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

The research, published in Physiological Reports by a team led by Takahiro Masuda and Masahide Yoshida of Jichi Medical University together with colleagues in Japan and the United States, examined whether the gene encoding SGLT2, known formally as Slc5a2, is switched on in the neurons that govern thirst and vasopressin synthesis. For years, physiologists have observed that SGLT2 inhibitors stimulate water intake and vasopressin secretion even when blood volume and plasma osmolality remain normal, which suggests that something beyond simple dehydration is driving these responses. Because the drugs can cross the blood-brain barrier and SGLT2 immunoreactivity had previously been reported in brain tissue, the team suspected that the transporter might be present in the very neurons that control drinking behavior and hormone release.

To find out, the researchers studied male Sprague-Dawley rats and combined two complementary techniques: droplet digital PCR, an ultra-sensitive method for quantifying gene transcripts, and in situ hybridization, which reveals exactly which cells express a given gene. Using droplet digital PCR on micro-punched tissue samples, they detected Sglt2 messenger RNA in four key regions: the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO), two sensory circumventricular organs that form the brain’s thirst center, and the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, where vasopressin is synthesized. The relative abundance of Sglt2 transcripts in these regions, normalized to the housekeeping gene Polr2a, fell in the range of 0.02 to 0.04, a level comparable to that of Agtr1a, the angiotensin II receptor type 1a gene that is well established as a central regulator of drinking and vasopressin release.

Brain expression was, unsurprisingly, far lower than in the kidney, the body’s dominant site of SGLT2 expression. Depending on which of three internal control genes was used for normalization, Sglt2 expression in the paraventricular nucleus, the region with the strongest signal, was roughly 76 to 205 times lower than in kidney tissue. Yet the authors argue that low abundance does not mean functional irrelevance. The fact that Sglt2 transcripts appear at levels similar to those of Agtr1a, a gene whose central role in thirst regulation is beyond dispute, suggests that even modest neuronal expression could be physiologically meaningful, particularly if the neurons involved are the direct targets of circulating drug.

The anatomical story became far more compelling when the team turned to double fluorescent in situ hybridization, a technique that can visualize two genes simultaneously within single cells. In the OVLT and the SFO, Sglt2 messenger RNA was clearly present in neurons that also express Nos1, the gene encoding neuronal nitric oxide synthase. These NOS1-expressing neurons are known from landmark studies to be the excitatory, thirst-promoting cells of the circumventricular organs; when activated, they drive drinking behavior, and they send direct projections to the vasopressin-producing nuclei of the hypothalamus. Quantification showed that approximately 48.1 percent of NOS1-positive neurons in the OVLT and 60.3 percent in the SFO expressed Sglt2. In other words, the molecular target of SGLT2 inhibitors sits within roughly half of the very neurons that command an animal to drink.

The co-localization in the hypothalamus was even more striking. In the supraoptic nucleus, 80.8 percent of vasopressin-expressing neurons carried Sglt2 transcripts, and in the paraventricular nucleus the figure reached 84.0 percent. The researchers also examined oxytocin neurons, the other major neuroendocrine population in these nuclei, and found Sglt2 expression in 58.9 percent of oxytocin neurons in the SON and 65.7 percent in the PVN. Chromogenic in situ hybridization confirmed the pattern at the tissue level, with Sglt2 signals appearing not only in the four fluid-regulating regions but also in the choroid plexus, consistent with earlier reports in human and mouse brains that identified the transporter in choroid plexus epithelial cells and ependymal cells. Prior work had also located SGLT2 in brain pericytes and in neurons of the rostral ventrolateral medulla, a master controller of sympathetic nerve activity, but this study is the first to pin the transporter down at single-cell resolution within the thirst and vasopressin circuits themselves.

These findings provide an anatomical basis for a hypothesis that has been gathering force in the literature: that SGLT2 inhibitors act directly on the brain, not merely through the kidney. Two features of the circumventricular organs make this plausible. First, the OVLT and SFO sit outside a functional blood-brain barrier, meaning drugs circulating in the bloodstream can reach them directly. Second, SGLT2 inhibitors as a class have been shown to penetrate the blood-brain barrier, and central administration of the drug tofogliflozin has already been demonstrated to stimulate water intake in non-diabetic rats, just as peripheral administration of ipragliflozin does in both diabetic and non-diabetic animals. If SGLT2 inhibitors enhance the excitability of NOS1 thirst neurons in the OVLT and SFO, that could trigger drinking independently of any actual fluid deficit, which would explain the paradoxical observation that these drugs increase vasopressin secretion and copeptin levels, a stable clinical surrogate for vasopressin, even under normal osmotic conditions.

The authors go further, weaving in evidence from glucose-sensing physiology. In the SFO, a subset of so-called glucose-inhibited neurons, cells that become excited when intracellular glucose falls, shares properties with NOS1 neurons, and many glucose-inhibited neurons also respond to angiotensin II, a potent dipsogenic hormone. Roughly 27 percent of SFO neurons show this glucose-inhibited character, and the majority of them respond to angiotensin II. The team speculates that by reducing intracellular glucose uptake through SGLT2, the inhibitors might directly stimulate a NOS1-positive, glucose-sensing population, initiating drinking before osmotic diuresis has had time to deplete body fluids. Intriguingly, a parallel logic operates in the kidney: in macula densa cells, which behave in many ways like neurons, SGLT1-mediated glucose uptake supports NOS1 activity that modulates tubuloglomerular feedback. The authors suggest that SGLT-dependent glucose sensing linked to nitric oxide synthase may thus push systemic fluid balance in a negative direction in both organs, a conceptual echo of coupled hunger-and-thirst sensing described in the fly brain.

Important caveats remain, and the authors are careful about them. This study mapped gene expression; it did not directly test function. Whether blocking SGLT2 in these neurons actually changes their electrical activity, drinking behavior, or vasopressin release has not yet been demonstrated, and global SGLT2 knockout mice, which drink more and secrete more vasopressin than wild-type animals, cannot disentangle central from renal mechanisms because fluid balance disturbances confound the interpretation. Brain-region-specific knockout models and intracerebroventricular drug administration will be needed to establish causality, along with electrophysiological recordings and activity markers such as Fos in SGLT2-expressing neurons. It is also uncertain how much of the vasopressin response during SGLT2 inhibition reflects direct central action versus classical osmotic pathways, since clinical studies show copeptin remains strongly tied to plasma osmolality during treatment. Still, the finding that Sglt2 is expressed in the majority of vasopressin neurons and roughly half of thirst-promoting NOS1 neurons reframes how scientists think about these drugs. Beyond fluid balance, vasopressin and oxytocin neurons influence social behavior, stress responses, and learning and memory, raising the speculative but testable possibility that SGLT2 inhibitors touch neuroendocrine circuits far beyond hydration. If the central mechanisms are confirmed, they could deepen understanding of the brain-kidney axis and help explain why a drug class designed to squeeze glucose out of urine has turned out to be one of the most versatile cardiorenal therapies ever developed.

Subject of Research: SGLT2 gene expression in thirst-promoting NOS1 neurons and vasopressin-synthesizing neurons in the rat brain

Article Title: SGLT2 gene expression in thirst‐promoting NOS1 neurons and vasopressin‐synthesizing neurons in male rats

Article References: Masuda, T., Yoshida, M., Kim, Y. C., Vallon, V., Morishita, Y., Nagata, D., & Onaka, T. (2026). SGLT2 gene expression in thirst‐promoting NOS1 neurons and vasopressin‐synthesizing neurons in male rats. Physiological Reports, 14(17), Article e71100. https://doi.org/10.14814/phy2.71100

Image Credits: AI Generated

DOI: 10.14814/phy2.71100

Keywords: SGLT2, Slc5a2, thirst, vasopressin, NOS1 neurons, subfornical organ, organum vasculosum laminae terminalis, supraoptic nucleus, paraventricular nucleus, fluid homeostasis, in situ hybridization, cardiorenal