The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch

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

JulieR. Ingelfinger, M.D., Editor

Nephron Protection in Diabetic Kidney Disease

HansJoachim Anders, M.D., JohnM. Davis, Ph.D., and Klaus Thurau, M.D.
Kidney disease is a critical determinant of death
from cardiovascular causes in persons with diabetes mellitus. Beyond medications that control
glycemia and blood pressure, only medications
that inhibit the reninangiotensin system (RAS)
have had robust renoprotective effects in randomized, controlled trials. A recently published secondary analysis of the EMPA-REG OUTCOME trial1
showed the renoprotective effects of empagliflozin,
an inhibitor of sodiumglucose cotransporter 2
(SGLT2) in type 2 diabetes. How and why is an
SGLT2 inhibitor protective of the kidneys?
The working units of the kidney are individual
nephrons; each nephron is formed by a glomerulus, which filters fluid from the blood, and a
tubule, which modifies the filtrate through the
resorption of water and some solutes and the
secretion of other solutes. The concentration of
the final product, urine, depends on hydration,
obligate solute excretion, osmotic load, and other
factors. In humans, the total number of nephrons
is set at birth and declines over time as a result
of injury and aging. Kidney excretory function is
commonly expressed as the glomerular filtration
rate (GFR), a dynamic measure that depends on
the single-nephron GFR (the GFR of an individual nephron) and the total number of nephrons.
A normal GFR is maintained in a submaximal

range with a functional renal reserve that can

increase to accommodate transient volume or
osmolyte loads. Any kind of nephron loss results
in an increase in the single-nephron GFR in order
to maintain a normal total GFR. Once nephron loss
is so great that a normal GFR cannot be maintained (which is seen in patients with stage 3, 4, or
5 chronic kidney disease), the single-nephron GFR
is increased persistently, often (but not always) as
a result of increased filtration pressure across the
filtration barrier in the glomerulus; this effect is
associated with podocyte stress and loss. The rate
of podocyte loss in patients who do not have kidney disease is estimated to be approximately one
podocyte per year per glomerulus, and that rate
drastically increases in the presence of high filtration pressure, genetic podocyte weakness, or metabolic, toxic, or immunologic insults. At a certain
threshold, podocyte loss leads to glomerulosclerosis and then to atrophy of the entire nephron.
Filtration pressure is constant across a wide
range of blood-pressure levels because of the
myogenic vascular response, which consists of
vascular smooth muscle contraction elicited by
pressure-dependent activation of stretch-sensitive
ion channels in the smooth musclecell membrane. The myogenic vascular response interacts
with tubuloglomerular feedback,2 a mechanism

Figure 1 (facing page). Glomerular Filtration Pressure That Drives Albuminuria, Podocyte Loss, and Glomerulosclerosis in Diabetes.
Diabetes initiates sodiumglucose cotransporter 2 (SGLT2)driven compromise of tubuloglomerular feedback. This process directly dilates
the afferent arteriole and indirectly induces vasoconstriction of the efferent arteriole. The result is an increase in both filtration pressure
and glomerular filtration rate (GFR). Reninangiotensin 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 sodiumpotassiumchloride cotransporter 2, and PGE2 prostaglandin E2.

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The New England Journal of Medicine

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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 tubular fluid into the release of adenosine and
tubular fluid. The macula densa transduces an into an increase in renin activity in the juxtagloNormal

Diabetes without therapy

Normal filtration pressure

Presence of glomerular hypertension and hyperfiltration

can result in increased filtration pressure and podocyte stress

Renal corpuscle

Efferent
arteriole
Ascending
limb of loop
of Henle

Constricted
efferent
arteriole

Proximal
tubule

GLOMERULUS

SGLT2: proximal
resorption of
glucose and Na+

Podocyte

Na+Cl

Adenosine signaling

NKCC2

PGE2 signaling

Ca++

NKCC2

Renin release

Afferent arteriole

Renin release

Dilated afferent
arteriole

Ca++

Vasoconstriction

Vasodilatation

Renal autoregulation

Compromises tubuloglomerular feedback

RAS inhibition

SGLT2 inhibition

Decrease in glomerular hypertension and hyperfiltration

decreases filtration pressure and podocyte stress

Normalization of filtration pressure and podocyte stress

Efferent
arteriole
constriction
reverses

Efferent
arteriole
constriction
reverses

SGLT2: proximal
resorption of
glucose and Na+

SGLT2 inhibition:
reduced proximal
resorption of glucose and Na+
Na+Cl
Glucose

PGE2 signaling

NKCC2

NKCC2
Dilated afferent
arteriole

Adenosine signaling

Renin release

Afferent arteriole
dilation reverses

Ca++

Restores tubuloglomerular feedback

Reduces glomerular afterload

nejm.org

Renin release

Vasoconstriction

Vasodilatation

n engl j med 375;21

Ca++

November 24, 2016

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2097

Basic Implications of Clinical Observations

merular apparatus, an effect that can be due to

direct activation or to an adenosine-mediated decrease of renin release. Stimulation of tubuloglomerular feedback leads to vasoconstriction of the
afferent arteriole and a decrease in the singlenephron GFR.2,3 A decrease in the sodium chloride concentration in tubular fluid at the macula
densa has the reverse effects.
The renoprotection that is achieved with RAS
inhibitors is related to vasodilatation of the renal
arterioles. Since vasodilatation of the efferent arteriole is greater than vasodilatation of the afferent arteriole, glomerular afterload and filtration
pressure are substantially decreased, especially if
glomerular hyperfiltration and hypertension are
present (Fig.1). Because the RAS is highly activated in nearly all forms of chronic kidney disease,
RAS inhibitors have nephron-protective effects
not only in diabetic but also in nondiabetic kidney diseases. Indeed, rigorous RAS inhibition
can even induce regression of nondiabetic kidney disease, a result that is not achievable in patients with diabetic kidney disease. Why is diabetic kidney disease different?
The kidney in a patient with diabetic kidney
disease differs from the kidney in a patient with
nondiabetic kidney disease because hyperglycemia persistently inhibits the direct vasoactive effect of tubuloglomerular feedback (Fig.1). This
occurrence was hard to target specifically until
SGLT2 inhibitors became available.4 SGLT2 is
expressed selectively in the proximal tubule and
facilitates the reuptake of filtered glucose and
sodium in a 1:1 ratio, and this process is stimulated maximally by the massive glucose filtration
in hyperglycemia.4 As a result, hyperglycemia
drastically lowers the concentration of sodium
to which the macula densa is exposed and thereby persistently inhibits tubuloglomerular feedback, dilates the afferent arteriole, and induces
glomerular hyperfiltration in many patients
(Fig.1).4 The inhibition of tubuloglomerular
feedback in diabetes persistently exposes the
delicate glomerular filtration barrier to an increased filtration pressure, which, in a patient
with intraglomerular hypertension, promotes
podocyte barotrauma and accelerates podocyte
and nephron loss. However, SGLT2 inhibitors
are able to terminate the massive SGLT2-driven
resorption of glucose and sodium in the proximal tubule and hence increase the sodium chloride concentration at the macula densa. This
change stimulates tubuloglomerular feedback,
2098

which normalizes filtration pressure and attenuates the loss of podocytes and nephrons (Fig.1)4
and thus restores the submaximal GFR. In certain patients, some SGLT2 inhibitors may lower
the GFR acutely and massively, even to the extent
of causing acute kidney failure (www
.
fda
.
gov/
Safety/Medwatch/SafetyInformation/SafetyAlerts
forHumanMedicalProducts/ucm506554.htm), although this has not yet been reported for empagliflozin.1 Restoration of the submaximal GFR by
means of SGLT2 or RAS inhibition is followed
by long-lasting stabilization of the GFR, which
is a true nephron-protective effect.1 Indeed, failing
kidneys are like failing hearts: they last longer
when they are protected from functional overload.
Fifty years after tubuloglomerular feedback
was defined, it now appears that SGLT2 inhibition may be able to correct the deactivation of
tubuloglomerular feedback that occurs in diabetes, a feat that, in combination with RAS inhibition, has nephron-protective effects. However, in
patients with hyperglycemia, the effects of combined SGLT2 and RAS inhibition on the intrarenal RAS remain to be delineated. In addition,
SGLT2 inhibition has numerous other mechanisms of action that contribute to its beneficial
effects in diabetes and is associated with microvascular and macrovascular complications of diabetes, which are discussed in detail elsewhere.4
(For example, SGLT2 inhibition blocks renal gluconeogenesis, which elicits a moderate antidiabetic effect.) Finally, SGLT2 inhibition induces
osmotic diuresis, which favorably affects body
weight, blood pressure, heart failure, and cardiovascular outcomes.5
Disclosure forms provided by the authors are available at
NEJM.org.
From Nephrologisches Zentrum, Medizinische Klinik und Polikli
nik IV, Klinikum der Ludwig-Maximilians-Universitt Mnchen
(H.-J.A.), and the Department of Physiology, Ludwig-MaximiliansUniversitt Mnchen (J.M.D., K.T.) both in Munich, Germany.
1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and
progression of kidney disease in type 2 diabetes. N Engl J Med
2016;375:323-34.
2. Carlstrm M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev 2015;95:405-511.
3. Thurau KW, Dahlheim H, Grner A, Mason J, Granger P.
Activation of renin in the single juxtaglomerular apparatus by
sodium chloride in the tubular fluid at the macula densa. Circ
Res 1972;31:Suppl 2:182-6.
4. Vallon V. The mechanisms and therapeutic potential of SGLT2
inhibitors in diabetes mellitus. Annu Rev Med 2015;66:255-70.
5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl
J Med 2015;373:2117-28.
DOI: 10.1056/NEJMcibr1608564
Copyright 2016 Massachusetts Medical Society.

n engl j med 375;21nejm.org November 24, 2016

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.