Renal Hyperfiltration Is Associated With Glucose-Dependent Changes in Fractional Excretion of Sodium in Patients With Uncomplicated Type 1 Diabetes

Abstract

OBJECTIVERenal hyperfiltration is a common abnormality associated with diabetic nephropathy in patients with type 1 diabetes (T1D). In animal models, increased proximal tubular sodium reabsorption results in decreased distal sodium delivery, tubuloglomerular feedback activation, afferent vasodilatation, and hyperfiltration. The role of tubular factors is less well understood in humans. The aim of the current study was therefore to compare the fractional sodium excretion (FE Na ) in hyperfiltering (T1D-H) versus normofiltering (T1D-N) patients and healthy control (HC) subjects, as well as the role of ambient hyperglycemia on FE Na . RESEARCH DESIGN AND METHODSBlood pressure, renal function (inulin for glomerular filtration rate [GFR], and paraaminohippurate for effective renal plasma flow), FE Na , and circulating neurohormones were measured in T1D-H (n = 28, GFR ‡135 mL/min/1.73 m 2 ), T1D-N (n = 30), and HC (n = 35) subjects during clamped euglycemia. Studies were repeated in a subset of patients during clamped hyperglycemia. RESULTSDuring clamped euglycemia, T1D-H exhibited lower FE Na than T1D-N and HC subjects (0.64 6 0.06% vs. 0.91 6 0.12% and 0.90 6 0.10%, P < 0.05). During clamped hyperglycemia, FE Na increased (D + 0.88 6 0.22% vs. D + 0.02 6 0.21%; betweengroup effect, P = 0.01) significantly in T1D-H, whereas FE Na did not change in T1D-N. When treated as continuous variables, elevated GFR values were associated with hyperglycemia-induced increases in FE Na (R 2 = 0.20, P = 0.007). CONCLUSIONSPatients with uncomplicated T1D-H exhibit lower FE Na under euglycemic conditions, which may help to identify patients with hyperfiltration outside of a controlled laboratory setting. Increased FE Na in T1D-H but not T1D-N under clamped hyperglycemic conditions suggests that the mechanisms responsible for increased sodium reabsorption leading to hyperfiltration can be saturated.

Shear Stress-Induced Alteration of Epithelial Organization in Human Renal Tubular Cells

“…As this was observed in absence of other mediators of tubular aggression (such as albuminuria, dilatation-induced stretch or hyperglycemia (data not shown)), our result strongly supports an in vivo role of pathologic FSS in tubular lesions after reduction in nephron number. Glomerular hyperfiltration has been incriminated as a common pathogenic mechanism leading to CKD progression in other conditions including diabetes mellitus, hypertension, obesity, polycystic kidney disease, sickle cell anemia, or the nephrotic syndrome [ 72 , 73 ]. It is therefore tempting to propose that tubular lesions induced by hyperfiltration in these situations may be caused, at least in part, by increased urinary FSS and its ability to trigger structural changes of renal tubular cells.…”

Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration

“…Whilst mechanisms for the development of hyperfiltration have not been agreed upon, several studies suggest that it is likely a multifactorial process. One suggestion has been that hyperfiltration exists as a compensatory mechanism to prevent glomerular injury , whilst another suggests that hyperfiltration results from proximal convoluted tubule hyperreabsorption of excess glucose or sodium within the filtrate. Our data support a hypothesis that renal hyperfiltration occurs to preserve systemic insulin sensitivity given the positive association between Ccr and change in GDR.…”

The impact of hyperfiltration on the diabetic kidney

“…Indeed, the fractional excretion rate of sodium was increased in HF T1DM patients during hyperglycaemic condition with increases in GFR being positively correlated with increases in the fractional excretion rate of Na. This finding suggests that the mechanisms responsible for increased Na reabsorption leading to HF can be saturated and that other factors such as activation of vasoactive substances are important in promoting HF in the setting of hyperglycaemia [41]. It is also worth noting that the mechanisms linking tubulo-glomerular feedback to HF are still not fully defined.…”