Sodium-Glucose Cotransporter 2 Inhibitor Combined with Conventional Diuretics Ameliorate Body Fluid Retention without Excessive Plasma Volume Reduction.

We previously reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (-1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin-angiotensin-aldosterone and sympathetic nervous systems.

Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial.

Sodium glucose cotransporter 2 (SGLT2) inhibitors have both glucose-lowering and diuretic effects. We recently reported that the SGLT2 inhibitor dapagliflozin exerts short-term fluid homeostatic action in patients with chronic kidney disease (CKD). However, the long-term effects of SGLT2 inhibitors on body fluid status in patients with CKD remain unclear. This was a prospective, non-randomized, open-label study that included a dapagliflozin treatment group (n = 73) and a control group (n = 24) who were followed for 6 months. Body fluid volume was measured using a bioimpedance analysis device. The extracellular water-to-total body water ratio (ECW/TBW), a predictor of renal outcomes, was used as a parameter for body fluid status (fluid retention, 0.400 ≤ ECW/TBW). Six-month treatment with dapagliflozin significantly decreased ECW/TBW compared with the control group (-0.65% ± 2.03% vs. 0.97% ± 2.49%, p = 0.0018). Furthermore, dapagliflozin decreased the ECW/TBW in patients with baseline fluid retention, but not in patients without baseline fluid retention (-1.47% ± 1.93% vs. -0.01% ± 1.88%, p = 0.0017). Vasopressin surrogate marker copeptin levels were similar between the control and dapagliflozin groups at 6 months (32.3 ± 33.4 vs. 30.6 ± 30.1 pmol/L, p = 0.8227). However, dapagliflozin significantly increased the change in copeptin levels at 1 week (39.0% ± 41.6%, p = 0.0010), suggesting a compensatory increase in vasopressin secretion to prevent hypovolemia. Renin and aldosterone levels were similar between the control and dapagliflozin groups at 6 months, while epinephrine and norepinephrine (markers of sympathetic nervous system activity) were significantly lower in the dapagliflozin group than in the control group. In conclusion, the SGLT2 inhibitor dapagliflozin ameliorated fluid retention and maintained euvolemic fluid status in patients with CKD, suggesting that SGLT2 inhibitors exert sustained fluid homeostatic actions in patients with various fluid backgrounds. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier [UMIN000048568].

Removal of calciprotein particles from the blood using an adsorption column improves prognosis of hemodialysis miniature pigs.

Hyperphosphatemia is a major risk for poor prognosis in patients with end-stage renal disease. However, the molecular mechanism behind this link remains elusive. We and others have demonstrated that serum phosphorus levels correlate positively with circulating levels of calciprotein particles (CPPs). CPPs are colloidal mineral-protein complexes containing insoluble calcium-phosphate precipitates and have been reported to induce calcification in cultured vascular smooth muscle cells and inflammatory responses in cultured macrophages. Hence, we hypothesize that CPPs may be responsible for disorders associated with hyperphosphatemia. Using hyperphosphatemic miniature pigs receiving hemodialysis, here we show that removal of CPPs from the blood with a newly developed CPP adsorption column improves survival and alleviates complications including coronary artery calcification, vascular endothelial dysfunction, metastatic pulmonary calcification, left ventricular hypertrophy, and chronic inflammation. The present study identifies CPPs as an effective therapeutic target and justifies clinical trials to determine whether the CPP adsorption column may be useful as a medical device for improving clinical outcomes of hemodialysis patients.

Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression.

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.