The new england journal of medicine

Clinical Implications of Basic Research

The Clinical Implications of Basic Research series has focused on highlighting laboratory research that could lead to advances in clinical therapeutics. However, the path between the laboratory and the bedside runs both ways: clinical observations often pose new questions for laboratory investigations that then lead back to the clinic. One of a series of occasional articles drawing attention to the bedside-to-bench flow of information is presented here, under the Basic Implications of Clinical Observations rubric. We hope our readers will enjoy these stories of discovery, and we invite them to submit their own examples of clinical findings that have led to insights in basic science.

Basic Implications of Clinical Observations Julie R. Ingelfinger, M.D., Editor Protection in Diabetic Disease

Hans‑Joachim Anders, M.D., John M. Davis, Ph.D., and Klaus Thurau, M.D.

Kidney disease is a critical determinant of death range with a functional renal reserve that can from cardiovascular causes in persons with dia- increase to accommodate transient volume or betes mellitus. Beyond medications that control osmolyte loads. Any kind of nephron loss results glycemia and , only medications in an increase in the single-nephron GFR in order that inhibit the – system (RAS) to maintain a normal total GFR. Once nephron loss have had robust renoprotective effects in random- is so great that a normal GFR cannot be main- ized, controlled trials. A recently published second- tained (which is seen in patients with stage 3, 4, or ary analysis of the EMPA-REG OUTCOME trial1 5 chronic kidney disease), the single-nephron GFR showed the renoprotective effects of empagliflozin, is increased persistently, often (but not always) as an inhibitor of sodium–glucose cotransporter 2 a result of increased filtration pressure across the (SGLT2) in type 2 diabetes. How and why is an filtration barrier in the ; this effect is SGLT2 inhibitor protective of the kidneys? associated with stress and loss. The rate The working units of the kidney are individual of podocyte loss in patients who do not have kid- ; each nephron is formed by a glomeru- ney disease is estimated to be approximately one lus, which filters fluid from the blood, and a podocyte per year per glomerulus, and that rate tubule, which modifies the filtrate through the drastically increases in the presence of high filtra- resorption of water and some solutes and the tion pressure, genetic podocyte weakness, or meta- secretion of other solutes. The concentration of bolic, toxic, or immunologic insults. At a certain the final product, urine, depends on hydration, threshold, podocyte loss leads to glomeruloscle- obligate solute excretion, osmotic load, and other rosis and then to atrophy of the entire nephron. factors. In humans, the total number of nephrons Filtration pressure is constant across a wide is set at birth and declines over time as a result range of blood-pressure levels because of the of injury and aging. Kidney excretory function is myogenic vascular response, which consists of commonly expressed as the glomerular filtration vascular smooth muscle contraction elicited by rate (GFR), a dynamic measure that depends on pressure-dependent activation of stretch-sensitive the single-nephron GFR (the GFR of an individ- ion channels in the smooth muscle–cell mem- ual nephron) and the total number of nephrons. brane. The myogenic vascular response interacts A normal GFR is maintained in a submaximal with tubuloglomerular feedback,2 a mechanism

Figure 1 (facing page). Glomerular Filtration Pressure That Drives Albuminuria, Podocyte Loss, and Glomerulosclerosis in Diabetes. Diabetes initiates sodium–glucose cotransporter 2 (SGLT2)–driven compromise of tubuloglomerular feedback. This process directly dilates the afferent arteriole and indirectly induces vasoconstriction of the . The result is an increase in both filtration pressure and glomerular filtration rate (GFR). Renin–angiotensin system (RAS) inhibition corrects the increased glomerular afterload but not the dilation of the afferent arteriole. This problem can be corrected only through SGLT2 inhibition, which restores tubuloglomerular feedback. Both SGLT2 inhibition and RAS inhibition lower the glomerular filtration pressure, and this translates into long-term renoprotective effects. ++ − + Ca denotes calcium, Cl chloride, Na sodium, NKCC2 sodium–potassium–chloride cotransporter 2, and PGE2 prostaglandin E2.

2096 n engl j med 375;21 nejm.org November 24, 2016 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on December 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Basic Implications of Clinical Observations

that regulates the GFR through the macula densa, increase in the sodium chloride concentration in which senses sodium chloride concentration in the into the release of adenosine and tubular fluid. The macula densa transduces an into an increase in renin activity in the juxtaglo-

Normal Diabetes without therapy Normal filtration pressure Presence of glomerular hypertension and hyperfiltration can result in increased filtration pressure and podocyte stress Efferent arteriole Ascending Constricted limb of loop efferent Proximal arteriole of Henle tubule

GLOMERULUS

Podocyte SGLT2: proximal resorption of glucose and Na+ + – Na Cl Adenosine signaling PGE2 signaling

↑Ca++ NKCC2 NKCC2 ↓Renin release ↑Renin release Afferent arteriole Dilated afferent ↑Ca++ arteriole

Vasoconstriction Vasodilatation

Renal Compromises tubuloglomerular feedback

RAS inhibition SGLT2 inhibition Decrease in glomerular hypertension and hyperfiltration Normalization of filtration pressure and podocyte stress decreases filtration pressure and podocyte stress

Efferent Efferent arteriole arteriole constriction constriction reverses reverses

SGLT2: proximal SGLT2 inhibition: resorption of reduced proximal glucose and Na+ resorption of glucose and Na+ + – Adenosine signaling PGE2 signaling Na Cl Glucose ↑Ca++ NKCC2 NKCC2 ↑Renin release ↓Renin release Dilated afferent Afferent arteriole arteriole dilation reverses ↑Ca++

Vasodilatation Vasoconstriction

Reduces glomerular afterload Restores tubuloglomerular feedback

n engl j med 375;21 nejm.org November 24, 2016 2097 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on December 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Basic Implications of Clinical Observations

merular apparatus, an effect that can be due to which normalizes filtration pressure and attenu- direct activation or to an adenosine-mediated de- ates the loss of and nephrons (Fig. 1)4 crease of renin release. Stimulation of tubuloglo- and thus restores the submaximal GFR. In cer- merular feedback leads to vasoconstriction of the tain patients, some SGLT2 inhibitors may lower afferent arteriole and a decrease in the single- the GFR acutely and massively, even to the extent nephron GFR.2,3 A decrease in the sodium chlo- of causing acute kidney failure (www​.­fda​.­gov/​ ride concentration in tubular fluid at the macula Safety/­ Medwatch/​­ SafetyInformation/​­ SafetyAlerts​­ densa has the reverse effects. forHumanMedicalProducts/​­ucm506554​.­htm), al- The renoprotection that is achieved with RAS though this has not yet been reported for empa- inhibitors is related to vasodilatation of the renal gliflozin.1 Restoration of the submaximal GFR by arterioles. Since vasodilatation of the efferent ar- means of SGLT2 or RAS inhibition is followed teriole is greater than vasodilatation of the affer- by long-lasting stabilization of the GFR, which ent arteriole, glomerular afterload and filtration is a true nephron-protective effect.1 Indeed, failing pressure are substantially decreased, especially if kidneys are like failing hearts: they last longer glomerular hyperfiltration and hypertension are when they are protected from functional overload. present (Fig. 1). Because the RAS is highly acti- Fifty years after tubuloglomerular feedback vated in nearly all forms of chronic kidney disease, was defined, it now appears that SGLT2 inhibi- RAS inhibitors have nephron-protective effects tion may be able to correct the deactivation of not only in diabetic but also in nondiabetic kid- tubuloglomerular feedback that occurs in diabe- ney diseases. Indeed, rigorous RAS inhibition tes, a feat that, in combination with RAS inhibi- can even induce regression of nondiabetic kid- tion, has nephron-protective effects. However, in ney disease, a result that is not achievable in pa- patients with hyperglycemia, the effects of com- tients with diabetic kidney disease. Why is dia- bined SGLT2 and RAS inhibition on the intrare- betic kidney disease different? nal RAS remain to be delineated. In addition, The kidney in a patient with diabetic kidney SGLT2 inhibition has numerous other mecha- disease differs from the kidney in a patient with nisms of action that contribute to its beneficial nondiabetic kidney disease because hyperglyce- effects in diabetes and is associated with micro- mia persistently inhibits the direct vasoactive ef- vascular and macrovascular complications of dia- fect of tubuloglomerular feedback (Fig. 1). This betes, which are discussed in detail elsewhere.4 occurrence was hard to target specifically until (For example, SGLT2 inhibition blocks renal glu- SGLT2 inhibitors became available.4 SGLT2 is coneogenesis, which elicits a moderate antidia- expressed selectively in the and betic effect.) Finally, SGLT2 inhibition induces facilitates the reuptake of filtered glucose and osmotic diuresis, which favorably affects body sodium in a 1:1 ratio, and this process is stimu- weight, blood pressure, heart failure, and car- lated maximally by the massive glucose filtration diovascular outcomes.5 in hyperglycemia.4 As a result, hyperglycemia Disclosure forms provided by the authors are available at drastically lowers the concentration of sodium NEJM.org. to which the macula densa is exposed and there- From Nephrologisches Zentrum, Medizinische Klinik und Polikli­ by persistently inhibits tubuloglomerular feed- nik IV, Klinikum der Ludwig-Maximilians-Universität München (H.-J.A.), and the Department of Physiology, Ludwig-Maximilians- back, dilates the afferent arteriole, and induces Universität München (J.M.D., K.T.) — both in Munich, Germany. glomerular hyperfiltration in many patients 4 1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and (Fig. 1). The inhibition of tubuloglomerular progression of kidney disease in type 2 diabetes. N Engl J Med feedback in diabetes persistently exposes the 2016;​375:​323-34. delicate glomerular filtration barrier to an in- 2. Carlström M, Wilcox CS, Arendshorst WJ. Renal autoregula- tion in health and disease. Physiol Rev 2015;​95:​405-511. creased filtration pressure, which, in a patient 3. Thurau KW, Dahlheim H, Grüner A, Mason J, Granger P. with intraglomerular hypertension, promotes Activation of renin in the single juxtaglomerular apparatus by podocyte barotrauma and accelerates podocyte sodium chloride in the tubular fluid at the macula densa. Circ Res 1972;​31:​Suppl 2:​182-6. and nephron loss. However, SGLT2 inhibitors 4. Vallon V. The mechanisms and therapeutic potential of SGLT2 are able to terminate the massive SGLT2-driven inhibitors in diabetes mellitus. Annu Rev Med 2015;​66:​255-70. resorption of glucose and sodium in the proxi- 5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, car- diovascular outcomes, and mortality in type 2 diabetes. N Engl mal tubule and hence increase the sodium chlo- J Med 2015;​373:​2117-28. ride concentration at the macula densa. This DOI: 10.1056/NEJMcibr1608564 change stimulates tubuloglomerular feedback, Copyright © 2016 Massachusetts Medical Society.

2098 n engl j med 375;21 nejm.org November 24, 2016 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on December 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.