Diabetes Drugs Show Surprising Power to Boost Dialysis Fluid Removal

A class of drugs celebrated for transforming the treatment of diabetes, heart failure, and chronic kidney disease may have one more trick up its sleeve. New clinical observations from a single Spanish dialysis center suggest that sodium–glucose cotransporter 2 inhibitors, widely known as SGLT2 inhibitors, could directly enhance the ability of peritoneal dialysis to remove excess fluid from the body. The finding, drawn from just seven patients, is far from definitive. But the way the responses unfolded, particularly in patients with no remaining kidney function, points toward something that has never been clearly demonstrated before: a direct pharmacological action on the peritoneal membrane itself.

Peritoneal dialysis is a home-based renal replacement therapy in which dialysis fluid is introduced into the abdominal cavity through a permanent catheter. The peritoneum, a thin membrane lining the abdominal wall, acts as a natural semipermeable barrier. Glucose dissolved in the dialysis solution draws water out of the bloodstream and tissues by osmosis, and the fluid is then drained away, carrying with it waste products and excess salt. It is an elegant system, but it has a fundamental weakness. The very glucose that powers ultrafiltration gradually damages the peritoneal membrane through oxidative stress, glucose degradation products, and progressive fibrosis. Over time, the membrane absorbs glucose faster, the osmotic gradient dissipates more quickly, and ultrafiltration fails. Fluid overload affects up to half of all peritoneal dialysis patients and independently predicts cardiovascular death.

SGLT2 inhibitors work by blocking glucose and sodium reabsorption in the proximal tubule of the kidney, inducing glucosuria and osmotic diuresis. Landmark trials including DAPA-CKD and EMPA-KIDNEY have demonstrated their cardiovascular and renal benefits across a broad range of kidney function. But translational studies have revealed something unexpected: SGLT2 is also expressed in the human peritoneum. Animal models show that inhibiting this transporter reduces glucose absorption from dialysis solution and mitigates peritoneal fibrosis. Despite this biological plausibility, no placebo-controlled trial has yet reported results in peritoneal dialysis patients, and clinical experience remains scattered across isolated case reports.

Now a team at Hospital Universitario Ramón y Cajal in Madrid, led by R. Haridian Sosa Barrios and colleagues, has published a descriptive case series in Frontiers in Nephrology documenting their systematic experience with these drugs in seven consecutive peritoneal dialysis patients treated between February 2023 and March 2025. All prescriptions were made outside the authorised conditions of use, under the Spanish regulatory framework for medicines used in special situations. Each decision was taken collectively in the Peritoneal Dialysis Unit clinical session, with indications ranging from recurrent congestive admissions in type 2 cardiorenal syndrome to insufficient peritoneal ultrafiltration with no conventional alternative, preservation of residual kidney function, and adjuvant therapy in one patient with histologically confirmed encapsulating peritoneal sclerosis.

The cohort was strikingly unrepresentative of the typical SGLT2 inhibitor population. Median age was 69 years, with a range from 43 to 73. Five of the seven were men. Only one patient had type 2 diabetes, making this a predominantly non-diabetic group in which the drugs’ metabolic effects could not explain the outcomes. Six patients received dapagliflozin 10 mg daily and one received empagliflozin 10 mg daily. Critically, the peritoneal dialysis prescription — modality, number and duration of dwells, glucose concentration, and use of icodextrin — was not modified during the treatment period in any patient. This design element is what gives the report its mechanistic teeth, because it excludes the most obvious alternative explanation for any change in ultrafiltration.

Paired baseline and follow-up ultrafiltration data were available for four patients, precisely those in whom the drug was introduced onto an established and unchanged dialysis prescription. Median ultrafiltration rose from 659 millilitres per 24 hours at baseline to 988 at one month and 1250 at three months. Three of the four patients increased their ultrafiltration substantially, by 1096, 842, and 340 millilitres per 24 hours at three months. One patient decreased it by 79 millilitres, and that individual was the sole low-average transporter in the group — the phenotype with the least baseline peritoneal glucose absorption and therefore the least to gain from blocking it. Both patients who were anuric at baseline increased their ultrafiltration, and in one of them peritoneal dialysis was the only feasible modality, with all vascular accesses exhausted and transplantation not an option.

The strongest mechanistic argument in the series arises from a dissociation observed within a single patient. Serum urate fell only in those with preserved diuresis, as the physiology predicts, since the uricosuric action of these agents requires urine flow. The anuric patients therefore acted as an internal control confirming that the renal route behaved as expected. Yet that same anuric patient, in whom no renal drug effect was demonstrable, showed the largest sustained ultrafiltration gain of the entire series. A response present in the peritoneum and absent in the kidney, in the same individual at the same time, argues for a direct peritoneal mechanism. That peritoneal transport category did not change in any patient with paired equilibration tests points the same way, suggesting improved osmotic conduction — slower dissipation of the glucose gradient — rather than altered small-solute permeability.

Beyond volume management, the drugs appeared to influence erythropoiesis. The erythropoietin resistance index, calculated as the weekly equivalent dose of erythropoiesis-stimulating agent divided by haemoglobin, decreased in all six patients receiving such agents at baseline. The magnitude varied widely and was clinically relevant in only three, ranging from complete withdrawal of erythropoiesis-stimulating therapy in one patient whose haemoglobin rose from 11.8 to 15.3 grams per decilitre, to changes below three per cent in two others. The authors attribute this to hypoxia-inducible factor 2α upregulation, a mechanism consistent with randomized trial data showing that SGLT2 inhibitors consistently increase haemoglobin. Median haemoglobin for the cohort rose from 10.4 to 10.8 grams per decilitre.

Safety findings were largely reassuring but carried one sobering observation. No hypoglycaemia, euglycaemic ketoacidosis, or genital mycotic infection was recorded. One patient required temporary withdrawal for acute kidney injury before dialysis initiation, with uneventful resumption. Three patients died during follow-up: two from end-stage cardiac disease in the context of type 2 cardiorenal syndrome, and one from fungal peritonitis after approximately six months of dapagliflozin. That patient, for whom peritoneal dialysis was the only available modality, was persistently non-adherent, subsequently declined treatment, and did not attend appointments, and the infection recurred in that setting. Causality cannot be inferred from a single case in a non-adherent patient. But the authors raise a biologically plausible concern: the very mechanism proposed for the ultrafiltration benefit — reduced peritoneal glucose absorption through inhibition of mesothelial SGLT2 — necessarily implies a higher residual intraperitoneal glucose concentration for a longer dwell period, which could constitute a route to increased fungal risk that has not previously been raised.

The authors are careful to frame their conclusions as hypothesis-generating rather than inferential. With seven patients, no hypothesis testing was attempted, and the observations are presented as individual trajectories. The retrospective, single-centre design without a control group prevents causal inference. The single diabetic patient is also the only one given empagliflozin, the largest ultrafiltration responder, and the only case of erythropoiesis-stimulating agent withdrawal, so both principal observations derive disproportionately from the least representative patient. Nevertheless, the report documents outcomes in clinical scenarios — anuria without alternative modality, recurrent congestive admissions, encapsulating peritoneal sclerosis — in which the peritoneal dialysis community currently improvises without evidence. The authors call for prospective controlled evaluation with explicit surveillance for fungal peritonitis and prespecified stratification by peritoneal transport phenotype, noting that the ongoing EMPOWERED trial, a randomized double-blind placebo-controlled crossover study, will be needed to quantify the effect these observations only hint at.

Subject of Research: Nephrology

Article Title: SGLT2 inhibitors as a strategy for volume management in peritoneal dialysis: a case series

Article References: Sosa Barrios, R. H., Domínguez-Tejedor, M., Moreno García, R., Burguera Vion, V. M., Fernández Lucas, M., & Rivera Gorrín, M. E. (2026). SGLT2 inhibitors as a strategy for volume management in peritoneal dialysis: a case series. Frontiers in Nephrology, 6, Article 1942462. https://doi.org/10.3389/fneph.2026.1942462

Image Credits: AI Generated

DOI: 10.3389/fneph.2026.1942462

Keywords: SGLT2, inhibitors, strategy, volume, management, peritoneal, dialysis, case, series, scientific research