Perspective
Sodium/Glucose Cotransporter 2 Inhibitors and Prevention of Diabetic Nephropathy: Targeting the Renal Tubule in Diabetes

https://doi.org/10.1053/j.ajkd.2014.02.010Get rights and content

Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose–dependent and –independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.

Section snippets

Glomerular Hyperfiltration

In the setting of DM, hyperglycemia is accompanied by an increase in GFR. Investigators have proposed several mechanisms to explain diabetic hyperfiltration, including impaired constriction of the afferent arteriole.6, 7, 8 These hemodynamic changes have been associated with activation of neurogenic, hormonal, and myogenic factors (known as the hemodynamic hypothesis). However, increased proximal tubular reabsorption also has been shown within the spectrum of the early changes observed in

Early renal alterations and prognosis

From the clinical perspective, it is essential to establish whether the early alterations detected in DM determine the prognosis. Until recently, there have been conflicting data about the prognostic role of diabetic hyperfiltration. Whereas some studies suggested that diabetic individuals with glomerular hyperfiltration have a higher risk of more rapid progression of CKD,46, 47 others did not confirm these findings.48, 49 The discrepancies likely are related to the heterogeneity and small

Overview

Various classes of agents (oral hypoglycemic agents, insulin, anti-RAS, and diuretics) currently are available for the prevention and treatment of DN; however, use of these agents can be limited by side effects. More important, there has been no substantial improvement in the prognosis of DM despite increasing awareness and screening of DM and implementation of more intensive and personalized therapies in these patients.5, 56, 57 Thus, new therapeutic strategies are desperately needed to limit

Conclusions

During the last decade, there has been a relentless increase in the number of diabetic individuals with CKD reaching chronic kidney failure. More burdensome is the observation that the prognosis has not changed significantly despite implementation of new drugs to treat diabetes and associated nephropathy. Two questions therefore arise: Should we explore new avenues? Should we move to intensify preventive strategies at earlier stages rather than therapy of overt disease?

The tubular hypothesis of

Acknowledgements

Support: None.

Financial Disclosure: The authors declare that they have no relevant financial interests.

References (74)

  • T. Moriya et al.

    Glomerular hyperfiltration and increased glomerular filtration surface are associated with renal function decline in normo and microalbuminuric type 2 diabetes

    Kidney Int

    (2012)
  • M. Hanefeld et al.

    Dapagliflozin, an SGLT2 inhibitor, for diabetes

    Lancet

    (2010)
  • F. Gaspari et al.

    The GFR and GFR decline cannot be accurately estimated in type 2 diabetics

    Kidney Int

    (2013)
  • W.T. Cefalu et al.

    Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial

    Lancet

    (2013)
  • L. Chen et al.

    The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives

    Nat Rev Endocrinol

    (2011)
  • L. De Nicola et al.

    Prognosis of CKD patients receiving outpatient nephrology care in Italy

    Clin J Am Soc Nephrol

    (2011)
  • F.C. Sasso et al.

    High cardiovascular risk in patients with type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study

    Nephrol Dial Transplant

    (2012)
  • V. Vallon et al.

    Pathophysiology of the diabetic kidney

    Compr Physiol

    (2011)
  • S.C. Thomson et al.

    Kidney function in early diabetes: the tubular hypothesis of glomerular filtration

    Am J Physiol Renal Physiol

    (2004)
  • Y.S. Kanwar et al.

    A glimpse of various pathogenetic mechanism of diabetic nephropaty

    Annu Rev Pathol

    (2011)
  • S.C. Thomson et al.

    Glomerulotubular balance, tubuloglomerular feedback, and salt homeostasis

    J Am Soc Nephrol

    (2008)
  • I.A. Miller

    Renal responses to sodium restriction in patients with early diabetes mellitus

    J Am Soc Nephrol

    (1997)
  • C.M. Miracle et al.

    Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

    Am J Physiol Renal Physiol

    (2008)
  • J. Ditzel et al.

    Renal sodium metabolism in relation to hypertension in diabetes

    Diabetes Metab

    (1989)
  • J.C. Mbanya et al.

    Increased proximal tubular sodium reabsorption in hypertensive patients with type 2 diabetes

    Diabet Med

    (1989)
  • V. Vallon et al.

    Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption

    J Am Soc Nephrol

    (1999)
  • S.C. Thomson et al.

    Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes

    J Clin Invest

    (2001)
  • M. Pruijm et al.

    Glomerular hyperfiltration and increased proximal sodium reabsorption in subjects with type 2 diabetes or impaired fasting glucose in a population of the African region

    Nephrol Dial Transplant

    (2010)
  • S. Scholl-Bürgi et al.

    Long-term outcome of renal glucosuria type 0: the original patient and his natural history

    Nephrol Dial Transplant

    (2004)
  • D.W. Barfuss et al.

    Differences in active and passive glucose transport along the proximal nephron

    Am J Physiol

    (1981)
  • V. Vallon et al.

    SGLT2 mediates glucose reabsorption in the early proximal tubule

    J Am Soc Nephrol

    (2011)
  • G.A. Quamme et al.

    Evidence for a high-affinity sodium-dependent D-glucose transport system in the kidney

    Am J Physiol

    (1987)
  • C.E. Mogensen

    Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects

    Scand J Clin Lab Invest

    (1971)
  • H. Rahmoune et al.

    Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes

    Diabetes

    (2005)
  • V. Gorboulev et al.

    Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion

    Diabetes

    (2012)
  • T. Rieg et al.

    Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacologic SGLT2 inhibition in euglycemia

    Am J Physiol Renal Physiol

    (2014)
  • D.R. Powell et al.

    Improved glycemic control in mice lacking SGLT1 and SGLT2

    Am J Physiol Endocrinol Metab

    (2013)

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