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American Journal of Kidney Diseases

Prediabetes as a Precursor to Diabetic Kidney Disease

      Related Article, p. 841
      Twenty years ago, Brenner et al
      • Brenner B.M.
      • Lawler E.V.
      • Mackenzie H.S.
      The hyperfiltration theory: a paradigm shift in nephrology.
      identified glomerular hyperfiltration as a key mediator of progressive kidney damage caused by a variety of initiating injuries, including diabetes mellitus. As the authors explained, micropuncture studies in rats had shown that an elevation in single-nephron glomerular filtration rate (GFR) is dependent on an increase in glomerular pressure and plasma flow. In addition, in all models of progressive kidney disease characterized by glomerular hyperfiltration, albuminuria had been a consistent finding. Furthermore, inhibition of the renin-angiotensin system was found to be effective in preventing glomerular hypertension and hyperfiltration, as well as in reducing albuminuria and kidney damage. These kidney-protective effects were mainly ascribed to the preferential vasodilating action on the efferent glomerular arteriole and the consequent reduction in glomerular pressure.
      • Brenner B.M.
      • Lawler E.V.
      • Mackenzie H.S.
      The hyperfiltration theory: a paradigm shift in nephrology.
      • Remuzzi G.
      • Benigni A.
      • Remuzzi A.
      Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.
      In subsequent decades, the “Brenner hypothesis” has been confirmed in patients with diabetes. A meta-analysis
      • Magee G.M.
      • Bilous R.W.
      • Cardwell C.R.
      • Hunter S.J.
      • Kee F.
      • Fogarty D.G.
      Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis.
      of 10 cohort studies dating from 1984 to 2006 that included patients with type 1 diabetes showed that during a median follow-up of 11.2 years, odds of progression from normoalbuminuria to micro- or macroalbuminuria (now referred to as moderately or severely increased albuminuria, respectively) was almost 3-fold higher in patients with glomerular hyperfiltration than in those with normofiltration. Moreover, GFR was on average 13.8 mL/min/1.73 m2 greater in patients who progressed to higher levels of albuminuria compared with those who did not (nonprogressors). The impact of glomerular hyperfiltration on prognosis was further supported by a recent analysis by Bjornstad et al
      • Bjornstad P.
      • Cherney D.Z.
      • Snell-Bergeon J.K.
      • et al.
      Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with type 1 diabetes.
      : in 646 patients with type 1 diabetes, glomerular hyperfiltration was an independent predictor of rapid GFR decline (annual loss > 3 mL/min/1.73 m2) during a 6-year follow-up. Similar results have been observed by Ruggenenti et al
      • Ruggenenti P.
      • Porrini E.L.
      • Gaspari F.
      • et al.
      for GFR Study Investigators
      Glomerular hyperfiltration and renal disease progression in type 2 diabetes.
      in a study of 600 patients with type 2 diabetes in which faster progression, in terms of worsening albuminuria and faster rate of GFR decline, was observed in patients with persistent glomerular hyperfiltration compared with those who did not display hyperfiltration. Ruggenenti et al
      • Ruggenenti P.
      • Porrini E.L.
      • Gaspari F.
      • et al.
      for GFR Study Investigators
      Glomerular hyperfiltration and renal disease progression in type 2 diabetes.
      also observed that amelioration of glomerular hyperfiltration was associated with a subsequent slower GFR decline.
      In this issue of the AJKD, Melsom et al
      • Melsom T.
      • Schei J.
      • Stefansson V.T.N.
      • et al.
      Prediabetes and risk of glomerular hyperfiltration and albuminuria in the general nondiabetic population: a prospective cohort study.
      extend to the prediabetes condition the relationship between chronic hyperglycemia, glomerular hyperfiltration, and albuminuria. The authors prospectively evaluated 1,261 individuals without diabetes (aged 50-62 years) sampled from the general population of Tromsø, Norway. Participants were followed up for a median of 5.6 years. The study showed that prediabetes was associated with the subsequent development of glomerular hyperfiltration and abnormal albuminuria. These associations were robust, persisting after multiple adjustments, including 24-hour ambulatory blood pressure at baseline and change in use of antihypertensive drugs between baseline and follow-up. The study’s strengths lie in its prospective design, involvement of a representative sample of a general middle-aged population, and measurement of GFR by single-sample plasma iohexol clearance, which is more accurate than estimated GFR in patients with diabetes who have normal or increased GFRs.
      • Gaspari F.
      • Ruggenenti P.
      • Porrini E.
      • et al.
      for GFR Study Investigators
      The GFR and GFR decline cannot be accurately estimated in type 2 diabetics.
      Two additional aspects of the study are worthy of mention. First, the authors identified prediabetes using 2 definitions: a fasting glucose level of 110 to 125 mg/dL (6.1-6.9 mmol/L) and/or glycated hemoglobin level of 6.0% to 6.4% (consistent with criteria of the International Expert Committee [IEC]) or a fasting glucose level of 100 to 125 mg/dL (5.6-6.9 mmol/L) and/or glycated hemoglobin level of 5.7% to 6.4% (matching criteria of the American Diabetes Association [ADA]). Compared to the less strict ADA definition, the IEC criteria classified a lower percentage of individuals as prediabetic (13.4% vs 47.2%). Interestingly, only the IEC cutoff values allowed identification of prediabetes as an independent predictor of hyperfiltration at follow-up. A second item to note in relation to the Melsom et al study is that ambulatory blood pressure recordings were obtained in all patients, allowing more accurate evaluation of blood pressure burden.
      • Minutolo R.
      • Gabbai F.B.
      • Agarwal R.
      • et al.
      Assessment of achieved clinic and ambulatory blood pressure recordings and outcomes during treatment in hypertensive patients with CKD: a multicenter prospective cohort study.
      Weaknesses of the study were the relatively small sample size, lack of information for number of participants with glomerular hyperfiltration at baseline, and the short follow-up. It is likely that these limitations prevented Melsom et al from properly testing the potential impact of glomerular hyperfiltration on the development and progression of kidney disease, which has been demonstrated in previous studies.
      • Magee G.M.
      • Bilous R.W.
      • Cardwell C.R.
      • Hunter S.J.
      • Kee F.
      • Fogarty D.G.
      Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis.
      • Bjornstad P.
      • Cherney D.Z.
      • Snell-Bergeon J.K.
      • et al.
      Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with type 1 diabetes.
      • Ruggenenti P.
      • Porrini E.L.
      • Gaspari F.
      • et al.
      for GFR Study Investigators
      Glomerular hyperfiltration and renal disease progression in type 2 diabetes.
      The findings of Melsom et al
      • Melsom T.
      • Schei J.
      • Stefansson V.T.N.
      • et al.
      Prediabetes and risk of glomerular hyperfiltration and albuminuria in the general nondiabetic population: a prospective cohort study.
      suggest a common pathway for hyperfiltration and albuminuria in prediabetes, as has been shown in the early stages of diabetes.
      • De Nicola L.
      • Gabbai F.
      • Liberti M.E.
      • Sagliocca A.
      • Conte G.
      • Minutolo R.
      Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.
      Figure 1 illustrates these potential pathophysiologic mechanisms. Theoretically, glomerulotubular balance and tubuloglomerular feedback are both involved in the early stage of diabetes. However, tubuloglomerular feedback likely plays a major role because experimental and clinical findings suggest that the primary derangement is of tubular origin with subsequent glomerular adaptation.
      • De Nicola L.
      • Gabbai F.
      • Liberti M.E.
      • Sagliocca A.
      • Conte G.
      • Minutolo R.
      Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.
      • Cherney D.Z.
      • Perkins B.A.
      • Soleymanlou N.
      • et al.
      Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.
      Persistent hyperglycemia increases proximal tubular reabsorption of glucose and sodium secondary to the induction of tubular growth and upregulated expression of type 2 sodium-glucose cotransporter (SGLT2). The increase in proximal reabsorption leads to a decrease in sodium delivery to the macula densa, with deactivation of tubuloglomerular feedback and a consequent increase in glomerular pressure and filtration. In turn, these hemodynamic changes lead to albuminuria. Clinical studies support this hypothesis by suggesting that hyperfiltration and albuminuria generally are associated with and contribute to the poor kidney prognosis of patients with diabetes.
      • Bjornstad P.
      • Cherney D.Z.
      • Snell-Bergeon J.K.
      • et al.
      Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with type 1 diabetes.
      • Ruggenenti P.
      • Porrini E.L.
      • Gaspari F.
      • et al.
      for GFR Study Investigators
      Glomerular hyperfiltration and renal disease progression in type 2 diabetes.
      • De Nicola L.
      • Gabbai F.
      • Liberti M.E.
      • Sagliocca A.
      • Conte G.
      • Minutolo R.
      Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.
      • Cherney D.Z.
      • Perkins B.A.
      • Soleymanlou N.
      • et al.
      Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.
      Figure thumbnail gr1
      Figure 1Hyperfiltration and albuminuria in a hyperglycemic state: postulated pathophysiologic mechanisms and potential treatment strategy. Abbreviations: GFR, glomerular filtration rate; Na, sodium; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter type 2.
      Prediabetes is a major health issue not only due to its high prevalence in apparently healthy populations, but also because it commonly heralds the future development of overt diabetic disease. The epidemiologic implications of prediabetes have recently been highlighted by a long-running prospective analysis
      • Ligthart S.
      • van Herpt T.T.
      • Leening M.J.
      • et al.
      Lifetime risk of developing impaired glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a prospective cohort study.
      of 10,050 individuals 45 years and older from the population-based Rotterdam Study in the Netherlands. At baseline, 14% of the population met criteria for prediabetes, which was similar to the prevalence rate observed by Melsom et al when using the IEC diagnostic criteria. More importantly, the Rotterdam Study observed that in a 45-year-old, the lifetime risk for developing prediabetes is 48.7%, and in people with prediabetes, the lifetime risk for progression to diabetes is as high as 74%.
      The Rotterdam Study and the current study from Melsom et al
      • Melsom T.
      • Schei J.
      • Stefansson V.T.N.
      • et al.
      Prediabetes and risk of glomerular hyperfiltration and albuminuria in the general nondiabetic population: a prospective cohort study.
      raise interest in prediabetes as a potential target for early treatment to prevent diabetic chronic kidney disease (CKD). These studies, although observational, become even more important when one considers that the incidence of chronic kidney failure has not declined during the last 2 decades, a finding at variance with other diabetes-related complications,
      • Gregg E.W.
      • Li Y.
      • Wang J.
      • et al.
      Changes in diabetes-related complications in the United States, 1990-2010.
      and that CKD remains a main modifier of cardiovascular risk in patients with diabetes.
      • Tancredi M.
      • Rosengren A.
      • Svensson A.M.
      • et al.
      Excess mortality among persons with type 2 diabetes.
      Failure of traditional therapy to lower the cardiovascular and kidney disease risk related to diabetic CKD therefore calls for action by all caregivers involved in the management of patients with diabetes. It is likely that a shift in the approach to this major public health problem is required, that is, from cure to prevention in terms of identification of disease at very early stages (prediabetes) and prompt treatment of early kidney abnormalities (hyperfiltration and albuminuria; Fig 1). Although diet and physical activity are the cornerstone of preventing disease progression in the early stages of diabetes,
      • Schellenberg E.S.
      • Dryden D.M.
      • Vandermeer B.
      • Ha C.
      • Korownyk C.
      Lifestyle interventions for patients with and at risk for type 2 diabetes: a systematic review and meta-analysis.
      we suggest that renin-angiotensin system–blocking agents and SGLT2 inhibitors may be the ideal pharmacologic combination strategy to correct hyperfiltration and albuminuria.
      In conclusion, the emerging role of prediabetes as a major risk factor for diabetic CKD has shed light on ways to limit disease burden. It is possible that the key to curbing this burden is to optimize prevention by identifying and treating at-risk patients rather than waiting for full-blown diabetic kidney disease, which is difficult to treat. Randomized clinical trials in the early phases of diabetic disease with long-term follow-up are urgently needed to verify these hypotheses.

      Acknowledgements

      Support: None.
      Financial Disclosure: Dr De Nicola has received fees from Abbvie, Astrazeneca, Janssen, and Roche for lectures and scientific consultations. Dr Conte has received fees from Abbvie as a member of its advisory board. Dr Minutolo declares that he has no relevant financial interests.
      Peer Review: Evaluated by a Co-Editor and the Editor-in-Chief.

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