This study demonstrates that treatment of CKD patients with an SGLT2 inhibitor leads to a reduction of OH that relates to baseline OH, the glucosuric response and the antialbuminuric effect. At the same time, treatment did not reduce adipose mass in contrast to previous findings in obese patients with diabetes mellitus and normal kidney function, in which after an initial reduction of OH adipose tissue continuously decreased (1, 17). This might be due to the fact that glucosuria and hence loss of calories is blunted in CKD patients with reduced GFR who also are not hyperglycemic. In our study, median glucosuria was 13 g/g creatinine which assuming a daily creatinine excretion of 1.0–1.5 g is far below values reported for patients with diabetes mellitus (up to 67 g/day) (18).
Another important difference to patients with obesity and diabetes mellitus is the finding that OH was highly prevalent in CKD patients reaching values of > 6 L/1.73m² at BL (Fig. 2E). Our data show that these patients particularly had a benefit from treatment with a SGLT2 inhibitor. Conversely, CKD patients without significant OH did not experience fluid loss and volume depletion, underscoring the good safety profile of SGLT2 inhibitors in CKD patients.
Since OH in CKD is the consequence of renal sodium and water retention, reduction of OH in CKD by SGLT2 inhibitors must relate to a natriuretic effect followed by loss of excess water. The failure to note any significant change in natriuresis does not abrogate this notion. First, spot urine samples do not allow to infer sodium excretion over a time period. Second, it also does not take into reflect sodium intake which still can exceed renal sodium excretion. Also, it must be remembered that natriuresis follows an infradian rhythm with a period up to one week (19). The situation gets more complicated as the natriuretic effects are counteracted by activation of renin-angiotensin-aldosterone system (Fig. 2G) (20). In our experience, OH measured by bioimpedance spectroscopy is an excellent surrogate of sodium and water retention, reflecting their balance over the previous days and weeks.
Overhydration is strongly associated with proteinuria and albuminuria in CKD (8). Confirming earlier findings from phase 3 studies such as the DAPA-CKD or EMPA-Kidney, we also noted the reduction of albuminuria by SGLT2 inhibitors in our cohort. We also found that SGLT2 inhibitors reduced proteasuria represented by urinary serine protease activity. Moreover, reduction of proteasuria was positively correlated with correction of OH at 6 months. Therefore, reduction of proteasuria and attenuation of proteolytic ENaC activation by SGLT2 inhibition might constitute another mechanism by which SGLT2 inhibitors affect OH in proteinuric CKD patients. Both OH and proteasuria are associated with progression of CKD (12) and it is conceivable that both factors might promote structural damage to the nephron. Hence, the correction of OH and reduction of proteasuria by SGLT2 inhibitors might represent another explanation for their nephroprotective effect. Given the interrelation of overhydration, proteasuria and progression of CKD, patients with (latent) overhydration and high proteinuria/proteasuria might benefit particularly from SGLT2 inhibition (Fig. 5). In this context SGLT2 inhibitors seem to have volume-controlling but not a volume-depleting effect and can therefore be used safely in these patients.
The study is limited by its small study size and its observational character. On the other hand, our analysis is among the first to explore body composition and fluid status in the context of CKD without type 2 diabetes. The use of bioimpedance spectroscopy provides an objective method and results with parameters directly transferable into daily clinical application. We present clinically important findings with implications for the use of SGLT2 inhibitors in CKD patients. We additionally present reduction of proteasuria and implications on the interrelation of overhydration and proteinuria / proteasuria as new aspects of underlying mechanisms of the nephroprotective effects of SGLT2 inhibitors. Moreover, we have very few losses to follow up.
In conclusion, SGLT2 inhibitors inhibit the pathophysiological interaction of overhydration, proteinuria / proteasuria and progression of CKD, which presents a potential mechanism for the nephroprotective effects of SGLT2 inhibitors.