From stones to system: integrating kidney stones disease into the cardiovascular-kidney-metabolic continuum.

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have emerged as a valuable class of medications for managing Type 2 Diabetes Mellitus (T2DM) due to their efficacy in glycemic control and cardiovascular and renal benefits. However, concerns have been raised regarding their potential association with an increased risk of kidney stone formation. Objective: This systematic review aimed to comprehensively evaluate the existing literature to determine the association between SGLT-2 inhibitors and kidney stone formation, elucidate potential underlying mechanisms, and discuss implications for clinical practice. Methods: A systematic search of databases including PubMed, Google Scholar, Web of Sciences, Medline, and Scopus was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant research articles investigating the utilization of SGLT-2 inhibitors in humans and their potential correlation with kidney stones were included. Data extraction and quality assessment were performed, and a mixed-methods synthesis approach was used for data analysis. Results: The systematic review identified several studies examining the association between SGLT-2 inhibitors and kidney stones. Overall, SGLT-2 inhibitors were found to be associated with a potential protective effect against kidney stone formation. Mechanistically, SGLT-2 inhibitors promote glycosuria and natriuresis, leading to increased urine flow rate and enhanced urinary volume, which may help dilute and flush out stone-forming substances. However, certain limitations and considerations, including potential adverse events and variations in study designs, were also highlighted. Conclusion: This systematic review provides valuable insights into the potential correlation between SGLT-2 inhibitors and kidney stones. While the observed protective effect against kidney stone formation is promising, further research with longer follow-up durations and larger sample sizes is warranted to establish a more conclusive understanding of this relationship. Nonetheless, clinicians should remain vigilant in monitoring patients using SGLT-2 inhibitors and carefully assess individual risk factors when prescribing these medications.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce chronic kidney disease (CKD) progression in individuals with type 2 diabetes, CKD, or heart failure. However, their effects in those with stage 4 CKD or little to no albuminuria remain uncertain. To assess whether estimated glomerular filtration rate (eGFR) or degree of albuminuria, measured by urinary albumin to creatinine ratio (UACR), modifies the effects of SGLT2 inhibitors on kidney outcomes. SGLT2 inhibitor trials participating in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium (SMART-C). Randomized, double-blind, placebo-controlled trials within SMART-C evaluating an SGLT2 inhibitor with label indications for reducing CKD progression including at least 500 participants in each group with at least 6 months of follow-up. Treatment effects in individual trials were pooled using inverse variance-weighted meta-analysis. CKD progression, defined as kidney failure, at least 50% reduction in eGFR, or death due to kidney failure. Other outcomes included annual rate of eGFR decline and kidney failure. Among 70 361 participants (mean [SD] age, 64.8 [8.7] years; 24 595 [35.0%] females) in 10 randomized trials, 2314 (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure. SGLT2 inhibitors reduced the risk of CKD progression (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57-0.68]), irrespective of baseline eGFR (HR of 0.61 [95% CI, 0.52-0.71] for eGFR ≥60 mL/min/1.73 m2; 0.57 [95% CI, 0.47-0.70] for eGFR of 45 to <60 mL/min/1.73 m2; 0.64 [95% CI, 0.54-0.75] for eGFR of 30 to <45 mL/min/1.73 m2; and 0.71 [95% CI, 0.60-0.83] for eGFR <30 mL/min/1.73 m2; P for trend = .16) and baseline albuminuria (HR of 0.58 [95% CI, 0.44-0.76] for albuminuria ≤30 mg/g; 0.74 [95% CI, 0.57-0.96] for >30-300 mg/g; and 0.57 [95% CI, 0.52-0.64] for more than 300 mg/g; P for trend = .49). Although the magnitude of protection varied, SGLT2 inhibitors reduced the annual rate of eGFR decline across all eGFR and UACR subgroups, including when participants with and without diabetes were analyzed separately. SGLT2 inhibitors also reduced the risk of kidney failure alone (HR, 0.66 [95% CI, 0.58-0.75]). In this meta-analysis, SGLT2 inhibitors were found to lower the risk of CKD progression regardless of baseline eGFR or albuminuria, including in patients with stage 4 CKD or minimal albuminuria, supporting their routine use to improve kidney outcomes across the full spectrum of kidney function among patients with type 2 diabetes, CKD, or heart failure.

IntroductionKidney stones are a global healthcare problem. Given high recurrence rates and the morbidity associated with symptomatic stone disease, effective medical prophylaxis is clearly an unmet need. Explanatory analyses of...

Urolithiasis (UL) is increasingly prevalent due to rising cardiorenometabolic diseases, posing significant management challenges despite advances in urological techniques. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, primarily used for type 2 diabetes mellitus, chronic kidney disease, and heart failure, have emerged as a potential novel approach for UL treatment. These inhibitors may help reduce the risk of urolithiasis, particularly in patients with diabetes, by improving glycemic control and altering urinary chemistry, which are crucial factors in stone formation. However, the changes in urinary composition induced by SGLT2 inhibitors might also increase the risk of uric acid stone formation. This review evaluates the potential of SGLT2 inhibitors in managing UL, highlighting both the benefits and the risks. While these inhibitors show promise in reducing new and recurrent urinary stones in patients with diabetes, data on their effects in patients without diabetes who form stones are limited. Current human evidence largely comes from post hoc analyses of randomized controlled trials (RCTs) and large-scale database studies, with only one study providing detailed stone composition data. Experimental studies in animal models and cell lines have focused on calcium oxalate (CaOx) stones, showing that SGLT2 inhibitors specifically target CaOx stone formation and related renal inflammation. Although primarily studied for CaOx stones, their potential impact on other calcium-containing stones, such as calcium phosphate, remains promising. Further research is needed to explore their therapeutic potential and optimize treatment strategies.

Temporal Changes in Kidney Stone Composition and in Risk Factors Predisposing to Stone Formation

Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood. We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to <22mmol/L (metabolic acidosis) or 22 to <30mmol/L (normal serum bicarbonate). Primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate over time. Cox proportional hazards models evaluated time to first occurrence of kidney stones during a median 3.2-year follow-up. A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post-index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0%vs 9.5%, P<.0001). Both lower baseline serum bicarbonate [hazard ratio (HR) 1.047; 95% confidence interval (CI) 1.036-1.057] and decreasing serum bicarbonate over time (HR 1.034; 95% CI 1.026-1.043) were associated with increased risk of kidney stone development. Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation.

Beverages, diet, and prevention of kidney stones.

Differences in the Food Consumption Between Kidney Stone Formers and Nonformers in the Swiss Kidney Stone Cohort

MP10-03 INFLUENCE OF SGLT2 INHIBITORS ON 24-HOUR URINE PARAMETERS AMONG KIDNEY STONE PATIENTS IN THE MEDICARE POPULATION

Risk of ESRD and Mortality in Kidney and Bladder Stone Formers

Calcium phosphate supersaturation regulates stone formation in genetic hypercalciuric stone-forming rats

Causes of Hypocitraturia in Recurrent Calcium Stone Formers: Focusing on Urinary Potassium Excretion

Inflammation plays an important role in the initiation and subsequent progression of chronic kidney disease. An increase in inflammatory markers including cytokines as well as markers of oxidative stress is associated with reduced kidney function. Inflammatory markers and the underlying mechanisms that contribute to the pathophysiology of kidney disease are not clear and likely are multifactorial. Another feature associated with renal dysfunction and inflammatory response is the formation of calcium oxalate stones formed from the crystal deposits in the tubular epithelial cells. The aim of the present study was to investigate changes in gene expression in the renal cortex obtained from cats with kidney disease or calcium oxalate stone formers (CaOx) at necropsy in order to identify novel inflammatory biomarkers associated with renal dysfunction. At the time of death the circulating levels of creatinine as well as symmetric dimethyl arginine (SDMA), both markers of kidney decline in cats, were significantly higher in cats with renal disease (n=11) or stone‐forming cats (CaOx, n=12) when compared to controls (n=19). Using RNAseq in kidney tissue, we found a significant increase in the expression of IL‐16, a T‐cell chemoattractant, in both cats with kidney disease (6.72 fold) and stone formers (7.03 fold) compared to controls (both p&lt;0.0001). There was also a significant increase in caspase recruitment domain family member 11 (CARD11), an activator of T and B‐lymphocytes and NFkB, in cats with kidney disease (9.2 fold) and stone formers (10 fold) compared to controls (p&lt;0001). However, some differences between the kidney disease and CaOx groups were also observed. In cats with kidney disease there was an increased expression of LY9 (CD299), found in T and B‐cells and thymocytes, IL2Rg, a marker of lymphocyte activation, and SPP1 (Osteopontin), expressed in activated T and B‐cells (all &gt;6‐fold) when compared to controls (p&lt;0.0001) but such increased expression was not seen in CaOx cats. In summary, while IL‐16 was increased in both groups, our results indicate important molecular differences in the pathogenesis of kidney dysfunction in cats with kidney disease and stone formers, and that distinct lymphocyte markers may be involved in the persistent decline of kidney function. Our studies suggest that the optimal nutritional therapy to slow the progression of kidney dysfunction may be different for cats with kidney disease or stone formers.Support or Funding InformationThis study was funded by Hill’s Pet Nutrition, Inc

Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. American College of Physicians. (PROSPERO: CRD42022322129).

ABSTRACTBackgroundRandomized controlled trials have demonstrated the benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2is) in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). However, real-world data on CKD progression and the development of end-stage kidney disease (ESKD) remains scarce. Our aim was to study renal outcomes of people with diabetic kidney disease (DKD) using SGLT2is in a highly prevalent DKD population.MethodsBetween 2016 and 2019 we recruited T2DM patients in the renal and diabetic clinics in a regional hospital in Singapore. Patients prescribed SGLT2is were compared with those on standard anti-diabetic and renoprotective treatment. The outcome measures were CKD progression [a ≥25% decrease from baseline and worsening of estimated glomerular filtration rate (eGFR) categories according to the Kidney Disease: Improving Global Outcomes guidelines] and ESKD (eGFR <15 mL/min/1.73 m2).ResultsWe analysed a total of 4446 subjects; 1598 were on SGLT2is. There was a significant reduction in CKD progression {hazard ratio [HR] 0.60 [95% confidence interval (CI) 0.49–0.74]} with SGLT2is. The HR for eGFR ≥45 mL/min/1.73 m2 and 15–44 mL/min/1.73 m2 was 0.60 (95% CI 0.47–0.76) and 0.43 (95% CI 0.23–0.66), respectively. There was also a reduction in risk for developing ESKD for the entire cohort [HR 0.33 (95% CI 0.17–0.65)] and eGFR 15–44 mL/min/1.73 m2 [HR 0.24 (95% CI 0.09–0.66)]. Compared with canagliflozin and dapagliflozin, empagliflozin showed a sustained risk reduction of renal outcomes across CKD stages 1–4.ConclusionsThis real-world study demonstrates the benefits of SGLT2is on CKD progression and ESKD. The effect is more pronounced in moderate to advanced CKD patients.