増田 貴博

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all cases of heart failure and is associated with poor outcomes. Large clinical trials have demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce hospitalizations for HFpEF and are now recommended as foundational therapy; these benefits have been authenticated in established HFpEF populations (EMPEROR-Preserved, DELIVER), whereas mechanistic and imaging studies have provided insights into the earlier pathogenesis of the disease. However, the precise mechanisms underlying their benefits in HFpEF remain incompletely understood. HFpEF represents a heterogeneous clinical syndrome encompassing multiple phenotypes, including obesity-related, amyloid, and congestion-predominant phenotypes. Among them, interstitial rather than intravascular fluid retention has emerged as a convergent mechanism particularly relevant to HFpEF in which congestion is the main symptom, driving myocardial stiffness, pulmonary congestion, and renal venous hypertension. Moreover, endothelial glycocalyx degradation and lymphatic dysfunction, often associated with comorbidities such as hypertension, diabetes, and obesity, further promote interstitial fluid accumulation, linking systemic inflammation and comorbidities to maladaptive cardiorenal interactions. Unlike conventional diuretics, SGLT2 inhibitors preferentially remove interstitial fluid while preserving plasma volume, potentially through enhanced lymphatic drainage and maintenance of capillary permeability, thereby improving diastolic function and alleviating pulmonary and renal congestion. However, although SGLT2 inhibitors alone provide sustained decongestion with good tolerability, their combination with loop or thiazide diuretics may result in greater interstitial fluid clearance and offer additional benefits in patients with overt congestion. Therefore, by targeting interstitial fluid retention-one of several key mechanisms contributing to HFpEF-SGLT2 inhibitors improve outcomes through integrated modulation of hemodynamic, renal, and molecular pathways. Targeting interstitial fluid retention and cardiorenal interactions in HFpEF: the role of SGLT2 inhibitors.

We previously demonstrated that combining a sodium-glucose cotransporter 2 (SGLT2) inhibitor with diuretics significantly reduces interstitial fluid volume without excessive depletion of circulating plasma volume or activation of the renin-angiotensin-aldosterone system (RAAS). However, the differential effects of SGLT2 inhibitor monotherapy versus combination therapy with diuretics on fluid dynamics in patients with pre-existing fluid retention remain unclear. This study included patients with fluid retention, defined by an extracellular water to total body water (ECW/TBW) ratio > 0.400, as measured by bioimpedance analysis. We evaluated 6-month changes in body fluid status and serum copeptin levels, a surrogate marker for vasopressin, between two groups: patients receiving SGLT2 inhibitor dapagliflozin monotherapy (SGLT2i group, n = 13; estimated glomerular filtration rate [eGFR] 25.0 ± 8.5 mL/min/1.73 m2) and those receiving dapagliflozin in combination with loop or thiazide diuretics (SGLT2i + diuretic group, n = 18; eGFR 29.8 ± 15.2 mL/min/1.73 m2). Changes in systolic blood pressure and estimated plasma volume did not significantly differ between groups. However, reductions in ECW/TBW, TBW, and interstitial fluid were significantly greater in the combination group than in the monotherapy group. Moreover, the increase in serum copeptin was significantly suppressed in the SGLT2i + diuretic group. No significant intergroup differences were observed in renin and aldosterone changes. These findings suggest that co-administration of SGLT2 inhibitor with diuretics can more effectively reduce interstitial fluid retention without inducing excessive plasma volume reduction or RAAS activation.

This case report describes an 80-year-old man with severe immunoglobulin G4-related tubulointerstitial nephritis (IgG4-TIN), characterized by storiform fibrosis with diffuse lymphocytic and plasma cell infiltration observed on a renal biopsy. Steroid pulse therapy administered immediately after confirming a remarkable increase in urinary β2-microglobulin (100,948 μg/L) along with no evidence of malignancy significantly improved the renal function and reduced the urinary β2-microglobulin levels. This study highlights the potential utility of urinary β2-microglobulin as a biomarker for early treatment selection in severe IgG4-TIN and emphasizes the need for timely intervention to prevent irreversible kidney damage.