Maximizing RAS blockade in IgA nephropathy

Primary GNmedium

A 43-year-old man presents to the nephrology clinic for ongoing management of IgA nephropathy. Four months ago, microscopic hematuria and 2+ proteinuria were detected during an insurance evaluation. An office BP at that time was 135/85 mm Hg. A 24-hour urine collection revealed 1.1 g protein (reference range, <100 mg/24 h). Serum creatinine was 0.9 mg/dL (reference range, 0.7–1.3). Kidney biopsy revealed IgA nephropathy with mild mesangial hypercellularity, but no crescents, interstitial fibrosis, or tubular atrophy (MEST-C score M1, E0, S0, T0, and C0). Home BP monitoring was instituted, and hypertension was diagnosed based on an average BP of 138/83 mm Hg. Lisinopril 20 mg/day was initiated 1 month ago. Today, the patient feels well, and brings a home BP log with average readings of 130/78 mm Hg and heart rate of 65/min. Physical examination is unremarkable. Spot urine protein-to-creatinine ratio (UPCR) is 1.2 mg/mg (reference range, <0.2). Which ONE of the following is the next BEST STEP in management?

  1. A.Prescribe amlodipine
  2. B.Prescribe losartan
  3. C.Repeat 24-hour urine albumin and creatinine
  4. D.Increase lisinopril doseCorrect

Explanation

The next best step in management for this patient with IgA nephropathy, whose BP is above optimal and proteinuria is estimated to be >1 g/d, is to increase the dose of lisinopril. The KDIGO Clinical Practice Guideline for Glomerulonephritis provides a 1B level of evidence for the use of renin-angiotensin-aldosterone inhibitors when proteinuria is >1 g/day. A weaker, grade 2C recommendation is given to titrate ACEI or ARB as high as tolerated to achieve proteinuria <1 g/day, primarily based on post hoc and subgroup analysis of the MDRD and AASK trials. KDIGO guidelines also make a grade 2B recommendation for a target systolic BP of <120 mm Hg in patients with glomerular disease. Although there are several approaches to achieve the double aim of reducing BP and proteinuria, the most straightforward approach would be to titrate the dose of the currently prescribed ACEI. If this were unsuccessful, addition of a thiazide diuretic or aldosterone receptor blocker could be considered. Amlodipine would be a reasonable addition if BP did not reach goal with the combination of an ACEI and diuretic or if those medications were not tolerated. New data from the DAPA-CKD study suggest that add-on therapy with dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, is also effective in improving outcomes in patients with IgA nephropathy. In large clinical trials, such as ONTARGET, the addition of an ARB to an ACEI decreased albuminuria but increased the risk of AKI and hyperkalemia, so prescribing losartan would not be advisable. Repeating a 24-hour urine collection to reassess urine albumin or protein excretion is unnecessary, as above, because there are no compelling data to support targeted albuminuria reduction. However, a 24-hour urine collection for sodium and creatinine may be used to assess compliance with dietary sodium restriction, because high sodium intake may blunt the proteinuria reduction benefit of ACEIs and ARBs.

Why each option

A.
Amlodipine lowers BP without reducing proteinuria and is reserved for BP above goal after maximal RAS blockade and a diuretic.
B.
Dual ACE inhibitor and ARB therapy reduced albuminuria in ONTARGET but increased AKI and hyperkalemia, so adding losartan is not advised.
C.
A spot protein-to-creatinine ratio already shows persistent proteinuria above 1 g/day; another collection would not change the need to intensify RAS blockade.
D.
Correct. Proteinuria above 1 g/day and BP above the systolic target of 120 mm Hg on 20 mg lisinopril call for titrating to the maximally tolerated dose.

Reference: KDIGO 2025 Clinical Practice Guideline for the Management of IgA Nephropathy and IgA Vasculitis; Wheeler DC, Kidney Int 2021 (DAPA-CKD IgA nephropathy subgroup)

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