IQR], 2.8 to 9.2) years, 8490 and 6848 subsequent measurements of eGFR and uACR were recorded, respectively. The mean annual eGFR decline was -3.06 (95% CI, -3.36 to -2.77) mL/min/1.73m² per year.¹

A total of 667 MAKE and 517 KRT events occurred, and 528 patients experienced >30% eGFR decline. Upon analysis, when uACR was expressed as a continuous variable, every 0.1 g/g increase in uACR was associated with a 3% increased risk of MAKE (Adjusted hazard ratio [HR], 1.03; 95% CI, 1.02 to 1.04). Compared with uACR <0.3 g/g, any greater uACR category was strongly and incrementally associated with the risk of MAKE. Similar graded relationships were observed for KRT (HR ranging from 1.39 to 4.65) and for >30% decline in eGFR (HR ranging from 1.76 to 3.47).¹

From the initial cohort of patients with IgAN, investigators identified 785 with repeated uACR measurements. Of these patients, 450 (57.3%) had a stable uACR, 198 (25.2%) experienced a decrease in uACR of 2-fold or greater, and 137 (17.5%) experienced an increase in uACR of 2-fold or greater within a year.¹

Over a median follow-up of 4.9 (IQR, 2.8 to 8.5) years, 448 MAKE and 318 KRT events occurred, and 406 patients experienced an eGFR decline of >30% from baseline. Compared to patients with stable uACR, the risk of kidney events was reduced when uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and greater when uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR.¹

Despite the significance of these findings, investigators were careful to call attention to several potential limitations. These included the use of a spot urine sample to measure uACR, the inability to enroll patients at the time of their diagnosis, the potential misclassification of patients whose IgAN was not confirmed by kidney biopsy, and the predominance of Caucasian ethnicity among the study population.¹

“This nationwide study of patients with IgAN-related advanced CKD shows that uACR is independently associated with the risk of adverse kidney outcomes, also in patients with low-grade uACR, a population traditionally considered at low risk of CKD progression,” investigators concluded.¹ “Any reduction in uACR, irrespective of baseline uACR, is associated with better kidney outcomes.”

References:

1. ^{Faucon AL, Lundberg S, Lando S, et al. Albuminuria predicts kidney events in IgA nephropathy, Nephrology Dialysis Transplantation. https://doi.org/10.1093/ndt/gfae085}
2. ^{Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021}