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SGLT2 inhibitors in peritoneal dialysis: a promising frontier toward improved patient outcomes

SGLT2 inhibitors in peritoneal dialysis: a promising frontier toward improved patient outcomes Peritoneal dialysis (PD) stands as an important modality among kidney replacement therapies for end-stage kidney disease, offering patients remarkable flexibility and autonomy. Despite its widespread use, challenges such as glu- cose-related complications, peritoneal membrane fibrosis, declining renal function, and cardiovascular risks persist, necessitating innovative therapeutic approaches. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed for treating type 2 diabetes mellitus, have recently shown promise as add-on therapy for patients with dia- betic and non-diabetic chronic kidney disease (CKD), even in advanced stages. This review describes the potential role of SGLT2 inhibitors as a breakthrough therapeutic option in PD, emphasizing their ability to address unmet clinical needs and improve patient outcomes. The multiple effects of SGLT2 inhibitors in CKD, including metabolic modulation, antihypertensive, diuretic, anemia-reducing, antioxidant, and antiinflammatory properties, are reviewed in the context of PD challenges. Additionally, the potentially protective influence of SGLT2 inhibitors on the integrity of the peritoneal membrane and the transport of solutes and water in the peritoneum are emphasized. Despite these encouraging results, the paper highlights the potential risks associated with SGLT2 inhibitors in PD and emphasizes the need for cautious and thorough investigation of dosing, long-term safety considerations, and patient-specific factors through comprehensive clinical trials. Looking forward, the review argues for well-designed studies to evaluate the expanded safety profile of SGLT2 inhibitors in PD, with particular attention paid to peritoneal membrane integrity and overall patient outcomes. Keywords Sodium–glucose cotransporter 2 inhibitors, Peritoneal dialysis, Benefits, Risks Background nonglycemic effects that intricately improve glomerular Sodium–glucose cotransporter 2 (SGLT2) inhibitors hemodynamics, modulate volume status, and influence have emerged as potential game changers in the man- local and systemic factors in CKD and cardiovascular agement of chronic kidney disease (CKD), showcasing disease (CVD) pathogenesis [1–3]. Robust evidence not only remarkable glycemic control but also profound from pivotal trials, such as SCORED, CREDENCE, and DAPA-CKD, demonstrates that SGLT2 inhibi- tors may prevent the development of CKD, delay the worsening of CKD, and reduce the risk of adverse car- *Correspondence: Natalia Stepanova diovascular events in patients with moderate-to-severe nmstep88@gmail.com CKD, including those without diabetes [4–6]. These Department of Nephrology and Dialysis, State Institution “O.O. Shalimov groundbreaking findings have prompted the expansion National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine”, Heroes of Sevastopol 30, of approved clinical indications for SGLT2 inhibitors, Kyiv 03680, Ukraine now encompassing patients with CKD, with or without © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Stepanova Renal Replacement Therapy (2024) 10:5 Page 2 of 16 diabetes, as well as those contending with heart fail- PD realities: a brief overview of the main benefits ure, with or without reduced ejection fraction [1, 2, 7, and challenges 8]. However, it is worth noting that the trials’ lowest PD emerges as a valuable modality for managing kid- estimated glomerular filtration rate (eGFR) inclusion ney failure, offering numerous advantages, such as criterion was 20 mL/min/1.73  m [9], leaving an unan- home treatment convenience, enhanced quality of life, swered query about the feasibility and safety of SGLT2 cost effectiveness in most countries, technical simplic - inhibitor prescription in patients with end-stage kidney ity, a slower decline in residual kidney function (RKF) disease (ESKD). compared with hemodialysis (HD), and improved sur- The existing evidence for the potential benefits of vival, especially in the initial years of therapy initiation SGLT2 inhibitors in patients with ESKD is limited, [13, 14]. However, these benefits are accompanied by a primarily originating from post hoc analyses of ran- distinctive set of challenges, including issues common domized clinical trials (RCTs), preclinical studies, or to the broader dialysis population due to kidney failure case reports. These investigations lend credence to the and specific intricacies unique to PD [13, 14]. Key chal- notion that, even with minimal diuresis and anticipated lenges shared with the HD population encompass a minimal delivery to the transporter in dialysis patients, decline in RKF, overhydration, hypertension, metabolic SGLT2 inhibitors may exert direct and indirect effects, disturbances, dyslipidemia, electrolyte imbalances, ane- offering potential protection against cardiovascular mia, oxidative stress, and chronic inflammation [13, 14]. events and mortality [10–12]. For example, the post hoc These challenges significantly contribute to heightened analysis of the DAPA-CKD study revealed that 14.5% of morbidity and mortality among patients undergoing patients, irrespective of diabetes status, exhibited CKD PD. For instance, patients on PD commonly experience stage 4 (eGFR < 30  mL/min/1.73  m ) [10]. Dapagliflo - a gradual decline in RKF, influenced by factors inher - zin demonstrated both safety and a significant reduc - ent to kidney failure and the dialysis process [15]. While tion in major kidney and cardiovascular events, while kidney replacement therapy typically begins at an eGFR mitigating progressive eGFR reduction [10]. Similar of 5–10 mL/min/1.73  m , most patients initiating dialy- promising outcomes emerged from a post hoc analysis sis possess some level of RKF [15, 16]. However, over of CREDENCE data, indicating a potential slowing of time, there has been a gradual decline in RKF, contrib- CKD progression, even in cases of advanced diabetic uting to increased morbidity and mortality among dialy- nephropathy [11]. sis patients [15–17]. Preserving RKF in patients treated Despite these promising findings, a critical gap per - with PD has demonstrated significant associations with sists in our understanding of the feasibility and safety reduced incidences of infections, depression, improved of prescribing SGLT2 inhibitors to patients with ESKD, nutrition, better volume and blood pressure control, as including those undergoing peritoneal dialysis (PD). well as diminished requirements for erythropoietin, and The nature of PD and its associated complications sug - decreased chronic inflammation [16–18]. This, in turn, gest several potential positive effects of SGLT2 inhi - holds the potential to lead to lower rates of PD technique bition, expounded upon in this review. This review failure and improved cardiovascular outcomes [16, 17, navigates through the multifaceted benefits that SGLT2 19]. Overhydration [20, 21], anemia [22], dyslipidemia inhibitors might confer in patients undergoing PD. [23, 24], and chronic inflammation [25] have also been Preservation of residual kidney function (RKF) and associated with PD technique failure and an increased prevention of volume depletion, pivotal factors influ - risk of all-cause and cardiovascular morbidity and mor- encing patient outcomes in PD, are scrutinized in light tality among PD patients. of the renoprotective effects attributed to SGLT2 inhib - PD-specific challenges encompass concerns related to itors. Improved control of glycemia and lipid levels, glucose absorption from PD solutions, PD-associated antiinflammatory effects, and potential cardiovascular infections and the longevity of the peritoneal mem- advantages are among the discussed potential benefits. brane [25–27]. Long-term exposure to glucose-based Concurrently, the impact of these agents on the perito- PD solutions and the accumulation of advanced glyca- neal membrane, a critical component in the success of tion end-products in the peritoneal membrane, due PD, is examined to determine whether SGLT2 inhibi- to prolonged exposure to glucose-based PD solutions, tors hold promise in maintaining peritoneal membrane have been proven to be associated with peritoneal mem- integrity. However, every therapeutic intervention brane damage and fibrosis, leading to the loss of peri - introduces a set of considerations, and SGLT2 inhibi- toneal ultrafiltration and technique failure [26, 28, 29]. tors are no exception. This review aims to dissect the Moreover, chronic exposure to hyperglycemic PD solu- intricate interplay between the potential benefits and tions induces oxidative stress in peritoneal mesothelial risks associated with the use of SGLT2 inhibitors in PD. cells (PMCs), causing them to generate a considerable S tepanova Renal Replacement Therapy (2024) 10:5 Page 3 of 16 amount of reactive oxygen species (ROS), which initiate gradient, and glucose enters the cell alongside Na in a downstream inflammatory signaling pathways, increase 1:1 ratio through the SGLT, following the N a concen- the expression of fibrogenic factors and enhance the pro - tration gradient. Subsequently, it exits the cell passively cess of epithelial-to-mesenchymal transition (EMT) [26, through basolateral glucose transporter 2 (GLUT2) [39]. 29, 30]. Consequently, this cascade of events leads to the SGLT2, primarily expressed in the kidney and located development and accelerated progression of peritoneal in the brush border membrane of the S1 segment of fibrosis [26, 28, 30]. Therefore, minimizing the glucose renal tubules, is a low-affinity, high-capacity transporter load and optimizing the biocompatibility of PD solutions responsible for approximately 90% of glucose reabsorp- are essential for preserving the longevity of the peritoneal tion [40–42]. Inhibiting SGLT2 thus reduces the reab- membrane and, consequently, PD technique survival. sorption of N a and glucose in the proximal tubule, Another major problem in PD is PD-related infections, thereby decreasing blood glucose levels [2, 43]. which affect clinical outcomes, such as peritoneal ultrafil - Studies have demonstrated that SGLT2 inhibitors can tration, technique failure, and cardiac and overall patient lower hemoglobin A1c (HbA1c) by 0.6–1% and preserve mortality [25, 31, 32]. Infection-related PD technique kidney function in T2DM patients [2, 43]. The result - failure has been associated with an increased risk of mor- ing glucosuria can exceed 100  g/d in T2DM patients tality, with 30% of patients dying within the first 2  years and ranges from 50 to 60  g/d in those without diabe- of PD technique failure [32]. The number of peritonitis tes [44, 45]. While glucosuric efficacy diminishes with a episodes has been shown to correlate with a decrease in decline in estimated glomerular filtration rate (eGFR) and RKF [33] and even a single episode of peritonitis leads to becomes minimal when eGFR falls below 30 ml/min per an increase in small solute transport and a decrease in the 1.73 m [2, 46], SGLT2 inhibitors offer various benefits ultrafiltration rate [34]. These challenges underscore the beyond glycemic control, underscoring their relevance in intricate balance required in managing patients under- the comprehensive management of patients with CKD [2, going PD to optimize the benefits of the modality while 7, 8]. The existing knowledge of the advantages of SGLT2 effectively addressing the unique hurdles it presents. inhibitors in the broader CKD population, as outlined However, the current strategies to preserve RKF, reduce below, may offer valuable perspectives for the manage - high glucose-induced transformation of the peritoneal ment of patients undergoing PD (Fig. 1). membrane, and consequently prolong PD treatment and patient survival are presently limited [13, 16, 35]. These SGLT2 inhibitors and hemodynamic regulation strategies include practices such as restricting the use The tubuloglomerular feedback (TGF) signaling pathway of hyperglycemic PD solutions, preventing peritonitis, is crucial in regulating GFR by influencing preglomeru - avoiding nephrotoxins, utilizing biocompatible PD fluids, lar vascular tone [47]. When preglomerular vasodilata- and incorporating renin–angiotensin–aldosterone sys- tion occurs, it enhances glomerular filtration, leading to tem (RAAS) inhibitors [16, 26, 35]. Within this complex increased sodium delivery to the macula densa within landscape, emerging evidence suggests that SGLT2 inhib- the juxtaglomerular apparatus [48, 49]. However, chronic itors might offer potential advantages in managing some hyperglycemia disrupts this process as the obligatory of the challenges associated with PD. reabsorption of sodium and glucose in the proximal tubule by SGLT2 results in reduced sodium delivery to Navigating SGLT2 inhibitors in CKD: insights for PD the distal tubule and macula densa [40, 49]. Treatment perspectives with SGLT2 inhibitors addresses this issue by attenu- SGLT2 inhibitors, a relatively recent class of pharma- ating glucose and sodium reabsorption in the proxi- cological agents initially designed for treating type 2 mal tubule, thereby maintaining sodium delivery to the diabetes mellitus (T2DM), primarily target the SGLT2 macula densa [47, 50]. Consequently, this prompts vaso- protein responsible for glucose reabsorption in the kid- constriction in the preglomerular afferent arterioles, ney’s proximal tubules [36–38]. The SGLT2 protein func - alleviating renal hyperfiltration and reducing glomerular tions by facilitating the reabsorption of glucose from pressure [51]. In a study by Thomson et al., diabetic rats the urine back into the bloodstream, and its mechanism given SGLT2 inhibitors showed a reduction of approxi- involves the coupled movement of sodium ions (Na ) mately 30% in proximal tubular sodium reabsorption, a and glucose [37, 39]. In the kidneys, glucose reabsorp- decrease in glomerular capillary hydrostatic pressure by tion is intertwined with the movement of Na , where 5–8 mmHg, and a decrease in measured GFR (mGFR) by + + the Na /K -ATPase at the basolateral membrane main- around 25% [50]. This study underscored the significance tains a lower Na concentration within tubular epithelial of TGF in responding to SGLT2 inhibition and suggested cells compared with the glomerular filtrate [39, 40]. Na that postglomerular vasorelaxation might contribute to passively moves into the cell along the electrochemical this response [50]. Clinical studies mirror these results, Stepanova Renal Replacement Therapy (2024) 10:5 Page 4 of 16 Fig. 1 Mechanistic perspectives of SGLT2 in the PD landscape demonstrating a transient decline in mGFR by 2–5  mL/ regardless of the individual’s hypertension status [59] and min/1.73  m upon SGLT2 inhibitor initiation, aligning is observed in patients with a low eGFR [45]. with the decrease in glomerular pressure in patients with type 1 diabetes mellitus (T1DM) exhibiting renal hyper- SGLT inhibitors, albuminuria, and kidney protection filtration (GFR ≥ 135 mL/min/1.73  m ) [47]. Patients with Clinical trials have consistently indicated that the use T2DM exhibited comparable reductions in glomerular of an SGLT2 inhibitor can provide kidney protection pressure [52, 53], and similar kidney-protective mecha- through a decreased rate of decline in eGFR and reduced nisms, including natriuresis-induced GFR dips, have onset or progression of albuminuria [6, 9, 60, 61]. The been demonstrated in non-diabetic patients with CKD pioneering CREDENCE trial was the first to explore the [54]. Therefore, SGLT2 inhibitors, through TGF, cause influence of SGLT2 inhibitors on kidney-related out - increased sodium passage along the nephron, sensed by comes [6]. Enrolling 4401 participants diagnosed with macula cells to constrict afferent glomerular arterioles, T2DM and albuminuric CKD, the trial included patients thereby protecting glomeruli by reducing intraglomeru- with an eGFR ranging from 30 to 90 mL/min/1.73  m and lar pressure. a urinary albumin-to-creatinine ratio (UACR) between Nevertheless, the influence of SGLT2 inhibitors tran - 300 and 5000  mg/g [6]. The participants were concur - scends the dynamics within the glomerulus to systemic rently on maximally tolerated background therapy with hemodynamics, resulting in a decrease in systolic blood renin–angiotensin system (RAS) inhibitors. The trial was pressure by approximately 3–6  mmHg and diastolic prematurely halted following a planned interim analysis blood pressure by around 1–2  mm Hg [46, 55]. This due to meeting preestablished efficacy criteria. Impor - hypotensive impact is orchestrated through mecha- tantly, the impact of SGLT2 inhibitors on kidney-related nisms such as natriuresis and associated plasma volume outcomes was consistent across diverse levels of renal contraction [56], mitigation of arterial stiffness [57], and function and albuminuria. The EMPA-KIDNEY trial enhancement of endothelial function [58]. Importantly, expanded the evidence supporting kidney protection to this reduction in blood pressure remains consistent the lowest eGFR range by including participants with S tepanova Renal Replacement Therapy (2024) 10:5 Page 5 of 16 or without T2DM and having an eGFR of 20–45  mL/ secretion by beta cells and insulin sensitivity in periph- min/1.73  m , regardless of albuminuria [9]. Alternatively, eral tissues [65, 66]. participants with an eGFR of 45–90  mL/min/1.73  m Additionally, SGLT2 inhibitors can induce weight and UACR ≥ 200  mg/g, who were already on maximally loss, a phenomenon well documented in various stud- tolerated RAS inhibitors were also enrolled. With 6609 ies involving patients with T2DM. For approved SGLT2 participants, this trial stands as the largest investigation inhibitors, an average weight loss of approximately of SGLT2 inhibitors in chronic kidney disease (CKD) 1.5–2 kg (placebo adjusted) is observed, and when com- patients. With a mean eGFR of 37.5 mL/min/1.73  m and bined with other drugs that possess anorectic effects or a median UACR of 412 mg/g, the trial provided compel- reduce hepatic glucose output, the weight loss can esca- ling evidence of efficacy, demonstrating a lower risk of late to 3–5 kg [67, 68]. CKD progression or death from cardiovascular causes Moreover, SGLT2 inhibitors exhibit noteworthy effects compared to the placebo [9]. on lipid metabolism, operating at various cellular levels A systematic review and meta-analysis of randomized [40, 69]. By diminishing lipid accumulation in visceral controlled trials revealed a statistically significant reduc - and subcutaneous fat, these inhibitors not only contrib- tion in albuminuria with SGLT2 inhibitors compared to ute to weight reduction but also bring about alterations placebo or active control, irrespective of the presence in body composition. They modulate key molecules or absence of renal dysfunction [62]. In a meta-analysis involved in lipid synthesis and oxidation, resulting in a using data from eligible cohorts in the Chronic Kidney decrease in circulating triglycerides and an increase in Disease Prognosis Consortium, Coresh et  al. demon- high-density lipoprotein cholesterol [69]. strated that SGLT2 inhibitors lowered albuminuria in A comprehensive meta-analysis of 60 randomized tri- patients with diabetic chronic kidney disease by at least als revealed that SGLT2 inhibition led to an increase in 30% over a 2-year period [61]. total, LDL, and HDL cholesterol while decreasing triglyc- The mechanisms underlying the beneficial effects of erides, with slight variations in effect sizes based on drug SGLT2 inhibitors on albuminuria and kidney function type, dosage, and ethnicity [70]. Consistent findings were in patients with CKD are not fully understood, but the reported in another systematic review and meta-analysis described mechanisms, such as a reduction in glomerular encompassing 48 randomized controlled trials, demon- hypertension and an improvement in tubular function, strating that SGLT2 inhibitors significantly increased have been proposed [60, 63]. Consequently, initiating total cholesterol, LDL cholesterol, non-HDL cholesterol, SGLT2 inhibition earlier in the progression of albuminu- and HDL cholesterol, while simultaneously decreasing ria yielded more favorable outcomes in terms of kidney triglycerides [71]. function preservation, as evidenced by the aforemen- tioned studies. This implies that protective effects on SGLT2 inhibitors and diuretic effect the kidneys can be realized irrespective of the extent of Although SGLT2 inhibitors are known to induce osmotic albuminuria. The presence of normo-albuminuria should diuresis and some natriuresis, their specific diuretic not be a justification for delaying treatment in conditions effects in patients with CKD are still being elucidated. prone to developing albuminuria, nor should it deter the Clinical studies have shown that SGLT2 increases urine initiation of treatment in conditions frequently associ- volume in patients with T2DM during the first few ated with non-albuminuric CKD, such as tubulointersti- days of treatment [72–74]. In the RECEDE-CHF trial, tial kidney disease [64]. which investigated the renal and cardiovascular effects The effects of SGLT2 inhibitors on kidneys in patients of SGLT2 inhibition in combination with loop diuret- with kidney failure are still uncertain. Nevertheless, a ics in patients with T2DM and chronic heart failure, retrospective study involving seven diabetic patients 26.1% of the recruited patients had CKD stage 3a (eGFR, undergoing incremental HD revealed the safety and 45–60 mL/min/1.73  m ) [75]. The study observed a mean effectiveness of SGLT2 inhibitors in preserving RKF and increase in 24-h urine volume of 535  ml 3  days after improving cardiovascular health [12]. This study indi - SGLT2 inhibitor initiation and 545 ml by 6 weeks in these cates that incorporating SGLT2 inhibitors into HD pro- patients, indicating a diuretic effect of SGLT2 inhibitors tocols may have the potential to alleviate interdialytic in the presence of CKD and heart failure [75]. weight gain and sustain RKF [12]. However, a comprehensive review of the diuretic effects of SGLT2 inhibitors highlighted the challenges in SGLT2 inhibitors and metabolic effects precisely quantifying the diuretic effect and the divergent The mitigation of chronic hyperglycemia and the alle - results from studies using indirect estimations [76]. The viation of glucose toxicity achieved through SGLT2 review emphasized that SGLT2 inhibitors present some inhibitors contribute to the enhancement of both insulin favorable properties compared with classical diuretics, Stepanova Renal Replacement Therapy (2024) 10:5 Page 6 of 16 such as reduced sympathetic activity, preserved potas- randomized double-blind study involving 42 patients sium balance, lower risk of acute kidney injury, and with T2DM found no significant effects on serum cal - decreased serum uric acid levels [76]. Another review cium [80]. The precise mechanisms underlying this phe - discussed the diuretic effects of SGLT2 inhibitors and nomenon are not fully understood, but it is speculated their influence on the renin–angiotensin system (RAS) to be associated with the osmotic diuresis induced by [77]. It was noted that the diuretic effects of SGLT2 SGLT2 inhibitors, potentially causing plasma volume inhibitors, including diuresis, natriuresis, and associated contraction and dehydration [78]. Additionally, SGLT2 body fluid loss, may activate the RAS, but these effects inhibitors might enhance intestinal and urinary calcium appear to be transient based on available data in patients absorption by inhibiting SGLT1, leading to carbohydrate with T2DM [77]. malabsorption and decreased pH, which could contrib- ute to increased calcium absorption [83]. SGLT2 inhibitors and serum electrolyte levels However, the most frequent clinical challenge in the SGLT2 inhibitors can cause a reduction in serum sodium care of patients with CKD poses hyperkalemia, and the levels due to their enhanced natriuresis effect [39]. This concern has been raised about the potential risk of hyper- effect is related to the inhibition of SGLT2 receptors, kalemia with the use of SGLT2 inhibitors in this popula- which promote glycosuria, natriuresis, and osmotic diu- tion [84, 85]. Nevertheless, existing evidence suggests resis, leading to changes in electrolyte levels [39, 78]. that SGLT2 inhibitors may influence potassium handling The reduction in serum sodium levels is usually mild by accelerating the rate of sodium and water delivery to and transient, and it is not a common side effect of the distal nephron, a pivotal regulator of kidney-medi- SGLT2 inhibitors [39, 79]. Apart from sodium, SGLT2 ated potassium handling [84, 86]. This mechanism could inhibitors may impact other electrolytes in patients with result in an augmentation of urinary potassium excretion, T2DM, including small increases in serum concentra- potentially impacting serum potassium levels [84–86]. tions of magnesium, phosphate and calcium [78, 80, 81]. Studies indicate that the use of SGLT2 inhibitors is safe In a recent meta-analysis involving 28,269 patients with in both diabetic and non-diabetic CKD patients, without T2DM and six SGLT2 inhibitors, an elevation in serum an increased risk of hyperkalemia [84, 85]. Illustratively, a magnesium by 0.07 mmol/L (95% CI, 0.06–0.08 mmol/L) recent meta-analysis encompassing 49,875 patients with and serum phosphate by 0.03  mmol/L (95% CI, 0.02– T2DM and elevated cardiovascular risk or CKD revealed 0.04 mmol/L) compared with placebo was demonstrated a significant reduction in the risk of severe hyperkalemia [81]. (≥ 6.0 mmol/L) with SGLT2 inhibitors, without a concur- The elevation in serum magnesium levels observed rent increase in the risk of hypokalemia [86]. with the use of SGLT2 inhibitors can be attributed to various mechanisms. These encompass the osmotic diu - SGLT2 inhibitors and anemia retic effect resulting from increased glucose excretion in SGLT2 inhibitors have also garnered attention for their the urine, causing heightened excretion of fluid and elec - potential impact on anemia in patients with CKD. Cur- trolytes, including magnesium, in the renal tubules [79]. rent evidence suggests that they may exhibit erythropoi- Additionally, SGLT2 inhibitors have demonstrated the etic effects, contributing to elevated hemoglobin levels ability to decrease the fractional excretion of magnesium, and potentially alleviating anemia in both diabetic and signifying enhanced tubular reabsorption [79, 82]. They non-diabetic CKD patients [87, 88]. In a recent study, induce magnesium reabsorption and contribute to extra- Osonoi et al. reported that dapagliflozin improves eryth - cellular fluid volume depletion by activating the renin– ropoiesis and iron metabolism in patients with T2DM angiotensin–aldosterone system [82]. Furthermore, these and anemia, suggesting that it has an erythropoietic inhibitors promote the upregulation of magnesium trans- effect and can help improve anemia in CKD [88]. A porters in the kidney or gut, leading to increased magne- recent post hoc analysis of the DELIGHT trial revealed sium reabsorption and diminished excretion [82]. that patients with T2DM and albuminuria, with a mean The elevation in serum phosphate concentration asso - eGFR level of 48.78 mL/min/1.73  m , treated with dapa- ciated with the use of SGLT2 inhibitors may result from gliflozin, experienced an increase in hemoglobin by increased renal tubular phosphate reabsorption, hormo- 5.7  g/L (95% CI 4.0, 7.3) and a reduction in ferritin by nal changes affecting phosphate regulation, such as para - 18.6% compared with the placebo group [89]. Another thyroid hormone (PTH) and fibroblast growth factor 23 post hoc analysis of DAPA-CKD demonstrated similar (FGF23), and direct pharmacological effects [79–81]. results, indicating that dapagliflozin was associated with The existing data on increased serum calcium levels the prevention or correction of anemia in patients with induced by SGLT2 inhibitors primarily stem from case CKD, both with and without T2DM. [87]. A comprehen- report studies [78, 83]. However, a placebo-controlled sive examination of both the mechanisms and clinical S tepanova Renal Replacement Therapy (2024) 10:5 Page 7 of 16 outcomes of the erythropoietic effects of SGLT2 inhibi - they influence the nod-like receptor (NLR) family pyrin tors and prolyl hydroxylase inhibitors in CKD and ane- domain containing 3 (NLRP3) inflammasome, contribute mia revealed that SGLT2 inhibitors lead to an increase to the modulation of ROS, and impact cellular calcium in hemoglobin levels of approximately 0.6–0.7 g/dL [90]. homeostasis, leading to an antiinflammatory and anti - Remarkably, the magnitude of this effect is comparable oxidative cellular environment [101, 102]. Furthermore, with that achieved with low-to-medium doses of prolyl SGLT2 inhibitors have demonstrated antiinflammatory hydroxylase inhibitors, and it remains evident even in effects by inhibiting lipopolysaccharide (LPS)-induced patients with advanced CKD [90]. Toll-like receptor 4 (TLR-4) overexpression and nuclear The proposed mechanism for the erythropoietic factor kappa B (NF-κB) activation in human endothelial effects of SGLT2 inhibitors revolves around the idea cells and differentiated macrophages [103]. that the heightened workload on renal tubule, caused by increased sodium delivery to the distal part after SGLT2 inhibition could induce renal medullary hypoxia [91]. Gastrointestinal insights into SGLT2 inhibitor effects This, in turn, is hypothesized to trigger the synthesis of One of the pivotal mechanisms through which SGLT2 erythropoietin, leading to an augmentation in hemo- inhibitors exert their effects in the gastrointestinal tract globin levels [92]. However, despite this hypothesis, the revolves around the impairment of small intestinal glu- magnetic resonance imaging study has not provided con- cose absorption [104]. This process facilitates the redirec - clusive evidence supporting the changes in renal cortical tion of glucose into the colon, culminating in an overall or medullary tissue oxygenation in healthy volunteers reduction in blood glucose levels, and is proposed to sup- undergoing SGLT2 inhibitor treatment [93]. This sug - press protein fermentation and the generation of uremic gests that the observed elevation in erythropoietin levels toxins such as phenols and indoles [104–106]. Treat- is likely influenced by the modulation of hypoxia-induci - ment with canagliflozin for 2 weeks significantly reduced ble factors, rather than direct evidence of renal hypoxia the plasma levels of p-cresyl sulfate and indoxyl sulfate [92]. in mice with kidney failure (compared with the vehicle group a 75% and 26% reduction, respectively) [105]. The hypothesized role of SGLT2 inhibition in fostering renal Antioxidant and antiinflammatory feathers of SGLT2 clearance of protein-bound uremic toxins adds a layer of inhibitors complexity to their gastrointestinal impact [104]. How- Research findings have consistently demonstrated the ever, although the initial findings are promising, there antioxidant and antiinflammatory effects of SGLT2 remains an urgent need for further experimental and inhibitors [94–97]. They function as indirect antioxidants clinical research to comprehensively unravel the effects by mitigating the oxidative stress induced by elevated of SGLT2 inhibitors on the production, toxicity, and glucose levels [95, 97]. Additionally, SGLT2 inhibitors elimination of gut-derived uremic toxins. exhibit the ability to reduce the generation of free radi- Beyond glucose regulation, SGLT2 inhibitors exhibit a cals, inhibit pro-oxidants, such as NADPH oxidase 4 and dual effect involving the heightened production of gas - thiobarbituric acid-reactive substances, and enhance trointestinal hormones, including glucagon-like peptide the expression of antioxidants, such as superoxide dis- 1 and peptide YY, which play a role in glucose regulation mutases and glutathione peroxidases [94, 98]. Further- and satiety [107, 108]. Concurrently, SGLT2 inhibitors more, studies have demonstrated a reduction in a wide influence intestinal bacterial flora, fostering an environ - array of pro-inflammatory cytokines, including interleu - ment characterized by a prevalence of balance-regu- kin 6 (IL-6), IL-1, tumor necrosis factor alpha (TNF-α), lating bacteria and an increase in short-chain fatty acid and others following SGLT2 inhibitor administration (SCFA)-producing bacteria [105, 109, 110]. In a recent [95–97, 99]. In a meta-analysis involving 6261 patients experimental study, Wu et  al. demonstrated the protec- with T2DM, treatment with SGLT2 inhibitors signifi - tive effect of dapagliflozin on diabetic kidney disease cantly lowered levels of serum ferritin, C-reactive pro- in db/db mice, which appears to be associated with a tein (CRP), and leptin compared to placebo or standard dynamic improvement in gut microbiota over time [111]. diabetes therapies [96]. While the precise mechanisms This improvement may be related to the effects of dapa - underlying the antioxidant and antiinflammatory effects gliflozin on the bile acid pool and its antioxidant activity of SGLT2 inhibitors remain unclear, studies have revealed [111]. In another diabetic nephropathy model, empagli- the intricate molecular pathways involved in these pro- flozin has also been shown to ameliorate T2DM-related cesses [94, 97, 99]. It has been suggested that SGLT2 diabetic nephropathy by altering the gut microbiota by inhibitors activate adenosine monophosphate-activated reducing LPS-producing bacteria and increasing SCFA- protein kinase, contributing to antiinflammatory effects producing bacteria in T2DM mice [112]. and the mitigation of oxidative stress [100]. Additionally, Stepanova Renal Replacement Therapy (2024) 10:5 Page 8 of 16 Cardiovascular protection by SGLT2 inhibitors PD‑specific effects of SGLT2 inhibitors The multifaceted effects of SGLT2 inhibitors described Several recent studies have shed light on the specific above offer a unique opportunity to address both the effects of SGLT2 inhibitors in the realm of PD. Despite local and systemic mechanisms involved in the patho- their somewhat limited scope, these studies indicate a genesis of CVD. These effects result in a reduction potential paradigm shift that could reshape our under- of preload and afterload by optimizing body weight, standing of the beneficial effects of SGLT2 inhibitors inducing osmotic diuresis, regulating intravascular vol- in addressing the distinctive challenges intrinsic to PD ume, influencing gut microbiota, enhancing endothelial (Table 1). function, and consequently mitigating vascular stiff - One of the primary focuses of these studies has been ness [1, 40, 92, 95, 112]. This collective action signifi - on the role of SGLT2 inhibitors in managing glucose cantly contributes to improved cardiac function—an absorption from PD solutions and, consequently, their especially pivotal aspect for patients with CKD who are impact on peritoneal solute and water transport. The predisposed to cardiovascular complications [1, 2, 7]. basis for these experiments stems from the finding that Beyond hemodynamic improvements, SGLT2 inhibi- human PMCs express GLUT1, GLUT3, SGLT1, and tors orchestrate a metabolic shift from free fatty acids SGLT2 receptors [121–123]. Therefore, SGLT2 inhibi - to glucose oxidation [69, 71]. This metabolic redirection tors may have the potential to influence peritoneal solute results in heightened cardiac ATP production, effec - and water transport. Supporting this hypothesis, Zhou tively preventing a decline in cardiac function [113]. et al. demonstrated a reduction in glucose uptake and an Numerous RCTs focusing on primary cardiovascular increase in ultrafiltration through the rat peritoneum, as outcomes, encompassing a substantial patient cohort well as an inhibition of glucose uptake by human PMCs with T2DM, provide compelling evidence of the signifi - mediated by empagliflozin [124]. Consistent results cant cardiovascular benefits of SGLT2 inhibitors [114– were found by Balzer [123] and Shentu [125], indicat- 116]. The outcomes reveal a noteworthy reduction in ing that SGLT2 inhibition in cellular and animal models the risk of heart failure, frequency of hospitalizations of PD was associated with reduced peritoneal fibrosis, due to heart failure, all-cause mortality, cardiovascu- decreased microvessel density, lower peritoneal glucose lar mortality and nonfatal myocardial infarction [113– absorption, and improved peritoneal ultrafiltration. In 117]. Although this robust evidence is less certain when contrast, Martus et  al. observed no significant effect of extrapolated to non-diabetic CKD [118, 119], a recent empagliflozin on changes in sodium or water transport meta-analysis conducted by Chen et  al., incorporating across the peritoneal membrane [126], and an increase in findings from 13 RCTs, concludes that SGLT2 inhibi - glucose concentration in the dialysate after 60 min of PD tors confer cardiovascular protection in CKD patients. dwell was observed only with phlorizin [127]. The analysis highlights a substantial reduction in the In addition to influencing peritoneal solute and water risk of cardiovascular disease, hospitalization for heart transport, the mentioned studies have shown that intra- failure, and all-cause mortality, all achieved without an peritoneal dapagliflozin alleviates peritoneal fibrosis in increased risk of serious adverse events and urinary a mouse model subjected to chronic exposure to high- tract infections [119]. Another meta-analysis involv- glucose dialysate [123]. The treatment with empagliflo - ing a total of 27,823 patients with stage 3–4 CKD found zin has led to a significant reduction in inflammatory that SGLT2 inhibitors significantly decreased the risk cytokine levels, including TNF-α, IL-1β, IL-6, and pro- of primary cardiovascular outcomes, and these benefits teins associated with transforming growth factor β (TGF- were consistent across different levels of kidney func - β)/Smad signaling, such as TGF-β1 and phosphorylated tion, even in stage 4 CKD [120]. The study highlighted Smad (p-Smad3) in both a mouse PD model and human the potential of SGLT2 inhibitors to reduce the risk of PMCs [125]. This effect may be attributed to the regula - adverse cardiovascular events in patients with poor tion of SGLT1 and SGLT2 in the peritoneal membrane, kidney function, which is particularly crucial given the as well as the suppression of glucose uptake and the inhi- increased risk of death and medical burden in this pop- bition of hypoxia-inducible factor 1 α (HIF-1α) [128]. ulation [120]. As ongoing research continues to unravel Canagliflozin significantly decreased HIF-1α abundance, the intricate mechanisms at play, the integration of inhibited TGF-β/p-Smad3 signaling, and decreased the SGLT2 inhibitors into the therapeutic landscape holds expression of fibrotic proteins (fibronectin, COL1A2, and significant promise for enhancing cardiovascular out - α-SMA) in human PMCs and rats exposed to chronic comes in CKD. high glucose [128]. Balzer et  al. have demonstrated that dapagliflozin reduced monocyte chemoattractant pro - tein-1 (MCP-1) specifically in the presence of a high- glucose environment within mesothelial cells [123]. S tepanova Renal Replacement Therapy (2024) 10:5 Page 9 of 16 Table 1 Summary of evidence on the role of SGLT2 inhibitors in PD Study Subjects SGLT2 inhibitors Key findings Alhwiesh et al. [129] 50 patients with T2DM on insulin, who were treated Dapagliflozin Decrease in insulin requirement by 2.6 units, HbA1c with APD by 1.6%, body weight by 2.6 kg, fasting blood glucose by 36.4 mg/dL, serum CRP by 2.0 mg/dL, serum ferritin by 261.3 µg/L, and mean systolic blood pressure by 14 mmHg; increase in urine volume by 253.2 mL/24 h, ultrafiltration volume by 229.9 mL. No effect on the status of the high-glucose transporter Lai et al. [130] 4 patients treated with PD Dapagliflozin Increase in peritoneal ultrafiltration Zhou et al. [124] Rat PD model Empagliflozin Reduction in glucose uptake and increase in ultrafiltra- tion through the rat peritoneum. Inhibition of glucose uptake by human PMCs Martus et al. [126] Rat PD model Empagliflozin Increased urinary glucose excretion and decreased plasma glucose levels after PD. No significant changes in sodium or water transport across the peritoneal membrane Martus et al. [127] Rat PD model Phlorizin Increase in urinary glucose excretion, decrease in plasma glucose, and increase in plasma creati- nine after PD. Increase in glucose concentration in the dialysate after 60 min and no difference after 120 min Balzer et al. [123] Mouse model of chronic peritoneal exposure Dapagliflozin Reduced PDE–TGF-β concentrations, peritoneal to high-glucose dialysate and human peritoneal thickening and fibrosis, and microvessel density, lead- samples in vitro ing to improved ultrafiltration. In vitro, dapagliflozin reduced the release of MCP-1. No effect on the status of the high-glucose transporter Shi et al. [98] Rat PD model and human PMCs in vitro Empagliflozin Improvement of peritoneal function, reduction of the thickness of the peritoneum and improvement of collagen accumulation. Inhibition of high glucose- induced EMT and oxidative stress by activating the Nrf2/HO-1 signaling pathway Shentu et al. [125] Mouse PD model and human PMCs in vitro Empagliflozin Protective effect on high glucose-induced perito - neal fibrosis by suppressing TGF-β/Smad signaling: reducing levels of inflammatory cytokines ( TNF-α, IL-1β, IL-6), TGF-β1, α-smooth muscle actin, collagen I and p-Smad3 accumulation in PMCs Wang et al. [128] Rat PD model and human PMCs in vitro Canagliflozin Improvement of peritoneal fibrosis and function by ameliorating peritoneal hypoxia and inhibiting the HIF-1α/TGF-β/p-Smad3 signaling pathway APD automated peritoneal dialysis, EMT epithelial to mesenchymal transformation, HbA1c hemoglobin A1c, HIF-1α hypoxia-inducible factor 1-alpha, IL interleukin, MCP-1 monocyte chemoattractant protein 1, PD peritoneal dialysis, PDE peritoneal dialysis effluent, PMCs peritoneal membrane cells, p-Smad3 phosphorylated Smad3, TGF-β transforming growth factor beta, TNF-α tumor necrosis factor alpha Furthermore, SGLT2 inhibition significantly decreased integrity of the peritoneum [98]. The antifibrogenic, anti - both MCP-1 and TNF-α in the presence of an inflamma - inflammatory, and antioxidant properties exhibited by tory stimulus such as LPS, suggesting the potential anti- SGLT2 inhibitors may have profound implications for inflammatory effects of SGLT2 inhibitors [123]. maintaining the integrity of the peritoneal membrane Moreover, Shi et  al. demonstrated the ability to miti- and, consequently, enhancing the longevity of the PD gate inflammatory signaling pathways activated by ROS, technique. which could be a key mechanism contributing to the Considering the limited number and experimental reduction of peritoneal inflammation in patients under - nature of the aforementioned studies, it is important to going PD [98]. High glucose can induce oxidative stress highlight two pioneering clinical studies. One involved 50 in PMCs and stimulate EMT, leading to peritoneal fibro - patients undergoing PD [129], while the other provided sis [26]. Empagliflozin has been found to inhibit high details on four clinical cases [130]. Notably, both studies glucose-induced EMT and reduce oxidative stress via the utilized dapagliflozin off-label, and neither study reported Nrf2/HO-1 signaling pathway in human and rat PMCs, any adverse effects. Alhwiesh et  al. demonstrated that a potentially protecting the structural and functional dose of 10  mg/day dapagliflozin significantly reduced Stepanova Renal Replacement Therapy (2024) 10:5 Page 10 of 16 insulin requirements, HbA1c, body weight, systolic blood glucose metabolism in diabetes, coupled with the pressure, blood glucose, and serum uric acid levels [129]. unique challenges of PD, may elevate susceptibility to Additionally, it increased urine and peritoneal ultrafiltra - EKA. However, on the flip side, as the glycosuric impact tion volumes in patients with insulin-dependent T2DM of SGLT2 inhibitors diminishes beyond stage 3 CKD, treated with automated PD [129]. However, the authors concerns regarding EKA are unlikely to be applicable did not observe any changes in the peritoneal transport to the PD population. Nevertheless, due to the absence status in these patients. Lai et  al. administered a daily of prior clinical trials investigating SGLT2 inhibitors dose of 5 mg dapagliflozin to four overhydrated patients in patients undergoing PD, it remains unclear whether undergoing PD for a duration of 14–28 days, continuing their use would increase the risk of EKA, for example, until a euvolemic status was achieved [130]. In line with a in patients with preserved RKF. report by Alhwiesh et al., all the patients demonstrated a The second concern involves the potential risk of PD- significant increase in peritoneal ultrafiltration rate [130]. associated infections. SGLT2 inhibitors are recognized Although these preliminary experimental and clini- for elevating the likelihood of genital and urinary tract cal results are promising, the inclusion of SGLT2 inhibi- infections [132, 133], with genital mycotic infections tors in PD protocols must be approached with caution. and urinary tract infections being the most frequently Robust clinical trials are required to confirm the benefits reported adverse effects [139, 140]. The incidence of and risks of SGLT2 inhibitors in patients undergoing PD. genital yeast infections associated with SGLT2 inhibi- tors is reported to be approximately three times higher compared with other treatments [141]. The adjusted Safety concerns in SGLT2 inhibitor utilization for PD incidence is reported as 135.5 per 1000 person-years for Despite the consistently favorable safety profile of SGLT2 SGLT2 inhibitors, contrasting with 48.5 per 1000 person- inhibitors in CKD [4, 35, 131] and the absence of prior years for alternative treatments, resulting in an excess clinical trials in PD, it is prudent to acknowledge that risk of 87.6 per 1000 person-years [141]. Importantly, the the reported side effects in broader patient populations risk of genital infections remains consistent across vari- may have relevance to PD patients. Adverse events such ous SGLT2 inhibitors and persists throughout the dura- as hypotension, hypoglycemia, infections, limb amputa- tion of therapy [141]. In addition, female sex, diabetes tions, bone fractures, and euglycemic ketoacidosis (EKA) duration of more than 10  years, and a previous genital have been documented in the product information pro- infection are risk factors that contribute to an increased vided by regulatory agencies and reported in multiple risk of infection [140, 142]. Considering the above, sev- systematic reviews and meta-analyses [132–134]. These eral factors might contribute to an elevated risk of PD- reported adverse events vary among different SGLT2 related infections in patients using SGLT2 inhibitors. inhibitors and depend on factors such as sex, the pres- In PD, where the peritoneal membrane is consistently ence of diabetes, and concurrent glucose-lowering ther- exposed to glucose-based solutions, the utilization of apy [133, 134]. Although most of these events (EKA, SGLT2 inhibitors may lead to an increase in glucose lev- amputations, and Fournier gangrene) are rare, they can els in the peritoneal cavity, particularly within the initial lead to serious and dangerous complications [132–134]. 60  min [127]. This heightened concentration of glucose In the context of PD, three of the mentioned challenges could provide a favorable environment for the growth of in SGLT2 inhibitor utilization may pose specific risks and microorganisms, potentially amplifying the risk of peri- should be detailed. toneal infections. Furthermore, PD patients encounter a EKA is a recognized complication of therapy with direct entry point for microorganisms into the peritoneal SGLT2 inhibitors and can occur in patients with normal cavity through the PD catheter. The presence of a higher or only slightly elevated plasma glucose concentrations, glucose peritoneal environment and the catheter may presenting a particular problem for individuals with potentially augment vulnerability to infections. Despite preexisting CKD [135, 136]. In patients undergoing PD, the minimal glycosuric effect of SGLT2 inhibitors in continuous exposure of the peritoneal membrane to patients with kidney failure, PD patients are already con- glucose-based PD solutions, along with the glycosuric fronted with an increased risk of infection. The suscepti - effect of SGLT2 inhibitors, may create an environment bility to genital and urinary tract infections may further conducive to metabolic imbalances, contributing to escalate the overall infection risk, including the poten- the risk of EKA [137]. Additionally, the higher propor- tially life-threatening complication of fungal PD-related tion of diabetic patients undergoing PD adds another peritonitis. It is essential to emphasize that these poten- layer of complexity. Diabetic patients already face an tial risks are theoretical, and there is a lack of empirical increased risk of metabolic disturbances, and the addi- evidence supporting an augmented risk of PD-associated tion of SGLT2 inhibitors may further accentuate this infections specifically related to SGLT2 inhibitors. risk [138]. The theoretical synergistic effect of altered S tepanova Renal Replacement Therapy (2024) 10:5 Page 11 of 16 Another significant issue is the possible impact of effects of SGLT2 inhibitors, including metabolic modu - SGLT2 inhibitors on CKD-associated mineral and bone lation, hypotensive, diuretic, antianemic, antioxidant, metabolism (MBD) in patients undergoing PD. Bone and antiinflammatory properties, along with their fractures are a recognized adverse effect of SGLT2, espe - protective impact on the peritoneal membrane and, cially in patients aged over 65 with both diabetes and consequently, solute and water transport, suggest a CKD [133, 134, 139, 143]. Several hypothesized mecha- promising avenue for addressing challenges unique to nisms suggest that SGLT2 inhibitors can directly influ - PD. The observed renal and cardiovascular benefits in ence calcium–phosphate balance and indirectly increase patients with T2DM and CKD underscore the poten- bone turnover by promoting weight loss [144]. The ele - tial of SGLT2 inhibitors to preserve RKF and mitigate vation in serum phosphate levels, a known class effect cardiovascular complications in this patient population. of SGLT2 inhibitors, is likely facilitated by increased Moreover, two preliminary clinical studies reported phosphate transport in the proximal tubule, leading to positive outcomes with the use of SGLT2 inhibitors, enhanced phosphate reabsorption and urinary calcium showing increased peritoneal ultrafiltration and other excretion due to sodium loss [144, 145]. This increase in benefits similar to the general CKD population. phosphate levels is thought to stimulate FGF23, result- However, caution is warranted given the need for ing in phosphaturia and the inhibition of 1.25-dihy- rigorous investigation into dosing, long-term safety, droxyvitamin D to maintain the phosphate balance. In and patient-specific factors through comprehensive a randomized crossover study involving healthy volun- clinical trials. Currently, five registered clinical trials teers using canagliflozin, the administration of 300  mg/ focused on PD are underway, aiming to address perito- day triggered the FGF23/1,25-dihydroxyvitamin D/PTH neal glucose uptake, mechanisms and safety of SGLT2 axis, leading to increased serum phosphate levels, plasma inhibition, and the impact on ultrafiltration among PD FGF23, and PTH, coupled with a decrease in 1,25-dihy- patients: (1) “Reduction of Peritoneal Glucose Uptake droxyvitamin D [144]. Although there is controversy sur- With the Use of SGLT2 in Humans Undergoing Perito- rounding the evidence that SGLT2 inhibitors cause bone neal Dialysis Treatment” (NCT05250752), (2) “Mecha- fractures [145, 146], the complex interplay of these fac- nisms and Safety of SGLT2 Inhibition in Peritoneal tors may have implications for mineral and bone health Dialysis” (NCT05715814), (3) “The Effect of Dapagli - in patients undergoing PD who already have MBD-CKD. flozin on Ultrafiltration Among Peritoneal Dialysis Lastly, some other potentially less serious problems Patients” (NCT04923295), (4) “Effect of Empagliflozin would require continuous monitoring, such as blood on Peritoneal and Kidney Function in End Stage Renal pressure, fluid and electrolyte balance, blood glucose Disease (EMPA-PD)” (NCT05671991), and (5) “The control, and drug interactions. SGLT2 inhibitors induce effects of empagliflozin on ultrafiltration in patients osmotic diuresis, which leads to increased urinary glu- with peritoneal dialysis” (jRCTs051230081). These trials cose excretion and fluid loss [39]. This diuretic effect are anticipated to provide comprehensive insights into may affect fluid status, potentially causing dehydration or the integration of SGLT2 inhibitors into PD protocols. affecting ultrafiltration requirements during PD. In addi - To address the potential risks associated with SGLT2 tion, the prescription of SGLT2 inhibitors in PD patients inhibitors in PD, such as EKA, infections, and effects may require adjustment of antihypertensive and/or dia- on MBD, focused attention is essential. Future research betic treatment due to their antihypertensive effect and should elucidate the underlying mechanisms and guide potential impact on peritoneal membrane function and risk mitigation strategies tailored to patients undergo- fluid balance [2, 147]. As PD patients often take multiple ing PD, acknowledging the heterogeneity of this popu- medications, it is important to consider potential inter- lation. Individualized approaches to prescribing SGLT2 actions between SGLT2 inhibitors and other prescribed inhibitors, considering factors such as age, diabetes medications [148]. Regular and careful monitoring is status, and PD-associated risks, should be explored. essential for optimal management of these various fac- Continuous monitoring of vital factors, including blood tors in PD patients treated with SGLT2 inhibitors. pressure, fluid and electrolyte balance, blood glucose control, and potential drug interactions, is paramount. The development of comprehensive management pro - Conclusions and future perspectives tocols will ensure the optimal and safe utilization of This review presents a compelling case for the potential SGLT2 inhibitors in PD. Longitudinal studies assess- integration of SGLT2 inhibitors into the management ing the extended safety profile of SGLT2 inhibitors in of patients undergoing PD, extending beyond their PD, particularly their impact on peritoneal membrane established benefits in patients with T2DM, non-dia - integrity and patient outcomes, will be instrumental in betic CKD, and cardiovascular health. The multifaceted establishing the long-term viability of these agents. Stepanova Renal Replacement Therapy (2024) 10:5 Page 12 of 16 References Together, while the initial evidence is promising, the inte- 1. Kansara A, Mubeen F, Shakil J. 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Diabetes Epidemiol Manag. 2022;7:100082. https:// doi. org/ 10. 1016/j. deman. 2022. 100082. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Renal Replacement Therapy Springer Journals

SGLT2 inhibitors in peritoneal dialysis: a promising frontier toward improved patient outcomes

Renal Replacement Therapy , Volume 10 (1) – Jan 31, 2024

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References (127)

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10.1186/s41100-024-00523-5
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Abstract

Peritoneal dialysis (PD) stands as an important modality among kidney replacement therapies for end-stage kidney disease, offering patients remarkable flexibility and autonomy. Despite its widespread use, challenges such as glu- cose-related complications, peritoneal membrane fibrosis, declining renal function, and cardiovascular risks persist, necessitating innovative therapeutic approaches. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed for treating type 2 diabetes mellitus, have recently shown promise as add-on therapy for patients with dia- betic and non-diabetic chronic kidney disease (CKD), even in advanced stages. This review describes the potential role of SGLT2 inhibitors as a breakthrough therapeutic option in PD, emphasizing their ability to address unmet clinical needs and improve patient outcomes. The multiple effects of SGLT2 inhibitors in CKD, including metabolic modulation, antihypertensive, diuretic, anemia-reducing, antioxidant, and antiinflammatory properties, are reviewed in the context of PD challenges. Additionally, the potentially protective influence of SGLT2 inhibitors on the integrity of the peritoneal membrane and the transport of solutes and water in the peritoneum are emphasized. Despite these encouraging results, the paper highlights the potential risks associated with SGLT2 inhibitors in PD and emphasizes the need for cautious and thorough investigation of dosing, long-term safety considerations, and patient-specific factors through comprehensive clinical trials. Looking forward, the review argues for well-designed studies to evaluate the expanded safety profile of SGLT2 inhibitors in PD, with particular attention paid to peritoneal membrane integrity and overall patient outcomes. Keywords Sodium–glucose cotransporter 2 inhibitors, Peritoneal dialysis, Benefits, Risks Background nonglycemic effects that intricately improve glomerular Sodium–glucose cotransporter 2 (SGLT2) inhibitors hemodynamics, modulate volume status, and influence have emerged as potential game changers in the man- local and systemic factors in CKD and cardiovascular agement of chronic kidney disease (CKD), showcasing disease (CVD) pathogenesis [1–3]. Robust evidence not only remarkable glycemic control but also profound from pivotal trials, such as SCORED, CREDENCE, and DAPA-CKD, demonstrates that SGLT2 inhibi- tors may prevent the development of CKD, delay the worsening of CKD, and reduce the risk of adverse car- *Correspondence: Natalia Stepanova diovascular events in patients with moderate-to-severe nmstep88@gmail.com CKD, including those without diabetes [4–6]. These Department of Nephrology and Dialysis, State Institution “O.O. Shalimov groundbreaking findings have prompted the expansion National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine”, Heroes of Sevastopol 30, of approved clinical indications for SGLT2 inhibitors, Kyiv 03680, Ukraine now encompassing patients with CKD, with or without © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Stepanova Renal Replacement Therapy (2024) 10:5 Page 2 of 16 diabetes, as well as those contending with heart fail- PD realities: a brief overview of the main benefits ure, with or without reduced ejection fraction [1, 2, 7, and challenges 8]. However, it is worth noting that the trials’ lowest PD emerges as a valuable modality for managing kid- estimated glomerular filtration rate (eGFR) inclusion ney failure, offering numerous advantages, such as criterion was 20 mL/min/1.73  m [9], leaving an unan- home treatment convenience, enhanced quality of life, swered query about the feasibility and safety of SGLT2 cost effectiveness in most countries, technical simplic - inhibitor prescription in patients with end-stage kidney ity, a slower decline in residual kidney function (RKF) disease (ESKD). compared with hemodialysis (HD), and improved sur- The existing evidence for the potential benefits of vival, especially in the initial years of therapy initiation SGLT2 inhibitors in patients with ESKD is limited, [13, 14]. However, these benefits are accompanied by a primarily originating from post hoc analyses of ran- distinctive set of challenges, including issues common domized clinical trials (RCTs), preclinical studies, or to the broader dialysis population due to kidney failure case reports. These investigations lend credence to the and specific intricacies unique to PD [13, 14]. Key chal- notion that, even with minimal diuresis and anticipated lenges shared with the HD population encompass a minimal delivery to the transporter in dialysis patients, decline in RKF, overhydration, hypertension, metabolic SGLT2 inhibitors may exert direct and indirect effects, disturbances, dyslipidemia, electrolyte imbalances, ane- offering potential protection against cardiovascular mia, oxidative stress, and chronic inflammation [13, 14]. events and mortality [10–12]. For example, the post hoc These challenges significantly contribute to heightened analysis of the DAPA-CKD study revealed that 14.5% of morbidity and mortality among patients undergoing patients, irrespective of diabetes status, exhibited CKD PD. For instance, patients on PD commonly experience stage 4 (eGFR < 30  mL/min/1.73  m ) [10]. Dapagliflo - a gradual decline in RKF, influenced by factors inher - zin demonstrated both safety and a significant reduc - ent to kidney failure and the dialysis process [15]. While tion in major kidney and cardiovascular events, while kidney replacement therapy typically begins at an eGFR mitigating progressive eGFR reduction [10]. Similar of 5–10 mL/min/1.73  m , most patients initiating dialy- promising outcomes emerged from a post hoc analysis sis possess some level of RKF [15, 16]. However, over of CREDENCE data, indicating a potential slowing of time, there has been a gradual decline in RKF, contrib- CKD progression, even in cases of advanced diabetic uting to increased morbidity and mortality among dialy- nephropathy [11]. sis patients [15–17]. Preserving RKF in patients treated Despite these promising findings, a critical gap per - with PD has demonstrated significant associations with sists in our understanding of the feasibility and safety reduced incidences of infections, depression, improved of prescribing SGLT2 inhibitors to patients with ESKD, nutrition, better volume and blood pressure control, as including those undergoing peritoneal dialysis (PD). well as diminished requirements for erythropoietin, and The nature of PD and its associated complications sug - decreased chronic inflammation [16–18]. This, in turn, gest several potential positive effects of SGLT2 inhi - holds the potential to lead to lower rates of PD technique bition, expounded upon in this review. This review failure and improved cardiovascular outcomes [16, 17, navigates through the multifaceted benefits that SGLT2 19]. Overhydration [20, 21], anemia [22], dyslipidemia inhibitors might confer in patients undergoing PD. [23, 24], and chronic inflammation [25] have also been Preservation of residual kidney function (RKF) and associated with PD technique failure and an increased prevention of volume depletion, pivotal factors influ - risk of all-cause and cardiovascular morbidity and mor- encing patient outcomes in PD, are scrutinized in light tality among PD patients. of the renoprotective effects attributed to SGLT2 inhib - PD-specific challenges encompass concerns related to itors. Improved control of glycemia and lipid levels, glucose absorption from PD solutions, PD-associated antiinflammatory effects, and potential cardiovascular infections and the longevity of the peritoneal mem- advantages are among the discussed potential benefits. brane [25–27]. Long-term exposure to glucose-based Concurrently, the impact of these agents on the perito- PD solutions and the accumulation of advanced glyca- neal membrane, a critical component in the success of tion end-products in the peritoneal membrane, due PD, is examined to determine whether SGLT2 inhibi- to prolonged exposure to glucose-based PD solutions, tors hold promise in maintaining peritoneal membrane have been proven to be associated with peritoneal mem- integrity. However, every therapeutic intervention brane damage and fibrosis, leading to the loss of peri - introduces a set of considerations, and SGLT2 inhibi- toneal ultrafiltration and technique failure [26, 28, 29]. tors are no exception. This review aims to dissect the Moreover, chronic exposure to hyperglycemic PD solu- intricate interplay between the potential benefits and tions induces oxidative stress in peritoneal mesothelial risks associated with the use of SGLT2 inhibitors in PD. cells (PMCs), causing them to generate a considerable S tepanova Renal Replacement Therapy (2024) 10:5 Page 3 of 16 amount of reactive oxygen species (ROS), which initiate gradient, and glucose enters the cell alongside Na in a downstream inflammatory signaling pathways, increase 1:1 ratio through the SGLT, following the N a concen- the expression of fibrogenic factors and enhance the pro - tration gradient. Subsequently, it exits the cell passively cess of epithelial-to-mesenchymal transition (EMT) [26, through basolateral glucose transporter 2 (GLUT2) [39]. 29, 30]. Consequently, this cascade of events leads to the SGLT2, primarily expressed in the kidney and located development and accelerated progression of peritoneal in the brush border membrane of the S1 segment of fibrosis [26, 28, 30]. Therefore, minimizing the glucose renal tubules, is a low-affinity, high-capacity transporter load and optimizing the biocompatibility of PD solutions responsible for approximately 90% of glucose reabsorp- are essential for preserving the longevity of the peritoneal tion [40–42]. Inhibiting SGLT2 thus reduces the reab- membrane and, consequently, PD technique survival. sorption of N a and glucose in the proximal tubule, Another major problem in PD is PD-related infections, thereby decreasing blood glucose levels [2, 43]. which affect clinical outcomes, such as peritoneal ultrafil - Studies have demonstrated that SGLT2 inhibitors can tration, technique failure, and cardiac and overall patient lower hemoglobin A1c (HbA1c) by 0.6–1% and preserve mortality [25, 31, 32]. Infection-related PD technique kidney function in T2DM patients [2, 43]. The result - failure has been associated with an increased risk of mor- ing glucosuria can exceed 100  g/d in T2DM patients tality, with 30% of patients dying within the first 2  years and ranges from 50 to 60  g/d in those without diabe- of PD technique failure [32]. The number of peritonitis tes [44, 45]. While glucosuric efficacy diminishes with a episodes has been shown to correlate with a decrease in decline in estimated glomerular filtration rate (eGFR) and RKF [33] and even a single episode of peritonitis leads to becomes minimal when eGFR falls below 30 ml/min per an increase in small solute transport and a decrease in the 1.73 m [2, 46], SGLT2 inhibitors offer various benefits ultrafiltration rate [34]. These challenges underscore the beyond glycemic control, underscoring their relevance in intricate balance required in managing patients under- the comprehensive management of patients with CKD [2, going PD to optimize the benefits of the modality while 7, 8]. The existing knowledge of the advantages of SGLT2 effectively addressing the unique hurdles it presents. inhibitors in the broader CKD population, as outlined However, the current strategies to preserve RKF, reduce below, may offer valuable perspectives for the manage - high glucose-induced transformation of the peritoneal ment of patients undergoing PD (Fig. 1). membrane, and consequently prolong PD treatment and patient survival are presently limited [13, 16, 35]. These SGLT2 inhibitors and hemodynamic regulation strategies include practices such as restricting the use The tubuloglomerular feedback (TGF) signaling pathway of hyperglycemic PD solutions, preventing peritonitis, is crucial in regulating GFR by influencing preglomeru - avoiding nephrotoxins, utilizing biocompatible PD fluids, lar vascular tone [47]. When preglomerular vasodilata- and incorporating renin–angiotensin–aldosterone sys- tion occurs, it enhances glomerular filtration, leading to tem (RAAS) inhibitors [16, 26, 35]. Within this complex increased sodium delivery to the macula densa within landscape, emerging evidence suggests that SGLT2 inhib- the juxtaglomerular apparatus [48, 49]. However, chronic itors might offer potential advantages in managing some hyperglycemia disrupts this process as the obligatory of the challenges associated with PD. reabsorption of sodium and glucose in the proximal tubule by SGLT2 results in reduced sodium delivery to Navigating SGLT2 inhibitors in CKD: insights for PD the distal tubule and macula densa [40, 49]. Treatment perspectives with SGLT2 inhibitors addresses this issue by attenu- SGLT2 inhibitors, a relatively recent class of pharma- ating glucose and sodium reabsorption in the proxi- cological agents initially designed for treating type 2 mal tubule, thereby maintaining sodium delivery to the diabetes mellitus (T2DM), primarily target the SGLT2 macula densa [47, 50]. Consequently, this prompts vaso- protein responsible for glucose reabsorption in the kid- constriction in the preglomerular afferent arterioles, ney’s proximal tubules [36–38]. The SGLT2 protein func - alleviating renal hyperfiltration and reducing glomerular tions by facilitating the reabsorption of glucose from pressure [51]. In a study by Thomson et al., diabetic rats the urine back into the bloodstream, and its mechanism given SGLT2 inhibitors showed a reduction of approxi- involves the coupled movement of sodium ions (Na ) mately 30% in proximal tubular sodium reabsorption, a and glucose [37, 39]. In the kidneys, glucose reabsorp- decrease in glomerular capillary hydrostatic pressure by tion is intertwined with the movement of Na , where 5–8 mmHg, and a decrease in measured GFR (mGFR) by + + the Na /K -ATPase at the basolateral membrane main- around 25% [50]. This study underscored the significance tains a lower Na concentration within tubular epithelial of TGF in responding to SGLT2 inhibition and suggested cells compared with the glomerular filtrate [39, 40]. Na that postglomerular vasorelaxation might contribute to passively moves into the cell along the electrochemical this response [50]. Clinical studies mirror these results, Stepanova Renal Replacement Therapy (2024) 10:5 Page 4 of 16 Fig. 1 Mechanistic perspectives of SGLT2 in the PD landscape demonstrating a transient decline in mGFR by 2–5  mL/ regardless of the individual’s hypertension status [59] and min/1.73  m upon SGLT2 inhibitor initiation, aligning is observed in patients with a low eGFR [45]. with the decrease in glomerular pressure in patients with type 1 diabetes mellitus (T1DM) exhibiting renal hyper- SGLT inhibitors, albuminuria, and kidney protection filtration (GFR ≥ 135 mL/min/1.73  m ) [47]. Patients with Clinical trials have consistently indicated that the use T2DM exhibited comparable reductions in glomerular of an SGLT2 inhibitor can provide kidney protection pressure [52, 53], and similar kidney-protective mecha- through a decreased rate of decline in eGFR and reduced nisms, including natriuresis-induced GFR dips, have onset or progression of albuminuria [6, 9, 60, 61]. The been demonstrated in non-diabetic patients with CKD pioneering CREDENCE trial was the first to explore the [54]. Therefore, SGLT2 inhibitors, through TGF, cause influence of SGLT2 inhibitors on kidney-related out - increased sodium passage along the nephron, sensed by comes [6]. Enrolling 4401 participants diagnosed with macula cells to constrict afferent glomerular arterioles, T2DM and albuminuric CKD, the trial included patients thereby protecting glomeruli by reducing intraglomeru- with an eGFR ranging from 30 to 90 mL/min/1.73  m and lar pressure. a urinary albumin-to-creatinine ratio (UACR) between Nevertheless, the influence of SGLT2 inhibitors tran - 300 and 5000  mg/g [6]. The participants were concur - scends the dynamics within the glomerulus to systemic rently on maximally tolerated background therapy with hemodynamics, resulting in a decrease in systolic blood renin–angiotensin system (RAS) inhibitors. The trial was pressure by approximately 3–6  mmHg and diastolic prematurely halted following a planned interim analysis blood pressure by around 1–2  mm Hg [46, 55]. This due to meeting preestablished efficacy criteria. Impor - hypotensive impact is orchestrated through mecha- tantly, the impact of SGLT2 inhibitors on kidney-related nisms such as natriuresis and associated plasma volume outcomes was consistent across diverse levels of renal contraction [56], mitigation of arterial stiffness [57], and function and albuminuria. The EMPA-KIDNEY trial enhancement of endothelial function [58]. Importantly, expanded the evidence supporting kidney protection to this reduction in blood pressure remains consistent the lowest eGFR range by including participants with S tepanova Renal Replacement Therapy (2024) 10:5 Page 5 of 16 or without T2DM and having an eGFR of 20–45  mL/ secretion by beta cells and insulin sensitivity in periph- min/1.73  m , regardless of albuminuria [9]. Alternatively, eral tissues [65, 66]. participants with an eGFR of 45–90  mL/min/1.73  m Additionally, SGLT2 inhibitors can induce weight and UACR ≥ 200  mg/g, who were already on maximally loss, a phenomenon well documented in various stud- tolerated RAS inhibitors were also enrolled. With 6609 ies involving patients with T2DM. For approved SGLT2 participants, this trial stands as the largest investigation inhibitors, an average weight loss of approximately of SGLT2 inhibitors in chronic kidney disease (CKD) 1.5–2 kg (placebo adjusted) is observed, and when com- patients. With a mean eGFR of 37.5 mL/min/1.73  m and bined with other drugs that possess anorectic effects or a median UACR of 412 mg/g, the trial provided compel- reduce hepatic glucose output, the weight loss can esca- ling evidence of efficacy, demonstrating a lower risk of late to 3–5 kg [67, 68]. CKD progression or death from cardiovascular causes Moreover, SGLT2 inhibitors exhibit noteworthy effects compared to the placebo [9]. on lipid metabolism, operating at various cellular levels A systematic review and meta-analysis of randomized [40, 69]. By diminishing lipid accumulation in visceral controlled trials revealed a statistically significant reduc - and subcutaneous fat, these inhibitors not only contrib- tion in albuminuria with SGLT2 inhibitors compared to ute to weight reduction but also bring about alterations placebo or active control, irrespective of the presence in body composition. They modulate key molecules or absence of renal dysfunction [62]. In a meta-analysis involved in lipid synthesis and oxidation, resulting in a using data from eligible cohorts in the Chronic Kidney decrease in circulating triglycerides and an increase in Disease Prognosis Consortium, Coresh et  al. demon- high-density lipoprotein cholesterol [69]. strated that SGLT2 inhibitors lowered albuminuria in A comprehensive meta-analysis of 60 randomized tri- patients with diabetic chronic kidney disease by at least als revealed that SGLT2 inhibition led to an increase in 30% over a 2-year period [61]. total, LDL, and HDL cholesterol while decreasing triglyc- The mechanisms underlying the beneficial effects of erides, with slight variations in effect sizes based on drug SGLT2 inhibitors on albuminuria and kidney function type, dosage, and ethnicity [70]. Consistent findings were in patients with CKD are not fully understood, but the reported in another systematic review and meta-analysis described mechanisms, such as a reduction in glomerular encompassing 48 randomized controlled trials, demon- hypertension and an improvement in tubular function, strating that SGLT2 inhibitors significantly increased have been proposed [60, 63]. Consequently, initiating total cholesterol, LDL cholesterol, non-HDL cholesterol, SGLT2 inhibition earlier in the progression of albuminu- and HDL cholesterol, while simultaneously decreasing ria yielded more favorable outcomes in terms of kidney triglycerides [71]. function preservation, as evidenced by the aforemen- tioned studies. This implies that protective effects on SGLT2 inhibitors and diuretic effect the kidneys can be realized irrespective of the extent of Although SGLT2 inhibitors are known to induce osmotic albuminuria. The presence of normo-albuminuria should diuresis and some natriuresis, their specific diuretic not be a justification for delaying treatment in conditions effects in patients with CKD are still being elucidated. prone to developing albuminuria, nor should it deter the Clinical studies have shown that SGLT2 increases urine initiation of treatment in conditions frequently associ- volume in patients with T2DM during the first few ated with non-albuminuric CKD, such as tubulointersti- days of treatment [72–74]. In the RECEDE-CHF trial, tial kidney disease [64]. which investigated the renal and cardiovascular effects The effects of SGLT2 inhibitors on kidneys in patients of SGLT2 inhibition in combination with loop diuret- with kidney failure are still uncertain. Nevertheless, a ics in patients with T2DM and chronic heart failure, retrospective study involving seven diabetic patients 26.1% of the recruited patients had CKD stage 3a (eGFR, undergoing incremental HD revealed the safety and 45–60 mL/min/1.73  m ) [75]. The study observed a mean effectiveness of SGLT2 inhibitors in preserving RKF and increase in 24-h urine volume of 535  ml 3  days after improving cardiovascular health [12]. This study indi - SGLT2 inhibitor initiation and 545 ml by 6 weeks in these cates that incorporating SGLT2 inhibitors into HD pro- patients, indicating a diuretic effect of SGLT2 inhibitors tocols may have the potential to alleviate interdialytic in the presence of CKD and heart failure [75]. weight gain and sustain RKF [12]. However, a comprehensive review of the diuretic effects of SGLT2 inhibitors highlighted the challenges in SGLT2 inhibitors and metabolic effects precisely quantifying the diuretic effect and the divergent The mitigation of chronic hyperglycemia and the alle - results from studies using indirect estimations [76]. The viation of glucose toxicity achieved through SGLT2 review emphasized that SGLT2 inhibitors present some inhibitors contribute to the enhancement of both insulin favorable properties compared with classical diuretics, Stepanova Renal Replacement Therapy (2024) 10:5 Page 6 of 16 such as reduced sympathetic activity, preserved potas- randomized double-blind study involving 42 patients sium balance, lower risk of acute kidney injury, and with T2DM found no significant effects on serum cal - decreased serum uric acid levels [76]. Another review cium [80]. The precise mechanisms underlying this phe - discussed the diuretic effects of SGLT2 inhibitors and nomenon are not fully understood, but it is speculated their influence on the renin–angiotensin system (RAS) to be associated with the osmotic diuresis induced by [77]. It was noted that the diuretic effects of SGLT2 SGLT2 inhibitors, potentially causing plasma volume inhibitors, including diuresis, natriuresis, and associated contraction and dehydration [78]. Additionally, SGLT2 body fluid loss, may activate the RAS, but these effects inhibitors might enhance intestinal and urinary calcium appear to be transient based on available data in patients absorption by inhibiting SGLT1, leading to carbohydrate with T2DM [77]. malabsorption and decreased pH, which could contrib- ute to increased calcium absorption [83]. SGLT2 inhibitors and serum electrolyte levels However, the most frequent clinical challenge in the SGLT2 inhibitors can cause a reduction in serum sodium care of patients with CKD poses hyperkalemia, and the levels due to their enhanced natriuresis effect [39]. This concern has been raised about the potential risk of hyper- effect is related to the inhibition of SGLT2 receptors, kalemia with the use of SGLT2 inhibitors in this popula- which promote glycosuria, natriuresis, and osmotic diu- tion [84, 85]. Nevertheless, existing evidence suggests resis, leading to changes in electrolyte levels [39, 78]. that SGLT2 inhibitors may influence potassium handling The reduction in serum sodium levels is usually mild by accelerating the rate of sodium and water delivery to and transient, and it is not a common side effect of the distal nephron, a pivotal regulator of kidney-medi- SGLT2 inhibitors [39, 79]. Apart from sodium, SGLT2 ated potassium handling [84, 86]. This mechanism could inhibitors may impact other electrolytes in patients with result in an augmentation of urinary potassium excretion, T2DM, including small increases in serum concentra- potentially impacting serum potassium levels [84–86]. tions of magnesium, phosphate and calcium [78, 80, 81]. Studies indicate that the use of SGLT2 inhibitors is safe In a recent meta-analysis involving 28,269 patients with in both diabetic and non-diabetic CKD patients, without T2DM and six SGLT2 inhibitors, an elevation in serum an increased risk of hyperkalemia [84, 85]. Illustratively, a magnesium by 0.07 mmol/L (95% CI, 0.06–0.08 mmol/L) recent meta-analysis encompassing 49,875 patients with and serum phosphate by 0.03  mmol/L (95% CI, 0.02– T2DM and elevated cardiovascular risk or CKD revealed 0.04 mmol/L) compared with placebo was demonstrated a significant reduction in the risk of severe hyperkalemia [81]. (≥ 6.0 mmol/L) with SGLT2 inhibitors, without a concur- The elevation in serum magnesium levels observed rent increase in the risk of hypokalemia [86]. with the use of SGLT2 inhibitors can be attributed to various mechanisms. These encompass the osmotic diu - SGLT2 inhibitors and anemia retic effect resulting from increased glucose excretion in SGLT2 inhibitors have also garnered attention for their the urine, causing heightened excretion of fluid and elec - potential impact on anemia in patients with CKD. Cur- trolytes, including magnesium, in the renal tubules [79]. rent evidence suggests that they may exhibit erythropoi- Additionally, SGLT2 inhibitors have demonstrated the etic effects, contributing to elevated hemoglobin levels ability to decrease the fractional excretion of magnesium, and potentially alleviating anemia in both diabetic and signifying enhanced tubular reabsorption [79, 82]. They non-diabetic CKD patients [87, 88]. In a recent study, induce magnesium reabsorption and contribute to extra- Osonoi et al. reported that dapagliflozin improves eryth - cellular fluid volume depletion by activating the renin– ropoiesis and iron metabolism in patients with T2DM angiotensin–aldosterone system [82]. Furthermore, these and anemia, suggesting that it has an erythropoietic inhibitors promote the upregulation of magnesium trans- effect and can help improve anemia in CKD [88]. A porters in the kidney or gut, leading to increased magne- recent post hoc analysis of the DELIGHT trial revealed sium reabsorption and diminished excretion [82]. that patients with T2DM and albuminuria, with a mean The elevation in serum phosphate concentration asso - eGFR level of 48.78 mL/min/1.73  m , treated with dapa- ciated with the use of SGLT2 inhibitors may result from gliflozin, experienced an increase in hemoglobin by increased renal tubular phosphate reabsorption, hormo- 5.7  g/L (95% CI 4.0, 7.3) and a reduction in ferritin by nal changes affecting phosphate regulation, such as para - 18.6% compared with the placebo group [89]. Another thyroid hormone (PTH) and fibroblast growth factor 23 post hoc analysis of DAPA-CKD demonstrated similar (FGF23), and direct pharmacological effects [79–81]. results, indicating that dapagliflozin was associated with The existing data on increased serum calcium levels the prevention or correction of anemia in patients with induced by SGLT2 inhibitors primarily stem from case CKD, both with and without T2DM. [87]. A comprehen- report studies [78, 83]. However, a placebo-controlled sive examination of both the mechanisms and clinical S tepanova Renal Replacement Therapy (2024) 10:5 Page 7 of 16 outcomes of the erythropoietic effects of SGLT2 inhibi - they influence the nod-like receptor (NLR) family pyrin tors and prolyl hydroxylase inhibitors in CKD and ane- domain containing 3 (NLRP3) inflammasome, contribute mia revealed that SGLT2 inhibitors lead to an increase to the modulation of ROS, and impact cellular calcium in hemoglobin levels of approximately 0.6–0.7 g/dL [90]. homeostasis, leading to an antiinflammatory and anti - Remarkably, the magnitude of this effect is comparable oxidative cellular environment [101, 102]. Furthermore, with that achieved with low-to-medium doses of prolyl SGLT2 inhibitors have demonstrated antiinflammatory hydroxylase inhibitors, and it remains evident even in effects by inhibiting lipopolysaccharide (LPS)-induced patients with advanced CKD [90]. Toll-like receptor 4 (TLR-4) overexpression and nuclear The proposed mechanism for the erythropoietic factor kappa B (NF-κB) activation in human endothelial effects of SGLT2 inhibitors revolves around the idea cells and differentiated macrophages [103]. that the heightened workload on renal tubule, caused by increased sodium delivery to the distal part after SGLT2 inhibition could induce renal medullary hypoxia [91]. Gastrointestinal insights into SGLT2 inhibitor effects This, in turn, is hypothesized to trigger the synthesis of One of the pivotal mechanisms through which SGLT2 erythropoietin, leading to an augmentation in hemo- inhibitors exert their effects in the gastrointestinal tract globin levels [92]. However, despite this hypothesis, the revolves around the impairment of small intestinal glu- magnetic resonance imaging study has not provided con- cose absorption [104]. This process facilitates the redirec - clusive evidence supporting the changes in renal cortical tion of glucose into the colon, culminating in an overall or medullary tissue oxygenation in healthy volunteers reduction in blood glucose levels, and is proposed to sup- undergoing SGLT2 inhibitor treatment [93]. This sug - press protein fermentation and the generation of uremic gests that the observed elevation in erythropoietin levels toxins such as phenols and indoles [104–106]. Treat- is likely influenced by the modulation of hypoxia-induci - ment with canagliflozin for 2 weeks significantly reduced ble factors, rather than direct evidence of renal hypoxia the plasma levels of p-cresyl sulfate and indoxyl sulfate [92]. in mice with kidney failure (compared with the vehicle group a 75% and 26% reduction, respectively) [105]. The hypothesized role of SGLT2 inhibition in fostering renal Antioxidant and antiinflammatory feathers of SGLT2 clearance of protein-bound uremic toxins adds a layer of inhibitors complexity to their gastrointestinal impact [104]. How- Research findings have consistently demonstrated the ever, although the initial findings are promising, there antioxidant and antiinflammatory effects of SGLT2 remains an urgent need for further experimental and inhibitors [94–97]. They function as indirect antioxidants clinical research to comprehensively unravel the effects by mitigating the oxidative stress induced by elevated of SGLT2 inhibitors on the production, toxicity, and glucose levels [95, 97]. Additionally, SGLT2 inhibitors elimination of gut-derived uremic toxins. exhibit the ability to reduce the generation of free radi- Beyond glucose regulation, SGLT2 inhibitors exhibit a cals, inhibit pro-oxidants, such as NADPH oxidase 4 and dual effect involving the heightened production of gas - thiobarbituric acid-reactive substances, and enhance trointestinal hormones, including glucagon-like peptide the expression of antioxidants, such as superoxide dis- 1 and peptide YY, which play a role in glucose regulation mutases and glutathione peroxidases [94, 98]. Further- and satiety [107, 108]. Concurrently, SGLT2 inhibitors more, studies have demonstrated a reduction in a wide influence intestinal bacterial flora, fostering an environ - array of pro-inflammatory cytokines, including interleu - ment characterized by a prevalence of balance-regu- kin 6 (IL-6), IL-1, tumor necrosis factor alpha (TNF-α), lating bacteria and an increase in short-chain fatty acid and others following SGLT2 inhibitor administration (SCFA)-producing bacteria [105, 109, 110]. In a recent [95–97, 99]. In a meta-analysis involving 6261 patients experimental study, Wu et  al. demonstrated the protec- with T2DM, treatment with SGLT2 inhibitors signifi - tive effect of dapagliflozin on diabetic kidney disease cantly lowered levels of serum ferritin, C-reactive pro- in db/db mice, which appears to be associated with a tein (CRP), and leptin compared to placebo or standard dynamic improvement in gut microbiota over time [111]. diabetes therapies [96]. While the precise mechanisms This improvement may be related to the effects of dapa - underlying the antioxidant and antiinflammatory effects gliflozin on the bile acid pool and its antioxidant activity of SGLT2 inhibitors remain unclear, studies have revealed [111]. In another diabetic nephropathy model, empagli- the intricate molecular pathways involved in these pro- flozin has also been shown to ameliorate T2DM-related cesses [94, 97, 99]. It has been suggested that SGLT2 diabetic nephropathy by altering the gut microbiota by inhibitors activate adenosine monophosphate-activated reducing LPS-producing bacteria and increasing SCFA- protein kinase, contributing to antiinflammatory effects producing bacteria in T2DM mice [112]. and the mitigation of oxidative stress [100]. Additionally, Stepanova Renal Replacement Therapy (2024) 10:5 Page 8 of 16 Cardiovascular protection by SGLT2 inhibitors PD‑specific effects of SGLT2 inhibitors The multifaceted effects of SGLT2 inhibitors described Several recent studies have shed light on the specific above offer a unique opportunity to address both the effects of SGLT2 inhibitors in the realm of PD. Despite local and systemic mechanisms involved in the patho- their somewhat limited scope, these studies indicate a genesis of CVD. These effects result in a reduction potential paradigm shift that could reshape our under- of preload and afterload by optimizing body weight, standing of the beneficial effects of SGLT2 inhibitors inducing osmotic diuresis, regulating intravascular vol- in addressing the distinctive challenges intrinsic to PD ume, influencing gut microbiota, enhancing endothelial (Table 1). function, and consequently mitigating vascular stiff - One of the primary focuses of these studies has been ness [1, 40, 92, 95, 112]. This collective action signifi - on the role of SGLT2 inhibitors in managing glucose cantly contributes to improved cardiac function—an absorption from PD solutions and, consequently, their especially pivotal aspect for patients with CKD who are impact on peritoneal solute and water transport. The predisposed to cardiovascular complications [1, 2, 7]. basis for these experiments stems from the finding that Beyond hemodynamic improvements, SGLT2 inhibi- human PMCs express GLUT1, GLUT3, SGLT1, and tors orchestrate a metabolic shift from free fatty acids SGLT2 receptors [121–123]. Therefore, SGLT2 inhibi - to glucose oxidation [69, 71]. This metabolic redirection tors may have the potential to influence peritoneal solute results in heightened cardiac ATP production, effec - and water transport. Supporting this hypothesis, Zhou tively preventing a decline in cardiac function [113]. et al. demonstrated a reduction in glucose uptake and an Numerous RCTs focusing on primary cardiovascular increase in ultrafiltration through the rat peritoneum, as outcomes, encompassing a substantial patient cohort well as an inhibition of glucose uptake by human PMCs with T2DM, provide compelling evidence of the signifi - mediated by empagliflozin [124]. Consistent results cant cardiovascular benefits of SGLT2 inhibitors [114– were found by Balzer [123] and Shentu [125], indicat- 116]. The outcomes reveal a noteworthy reduction in ing that SGLT2 inhibition in cellular and animal models the risk of heart failure, frequency of hospitalizations of PD was associated with reduced peritoneal fibrosis, due to heart failure, all-cause mortality, cardiovascu- decreased microvessel density, lower peritoneal glucose lar mortality and nonfatal myocardial infarction [113– absorption, and improved peritoneal ultrafiltration. In 117]. Although this robust evidence is less certain when contrast, Martus et  al. observed no significant effect of extrapolated to non-diabetic CKD [118, 119], a recent empagliflozin on changes in sodium or water transport meta-analysis conducted by Chen et  al., incorporating across the peritoneal membrane [126], and an increase in findings from 13 RCTs, concludes that SGLT2 inhibi - glucose concentration in the dialysate after 60 min of PD tors confer cardiovascular protection in CKD patients. dwell was observed only with phlorizin [127]. The analysis highlights a substantial reduction in the In addition to influencing peritoneal solute and water risk of cardiovascular disease, hospitalization for heart transport, the mentioned studies have shown that intra- failure, and all-cause mortality, all achieved without an peritoneal dapagliflozin alleviates peritoneal fibrosis in increased risk of serious adverse events and urinary a mouse model subjected to chronic exposure to high- tract infections [119]. Another meta-analysis involv- glucose dialysate [123]. The treatment with empagliflo - ing a total of 27,823 patients with stage 3–4 CKD found zin has led to a significant reduction in inflammatory that SGLT2 inhibitors significantly decreased the risk cytokine levels, including TNF-α, IL-1β, IL-6, and pro- of primary cardiovascular outcomes, and these benefits teins associated with transforming growth factor β (TGF- were consistent across different levels of kidney func - β)/Smad signaling, such as TGF-β1 and phosphorylated tion, even in stage 4 CKD [120]. The study highlighted Smad (p-Smad3) in both a mouse PD model and human the potential of SGLT2 inhibitors to reduce the risk of PMCs [125]. This effect may be attributed to the regula - adverse cardiovascular events in patients with poor tion of SGLT1 and SGLT2 in the peritoneal membrane, kidney function, which is particularly crucial given the as well as the suppression of glucose uptake and the inhi- increased risk of death and medical burden in this pop- bition of hypoxia-inducible factor 1 α (HIF-1α) [128]. ulation [120]. As ongoing research continues to unravel Canagliflozin significantly decreased HIF-1α abundance, the intricate mechanisms at play, the integration of inhibited TGF-β/p-Smad3 signaling, and decreased the SGLT2 inhibitors into the therapeutic landscape holds expression of fibrotic proteins (fibronectin, COL1A2, and significant promise for enhancing cardiovascular out - α-SMA) in human PMCs and rats exposed to chronic comes in CKD. high glucose [128]. Balzer et  al. have demonstrated that dapagliflozin reduced monocyte chemoattractant pro - tein-1 (MCP-1) specifically in the presence of a high- glucose environment within mesothelial cells [123]. S tepanova Renal Replacement Therapy (2024) 10:5 Page 9 of 16 Table 1 Summary of evidence on the role of SGLT2 inhibitors in PD Study Subjects SGLT2 inhibitors Key findings Alhwiesh et al. [129] 50 patients with T2DM on insulin, who were treated Dapagliflozin Decrease in insulin requirement by 2.6 units, HbA1c with APD by 1.6%, body weight by 2.6 kg, fasting blood glucose by 36.4 mg/dL, serum CRP by 2.0 mg/dL, serum ferritin by 261.3 µg/L, and mean systolic blood pressure by 14 mmHg; increase in urine volume by 253.2 mL/24 h, ultrafiltration volume by 229.9 mL. No effect on the status of the high-glucose transporter Lai et al. [130] 4 patients treated with PD Dapagliflozin Increase in peritoneal ultrafiltration Zhou et al. [124] Rat PD model Empagliflozin Reduction in glucose uptake and increase in ultrafiltra- tion through the rat peritoneum. Inhibition of glucose uptake by human PMCs Martus et al. [126] Rat PD model Empagliflozin Increased urinary glucose excretion and decreased plasma glucose levels after PD. No significant changes in sodium or water transport across the peritoneal membrane Martus et al. [127] Rat PD model Phlorizin Increase in urinary glucose excretion, decrease in plasma glucose, and increase in plasma creati- nine after PD. Increase in glucose concentration in the dialysate after 60 min and no difference after 120 min Balzer et al. [123] Mouse model of chronic peritoneal exposure Dapagliflozin Reduced PDE–TGF-β concentrations, peritoneal to high-glucose dialysate and human peritoneal thickening and fibrosis, and microvessel density, lead- samples in vitro ing to improved ultrafiltration. In vitro, dapagliflozin reduced the release of MCP-1. No effect on the status of the high-glucose transporter Shi et al. [98] Rat PD model and human PMCs in vitro Empagliflozin Improvement of peritoneal function, reduction of the thickness of the peritoneum and improvement of collagen accumulation. Inhibition of high glucose- induced EMT and oxidative stress by activating the Nrf2/HO-1 signaling pathway Shentu et al. [125] Mouse PD model and human PMCs in vitro Empagliflozin Protective effect on high glucose-induced perito - neal fibrosis by suppressing TGF-β/Smad signaling: reducing levels of inflammatory cytokines ( TNF-α, IL-1β, IL-6), TGF-β1, α-smooth muscle actin, collagen I and p-Smad3 accumulation in PMCs Wang et al. [128] Rat PD model and human PMCs in vitro Canagliflozin Improvement of peritoneal fibrosis and function by ameliorating peritoneal hypoxia and inhibiting the HIF-1α/TGF-β/p-Smad3 signaling pathway APD automated peritoneal dialysis, EMT epithelial to mesenchymal transformation, HbA1c hemoglobin A1c, HIF-1α hypoxia-inducible factor 1-alpha, IL interleukin, MCP-1 monocyte chemoattractant protein 1, PD peritoneal dialysis, PDE peritoneal dialysis effluent, PMCs peritoneal membrane cells, p-Smad3 phosphorylated Smad3, TGF-β transforming growth factor beta, TNF-α tumor necrosis factor alpha Furthermore, SGLT2 inhibition significantly decreased integrity of the peritoneum [98]. The antifibrogenic, anti - both MCP-1 and TNF-α in the presence of an inflamma - inflammatory, and antioxidant properties exhibited by tory stimulus such as LPS, suggesting the potential anti- SGLT2 inhibitors may have profound implications for inflammatory effects of SGLT2 inhibitors [123]. maintaining the integrity of the peritoneal membrane Moreover, Shi et  al. demonstrated the ability to miti- and, consequently, enhancing the longevity of the PD gate inflammatory signaling pathways activated by ROS, technique. which could be a key mechanism contributing to the Considering the limited number and experimental reduction of peritoneal inflammation in patients under - nature of the aforementioned studies, it is important to going PD [98]. High glucose can induce oxidative stress highlight two pioneering clinical studies. One involved 50 in PMCs and stimulate EMT, leading to peritoneal fibro - patients undergoing PD [129], while the other provided sis [26]. Empagliflozin has been found to inhibit high details on four clinical cases [130]. Notably, both studies glucose-induced EMT and reduce oxidative stress via the utilized dapagliflozin off-label, and neither study reported Nrf2/HO-1 signaling pathway in human and rat PMCs, any adverse effects. Alhwiesh et  al. demonstrated that a potentially protecting the structural and functional dose of 10  mg/day dapagliflozin significantly reduced Stepanova Renal Replacement Therapy (2024) 10:5 Page 10 of 16 insulin requirements, HbA1c, body weight, systolic blood glucose metabolism in diabetes, coupled with the pressure, blood glucose, and serum uric acid levels [129]. unique challenges of PD, may elevate susceptibility to Additionally, it increased urine and peritoneal ultrafiltra - EKA. However, on the flip side, as the glycosuric impact tion volumes in patients with insulin-dependent T2DM of SGLT2 inhibitors diminishes beyond stage 3 CKD, treated with automated PD [129]. However, the authors concerns regarding EKA are unlikely to be applicable did not observe any changes in the peritoneal transport to the PD population. Nevertheless, due to the absence status in these patients. Lai et  al. administered a daily of prior clinical trials investigating SGLT2 inhibitors dose of 5 mg dapagliflozin to four overhydrated patients in patients undergoing PD, it remains unclear whether undergoing PD for a duration of 14–28 days, continuing their use would increase the risk of EKA, for example, until a euvolemic status was achieved [130]. In line with a in patients with preserved RKF. report by Alhwiesh et al., all the patients demonstrated a The second concern involves the potential risk of PD- significant increase in peritoneal ultrafiltration rate [130]. associated infections. SGLT2 inhibitors are recognized Although these preliminary experimental and clini- for elevating the likelihood of genital and urinary tract cal results are promising, the inclusion of SGLT2 inhibi- infections [132, 133], with genital mycotic infections tors in PD protocols must be approached with caution. and urinary tract infections being the most frequently Robust clinical trials are required to confirm the benefits reported adverse effects [139, 140]. The incidence of and risks of SGLT2 inhibitors in patients undergoing PD. genital yeast infections associated with SGLT2 inhibi- tors is reported to be approximately three times higher compared with other treatments [141]. The adjusted Safety concerns in SGLT2 inhibitor utilization for PD incidence is reported as 135.5 per 1000 person-years for Despite the consistently favorable safety profile of SGLT2 SGLT2 inhibitors, contrasting with 48.5 per 1000 person- inhibitors in CKD [4, 35, 131] and the absence of prior years for alternative treatments, resulting in an excess clinical trials in PD, it is prudent to acknowledge that risk of 87.6 per 1000 person-years [141]. Importantly, the the reported side effects in broader patient populations risk of genital infections remains consistent across vari- may have relevance to PD patients. Adverse events such ous SGLT2 inhibitors and persists throughout the dura- as hypotension, hypoglycemia, infections, limb amputa- tion of therapy [141]. In addition, female sex, diabetes tions, bone fractures, and euglycemic ketoacidosis (EKA) duration of more than 10  years, and a previous genital have been documented in the product information pro- infection are risk factors that contribute to an increased vided by regulatory agencies and reported in multiple risk of infection [140, 142]. Considering the above, sev- systematic reviews and meta-analyses [132–134]. These eral factors might contribute to an elevated risk of PD- reported adverse events vary among different SGLT2 related infections in patients using SGLT2 inhibitors. inhibitors and depend on factors such as sex, the pres- In PD, where the peritoneal membrane is consistently ence of diabetes, and concurrent glucose-lowering ther- exposed to glucose-based solutions, the utilization of apy [133, 134]. Although most of these events (EKA, SGLT2 inhibitors may lead to an increase in glucose lev- amputations, and Fournier gangrene) are rare, they can els in the peritoneal cavity, particularly within the initial lead to serious and dangerous complications [132–134]. 60  min [127]. This heightened concentration of glucose In the context of PD, three of the mentioned challenges could provide a favorable environment for the growth of in SGLT2 inhibitor utilization may pose specific risks and microorganisms, potentially amplifying the risk of peri- should be detailed. toneal infections. Furthermore, PD patients encounter a EKA is a recognized complication of therapy with direct entry point for microorganisms into the peritoneal SGLT2 inhibitors and can occur in patients with normal cavity through the PD catheter. The presence of a higher or only slightly elevated plasma glucose concentrations, glucose peritoneal environment and the catheter may presenting a particular problem for individuals with potentially augment vulnerability to infections. Despite preexisting CKD [135, 136]. In patients undergoing PD, the minimal glycosuric effect of SGLT2 inhibitors in continuous exposure of the peritoneal membrane to patients with kidney failure, PD patients are already con- glucose-based PD solutions, along with the glycosuric fronted with an increased risk of infection. The suscepti - effect of SGLT2 inhibitors, may create an environment bility to genital and urinary tract infections may further conducive to metabolic imbalances, contributing to escalate the overall infection risk, including the poten- the risk of EKA [137]. Additionally, the higher propor- tially life-threatening complication of fungal PD-related tion of diabetic patients undergoing PD adds another peritonitis. It is essential to emphasize that these poten- layer of complexity. Diabetic patients already face an tial risks are theoretical, and there is a lack of empirical increased risk of metabolic disturbances, and the addi- evidence supporting an augmented risk of PD-associated tion of SGLT2 inhibitors may further accentuate this infections specifically related to SGLT2 inhibitors. risk [138]. The theoretical synergistic effect of altered S tepanova Renal Replacement Therapy (2024) 10:5 Page 11 of 16 Another significant issue is the possible impact of effects of SGLT2 inhibitors, including metabolic modu - SGLT2 inhibitors on CKD-associated mineral and bone lation, hypotensive, diuretic, antianemic, antioxidant, metabolism (MBD) in patients undergoing PD. Bone and antiinflammatory properties, along with their fractures are a recognized adverse effect of SGLT2, espe - protective impact on the peritoneal membrane and, cially in patients aged over 65 with both diabetes and consequently, solute and water transport, suggest a CKD [133, 134, 139, 143]. Several hypothesized mecha- promising avenue for addressing challenges unique to nisms suggest that SGLT2 inhibitors can directly influ - PD. The observed renal and cardiovascular benefits in ence calcium–phosphate balance and indirectly increase patients with T2DM and CKD underscore the poten- bone turnover by promoting weight loss [144]. The ele - tial of SGLT2 inhibitors to preserve RKF and mitigate vation in serum phosphate levels, a known class effect cardiovascular complications in this patient population. of SGLT2 inhibitors, is likely facilitated by increased Moreover, two preliminary clinical studies reported phosphate transport in the proximal tubule, leading to positive outcomes with the use of SGLT2 inhibitors, enhanced phosphate reabsorption and urinary calcium showing increased peritoneal ultrafiltration and other excretion due to sodium loss [144, 145]. This increase in benefits similar to the general CKD population. phosphate levels is thought to stimulate FGF23, result- However, caution is warranted given the need for ing in phosphaturia and the inhibition of 1.25-dihy- rigorous investigation into dosing, long-term safety, droxyvitamin D to maintain the phosphate balance. In and patient-specific factors through comprehensive a randomized crossover study involving healthy volun- clinical trials. Currently, five registered clinical trials teers using canagliflozin, the administration of 300  mg/ focused on PD are underway, aiming to address perito- day triggered the FGF23/1,25-dihydroxyvitamin D/PTH neal glucose uptake, mechanisms and safety of SGLT2 axis, leading to increased serum phosphate levels, plasma inhibition, and the impact on ultrafiltration among PD FGF23, and PTH, coupled with a decrease in 1,25-dihy- patients: (1) “Reduction of Peritoneal Glucose Uptake droxyvitamin D [144]. Although there is controversy sur- With the Use of SGLT2 in Humans Undergoing Perito- rounding the evidence that SGLT2 inhibitors cause bone neal Dialysis Treatment” (NCT05250752), (2) “Mecha- fractures [145, 146], the complex interplay of these fac- nisms and Safety of SGLT2 Inhibition in Peritoneal tors may have implications for mineral and bone health Dialysis” (NCT05715814), (3) “The Effect of Dapagli - in patients undergoing PD who already have MBD-CKD. flozin on Ultrafiltration Among Peritoneal Dialysis Lastly, some other potentially less serious problems Patients” (NCT04923295), (4) “Effect of Empagliflozin would require continuous monitoring, such as blood on Peritoneal and Kidney Function in End Stage Renal pressure, fluid and electrolyte balance, blood glucose Disease (EMPA-PD)” (NCT05671991), and (5) “The control, and drug interactions. SGLT2 inhibitors induce effects of empagliflozin on ultrafiltration in patients osmotic diuresis, which leads to increased urinary glu- with peritoneal dialysis” (jRCTs051230081). These trials cose excretion and fluid loss [39]. This diuretic effect are anticipated to provide comprehensive insights into may affect fluid status, potentially causing dehydration or the integration of SGLT2 inhibitors into PD protocols. affecting ultrafiltration requirements during PD. In addi - To address the potential risks associated with SGLT2 tion, the prescription of SGLT2 inhibitors in PD patients inhibitors in PD, such as EKA, infections, and effects may require adjustment of antihypertensive and/or dia- on MBD, focused attention is essential. Future research betic treatment due to their antihypertensive effect and should elucidate the underlying mechanisms and guide potential impact on peritoneal membrane function and risk mitigation strategies tailored to patients undergo- fluid balance [2, 147]. As PD patients often take multiple ing PD, acknowledging the heterogeneity of this popu- medications, it is important to consider potential inter- lation. Individualized approaches to prescribing SGLT2 actions between SGLT2 inhibitors and other prescribed inhibitors, considering factors such as age, diabetes medications [148]. Regular and careful monitoring is status, and PD-associated risks, should be explored. essential for optimal management of these various fac- Continuous monitoring of vital factors, including blood tors in PD patients treated with SGLT2 inhibitors. pressure, fluid and electrolyte balance, blood glucose control, and potential drug interactions, is paramount. The development of comprehensive management pro - Conclusions and future perspectives tocols will ensure the optimal and safe utilization of This review presents a compelling case for the potential SGLT2 inhibitors in PD. Longitudinal studies assess- integration of SGLT2 inhibitors into the management ing the extended safety profile of SGLT2 inhibitors in of patients undergoing PD, extending beyond their PD, particularly their impact on peritoneal membrane established benefits in patients with T2DM, non-dia - integrity and patient outcomes, will be instrumental in betic CKD, and cardiovascular health. The multifaceted establishing the long-term viability of these agents. Stepanova Renal Replacement Therapy (2024) 10:5 Page 12 of 16 References Together, while the initial evidence is promising, the inte- 1. Kansara A, Mubeen F, Shakil J. 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Journal

Renal Replacement TherapySpringer Journals

Published: Jan 31, 2024

Keywords: Sodium–glucose cotransporter 2 inhibitors; Peritoneal dialysis; Benefits; Risks

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