Artículo Médico

Reviews
Glomerular hyperfiltration
Monica Cortinovis 1,4, Norberto Perico1,4, Piero Ruggenenti1,2, Andrea Remuzzi3
and Giuseppe Remuzzi 1 ✉
Abstract | Circulating blood is filtered across the glomerular barrier to form an ultrafiltrate of
plasma in the Bowman’s space. The volume of glomerular filtration adjusted by time is defined
as the glomerular filtration rate (GFR), and the total GFR is the sum of all single-nephron GFRs.
Thus, when the single-nephron GFR is increased in the context of a normal number of functioning
nephrons, single glomerular hyperfiltration results in ‘absolute’ hyperfiltration in the kidney.
‘Absolute’ hyperfiltration can occur in healthy people after high protein intake, during pregnancy
and in patients with diabetes, obesity or autosomal-dominant polycystic kidney disease. When
the number of functioning nephrons is reduced, single-nephron glomerular hyperfiltration can
result in a GFR that is within or below the normal range. This ‘relative’ hyperfiltration can occur in
patients with a congenitally reduced nephron number or with an acquired reduction in nephron
mass consequent to surgery or kidney disease. Improved understanding of the mechanisms that
underlie ‘absolute’ and ‘relative’ glomerular hyperfiltration in different clinical settings, and of
whether and how the single-nephron haemodynamic and related biomechanical forces that
underlie glomerular hyperfiltration promote glomerular injury, will pave the way toward the
development of novel therapeutic interventions that attenuate glomerular hyperfiltration
and potentially prevent or limit consequent progressive kidney injury and loss of function.
The primary function of the kidney is to maintain homeo In this Review, we describe the determinants of ‘abso
stasis in the body through the selective retention or lute’ and ‘relative’ glomerular hyperfiltration in health
elimination of water, electrolytes and other solutes. This and disease and discuss single-nephron haemodynamic
function is achieved through the filtration of circulating changes as predictors and pathophysiological factors that
blood across the glomerular barrier to form an ultrafil might result in progressive kidney injury and an inexora
trate of plasma in the Bowman’s space, combined with ble decline in kidney function. Furthermore, we discuss
selective reabsorption and secretion across cells lining the how mitigating glomerular hyperfiltration with lifestyle
1
Department of Renal renal tubule. The volume of glomerular filtration adjusted or pharmacological interventions might translate into
Medicine, Clinical Research
by time is defined as the glomerular filtration rate (GFR) long-term renoprotection.
Centre for Rare Diseases
“Aldo e Cele Daccò”: Istituto
and the total GFR is the sum of all single-nephron GFRs
di Ricerche Farmacologiche (SNGFRs). Thus, an increase in the SNGFR in a kidney The determinants of single-nephron GFR
Mario Negri IRCCS, Ranica, with a normal number of functioning nephrons will result The determinants of SNGFR were first described by
Bergamo, Italy. in ‘absolute’ hyperfiltration (that is, an increase in the total Deen and coworkers in 1972, using a sophisticated and
2
Unit of Nephrology GFR). Such ‘absolute’ hyperfiltration can occur in healthy fairly complex mathematical model1. In 2014, Pollak
and Dialysis, Azienda
people after high protein intake, during pregnancy or in and coworkers revisited the topic and emphasized that
Socio-Sanitaria Territoriale
Papa Giovanni XXIII, patients with diabetes, obesity or autosomal-dominant the transcapillary flow of water across the glomerular
Bergamo, Italy. polycystic kidney disease (ADPKD). capillaries is regulated by the same Starling forces that
3
Department of Management When the number of functioning nephrons is control fluid flow across all capillary beds2. Water ultra
Information and Production reduced, an increase in SNGFR can result in a total GFR filtration across the glomerular barrier is sustained by
Engineering, University of that is normal or reduced compared with that of an an imbalance between the mean transcapillary hydraulic
Bergamo, Dalmine, Italy.
individual with a normal nephron number and SNGFR. pressure gradient (ΔP, defined as the difference between
4
These authors contributed Such ‘relative’ hyperfiltration can occur in patients with a the mean intracapillary hydraulic pressure (PGC) and the
equally: Monica Cortinovis,
Norberto Perico.
reduced nephron number because of a congenital solitary hydraulic pressure within the Bowman’s space (PΤ)) and
✉e-mail: giuseppe.remuzzi@ functioning kidney or a low nephron endowment owing the mean transcapillary oncotic gradient (Δπ, defined as the
marionegri.it to preterm birth and/or intrauterine growth restriction as difference between the mean intracapillary oncotic
https://doi.org/10.1038/ well as in patients with a reduction in nephron number pressure (πGC) and the oncotic pressure within the
s41581-022-00559-y owing to surgery or kidney disease. Bowman’s space (πΤ)). ΔP favours filtration, whereas Δπ
NAtuRe RevIewS | NEPhRoLoGy volume 18 | July 2022 | 435
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Reviews
Key points or diethylenetriaminepentaacetic acid, to measure

the GFR. Other studies have estimated the GFR using
• ‘Absolute’ hyperfiltration is a supraphysiological elevation in glomerular filtration creatinine- or cystatin-based equations. However, these
rate (GFR) that occurs when the single-nephron glomerular filtration rate (SNGFR) formulas do not provide a reliable assessment of kidney
increases in a kidney with a normal number of functioning nephrons.
function4, and tend to underestimate measured GFR
• ‘Absolute’ hyperfiltration can occur in healthy people following consumption of a within the normal or high-normal ranges5.
high protein meal and during pregnancy as well as in patients with obesity, diabetes Average SNGFR has also been calculated by divid
mellitus or autosomal-dominant polycystic kidney disease.
ing the measured GFR by the total number of nephrons
• ‘Relative’ hyperfiltration is an increase in SNGFR in the setting of a reduced number defined as the product of the density of functioning
of functioning nephrons, which can result in a GFR that is within or below the normal
nephrons determined in a kidney biopsy sample and the
range.
total renal cortical volume assessed using CT6. This inva
• ‘Relative’ hyperfiltration can occur in patients with a congenitally reduced number of
sive approach is difficult to apply in routine clinical prac
nephrons and in those with an acquired reduction in kidney mass as a result of surgery
or kidney disease.
tice. However, a study of 1,388 living kidney donors who
underwent a CT scan of the kidney, iothalamate-based
• Independent of ‘absolute’ or ‘relative’ hyperfiltration, persistent increases in the
SNGFR that are associated with glomerular hypertension can eventually lead to
measurement of GFR during donor evaluation and
proteinuria, glomerulosclerosis and a decline in kidney function. a kidney biopsy at donation reported a mean GFR of
• Improved understanding of the underlying mechanisms could lead to the development
115 ± 24 ml/min, a mean of 860,000 ± 370,000 nephrons
of novel therapeutic interventions to attenuate glomerular hyperfiltration and protect per kidney and a mean SNGFR of 80 ± 40 nl/min6.
the kidney. Higher SNGFR was associated with obesity, a family
history of kidney failure, height >190 cm and larger
nephrons6,7. Nephrosclerosis was also associated with a
opposes filtration. Glomerular filtration is also modu higher SNGFR, independent of nephron size, suggest
lated by the hydraulic conductivity of the glomerular ing that large nephron size determined using a kidney
barrier (Kf ), which in turn depends on the intrinsic biopsy is not a perfect surrogate for a higher SNGFR6.
permeability of the barrier (k) and the total surface area Glomerular hyperfiltration can be identified indi
of the glomerular barrier available for filtration (S). rectly based on an evaluation of the loss of renal func
Thus, the determinants of the SNGFR can be described tional reserve, that is, the capacity of the kidney to
in the following equation: increase its GFR in response to stimuli such as a protein
meal or systemic infusion of dopamine8,9 (whether renal
SNGFR = k × S ×[(PGC − PT ) − (πGC − πT )] (1) functional reserve can also be assessed using intravenous
amino acid infusion is controversial)10. The higher the
Assuming — in an over-simplification of the model — basal glomerular hyperfiltration, the lower the increase
that glomerular barrier conductivity (k × S), PΤ and in GFR observed after an exogenous stimulus11,12. Thus,
the difference between πGC and πΤ are kept constant, the kidneys of patients who show no evidence of renal
changes in SNGFR will largely depend on changes functional reserve are assumed to have exploited their
in PGC. Thus, increases in systemic blood pressure that entire filtration capacity to compensate for the loss of
translate into increases in glomerular perfusion pressure functioning nephrons. Renal functional reserve test
will increase the SNGFR, resulting in glomerular hyper ing has been established for decades, but has not been
filtration. Similar effects will be obtained by reductions adopted into routine clinical practice because its clini
in pre-glomerular resistance, which will facilitate the cal value has not been studied rigorously13. Moreover,
transmission of pre-glomerular perfusion pressure to the finding that the kidneys of patients with advanced
the capillary network (as observed in patients with dia chronic kidney disease (CKD) retain the ability to
betes or after a high-protein meal) and by increases in increase their GFR in response to appropriate stimuli14,
post-glomerular resistance that oppose plasma outflow and that this increase may exceed 60% in patients with
from the capillary network, as observed in clinical con diabetic kidney disease (DKD) and severe renal insuf
ditions that are associated with the over-activation of ficiency exposed to acute hyperglycaemia15, appears to
the renin–angiotensin–aldosterone system (RAAS) such challenge the reliability of renal functional reserve test
as congenital or acquired reduction in renal mass. ing as a potential tool for identifying a hyperfiltering
state in patients with severely impaired kidney function.
Absolute hyperfiltration
‘Absolute’ glomerular hyperfiltration is generally High protein intake
defined as a GFR greater than two standard deviations In the early 1980s, Brenner and colleagues hypothesized
above the mean for individuals of the same age and sex. that changes in kidney function in response to protein
Nevertheless, several operational thresholds of GFR intake might mirror the evolutionary adaptation of the
have been used to define absolute glomerular hyperfil kidney to meet the excretory needs of carnivorous ani
tration, ranging from 90.7 to 175 ml/min/1.73 m2 (ref.3). mals with intermittent protein intake16. They posited
Differences in the definition of glomerular hyperfiltra that in remote human ancestors who hunted and scav
tion are compounded by the use of a wide variety of enged for meat, renal plasma flow (RPF) and the GFR
methods to evaluate the GFR. Some studies have used might have increased in the immediate post-prandial
the clearance of exogenous compounds, such as inulin, period but declined to baseline levels during relatively
iohexol, iothalamate or isotopically labelled markers, long periods of fasting between meals, to conserve water
such as iothalamate, ethylenediaminetetraacetic acid and electrolytes while intake was low (Fig. 1). In most
436 | July 2022 | volume 18 www.nature.com/nrneph
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modern human societies, protein-rich food is availa haemodynamic changes in the kidney seem to include
ble ad libitum and individual meals are small but fre a complex interplay of hormonal responses (e.g. gluca
quent, resulting in a substantially larger overall amount gon and the RAAS), changes in the balance of paracrine
of food consumption. RPF and the GFR are therefore vasoactive mediators (e.g. nitric oxide and vasodilator
maintained at high levels but with less post-prandial prostaglandins) and modulation of the activity of the
elevation, as individual meals are relatively small. This tubuloglomerular feedback system22–25. Intriguingly, veg
hypothesis has been strengthened by experimental and etable proteins and branched-chain amino acids have a
clinical studies that demonstrated that a protein-rich limited effect on the GFR24,26, whereas proteins derived
meal or intravenous infusion of amino acids leads to an from meat and amino acids, such as arginine or glycine,
acute decline in renal vascular resistance, accompanied lead to a 15–25% increase in the GFR24,26.
by an increase in RPF and GFR17,18. Filtration fraction, The role of prolonged, recurrent glomerular hyper
that is, the ratio of GFR to RPF, seems to change only filtration caused by high protein intake in the onset
minimally during this physiological response, suggest and progression of CKD is a topic of renewed interest
ing that vasodilation of both afferent and efferent arte given the increasing popularity of high-protein, low-
rioles is involved19–21. The underlying factors in these carbohydrate and low-fat diets for weight loss. Rodents
that were fed long-term high-protein diets (35%27 or
a Intermittent high-protein feeding 40%28 of energy intake) showed glomerular hypertrophy,
SNGFR hyperfiltration and proteinuria as well as a greater preva
RA RE lence of kidney histological damage compared with con
trols on a normal diet. Similarly, pigs fed a high-protein
QA diet (35% of energy intake) for 8 months exhibited an
Between meals Low basal GFR initial rise in their GFR, followed by the development
of glomerulosclerosis and kidney fibrosis29. In the clin
ical context, the effects of a continuous high-protein
diet on kidney health are unclear. Several30–34, but not
SNGFR all35–37, long-term observational studies have reported
an association between high protein intake and kidney
RA RE
function decline in individuals with or without CKD.
The interpretation of these findings is hampered by
QA
Immediate post- ‘Absolute’ glomerular residual confounding, such as challenges in accurately
prandial period hyperfiltration measuring protein consumption over a prolonged period
and the lack of a uniform definition of a high-protein
Vasodilation Vasodilation
diet. Some randomized controlled trials (RCTs) in obese
patients with or without type 2 diabetes mellitus (T2DM),
b Ad libitum high-protein feeding found that long-term (>6 months) high-protein diets had
SNGFR
little to no effect on kidney function38–41. Nevertheless,
RA RE these studies were limited by their creatinine-based
assessment of kidney function and sizable attrition rates.
QA
Between meals High basal GFR
Pregnancy
Healthy pregnancies are characterized by profound
changes in kidney function and physiology. Some of
the most important physiological adaptations include
SNGFR
increased cardiac output, volume expansion with sodium
and water retention and vasodilation42. The kidneys
RA RE
contribute to this vasodilator response through a mar
QA
Immediate post- ‘Absolute’ glomerular ked increase in the GFR and RPF. In pregnant rats, the GFR
prandial period hyperfiltration increases to a maximum of 30–40% above non-pregnant
values and then decreases towards the baseline value as
Vasodilation Vasodilation
pregnancy approaches term (22 days)43,44. Glomerular
Fig. 1 | Changes in kidney function during feeding. a | Hypothetically, in human micropuncture studies showed that the increase in the
ancestors with intermittent high-protein feeding, marked reductions in both glomerular GFR is paralleled by an increase in the SNGFR, which
afferent arteriolar resistance (RA) and efferent arteriolar resistance (RE) would have occurred is secondary to an increase in glomerular plasma flow43.
in the immediate post-prandial period owing to the large amount of food consumed, Intraglomerular capillary hydraulic pressure does not
resulting in vasodilation, reduced renal vascular resistance and very large increases in change as glomerular plasma flow increases because
the plasma volume flow rate in the glomerular capillaries (QA) and single-nephron GFR the pre- and post-glomerular resistance vessels dilate in
(SNGFR). During the lengthy interval between meals, vasodilation, RA and RE would return
parallel43,44. Whether glomerular transcapillary hydraulic
to basal levels, as would QA, RVR and SNGFR. b | In modern humans, glomerular filtration
rate (GFR) is maintained at a high level with less post-prandial elevation as individual meals pressure increases in human pregnancy is unclear.
are relatively small. Post-prandial increases in GFR are sustained by ‘absolute’ glomerular In healthy pregnant women, the relationship between
hyperfiltration resulting from reductions in RA and RE that cause vasodilation and an RPF and GFR changes as gestation proceeds (Fig. 2).
elevation in QA. Given the frequency of individual meals, vasodilation of both afferent and In early to mid-pregnancy, the increase in RPF (approx
efferent arterioles is maintained between meals with a persistently high level of SNGFR. imately 60–80%) exceeds the increase in the GFR
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with non-pregnant levels (%)

Gestation Post-partum
Change in RPF compared

60
40
20
0
0 12–26 Term 6–8
Time (weeks)
with non-pregnant levels (%)

Gestation Post-partum
Change in GFR compared

60
40
20
0
0 12–26 Term 6–8
Time (weeks)
b
SNGFR SNGFR SNGFR
RA RE RE
RA RE RA
QA QA QA
Increase in Kf Increase in Kf
‘Absolute’ glomerular ‘Absolute’ glomerular GFR progressively returns

hyperfiltration hyperfiltration to non-pregnant levels
Fig. 2 | Kidney function during pregnancy. a | Changes in the glomerular filtration rate (GFR) and renal plasma flow (RPF)
during gestation and post-partum in healthy women45–49. The GFR and RPF profile suggests that intraglomerular changes
occur early in pregnancy, from 12–26 weeks’ gestation until term, and for 6–8 weeks following delivery. b | In early to
mid-pregnancy, the increase in RPF surpasses that of the GFR. Thus, during the first and second trimesters, the rise in the
GFR has been attributed to an increase in RPF resulting from parallel decreases in afferent arteriolar resistance (RA) and
efferent arteriolar resistance (RE). From 12–26 weeks’ gestation until term, RPF decreases towards pre-pregnancy values,
whereas the GFR remains elevated. The maintenance of a high GFR despite a decrease in RPF has been attributed to an
increase in the hydraulic conductivity of the glomerular barrier (Kf). The GFR remains elevated 2 weeks after delivery.
This elevation requires either a 16% increase in transcapillary hydraulic pressure, a 50% increase in Kf, or a combination
of smaller increases in both compared with non-pregnant values49. RPF and the GFR normalize 6–8 weeks post-partum.
RVR, renal vascular resistance; SNGFR, single-nephron GFR; QA, glomerular capillary plasma flow; Kf, glomerular capillary
ultrafiltration coefficient.
(approximately 40–60%), resulting in a slight decrease ultrafiltration, this elevation could be attributed to a 50%
in filtration fraction. From 12–26 weeks of gestation increase in Kf, a 16% increase in transcapillary hydraulic
until term, RPF decreases towards pre-pregnancy levels, pressure or smaller increases in both values.
whereas the GFR remains elevated, resulting in an Multiple mechanisms are thought to be involved in
increased filtration fraction45,46. RPF, GFR and filtra the characteristic kidney vasodilation and glomerular
tion fraction normalize 6–8 weeks following delivery47. hyperfiltration that occurs in normal pregnancy. Rodent
During the first and second trimesters, the rise in GFR studies have shown that relaxin, a pregnancy hormone
has therefore been attributed exclusively to a rise in secreted by the corpus luteum, decidua and placenta,
RPF48. In the third trimester, the maintenance of a high increases the GFR and RPF by upregulating vascular
GFR, despite a decrease in RPF, has been attributed to an gelatinase activity, which contributes to renal vasodila
increase in the hydraulic conductivity of the glomerular tation through activation of the endothelin receptor type
barrier (Kf ) together with a potential contribution from a B–nitric oxide pathway50. In women, no correlation was
decrease in glomerular intracapillary oncotic pressure48. found between serum relaxin levels and mean arterial
Two weeks following delivery, GFR has been reported pressure, the GFR or RPF during the third trimester
to remain 20% higher than normal non-pregnant val or early postpartum period51. However, these findings
ues49. According to a mathematical model of glomerular do not exclude the possibility that relaxin is involved
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in early gestational kidney haemodynamic adapta model of obesity caused by overfeeding, early weight
tion. Angiotensin II is also upregulated during normal gain correlated with renal vasodilatation and an increase
pregnancy but the sensitivity of the systemic and renal in the GFR and RPF60. Moreover, abnormal kidney
circulations to the vasoconstrictory actions of this hor haemodynamic parameters, including increases in
mone is reduced52,53. The blunted pressor response to GFR and/or RPF, have been reported in people who are
angiotensin II during pregnancy can be explained by overweight or obese61–63. The fact that RPF increases
hormones and other vasoactive mediators, including to a lesser extent than GFR, with a consequent eleva
progesterone and prostacyclins54. Furthermore, during tion of the filtration fraction, is consistent with a state
healthy pregnancy, angiotensin II type 1 receptors are of hyperfiltration that could theoretically be explained
in a monomeric rather than a heterodimeric state55. by a decrease in pre-glomerular resistance and/or an
Angiotensin II type 1 receptor monomers can be inacti increase in post-glomerular resistance (with an increase
vated by reactive oxygen species and have reduced sen in intraglomerular hydraulic pressure), an increase in
sitivity to angiotensin II compared with angiotensin II glomerular barrier hydraulic permeability and/or an
type 1 receptor heterodimers. increase in filtering surface area. An analysis that used
In contrast to the long-lasting glomerular hyper a theoretical model of dextran transport through a
filtration observed in patients with CKD, physio heteroporous membrane, showed that the main factor
logical glomerular hyperfiltration in pregnant women that might account for the increase in GFR (secondary
is short-lived and is not associated with kidney injury. to glomerular hyperfiltration) in severely obese individ
A study of women who had experienced multiple preg uals is an increase in the transcapillary hydraulic pres
nancies found no adverse effects on kidney function56. sure gradient, consequent to increased intraglomerular
However, pregnancy can increase the rate of kidney hydraulic pressure61.
function loss in women who already have underlying Two theories have been suggested to explain the ori
kidney disease57. gins of obesity-related glomerular hyperfiltration (Fig. 3).
According to the haemodynamic hypothesis, glomeru
Obesity lar hyperfiltration is the result of an imbalance of vaso
Obesity is an independent risk factor for CKD58,59 and active mediators that regulate the tone of the afferent
glomerular hyperfiltration provides a potential path and efferent arterioles64. The factors that contribute
ogenic link between CKD and obesity. In an animal to the increase in efferent arteriolar resistance include
RAAS activation, with enhanced local production of
angiotensin II, as well as activation of the endothelin-1
a Haemodynamic hypothesis SNGFR pathway, whereas various vasodilatory mediators, such
as cyclooxygenase 2 (COX2)-derived prostanoids and
Imbalance of vasoactive mediators
RA RE nitric oxide, induce a reduction in afferent arteriolar
• RAAS activation QA resistance.
• Activation of the endothelin-1 ΔP By contrast, the tubular hypothesis suggests that glo
pathway
• COX2-derived prostanoids merular hyperfiltration is triggered by an increase in
• Nitric oxide sodium reabsorption in the proximal tubule, resulting
Vasodilation Vasoconstriction
in reduced delivery of sodium chloride to the macula
'Absolute' glomerular hyperfiltration densa, deactivation of tubuloglomerular feedback and
b Tubular hypothesis a consequent reduction in afferent arteriole resistance,
JGA which over time increases glomerular perfusion and
filtration.
SNGFR
A number of mechanisms enhance kidney sodium
RE reabsorption in obesity, including compression of the
RA
kidney parenchyma by visceral, perirenal and renal sinus
↑ Na
QA fat, and activation of the RAAS and sympathetic nerv
ΔP
reabsorption ous system65. Changes in adipokine profiles secondary to
obesity-induced remodelling and the expansion of adi
Vasodilation pose tissue also have the potential to influence sodium
handling by the kidney. In obesity, elevated plasma
'Absolute' glomerular hyperfiltration
↓ Na delivery to JGA leptin concentrations cause an increase in sympathetic
activity66,67, triggering RAAS activation and sodium
Fig. 3 | Potential origins of obesity-related glomerular hyperfiltration. a | According retention in the kidney.
to the haemodynamic hypothesis, activation of vasoactive hormones in obesity results In addition to hormone-mediated glomerular haemo
in a reduction in glomerular afferent arteriolar resistance (RA) and an increase in efferent dynamic changes and those that occur secondary to
arteriolar resistance (RE), which lead to an increase in glomerular transcapillary hydraulic tubular sodium reabsorption, the increased arterial
pressure difference (ΔP) and eventually an increase in single-nephron glomerular
blood pressure that is often associated with obesity can
filtration rate (SNGFR) and ‘absolute’ glomerular hyperfiltration. b | According to the
tubular hypothesis, increased sodium reabsorption in the proximal tubule in obesity be transmitted to the glomerular circulation through
results in a reduction in sodium chloride delivery to the juxtaglomerular apparatus the predominantly dilated afferent arterioles, thereby
(JGA) and the deactivation of tubuloglomerular feedback, eventually leading to a enhancing glomerular hydraulic pressure and eventu
reduction in RA and thus increasing SNGFR. QA, glomerular capillary plasma flow; ally the GFR. In the long term, this increased intraglo
RAAS, renin–angiotensin–aldosterone system. merular hydraulic pressure can damage the glomerular
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filtration barrier. Some individuals with obesity develop a missed when the measured GFR was indexed for body
clinico-pathological syndrome known as obesity-related surface area70–72,91 (Table 1). This adjustment might
glomerulopathy and subsequently progress to kidney not be appropriate for comparing GFR values in indi
failure68. The histological hallmark of this syndrome is viduals before and after weight loss because the num
glomerulomegaly, which is commonly accompanied by ber of nephrons does not change as body surface area
perihilar focal segmental glomerulosclerosis. The most decreases92. Measurement of the GFR via clearance of
frequent clinical presentation is subnephrotic protein exogenous filtration tracers (i.e. iohexol or iothalamate)
uria that gradually increases over time. Some patients without indexing to body surface area should therefore
have massive proteinuria (>5–10 g per day) but the other be the gold standard for longitudinally tracking kidney
components of nephrotic syndrome (oedema, hyperlipi function in patients who are obese and in those who
daemia and hypoalbuminemia) are usually absent. This experience changes in weight84.
particular feature of obesity-related glomerulopathy Whether an improvement in obesity-associated glo
is helpful in making a differential diagnosis between merular hyperfiltration induced by weight reduction
this syndrome and other proteinuric kidney diseases, translates into long-term kidney benefits remains to
including primary focal segmental glomerulosclerosis, be seen. A large cohort study observed improvements
minimal change disease and membranous nephropathy, in CKD risk category at 7 years after bariatric surgery in
which can also affect people who are obese68. 53% and 56% of patients whose baseline risk of CKD was
moderate and high, respectively93. These findings should
Effects of weight loss on kidney function. Observational be interpreted with caution, however, because GFR was
studies and a few RCTs have evaluated the effects of estimated rather than measured. To date, and to our
weight reduction on kidney function in people who knowledge, no study has been designed specifically to
are obese, including those with CKD. In patients with examine the effects of weight loss on robust outcomes
out overt kidney disease, bariatric surgery resulted in such as kidney failure.
a reduction in glomerular hyperfiltration, defined as a Given the central role of RAAS activation in the
decrease in either the measured GFR69–72 or 24-h creati pathogenesis of obesity-related glomerular hyperfil
nine clearance73,74 as well as a reduction in albuminuria tration, RAAS blockade with angiotensin-converting
and proteinuria69,72,73. In eight morbidly obese patients enzyme (ACE) inhibitors or angiotensin receptor block
who underwent gastroplasty, the measured GFR and ers (ARB) is an effective therapeutic strategy to prevent
RPF declined by 24% and 13%, respectively, 12 months kidney disease progression. A post hoc analysis of the
after the intervention69. Similar findings were observed REIN trial found that ACE inhibition with ramipril
when weight loss was achieved through dietary interven compared with placebo reduced the incidence of kidney
tion. In 34 patients with T2DM, abdominal obesity and failure among patients with obesity by 86%, compared
normal kidney function, a 6-month calorie restricted with reductions of 45% among those who were over
diet with adequate nutrition was associated with weight and 42% among those with normal weight94. This
improvements in insulin sensitivity and a significant finding suggests that patients with obesity are particu
reduction in the measured GFR, suggesting amelioration larly responsive to the renoprotective effects of RAAS
of glomerular hyperfiltration75. inhibition.
In patients with CKD, weight loss achieved through The manipulation of tubuloglomerular feedback
either bariatric surgery or dietary intervention con seems to be a promising approach to decreasing obesity-
sistently results in a considerable reduction in protein related glomerular hyperfiltration. A RCT showed that
uria76,77. However, the effects on kidney function are intravenous administration of acetazolamide, a carbonic
variable, with studies reporting increases78,79, decreases80 anhydrase inhibitor that inhibits salt reabsorption in the
or no change81–83 in the GFR. This variability might be proximal tubule, led to an acute 21% reduction in meas
explained by differences in the methods employed to ured GFR in non-diabetic patients with obesity and
assess kidney function; the majority of studies rely on glomerular hyperfiltration95. As the effect on GFR was
the estimated GFR. A prospective study in patients with analysed 60 min after acetazolamide infusion, these
CKD and severe obesity reported an acute decrease in short-term data do not enable any inferences to be
the measured GFR during the first few months after drawn regarding the long-term effects of acetazolamide
bariatric surgery, followed by stabilization of the GFR on GFR in this patient population.
during a follow-up of up to 24 months80. In contrast to
the measured GFR, the estimated GFR did not show an Diabetes mellitus
acute decrease following massive weight loss in severely The leading cause of kidney failure is DKD, which
obese patients with or without CKD71,72,80. Estimating the accounts for almost half of all incident cases in the
GFR poses several challenges that are particularly sali Western world96. In diabetes mellitus, the classic sce
ent in people who are obese and/or experience changes nario of kidney function evolution involves an initial
in weight84,85. Specifically, GFR-estimating equations glomerular hyperfiltration phase, followed by elevated
based on serum creatinine and/or cystatin C levels urinary albumin excretion and progressive GFR decline.
are based mostly on non-obese populations86–88. In addi This decline eventually leads to CKD and kidney failure
tion, serum levels of creatinine and cystatin C are influ (Fig. 4). Increases in GFR have been reported early in the
enced by muscle and fat mass, respectively89,90, which both course of type 1 diabetes mellitus (T1DM) and T2DM,
vary with weight loss. The acute drop in the measured with prevalences of 10–67% and 6–73%, respectively97.
GFR that was observed following weight loss was also Several factors may account for the wide variation in
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Table 1 | Measured glomerular filtration rate after body weight reduction

Type Patients Intervention Follow- up BMI or body weight Measured GFR Ref.
(female) (months)
Baseline End of follow- up Method Baseline End of follow- up
Prospective 8 (7) Bariatric 12 136.4 (109–165) 87.8 (69–105) kga Cr51- EDTA 153 ± 16 ml/min 123 ± 27 ml/min 256
cohort surgery kga clearance

Prospective 8 (4) Bariatric 12–17 48 ± 2.4 kg/m2b 32.1 ± 1.5 kg/m2b Inulin 145 ± 14 ml/minb 110 ± 7 ml/minb 69
cohort surgery clearance

Prospective 11 (11) Bariatric 12 45.7 ± 5.0 kg/m2 28.4 ± 2.0 kg/m2 Iothalamate 121 ± 32 ml/min 90 ± 24 ml/min 71

95 ± 26 ml/ 85 ± 20 ml/
min/1.73 m2 min/1.73 m2
Retrospective 36 (28) Bariatric 10 46 ± 9 kg/m2 33 ± 8 kg/m2 Iohexol 117 ± 40 ml/min 100 ± 35 ml/min 70
surgery clearance
87 ± 29 ml/ 87 ± 30 ml/
min/1.73 m2 min/1.73 m2
Prospective 13 (1) Bariatric 12 51.0 [36.8–57.8] 34.4 [30.8–46.7] [125I]sodium 82.0 [60.9–89.7] 80.5 [63.0–111.5] 83
cohort surgery kg/m2 kg/m2 iothalamate ml/min ml/min

clearance
50.0 [44.0–58.0] 64.0 [48.0–87.0] ml/
ml/min/1.73 m2 min/1.73 m2
Prospective 16 (12) Bariatric 6 43.9 ± 7.3 kg/m2 35.2 ± 5.7 kg/m2 Iohexol 109.3 (57.0–194.0) 93.0 (53.8–167.0) 257
cohort surgery clearance ml/min ml/min

92.3 (45.6–125.5) 84.1 (46.6–117.7)
ml/min/1.73 m2 ml/min/1.73 m2
Prospective 19 (14) Bariatric 6 128 ± 19 kg 101 ± 18 kg Cr51- EDTA 122 ± 24 ml/min 113 ± 21 ml/min 72

88 ± 17 ml/ 90 ± 16 ml/
min/1.73 m2 min/1.73 m2
Randomized 34 (7) Calorie 6 30.0 ± 3.9 kg/m2 28.4 ± 3.8 kg/m2 Iohexol 107.8 ± 21 ml/min 100.2 ± 16.5 ml/min 75
controlled restriction clearance

trial (25%)
Prospective 9 (4) Bariatric 12 45.5 [42.2–47.8] 34.3 [29.3–38.3] Cr51- EDTA 58.0 [48.5–91.0] 59.0 [48.9–72.5] 258
cohort surgery kg/m2 kg/m2 clearance ml/min ml/min

43.6 [37.0–65.0] 45.8 [41.7–63.2] ml/
ml/min/1.73 m2 min/1.73 m2
Prospective 27 (18) Bariatric 6 49.5 ± 9.4 kg/m2 35.6 ± 6.6 kg/m2 Iohexol 117.3 ± 34.1 ml/ 108.2 ± 24.2 ml/min 91
cohort surgery clearance min

84.1 ± 22.0 ml/ 89.2 ± 19.9 ml/
min/1.73 m2 min/1.73 m2
Prospective 12 (5) Bariatric 24 41.6 ± 5.4 kg/m2 26.4 ± 4.6 kg/m2 Iohexol 94 ± 43.7 ml/min 79.6 ± 44.5 ml/min 80

Data are mean ± s.d., median [interquartile range], median (range) or median (95% CI), unless stated otherwise. amean (range), bmean ± s.e.m. BMI, body mass
index; GFR, glomerular filtration rate.
prevalence of glomerular hyperfiltration, including predominant afferent vasoconstriction in patients

the duration of diabetes, biological differences in study with T1DM and CKD102. Increased nitric oxide and
populations and methods used to evaluate GFR. COX2-derived prostanoid synthesis has been implicated
Similar to obesity-related glomerular hyperfiltra in vasodilatation of the afferent arteriole103,104. According
tion, both haemodynamic and tubular theories have to the tubular hypothesis, glomerular hyperfiltration in
been used to explain the development of glomerular the early stages of diabetes occurs mainly in response to
hyperfiltration in diabetes (Fig. 4). In the early 1980s, signals passed from the tubule to the glomerulus. High
micropuncture studies in a rat model of T1DM sug concentrations of glucose in the glomerular filtrate drive
gested that the main determinants of glomerular greater sodium-coupled glucose reabsorption through
hyperfiltration were renal haemodynamic function sodium-glucose co-transporter 2 (SGLT2) in the prox
abnormalities (increases in intra-glomerular capillary imal tubule. Reduced sodium chloride delivery to the
plasma flow and mean glomerular capillary hydraulic macula densa inhibits ATP conversion into adenosine,
pressure) due to changes in afferent and efferent arte leading to lower levels of this vasoconstrictor and a
riolar resistance98,99. The RAAS, COX2 and nitric oxide reduction in afferent arteriolar tone, which eventually
systems are thought to be involved in the regulation of increases renal blood flow and raises intraglomerular
glomerular arteriolar tone in diabetes100. RAAS acti hydraulic pressure105.
vation is generally assumed to lead to greater efferent One of the major contributors to the pathogenesis of
than afferent vasoconstriction101. However, this view glomerular hyperfiltration in diabetes mellitus is hyper
was challenged by a study that reported evidence of glycaemia, which leads to enhanced synthesis and/or
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a Kidney
Normoalbuminuria Microalbuminuria Macroalbuminuria
failure
150
GFR (ml/min/1.732)
100
50
‘Absolute’ glomerular
hyperfiltration
0
Time (years)
b Haemodynamic hypothesis SNGFR
RE
RA
Increases in vasoactive hormones
• RAAS activation QA
• Increased nitric oxide synthesis ΔP
• Increased COX2-derived
prostanoid synthesis
Vasodilation Vasoconstriction
'Absolute' glomerular hyperfiltration
c Tubular hypothesis JGA

SNGFR
SGLT2 RE
↑ Glucose and RA
Na reabsorption SGLT1 QA
ΔP
↓ Na delivery ↑ Glucose Vasodilation Vasoconstriction

to JGA excretion 'Absolute' glomerular hyperfiltration
Fig. 4 | ‘Absolute’ glomerular hyperfiltration in diabetes mellitus. a | During the course of diabetes, an early increase
in the glomerular filtration rate (GFR) is often followed by a progressive increase in urinary albumin excretion, and
subsequent progressive loss of kidney function, which is greatly accelerated by the onset of macroalbuminuria or overt
proteinuria. b | According to the haemodynamic hypothesis, the activation of vasoactive hormones leads to a reduction
in afferent arteriolar resistance (RA) and a parallel increase in efferent arteriolar resistance (RE), resulting in increases in
glomerular capillary plasma volume flow rate (QA), glomerular transcapillary hydraulic pressure difference (ΔP) and
eventually single-nephron GFR (SNGFR). c | According to the tubular hypothesis, increased glucose in the glomerular
ultrafiltrate leads to augmented glucose delivery to the proximal tubule and increased sodium-coupled glucose
reabsorption through sodium-glucose co-transporter-2 (SGLT2) and sodium-glucose co-transporter-1 (SGLT1), resulting
in a reduction in sodium delivery to the juxtaglomerular apparatus (JGA). These effects reduce the tubuloglomerular
feedback signal by promoting the local release of renin and angiotensin, which results in a reduction in adenosine
production and consequently a reduction in RA and an increase in RE. The resulting intraglomerular haemodynamic
changes lead to an increase in intraglomerular hydraulic pressure and SNGFR.
bioavailability of vasoactive mediators and inhibition of used a theoretical model of selective macromolecule
tubuloglomerular feedback106. Thus, glomerular hyper transport through a membrane demonstrated that the
filtration presenting in the first few years following the hyperglycaemia-induced increase in GFR was medi
onset of T1DM can resolve after a normoglycaemic state ated by an increase in glomerular permeability to small
is re-established107,108. Hyperglycaemia is an important macromolecules and in the Kf15.
modulator of the GFR even in advanced DKD15,109. Glycaemia-related changes in kidney function
A study in 7 patients with T1DM and overt nephro have important implications for the progression of
pathy showed that high plasma glucose concentrations DKD. Some studies have provided evidence that acute
induced a substantial elevation in the GFR15. Similarly, hyperglycaemia increases GFR in patients with diabe
an acute rise in plasma glucose, from sustained eugly tes but does not significantly change RPF, eventually
caemia to sustained hyperglycaemia, resulted in a sig resulting in an increase in the filtration fraction15. In
nificant increase in the GFR of approximately 35% in chronic hyperglycaemia, a sustained increase in the
patients with T1DM and proteinuria109. An analysis of filtration fraction, which reflects glomerular hyper
the fractional clearances of size-graded neutral dextrans filtration at the single-nephron level, might contrib
in patients with T1DM and overt nephropathy that ute to the onset or progression of DKD. Several110–112,
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Microalbuminuria
but not all113–115, observational studies have reported RAAS blockade consistently preserved glomerular
A moderate increase in associations between absolute glomerular hyperfil size selectivity and prevented overt proteinuria131,132.
albuminuria indicating tration, rapid loss of kidney function and the onset or SGLT2 inhibitors prevent the reabsorption of fil
incipient nephropathy. progression of nephropathy in patients with T1DM or tered glucose in the proximal convoluted tubule, thereby
Macroalbuminuria
T2DM. The use of GFR-estimating equations, which inducing glucosuria and reducing plasma glucose levels
A severe increase in have failed to provide a sound assessment of kidney in patients with T2DM. However, these medications have
albuminuria characteristic function and kidney function change over time, espe kidney and cardiovascular protective effects, independ
of overt nephropathy. cially in patients with diabetes who do not have overt ent of their effect on blood glucose. The CREDENCE
nephropathy5, might explain why some large studies did study in patients with T2DM and albuminuric CKD
not find such associations113–115. demonstrated that treatment with canagliflozin reduced
In a study of 600 patients with T2DM and normo the risk of progression to the composite outcome of kid
albuminuria or microalbuminuria , whose GFR was ney failure, doubling of serum creatinine levels or death
measured every 6 months, 90 (15%) were categorized from renal causes by 34% (hazard ratio 0.66; 95% CI
as having hyperfiltration (GFR >120 ml/min/1.73 m2) 0.53 to 0.81; P < 0.001)133. These benefits reflected reduc
at inclusion. Compared with patients who had normal tions in secondary kidney end points, such as kidney
GFR at baseline or in whom glomerular hyperfiltration failure, doubling of serum creatinine levels or reduc
was improved at 6 months by metabolic and blood pres tions in estimated GFR and all-cause mortality, that
sure control, those with persistent glomerular hyperfil were observed in large cardiovascular outcome trials of
tration tended to experience more rapid GFR decline SGLT2 inhibitors in patients with T2DM134–136. The pri
and were more likely to develop microalbuminuria or mary efficacy outcome of the DAPA-CKD trial, which
macroalbuminuria over a median follow-up period of included 4,304 patients with diabetic or non-diabetic
4 years111. However, 40–60% of white patients with T2DM CKD (estimated GFR 25–75 ml/min/1.73 m2 and uri
present with early GFR decline and rapid progression nary albumin-to-creatinine ratio 200–5,000 mg/g), was
to kidney failure before or without developing microal a combined end point of sustained decline in estimated
buminuria or macroalbuminuria116–119. These findings GFR of at least 50% versus baseline, kidney failure or
might be explained by factors other than or in addition death from renal or cardiovascular causes137. During a
to glomerular hyperfiltration that might contribute to median follow-up of 2.4 years, treatment with dapagli
kidney damage in diabetes, including ageing, obesity, flozin reduced the incidence of the primary renal out
smoking habits, insulin resistance and advanced glyca come by 39% compared with placebo (hazard ratio 0.61.
tion end products61,116,120–122. Notably, in T2DM, hyperg 95% CI 0.51 to 0.72). This beneficial effect was similar
lycaemia is often associated with or preceded by arterial in patients with or without T2DM. A renoprotective
hypertension, which is a major risk factor for accelerated effect of SGLT2 inhibitors has also been demonstrated in
loss of kidney function120,123. The available data suggest patients with T2DM and nephrotic range proteinuria138.
that essential hypertension facilitates the onset and pro Several mechanisms have been proposed to explain
gression of CKD through a number of mechanisms, such the renoprotective effects of SGLT2 inhibitors, with a
as excess pre-glomerular vasoconstriction and conse reduction in intraglomerular hydraulic pressure being
quent glomerular hypoperfusion, arterial system remod the most prominent (Fig. 5). Clinically, this reduction
elling and atherosclerosis with secondary chronic kidney manifests as an acute dip in the GFR of approximately
ischaemia and dysfunction124,125. This hypothesis is con 2–5 ml/min/1.73 m2 after treatment initiation, followed
sistent with evidence that an increased pre-glomerular by attenuation of kidney function decline over time134.
to post-glomerular resistance ratio was associated with A mechanistic study involving young patients (aged
accelerated GFR decline in patients with T2DM and 23.5 ± 4.1 years) with T1DM and glomerular hyperfil
hypertension who did not have proteinuria126. tration (GFR ≥135 ml/min/1.73 m2), suggested that the
acute drop in the GFR that is induced by SGLT2 inhib
Effects of interventions that reduce glomerular hyperfil- ition is mediated by tubuloglomerular feedback mech
tration. The importance of glomerular hyperfiltration anisms that induce afferent arteriolar vasoconstriction
as a contributing factor in the pathogenesis of DKD has and increased renal vascular resistance139. Consistent
been confirmed by the efficacy of therapeutic interven with this hypothesis, SGLT2 inhibition ameliorated
tions that slow kidney disease progression by reducing glomerular hyperfiltration by decreasing afferent arte
intraglomerular hydraulic capillary pressure, including riolar diameter (measured in vivo using multiphoton
RAAS blockers and SGLT2 inhibitors. A number of land microscopy) in a mouse model of T1DM140. By contrast,
mark RCTs demonstrated that RAAS blockade with ACE two mechanistic studies in older patients with T2DM
inhibitors or ARBs reduced albuminuria and delayed (aged 63 ± 7 years), showed that SGLT2 inhibition
progression to kidney failure independent of systemic reduced measured GFR without increasing renal vas
blood pressure control127,128. These agents have become cular resistance, suggesting vasodilatory effects on the
the cornerstones of renoprotective interventions for efferent arterioles141,142. A micropuncture study in dia
patients with CKD and DKD. Micropuncture studies in betic rats showed that acute SGLT2 blockade reduced
diabetic rats showed that blocking angiotensin II synthe glomerular capillary hydraulic pressure through a tub
sis normalized glomerular capillary hydraulic pressure129. uloglomerular feedback response that involved both
Angiotensin II might also directly impair glomerular pre-glomerular vasoconstriction and post-glomerular
barrier sieving function independent of its haemod vasorelaxation143. In addition to renal haemodynamic
ynamic effects130. In experimental models of diabetes, effects, amelioration of kidney hypoxia and fibrosis have
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JGA
SGLT2 inhibitor
SNGFR
↓ Glucose and SGLT2 RA RE

Na reabsorption
SGLT1 QA
ΔP
↑ Na delivery Vasoconstriction Vasodilation

to JGA
↑ Glucose Normal GFR
excretion
Fig. 5 | The effects of SGLT2 inhibition on ‘absolute’ glomerular hyperfiltration in diabetes mellitus. In patients with
diabetes and poor glycaemic control, sodium-glucose linked co-transporter-2 (SGLT2) inhibition reduces reabsorption
of glucose and sodium in the proximal tubule. The resulting increase in sodium delivery to the juxtaglomerular apparatus
(JGA) leads to vasoconstriction of the afferent arteriole, whereas the vascular tone of the efferent arteriole is unaffected
or decreases. The glomerular plasma flow rate (QA) and intraglomerular capillary pressure decreases and single-nephron
glomerular filtration rate (SNGFR) returns to normal levels. ΔP, glomerular transcapillary hydraulic pressure difference; RA,
afferent arteriolar resistance; RE, efferent arteriolar resistance.
been suggested to underlie the renoprotective effects of GFR within the normal range (80–120 ml/min/1.73 m2),
SGLT2 inhibitors144,145. whereas approximately one-fourth of the patients
with ADPKD had a GFR >120 ml/min/1.73 m 2 .
Autosomal-dominant polycystic kidney disease Unfortunately, no separate data were reported for this
ADPKD is the most common monogenic kidney dis subgroup of patients with potential glomerular hyper
order and affects 8–10% of patients who undergo kid filtration. Thus, the existence of a subgroup of patients
ney replacement therapy146,147. ADPKD is characterized with ADPKD, hyperfiltration and a reduced kidney
by progressive and substantial enlargement of the functional reserve capacity cannot be ruled out.
kidneys, caused by the sustained expansion of many Glomerular hyperfiltration might be a risk factor
fluid-filled cysts due to aberrant tubular epithelial cell for ADPKD progression. In the cohort of 180 children
proliferation148,149. Uncontrolled cyst growth results with ADPKD mentioned above, those with glomerular
in crowding of adjacent nephrons, destruction of the hyperfiltration at baseline experienced a more rapid
normal renal parenchyma and eventually progression decline in kidney function than those without hyperfil
to kidney failure149. Despite slow and steady cyst growth, tration158. Similarly, among 91 adults with ADPKD (aged
kidney function in patients with ADPKD stays within 18–35 years), those with glomerular hyperfiltration at
the normal range for several decades, typically remain baseline (n = 11; GFR >140 ml/min/1.73 m2) had greater
ing fairly stable until a critical kidney size is reached, GFR loss during 15 years of follow-up than those with
after which the decline in function is more rapid149,150. normal GFR at baseline160. Notably, higher baseline GFR
Longitudinal studies of the natural history of ADPKD correlated significantly with faster GFR decline during
showed a correlation between the rate of kidney func follow-up (P < 0.0001).
tion decline and the rate of increase in absolute kidney A role of glomerular hyperfiltration in ADPKD pro
volume151–154. In young adults with ADPKD, early kid gression is also supported by evidence from the ALADIN
ney vasoconstriction and reduced kidney blood flow can RCT, which investigated the effects of the long-acting
occur before a decline in GFR, resulting in an increase in somatostatin analogue octreotide-LAR in 73 patients
filtration fraction155,156. with ADPKD and a normal GFR or mild kidney
In 18 children with ADPKD, the mean GFR meas dysfunction161. Patients in the octreotide-LAR group
ured using diethylenetriaminepentaacetic acid clearance showed an initial reduction in measured GFR followed by
was significantly higher than in 41 matched control indi stabilization until 3 years of follow-up, suggesting that
viduals (142 versus 110 ml/min/1.73 m2)157. Moreover, the drug might slow progressive loss of kidney function
32 of 180 children (aged 4–18 years) with ADPKD in ADPKD161. Somatostatin acutely decreases GFR in
had glomerular hyperfiltration defined as creatinine healthy individuals162 and in patients with T1DM163 or
clearance >140 ml/min/1.73 m2 (ref.158). By contrast, a liver cirrhosis164 via haemodynamic mechanisms that are
cross-sectional study reported no difference in the mean probably mediated by the inhibition of growth hormone
GFR (measured using [125I]iothalamate infusion) and secretion and action165. Thus, the ALADIN results con
higher kidney functional reserve capacity (determined firm that glomerular hyperfiltration occurs in patients
using dopamine infusion) in patients with ADPKD with ADPKD and suggest that by acutely reducing GFR,
aged 18–29 years compared with age- and sex-matched octreotide-LAR treatment might reduce the maladaptive
healthy individuals159. However, the wide standard devi compensatory hyperfiltration of the glomeruli that survive
ation in mean GFR in the patients with ADPKD com the disruptive effects of uncontrolled cyst growth.
pared with the control group (103 ± 21 versus 111 ± 9 ml/ Glomerular hyperfiltration in ADPKD might also
min/1.73 m2) clearly reflects a wide variability in single be mediated by angiotensin II, which exerts a vasocon
GFR values. Almost all of the healthy volunteers had a strictor effect predominantly on the efferent glomerular
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arterioles, thereby increasing glomerular capillary water flow and small solutes with efficient retention
hydraulic pressure166. The kidney RAAS is activated of plasma proteins the size of albumin or larger 179.
in patients with ADPKD167,168. Moreover, a prospective Normal plasma water filtration depends on the ultra
RCT in children with ADPKD and borderline hyper structure of the three layers of the glomerular filtration
tension (75th–95th percentile blood pressure for their barrier: the endothelial cell layer, the glomerular base
age), showed that those who were treated with an ACE ment membrane (GBM) and the filtration slit of the
inhibitor had stable creatinine clearance, whereas those podocyte foot process layer. Together with the sieving
in the control group experienced a significant decline in function of the endothelial glycocalyx180, the podocyte
creatinine clearance during 5 years of follow-up 169. slit diaphragms enable a high water filtration rate and
This finding suggests that intrarenal RAAS activation almost complete retention of plasma proteins130,181,182.
in ADPKD might have a role in disease progression, Studies of glomerular biomechanical forces indi
possibly by sustaining maladaptive glomerular hyper cate that increases in glomerular capillary hydraulic
filtration, which is limited by ACE inhibition. In study pressure, which are often observed in single-nephron
A of the HALT-PKD trial, which enrolled 558 patients hyperfiltration, stretch the capillary wall, creating ten
(aged 15–49 years) with ADPKD and an estimated GFR sile stress and fluid flow-induced shear stress, which
>60 ml/min/1.73 m2, those in the low blood pressure leads to an increase in GBM length and is associated
target group who received either ACE inhibitor mono with an increase in podocyte foot process length that
therapy or ACE inhibitor plus ARB combination therapy enables adequate GBM coverage to be maintained183,184.
showed a greater short-term (4 months) reduction in the Over years or decades of single-nephron hyperfiltration,
estimated GFR than those in the standard blood pressure glomeruli progressively undergo changes in capillary
target group170, suggesting that ACE inhibition reduced membrane permeability to water and macromolecules
glomerular hyperfiltration in the remaining nephrons. that may ultimately result in less water filtration and
Plasma concentrations of vasopressin (AVP), meas increased protein leakage owing to podocyte injury.
ured using its surrogate marker copeptin, are increased Changes to intercellular junctions and the cytoskeletal
in patients with ADPKD171. In addition to promoting structure of the foot processes eventually lead to foot
cyst growth171, AVP might have a detrimental effect on process effacement185,186. As podocytes have a very lim
GFR. Experimental studies have shown that AVP or ited capacity for self-renewal187–190, the loss of these cells
its selective V2 receptor (V2R) agonist desmopressin, owing to detachment or cell death leads to irreversible
induces substantial glomerular hyperfiltration and an damage and scarring of the kidney filtration units191.
increase in urine osmolality172. In patients with ADPKD, Over the last few decades, research on the glomerular
the GFR decreases when treatment with the V2R antag filtration barrier using animal models combined with
onist tolvaptan is initiated and increases after the drug biophysical models has led to improved understand
is withdrawn173,174. However, the AVP mechanism is ing of the pathophysiological mechanisms through
probably indirect, and might depend on the inhibition which structural alterations reduce glomerular water
of tubuloglomerular feedback control of the GFR172. filtration in the long term, resulting in a progressive
AVP could decrease the delivery of sodium and chloride decrease in GFR. Experimental studies have shown
to the macula densa by increasing chloride reabsorp that in healthy kidneys, the filtration slit has ellipsoidal
tion in the ascending thin limb of the loop of Henle175. and circular pores that are heterogeneous in size and
AVP might also have a direct effect on the macula shape192–194. The slit ultrastructure organization is more
densa, which expresses AVP receptors176. However, it complex than the zipper-like model that was proposed
is unlikely that AVP is a primary determinant of glo in 1974 (ref.195) and likely involves dynamic cell–cell
merular hyperfiltration in ADPKD. Indeed, ADPKD is contacts that might influence water filtration179. In
a renal tubular disease associated with increased water addition, biophysical theoretical models of glomeru
and sodium losses into the urine because of impaired lar ultrafiltration have indicated that the capillary wall
concentrating capacity177,178. Excess diuresis and natriu is subject to remarkable intraluminal hydraulic pres
resis may result in hypovolaemia, with a consequent sure that exerts physical forces that are counteracted
reduction in glomerular perfusion and decrease in the by the GBM and by podocytes196,197. Researchers have
GFR. In patients with ADPKD, compensatory AVP suggested that glomerular permselective dysfunction
production in response to enhanced natriuresis and and albumin filtration depend on the reduced capac
diuresis acts to maintain fluid volume and prevent ity of effaced podocyte foot processes to counteract a
hypovolaemia-induced kidney hypoperfusion rather transmembrane pressure of 40 mmHg, with less com
than to sustain glomerular hyperfiltration. pression of the GBM198. However, this hypothesis does
not account for the role of the sub-podocyte space199,
‘Relative’ glomerular hyperfiltration which surrounds a small fraction of the filtration mem
‘Relative’ glomerular hyperfiltration results from an brane under normal conditions, but enlarges to cover
increase in SNGFR in the context of a reduced num a wider filtering surface area during progression of
ber of functioning nephrons. In both ‘absolute’ and glomerular disease. Evidence from studies that used
‘relative’ glomerular hyperfiltration, a possible link Munich Wistar Frömter rats, an experimental model
between single-nephron hyperfiltration and struc of spontaneous proteinuria and glomerulosclerosis200,
tural injury of single glomeruli and nephrons has been suggests that the loss of glomerular filtration function
extensively investigated. The permeability properties of depends strongly on the disarrangement of podocytes,
the glomerular capillary wall enable filtration of high which causes expansion of the sub-podocyte space, an
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increase in its hydraulic resistance to filtered water, This finding supports the hypothesis that the eventual
and increased force acting within the sub-podocyte destruction of hyperfiltrating remnant nephrons is exac
space, which tends to detach podocytes from the cap erbated by the initial glomerular haemodynamic adapta
illary membrane201. Single glomerular hyperfiltration tions to a reduction in renal mass. However, in rats that
might itself induce elevation of hydraulic pressure in develop spontaneous proteinuria and glomerulosclerosis
the sub-podocyte space and an increase in the force with age, such as male Munich Wistar Frömter/Ztm rats,
that tends to detach podocytes from the GBM, leading ACE inhibition not only affects the glomerular micro
to podocyte loss, damage of the glomerular capillary circulation but also directly influences the functional
wall and eventually glomerulosclerosis. This hypoth properties of the glomerular membrane by reducing
esis is further supported by the finding that the podo membrane pore size and simultaneously increasing the
cyte structure is normalized by ACE inhibition, which hydraulic permeability of the capillary wall215. These
reduces the spatial expansion of the sub-podocyte findings indicate that the beneficial effects of ACE inhib
space and ameliorates the hydrodynamic detaching itors on kidney disease progression in several rat models
forces that act on podocytes, eventually normalizing are related to the concomitant preservation of glomer
water filtration and glomerular barrier function 201. ular membrane size-selective and hydraulic permeabi
Based on this evidence, it is tempting to speculate that lity function, as well as the prevention or limitation of
healthy podocytes can resist the detaching forces glomerular hypertension.
that are transiently induced by hyperfiltration, such as Unilateral nephrectomy induced by procedures
those caused by a high protein load. However, in the such as kidney irradiation216, injection of nephrotoxic
setting of a pathological condition, podocytes might not serum217 and repeated puromycin aminonucleoside
be able to resist transient increases in these mechanical administration218, also increases intraglomerular cap
stresses and will therefore start to detach. Consistent illary hydraulic pressure and flow and accelerates the
with this theory, increased urinary excretion of progression of glomerular sclerosis. In the New Zealand
podocytes has been reported in CKD202–204. Black/New Zealand White mouse model of lupus ery
thematosus, unilateral nephrectomy increases azotae
Glomerular adaptation to nephron loss mia and renal histopathology injury219, suggesting that
In rat models, the nephrons that remain when kidney uninephrectomy adds to the haemodynamic burden of
mass is reduced (for example, by three-quarters or glomerular capillaries that have already been exposed
five-sixths nephrectomy) undergo functional adapta to other injuries. Together, these studies highlight the
tion and structural hypertrophy205. Adaptations in the possibility that adverse intraglomerular adaptations to
microcirculation of the remnant glomeruli, such as renal a reduction in kidney mass might be a common path
arteriolar vasodilatation, which causes elevation in flows towards the destruction of remnant nephrons after any
and pressures in the capillaries, result in an increased one of a variety of initial injuries has reduced kidney
mean driving force for filtration and, therefore, a marked mass below a critical level.
increase in filtration rate206. The magnitude of increase
in SNGFR correlates closely with the amount of renal Outcomes of loss of kidney mass
mass that has been lost. Thus, greater degrees of abla Conditions that are characterized by congenital or
tion result in larger increases in SNGFR in residual acquired kidney mass reduction, such as unilateral renal
nephrons207. Single-nephron hyperfiltration is gener agenesis, congenital oligonephropathy or unilateral
ally considered to be beneficial because it ameliorates nephrectomy owing to living kidney donation, malignancy
the reduction of total GFR that would otherwise occur or trauma, are considered to be the clinical equivalent
following loss of renal mass208. However, a pathological of experimental models of kidney mass reduction.
process of sclerosis occurs in the glomeruli of the resid
ual nephrons209–213. Unilateral nephrectomy and partial Congenital kidney mass reduction. A congenital soli
ablation of the remaining kidney eventually leads to tary functioning kidney is mainly caused by unilateral
sclerotic destruction of the remnant glomeruli, which renal agenesis or multicystic dysplastic kidney220,221.
is accompanied by progressive azotaemia, proteinu The healthy kidney normally undergoes compensa
ria and arterial hypertension209–211. Higher-grade renal tory hypertrophy. In humans, this phenomenon begins
ablation causes earlier structural changes in the remnant during the 20th week of gestation and by the 36th week
glomeruli and is associated with a greater increase in results in a mean 11% enlargement of the single func
glomerular capillary hydraulic pressure and flows213. tioning kidney, compared with gestational age-matched
Notably, interventions that attenuate adaptive glomer controls 222. In addition to kidney growth, SNGFR
ular haemodynamic changes can slow the development increases to maintain total GFR within the normal
of glomerular structural injury following renal abla range. In children with a congenital single functioning
tion. In rats with reduced kidney mass, dietary protein kidney, a mean measured GFR of 107 ml/min/1.73 m2
restriction lowered SNGFR by normalizing glomeru was reported at the age of ~8 years223. The mechanisms
lar capillary hydraulic pressures and flows and thereby that facilitate compensatory adaptations to a reduction
slowed the development of glomerular sclerosis in the in kidney mass in early life might also contribute to kid
hyperfiltrating kidneys28. Use of ACE inhibitors reduced ney injury in the long term. Around 13% of children
the transcapillary hydraulic pressure gradient and glo who are born with a solitary functioning kidney develop
merular injury in the same rat model but had no signifi proteinuria by the age of 10, and 20–50% progress to
cant effect on glomerular plasma flow rate or SNGFR214. kidney failure by the age of 30 (refs224,225).
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Similar outcomes have been reported in patients that some donors might be at risk of long-term kid
with congenital oligonephropathy, such as those with ney dysfunction owing to glomerular hypertension236.
low birthweight associated with preterm birth and/or These at-risk donors might be those with lower kidney
intrauterine growth restriction226,227. Maternal and fetal functional reserve at the time of kidney harvesting238,239.
under-nutrition have a central role in these program Two epidemiological studies reported that living
ming defects. However, low nephron endowment is also kidney donors had an 8 times and 11 times higher risk
related to genetic variants, such as the apolipoprotein L1 of kidney failure than matched healthy individuals dur
(APOL1) G1 and G2 variants that are relatively frequent ing their respective follow-up periods of 7.6 years and
among people with African ancestry228. Regardless of 15.1 years, although the absolute risk of kidney failure
the initial cause, neonates with congenitally reduced remained low240,241. Common causes of kidney failure in
nephron number are at an increased risk of high blood living kidney donors include glomerulonephritis, diabe
pressure, proteinuria and progressive kidney function tes mellitus and hypertension241,242. Thus, a ‘second hit’
loss over time229. The risk of premature glomerular to the remaining kidney in living donors resulting from
senescence seems to be mediated by compensatory immunological or non-immunological events, rather
glomerular hyperfiltration and glomerulomegaly230, than CKD owing to hyperfiltration, seems to be the most
which may result in proteinuria and progressive kidney common cause of kidney failure241,242.
destruction231. Kidney dysfunction can be accelerated The long-term safety of kidney donation seems to
when nephron number is further reduced by superim be somewhat inconsistent with findings of kidney func
posed glomerular disease, such as post-streptococcal tion impairment after radical nephrectomy for renal
glomerulonephritis232, or when metabolic demands cancer243. The stringent health screening that is pro
are increased by post-pubertal obesity, diabetes or vided to candidates for kidney donation might explain
excessive alcohol intake, with consequent weight gain the lower impact of kidney removal in this population
in adulthood233. Smoking can also accelerate kidney than in patients with cancer. Indeed, a retrospective
dysfunction and double the risk of kidney failure234, study showed that selected patients with kidney cancer
possibly by reducing kidney blood supply231. These risk and few associated comorbidities had the same esti
factors are particularly prevalent in low-income coun mated GFR decline of about 30% after nephrectomy as
tries and among disadvantaged minority ethnic pop living kidney donors, but their lower preoperative kid
ulations, such as African Americans and Indigenous ney function had led to a higher risk of CKD by 4 years
Australians, who are at an increased risk of malnutri of follow-up244.
tion and low birthweight. Subsequent over-nutrition In transplant recipients, small donor and/or kidney
and post-pubertal obesity make patients with congen size relative to recipient body size was associated with
ital oligonephropathy more vulnerable to the adverse a higher risk of graft failure in most245–248, but not all
consequences of dysregulation of developmental studies249,250. Researchers have suggested that when a
programming229. Among Aboriginal Australians, female kidney from a small donor is transplanted into a large
sex has emerged as an additional independent risk fac recipient, the resulting high metabolic demands on the
tor for kidney failure, possibly because of lower nephron donor kidney with relative nephron underdosing could
numbers in women than in men, even in the context of lead to hyperfiltration251. Such hyperfiltration would
oligonephropathy232. precipitate glomerular hypertension, ultimately resulting
Preventive interventions should be aimed at correct in glomerulosclerosis and progressive decline in kidney
ing maternal lifestyle factors that may affect nephrogen function252. The fact that some studies do not confirm
esis, such as over- or under-nutrition, excessive alcohol a relationship between donor–recipient size mismatch
intake and smoking, and to protect endowed glomer ing and kidney graft longevity might be due to a lack of
uli from risk factors that, according to the multi-hit statistical power to rigorously test this hypothesis249,250.
hypothesis235, might accelerate glomerular obsolescence
in patients with congenital oligonephropathy. Prevention Conclusions
of infections, blood pressure control and reducing pro An absolute, supraphysiological elevation of GFR might
teinuria using ACE inhibitors and/or ARBs are the occur in healthy individuals, and more frequently in
cornerstones of renoprotection in this clinical context231. patients in the early phases of kidney disease, such as
those with obesity or diabetes. Clinical conditions that
Acquired kidney mass reduction. Following donor involve a reduced number of functioning nephrons
nephrectomy, GFR in the remnant kidney increases secondary to congenital or acquired kidney mass
by about 40% over baseline within the first few weeks reduction are characterized by a relative elevation in
post-donation 236 and remains stable for several GFR. Both settings imply glomerular hyperfiltration
years236,237. A study in human kidney donors suggested at the single-nephron level, which has classically been
that the compensatory increase in single-nephron GFR suggested to predispose to irreversible kidney disease.
following donation is sustained by an elevation in RPF Although the concept of glomerular hyperfiltration as
and Kf, resulting from glomerular enlargement, with a uniform injury in kidney disease is over 40 years old,
the estimated glomerular transcapillary hydraulic pres evidence that hyperfiltration has a role in progressive
sure gradient (ΔP) remaining constant236. However, kidney damage has accumulated in the past decade, in
the researchers acknowledged that an isolated, modest parallel with an increased understanding of the func
increase in ΔP might account for the observed level of tion of glomerular capillary filters and the mechanisms
glomerular hyperfiltration, leaving open the possibility underlying proteinuria.
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CKD is a highly prevalent condition that contributes as obesity, diabetes and primary kidney diseases with
to a substantial proportion of the global disease burden253 nephron mass reduction. If ongoing clinical trials of novel
and current strategies for managing disease progression treatments, such as SGLT2 inhibitors, glucagon-like pep
are not always sufficient to eliminate renal risk in individ tide 1 receptor agonists, endothelin receptor antagonists
uals with absolute or relative glomerular hyperfiltration. and the non-steroidal selective mineralocorticoid recep
The revived interest in glomerular hyperfiltration as a tor antagonist finerenone, demonstrate or further con
prognostic and pathophysiological factor might lead to firm their beneficial effects on kidney outcomes, these
improved detection of progressive kidney disease. More agents should be incorporated into the current multi
importantly, improved understanding of glomerular drug approach to blunt proteinuria254,255 with the aim of
hyperfiltration could provide new opportunities for protecting the kidney by interrupting or even reversing
developing mechanism-based therapies that regulate the maladaptive process initiated by single-nephron
glomerular haemodynamics and/or limit the underlying hyperfiltration.
dysfunction of the glomerular capillary barrier to pre
vent progressive CKD in various clinical settings, such Published online 1 April 2022
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NAtuRe RevIewS | NEPhRoLoGy volume 18 | July 2022 | 435

Key points or diethylenetriaminepentaacetic acid, to measure

436 | July 2022 | volume 18 www.nature.com/nrneph

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with non-pregnant levels (%)

Change in RPF compared

with non-pregnant levels (%)

Change in GFR compared

SNGFR SNGFR SNGFR

‘Absolute’ glomerular ‘Absolute’ glomerular GFR progressively returns

438 | July 2022 | volume 18 www.nature.com/nrneph

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440 | July 2022 | volume 18 www.nature.com/nrneph

Table 1 | Measured glomerular filtration rate after body weight reduction

cohort surgery kga clearance

cohort surgery clearance

cohort surgery clearance

cohort surgery kg/m2 kg/m2 iothalamate ml/min ml/min

cohort surgery clearance ml/min ml/min

cohort surgery clearance

controlled restriction clearance

cohort surgery kg/m2 kg/m2 clearance ml/min ml/min

cohort surgery clearance min

cohort surgery clearance

prevalence of glomerular hyperfiltration, including predominant afferent vasoconstriction in patients

NAtuRe RevIewS | NEPhRoLoGy volume 18 | July 2022 | 441

b Haemodynamic hypothesis SNGFR

c Tubular hypothesis JGA

↓ Na delivery ↑ Glucose Vasodilation Vasoconstriction

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↓ Glucose and SGLT2 RA RE

↑ Na delivery Vasoconstriction Vasodilation

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