The edition · Nephrology
The renal case for SGLT2 inhibition, and a three-day window after ischaemic injury
The renal basis for SGLT2 inhibition set out in full, a rodent experiment that dates the window for repair after ischaemic injury, a peroxisomal pathway in APOL1 podocytopathy, and the guideline framework that already covers cardiovascular-kidney-metabolic disease.
The edition in brief
This is a mechanistic day on the nephrology desk rather than a trial day, and the sections are labelled accordingly. A review by Cersosimo and DeFronzo sets out the kidney's role in glucose homeostasis and uses it to explain the pharmacology of SGLT2 inhibition and why its renal and cardiovascular benefits extend well beyond glucose lowering. Six rodent experiments show that removing the contralateral kidney three days after unilateral ischaemic injury produces full functional recovery, while doing so at 10 or 20 days does not, with early nephrectomy reducing tubular atrophy, fibrosis and inflammation, expanding tubular progenitor clones and preventing the persistent tubular polyploidisation that accompanies progression to chronic disease. A genome-wide RNA interference screen in cells carrying APOL1 G1 or G2 risk variants identifies peroxisomal biogenesis genes as modifiers of hypoxia-driven cytotoxicity: silencing them worsened cell death, enhancing peroxisomal function reduced it, and a peroxisomal targeting signal at the APOL1 C-terminus mediates the trafficking involved. The practice-changer is organisational: a KDIGO review maps its existing guidelines on chronic kidney disease, blood pressure, diabetes and lipids, plus controversies reports on obesity and prevention, onto the cardiovascular-kidney-metabolic syndrome the American Heart Association defined in 2023 — arguing that the framework a nephrologist needs for this patient already exists across documents most clinicians read separately.
Why SGLT2 inhibition does more than lower glucose
Prescribe and explain SGLT2 inhibitors as renal haemodynamic agents rather than glucose-lowering drugs — and teach euglycaemic ketoacidosis at the first prescription.
A three-day window for repair after ischaemic injury, in rodents
Nothing to change today — but the window in which acute injury can still be steered away from chronic disease may be much shorter than post-AKI clinics assume.
Peroxisomes emerge as the second hit in APOL1 kidney disease
Nothing to act on — but if APOL1 kidney disease becomes treatable, this suggests the target will be the stress response rather than the variant.
Give the sick-day list when you start the drug, not when they get ill
Hand over a written sick-day list naming the patient's own drugs at the time you prescribe them — and include that a normal glucose does not rule out ketoacidosis.
The guidelines for cardiovascular-kidney-metabolic disease already exist; they are just filed separately
Manage albuminuria, blood pressure, glucose, lipids and weight in one consultation with one owner for each target — the guidelines already assume you will.
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