SGLT-2 inhibitors and nephrolithiasis risk: a meta-analysis.

BACKGROUND AND AIM: Sodium-glucose cotransporter (SGLT)-2 inhibitors are novel anti-diabetic medications with potential beneficial effects on cardiovascular and renal outcomes, metabolic parameters, and body weight. In addition to the beneficial effects on renal functions, including estimated glomerular filtration rate and reduction in proteinuria, recent studies have investigated the potential role of SGLT-2 inhibitor therapy on nephrolithiasis development. Nephrolithiasis, a condition affecting almost 10% of the general population at least once during a lifetime, is a common disorder with considerable risk for acute and chronic kidney injury and relatively few effective therapeutic options. MATERIALS AND METHODS: We have performed a literature search through multiple databases, including PubMed, Ovid/Medline, Web of Science, Scopus, and Cochrane Library. We have followed the systematic review and meta-analysis guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.We have included a total of 11 635 698 patients who experienced nephrolithiasis from six clinical trials to conduct this meta-analysis study. In the pooled analysis, nephrolithiasis occurred in 1,27% of patients from the SGLT2i group (n = 739 197), compared to 1,56% of patients (n = 10 896 501) from the control arm (active control, placebo or no therapy). RESULTS: We have included a total of 11 635 698 participants who experienced nephrolithiasis from a total of six clinical studies with nephrolithiasis rates of 1,27% in the SGLT2i group (n = 739 197), compared to 1,56% in the control arm (n = 10 896 501). SGLT-2 inhibitor therapy has been associated with a lower risk for nephrolithiasis compared to placebo (OR 0.61, 95% CI, 0.53-0.70, p < 0.00001) or active therapy such as glucagon-like peptide 1 and dipeptidyl peptidase-IV inhibitors (OR 0.66, 95% CI, 0.47-0.93, p = 0.02). CONCLUSION: We have demonstrated a lower risk of nephrolithiasis risk with SGLT-2 inhibitor therapy compared to placebo or active control. Potential underlying mechanisms include osmotic diuresis leading to a reduction in the concentration of lithogenic substances, anti-inflammatory and anti-fibrotic effects, and an increase in urine pH. There is a clear need for future large-scale randomized clinical trials evaluating such associations for better understanding.

The role of serum osmolality in Meniere's disease with acute sensorineural hearing loss.

OBJECTIVE: This study investigated the role of serum osmolality in Meniere's disease (MD) patients with acute sensorineural hearing loss (SNHL). DESIGN: Retrospective study. STUDY SAMPLES: Twenty definite MD patients with acute unilateral SNHL were treated with an osmotic diuretic (Isosorbide, 100 mL daily) and assigned to Group A. Another 20 age- and sex-matched definite MD patients with acute SNHL were not given Isosorbide and assigned to Group B. Both groups underwent audiometry and blood examination for serum osmolality before and after treatment. RESULTS: Group A revealed a significant increase in serum osmolality after treatment. The optimal cut-off values for increased serum osmolality in Group A were +1.5 mOSM/L for predicting hearing improvement at frequencies of 250-1000 Hz, and +2.5 mOSM/L at 2000-4000 Hz. Comparing increased levels of serum osmolality (> +2.0 vs. ≤ +2.0 mOSM/L), Isosorbide dosing at 3.0 L vs. 1.0 L, significantly differed in the odds ratio (OR). Isosorbide at a total dosage of 3.0 L thus improves the hearing threshold by >10 dB at frequencies of 250-2000 Hz. CONCLUSION: The Isosorbide at a total dosage of 3.0 L may increase serum osmolality by > +2.0 mOSM/L, and improve the hearing threshold for hydropic ears at least >10 dB at low- and mid-frequencies.

Sodium/glucose cotransporter 2 and renoprotection: From the perspective of energy regulation and water conservation.

Sodium/glucose cotransporter 2 (SGLT2) is a renal low-affinity high-capacity sodium/glucose cotransporter expressed in the apical membrane of the early segment of proximal tubules. SGLT2 reabsorbs filtered glucose in the kidney, and its inhibitors represent a new class of oral medications used for type 2 diabetes mellitus, which act by increasing glucose and sodium excretion in urine, thereby reducing blood glucose levels. However, clinical trials showed marked improvement of renal outcomes, even in nondiabetic kidney diseases, although the underlying mechanism of this renoprotective effect is unclear. We showed that long-term excretion of salt by the kidneys, which predisposes to osmotic diuresis and water loss, induces a systemic body response for water conservation. The energy-intensive nature of water conservation leads to a reprioritization of systemic body energy metabolism. According to current data, use of SGLT2 inhibitors may result in similar reprioritization of energy metabolism to prevent dehydration. In this review article, we discuss the beneficial effects of SGLT2 inhibition from the perspective of energy metabolism and water conservation.

Spontaneous bilateral renal pelvis rupture during CT in the absence of urinary tract obstruction: case report.

BACKGROUND: Atraumatic renal pelvis rupture without pre-existing renal or ureteric pathology is an uncommon event. It is reported in the setting of acute urinary tract obstruction, most often secondary to ureteric calculi. Typical symptoms include acute flank pain and nausea, mimicking pyelonephritis or other causes of acute abdomen. Spontaneous rupture occurring bilaterally without identifiable urinary tract obstruction is exceedingly rare, and has yet to be reported in current English literature. Possible contributing pathophysiological mechanisms can be postulated from reported cases of rupture with observed obstruction. CASE PRESENTATION: A 58-year-old woman undergoing multiphasic computed tomography (CT) for evaluation of asymptomatic microscopic haematuria developed on-table bilateral renal pelvis rupture seen only after contrast administration, on the delayed phase. There was no significant past medical history of note. The patient remained asymptomatic throughout and after the study, and was managed conservatively. Follow-up radiographical imaging over a month showed resolution of urinoma and no further contrast extravasation. No complications or recurrence was subsequently noted. CONCLUSIONS: Spontaneous rupture of the renal pelvis can be a rare complication of intravenous contrast administration even in cases without identifiable urinary tract obstruction, and it can occur bilaterally. Cases can uncommonly be asymptomatic but typical symptoms should prompt evaluation of the kidneys, particularly when they are not included in the initial study or no delayed phase is protocolled. Interval imaging for resolution of urinoma and contrast extravasation is clinically relevant to monitor for and avoid infective sequelae.

Hypernatremia due to Urea-Induced Osmotic Diuresis: Physiology at the Bedside.

Hypernatremia secondary to urea-induced solute diuresis is due to the renal excretion of electrolyte-free water. This concept is explained here step-wise physiologically with the help of a clinical vignette.

Combination treatment of nocturnal enuresis with desmopressin and indomethacin.

BACKGROUND: We investigated the effect of combining indomethacin and desmopressin in treating children with monosymptomatic nocturnal enuresis (MNE) and desmopressin-resistant nocturnal polyuria. METHODS: Twenty-three children with MNE, nocturnal polyuria, and partial or no response to desmopressin were recruited from incontinence clinics of our tertiary referral center. We used a randomized single-arm crossover placebo-controlled study design consisting of two 3-week treatment periods with a combination of desmopressin (0.4 mg) and indomethacin (50 mg) or desmopressin and placebo at bedtime. Home recordings at baseline and for the final 2 weeks of each treatment period were performed and included nocturnal urine output measurements. The number of dry nights achieved and reduction in the nocturnal urine output were the main effect parameters. Student's t test and Pearson's correlation coefficient were used for statistical analysis. RESULTS: The addition of indomethacin to desmopressin significantly reduced nocturnal urine output (from 324 ± 14 ml to 258 ± 13 ml, p < 0.001). This did not lead to more dry nights in all children, and we found no statistically significant reduction in enuresis frequency (from 68 % ± 0.1 to 56 % ± 0.1, p = 0.24). CONCLUSIONS: Addition of indomethacin to desmopressin can further reduce nocturnal urine output in children with MNE and desmopressin-resistant nocturnal polyuria. The combination treatment does not, however, improve outcome in terms of frequency of nights with enuresis. The dissociation of antidiuretic and antienuretic effect may reflect nocturnal bladder reservoir dysfunction in children who present with normal daytime bladder function.

Dapagliflozin induced hypernatremia via osmotic diuresis: a case report.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been widely used. They inhibit proximal tubular glucose reabsorption, resulting in glycosuria. Herein, we report the case of a 65-year-old woman who presented with hypernatremia during the perioperative period of a subarachnoid hemorrhage. The patient continued to take dapagliflozin postoperatively and subsequently developed severe hypernatremia. Based on the urinalysis findings, we diagnosed osmotic diuresis due to glycosuria as contributing to hypernatremia. Hypernatremia improved with the discontinuation of dapagliflozin and the administration of a hypotonic infusion. In the perioperative period, physicians should discontinue SGLT2 inhibitors owing to concerns about the development of hypernatremia.

Hypernatremia in Hyperglycemia: Clinical Features and Relationship to Fractional Changes in Body Water and Monovalent Cations during Its Development.

In hyperglycemia, the serum sodium concentration ([Na]S) receives influences from (a) the fluid exit from the intracellular compartment and thirst, which cause [Na]S decreases; (b) osmotic diuresis with sums of the urinary sodium plus potassium concentration lower than the baseline euglycemic [Na]S, which results in a [Na]S increase; and (c), in some cases, gains or losses of fluid, sodium, and potassium through the gastrointestinal tract, the respiratory tract, and the skin. Hyperglycemic patients with hypernatremia have large deficits of body water and usually hypovolemia and develop severe clinical manifestations and significant mortality. To assist with the correction of both the severe dehydration and the hypovolemia, we developed formulas computing the fractional losses of the body water and monovalent cations in hyperglycemia. The formulas estimate varying losses between patients with the same serum glucose concentration ([Glu]S) and [Na]S but with different sums of monovalent cation concentrations in the lost fluids. Among subjects with the same [Glu]S and [Na]S, those with higher monovalent cation concentrations in the fluids lost have higher fractional losses of body water. The sum of the monovalent cation concentrations in the lost fluids should be considered when computing the volume and composition of the fluid replacement for hyperglycemic syndromes.

A profile of SGLT-2 inhibitors in hyponatremia: The evidence to date.

Hyponatremia is the most common electrolyte disorder in clinical practice, which may lead to life-threatening complications. Several lines of evidence suggest that hyponatremia is associated not only with significant increases in length of stay, cost, and financial burden, but also with increased morbidity and mortality. Hyponatremia is also considered to be a negative prognostic factor in patients with heart failure and cancer. Although multiple therapeutic methods are available for treating hyponatremia, most have some limitations, such as poor compliance, rapid correction of serum Na+, other negative side effects and high cost. Given these limitations, identifying novel therapies for hyponatremia is essential. Recent clinical studies have shown that SGLT-2 inhibitors (SGLT 2i) significantly increased serum Na+ levels and were well tolerated by patients who underwent this treatment. Therefore, oral administration of SGLT 2i appears to be an effective treatment for hyponatremia. This article will briefly review the etiology of hyponatremia and integrated control of sodium within the kidney, current therapies for hyponatremia, potential mechanisms and efficacy of SGLT 2i for hyponatremia, and the benefits in cardiovascular, cancer, and kidney disease by regulating sodium and water balance.

Case Report: Severe Hypernatremia From Ingestion of One's Own Urine.

An often unrecognized cause of hypernatremia is the ingestion of fluids or substances with high osmolality. We hereby report a case of severe hypernatremia with acute kidney injury in a severely debilitated patient with acute gouty arthritis who resorted to ingesting his own urine. Hypernatremia induced by drinking urine could be attributed to many underlying mechanisms, one of the important possible causes is the resultant high serum urea that leads to significant osmotic diuresis and a further increase in free water clearance. To the best of our knowledge this is the first case report that describes this unique cause of hypernatremia.

The diuretic effects of SGLT2 inhibitors: A comprehensive review of their specificities and their role in renal protection.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are new oral glucose-lowering agents that provide cardiovascular and renal protection in both patients with and without type 2 diabetes. Because of their unique mechanism of action, increased glucosuria is associated with osmotic diuresis and some natriuresis, yet the latter seems mostly transient. The potential role of the diuretic effect in overall cardiovascular and renal protection by SGLT2is remains a matter of debate. Precise evaluation of the diuretic effect is not so easy and most studies relied upon indirect estimations that led to divergent results, presumably also explained by different study designs and population characteristics. Everybody agrees upon the fact that SGLT2is are different from other classical diuretics (thiazides and loop diuretics) as they present some favourable properties, i.e. reduced sympathetic activity, preserved potassium balance, lower risk of acute renal injury, decrease of serum uric acid level. The potential role of the diuretic effect of SGLT2is on renal outcomes is still unclear, yet their ability to reduce albuminuria and dampen the risk of heart failure may contribute to improve renal prognosis besides other complex underlying mechanisms. In this comprehensive review we first critically analyse the results obtained with indirect methods that assess a diuretic effect of SGLT2is, second we describe the specificities of the diuretic activity of SGLT2is compared with other classical diuretics, and third we discuss the potential mechanisms by which the diuretic effect of SGLT2is could contribute to the improvement of renal outcomes consistently reported with this innovative amazing pharmacological class.

Urinary Concentration Defect and Renal Glycosuria in Cyclosporine-treated Rats.

BACKGROUND: Urinary concentration impairment is a major feature of cyclosporine nephrotoxicity. METHODS: We explored two possible mechanisms that may underlie cyclosporine-induced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II). RESULTS: In Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88±3%, p<0.05). CONCLUSION: Both water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Hyperosmolar hyperglycemic syndrome in a young boy.

We describe a 6-year-old boy who presented to the emergency department with the complaint of nausea and vomiting with diarrhea. Workup revealed a glucose level of 1904 mg/dL, and hyperglycemic hyperosmolar syndrome was diagnosed. Hyperglycemic hyperosmolar syndrome is very rare in the pediatric population, but recent published reports suggest that the incidence of this disorder may be increasing.

Post-obstructive Diuresis: A Cautionary Tale.

Post-obstructive diuresis (POD) following decompression of urinary tract obstruction is usually a self-limiting phenomenon. However, prolonged bilateral ureteral obstruction (BUO) can cause severe structural and functional tubular damage. We present a case of POD resulting from partial nephrogenic diabetes insipidus and discuss the diagnosis, treatment, and prognosis.

Principles of quantitative water and electrolyte replacement of losses from osmotic diuresis.

Osmotic diuresis results from urine loss of large amounts of solutes distributed either in total body water or in the extracellular compartment. Replacement solutions should reflect the volume and monovalent cation (sodium and potassium) content of the fluid lost. Whereas the volume of the solutions used to replace losses that occurred prior to the diagnosis of osmotic diuresis is guided by the clinical picture, the composition of these solutions is predicated on serum sodium concentration and urinary sodium and potassium concentrations at presentation. Water loss is relatively greater than the loss of sodium plus potassium leading to hypernatremia which is seen routinely when the solute responsible for osmotic diuresis (e.g., urea) is distributed in body water. Solutes distributed in the extracellular compartment (e.g., glucose or mannitol) cause, in addition to osmotic diuresis, fluid transfer from the intracellular into the extracellular compartment with concomitant dilution of serum sodium. Serum sodium concentration corrected to euglycemia should be substituted for actual serum sodium concentration when calculating the composition of the replacement solutions in hyperglycemic patients. While the patient is monitored during treatment, the calculation of the volume and composition of the replacement solutions for losses of water, sodium and potassium from ongoing osmotic diuresis should be based directly on measurements of urine volume and urine sodium and potassium concentrations and not by means of any predictive formulas. Monitoring of clinical status, serum sodium, potassium, glucose, other relevant laboratory values, urine volume, and urine sodium and potassium concentrations during treatment of severe osmotic diuresis is of critical importance.

Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) exhibit an increased risk for cardiovascular (CV) events. Hyperglycemia itself contributes to the pathogenesis of atherosclerosis and heart failure (HF) in these patients, but glucose-lowering strategies studied to date have had little or no impact on reducing CV risk, especially in patients with a long duration of T2DM and prevalent CV disease (CVD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the new class of glucose-lowering medications that increase urinary glucose excretion, thus improving glycemic control, independent of insulin. The recently published CV outcome trial, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), demonstrated that the SGLT2 inhibitor empagliflozin significantly reduced the combined CV end point of CV death, nonfatal myocardial infarction, and nonfatal stroke vs. placebo in a population of patients with T2DM and prevalent atherosclerotic CVD. In addition, and quite unexpectedly, empagliflozin significantly and robustly reduced the individual end points of CV death, overall mortality, and hospitalization for HF in this high-risk population. Several beneficial factors beyond glucose control, such as weight loss, lowering blood pressure, sodium depletion, renal hemodynamic effects, effects on myocardial energetics, and/or neurohormonal effects, have been seen with SGLT2 inhibition.

Hypertonicity: Clinical entities, manifestations and treatment.

Hypertonicity causes severe clinical manifestations and is associated with mortality and severe short-term and long-term neurological sequelae. The main clinical syndromes of hypertonicity are hypernatremia and hyperglycemia. Hypernatremia results from relative excess of body sodium over body water. Loss of water in excess of intake, gain of sodium salts in excess of losses or a combination of the two are the main mechanisms of hypernatremia. Hypernatremia can be hypervolemic, euvolemic or hypovolemic. The management of hypernatremia addresses both a quantitative replacement of water and, if present, sodium deficit, and correction of the underlying pathophysiologic process that led to hypernatremia. Hypertonicity in hyperglycemia has two components, solute gain secondary to glucose accumulation in the extracellular compartment and water loss through hyperglycemic osmotic diuresis in excess of the losses of sodium and potassium. Differentiating between these two components of hypertonicity has major therapeutic implications because the first component will be reversed simply by normalization of serum glucose concentration while the second component will require hypotonic fluid replacement. An estimate of the magnitude of the relative water deficit secondary to osmotic diuresis is obtained by the corrected sodium concentration, which represents a calculated value of the serum sodium concentration that would result from reduction of the serum glucose concentration to a normal level.

Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are reported to have BP-lowering effect in addition to blood glucose-lowering effect, however, its mechanism is still unknown. This study aimed to investigate the mechanism of blood pressure (BP) lowering effects of SGLT2 inhibitors using 24-h urinary collection in obese type 2 diabetes patients. METHODS: Twenty patients with type 2 diabetes (age 48.2 ± 10.7 years, BMI 33.0 ± 4.9 kg/m2) were enrolled. Urine volume, 24-h urinary glucose and sodium excretion, and BP at baseline and 2 weeks and 6 months after administration were measured. Body weight, glycosylated hemoglobin, and BP were evaluated before and 1, 3, and 6 months after SGLT2 inhibitor administration. We evaluated the changes in urine volume and urinary excretion of glucose and sodium as well as correlations among urine volume and urinary sodium glucose excretion at 2 weeks and 6 months after administration of the SGLT2 inhibitors. Furthermore, we investigated the correlations between changes in BP and urinary excretion of sodium and glucose at the same time. RESULTS: Two weeks after administration, systolic BP (SBP) significantly decreased (128.5 ± 11.0 to 123.2 ± 9.8 mmHg, P = 0.0314), but diastolic BP (DBP) did not (74.4 ± 10.4 to 73.4 ± 8.5 mmHg, P = 0.5821). The decreased SBP significantly correlated with increased urinary glucose excretion (R = -0.62, P = 0.0073), but not increased urinary sodium excretion. At 6 months, SBP (118.6 ± 11.0 mmHg, P = 0.0041) and DBP (68.4 mmHg, P = 0.0363) significantly decreased. The decreased SBP significantly correlated with increased urinary sodium excretion (R = -0.60, P = 0.0014), but not increased urinary glucose excretion. CONCLUSIONS: SGLT2 inhibitors significantly decreased SBP after 1 month and DBP after 6 months in obese patients with type 2 diabetes. The main mechanism of the BP-lowering effect may be plasma volume reduction by osmotic diuresis at 2 weeks and by natriuresis at 6 months after SGLT2 inhibitor administration.

Sporadic hypokalemic paralysis caused by osmotic diuresis in diabetes mellitus.

A wide variety of neurological manifestations are known in patients with diabetes mellitus. We describe a 40-year-old man who presented with hypokalemic paralysis. On evaluation, we found that the cause of the hypokalemia was osmotic diuresis induced by marked hyperglycemia due to undiagnosed diabetes mellitus. The patient had an uneventful recovery with potassium replacement, followed by glycemic control with insulin. Barring a few instances of symptomatic hypokalemia in the setting of diabetic emergencies, to our knowledge uncomplicated hyperglycemia has not been reported to result in hypokalemic paralysis.