REVIEWS

New treatment paradigms for ADPKD:

moving towards precision medicine
Matthew B. Lanktree1 and Arlene B. Chapman2
Abstract | The natural history of autosomal dominant polycystic kidney disease (ADPKD) is
characterized by a variable rate of cyst development and increase in total kidney volume
(TKV), variable kidney function decline and age of onset of end-stage renal disease (ESRD), and
variable presentation of renal and extrarenal manifestations. Precision medicine is proposed
to improve patient outcomes by tailoring therapy to the specific genetic background,
pathophysiology, disease burden, prognosis and status of each individual. This approach to the
management of patients with ADPKD is nearing clinical implementation owing to advances in
genetics, imaging, biomarker development and therapeutics. In this Review, we discuss
pharmacological and non-pharmacological interventions for the treatment of hypertension
and proteinuria, and for slowing the rate of cyst growth in patients with ADPKD before the
development of ESRD. We provide recommendations for the management of renal
complications, including cyst infection, nephrolithiasis, haematuria and chronic pain.
The early treatment of patients with ADPKD who are largely asymptomatic is associated with
a therapeutic burden but slows cyst growth and delays subsequent loss of kidney function,
which ultimately delays the need for renal replacement therapy and has a positive effect on
the quality of life of patients.

1
Nephrology Division,
Department of Medicine,
McMaster University, St
Joseph’s Healthcare Hamilton,
50 Charlton Avenue E,
Hamilton, Ontario L8N 4A6,
Canada.
2
Department of Medicine,
Section of Nephrology,
University of Chicago, 5841 S
Maryland Avenue, W503,
Chicago, Illinois 60637, USA.
Correspondence to A.B.C.
achapman1@
medicine.bsd.uchicago.edu
doi:10.1038/nrneph.2017.127
Published online 9 Oct 2017
Autosomal dominant polycystic kidney disease
(ADPKD) is a systemic disease that affects 1 in 2,000
individuals and is the most common hereditary kid-
ney disease1–3. ADPKD is equally represented among
ethnicities and is more common than sickle cell dis-
ease, cystic fibrosis, Down syndrome, haemophilia and
Huntington disease combined1. ADPKD is completely
penetrant and is characterized by the development of
renal cysts and increasing total kidney volume (TKV),
leading to urinary concentrating defects, hypertension,
polyuria, nocturia, pain, nephrolithiasis, haematuria,
infections and progressive loss of kidney function1.
However, symptoms at disease presentation and the
disease course are both highly variable. Patients with
ADPKD, on average, progress to end-stage renal dis-
ease (ESRD) by the age of 60 years, with 70% of patients
requiring renal replacement therapy (RRT) by the age
of 70 years3. In Europe, 1 in 10 patients with ESRD has
ADPKD3, and 1 in 20 patients with ESRD in the USA,
Australia and New Zealand has ADPKD2,4. Reducing
the incidence of complications related to cyst burden
(for example, hypertension, pain, haematuria, infection
and nephrolithiasis) or delaying progressive loss of kid-
ney function or the onset of ESRD provide significant
improvements in quality of life.
The average age at which ESRD is reached in patients
with ADPKD has not improved, despite improved over-
all survival owing to a higher prevalence of renal trans-
plantation and better ESRD care3. Our understanding of
the pathogenesis of cyst formation and growth has also
increased dramatically, improving our ability to diagnose,
evaluate and prognosticate disease severity in patients
with ADPKD. Data from randomized controlled trials
and observational cohort studies are beginning to affect
treatment decisions in an evidence-based fashion5–8.
As such, the goal of disease management for patients
with ADPKD has shifted towards creating meaningful
changes in clinical outcomes, and the potential to provide
­personalized care strategies to delay the onset of ESRD.
Precision medicine entails a ‘new taxonomy’ for
disease that includes traditional signs, symptoms and
clinical manifestations, but adds genetic information
in conjunction with the findings of advanced imaging
techniques and biomarker analyses, and incorporates the
experience and expectations of the individual patient9.
Using this approach, patients who are unlikely to benefit
from therapy can be spared an unnecessary therapeutic
burden (such as adverse effects, psychological effects and
financial costs) of ineffective, intolerable or unneeded
interventions. Owing to advances in our understanding

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REVIEWS
Key points
• Clinicians are now able to identify which patients with autosomal dominant
polycystic kidney disease (ADPKD) are at highest risk of progression and most likely
to benefit from early therapy
• MRI measurement of total kidney volume (TKV) is a valuable method to predict future
rate of increase in TKV, rate of decline in kidney function and risk of end-stage renal
disease (ESRD)
• The availability of genetic testing will continue to increase and can provide a
diagnosis in unusual or atypical cases or in young (<30 years of age) patients being
assessed for kidney donation
• ADPKD is typically the result of germline PKD1 or PKD2 mutations, with somatic
mutations, genetic mosaicism and modifier mutations occasionally contributing to
the ADPKD phenotype
• Disruption of polycystin trafficking and signalling, environmental exposures and the
compounding ‘snowball’ effects of regional ischaemia, inflammation and tubular
obstruction further contribute to disease progression
• Novel strategies intended to limit cyst burden have provided encouraging results,
whereas treatment of hypertension and proteinuria remain the mainstays of medical
management of ADPKD
• Assessment and treatment of ADPKD-related complications, including cyst
haemorrhage, cyst infection, nephrolithiasis and chronic pain, require special
consideration and attention
of the progression and the genetics of ADPKD and their
contribution to the variability in ADPKD presenta-
tion, the opportunity to tailor therapy to the individual
patient is approaching.
In this Review, we summarize the evidence for opti-
mizing the management of patients with ADPKD. We
focus on the care of patients before kidney transplan-
tation or dialysis, with the ultimate goal of delaying the
onset of ESRD. We discuss therapies and their targets for
the management of hypertension and proteinuria, treat-
ments aimed at reducing cyst burden, management of
acute and chronic complications of ADPKD, including
pain, nephro­lithiasis, cyst infection and haemorrhage,
and d ­ ietary recommendations for salt, protein and
water intake.
Pathophysiology of ADPKD
The manifestations of ADPKD are caused by functional
deficits in polycystin 1 (PC1; encoded by PKD1) or poly­
cystin 2 (PC2; encoded by PKD2). Deficiencies in either
of these proteins results in abnormal primary ciliary
function, leading to a cascade of altered cell signalling
and aberrant cellular proliferation and fluid secretion
resulting in the formation and growth of cysts10,11 (FIG. 1).
A number of factors might contribute to the pathogenesis
and phenotypic variation of ADPKD: haploinsufficiency,
defined as having only a single functional copy of PKD1
or PKD2, owing to either heterozygous loss‑of‑function
mutations or hypomorphic (reduced function) alleles;
somatic mutations; altered gene expression; disruption
of the trafficking and post-translational modification of
PC1 or PC2; genetic variation in downstream signalling
pathways and provocation by environmental factors10–13.
Alterations in PC1 or PC2 function result in changes
in intracellular calcium and cAMP levels, and subse-
quent alteration in the mechanistic target of rapamycin
(mTOR) pathway10. Evidence from cell lines and model
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organisms suggests that metabolic reprogramming takes
place in ADPKD, with increased utilization of aerobic
glycolysis and downregulation of oxidative phosphory­
lation14. Supporting a central role of arginine vasopressin
(AVP) in disease pathogenesis, the offspring of a cross
between Pkhd1‑knockout rats — a model of autosomal
recessive polycystic kidney disease (ARPKD) — and the
Avp-knockout Brattelboro rat that is incapable of pro-
ducing AVP, have normal appearing and functioning
kidneys15. Administration of 1‑desamino-8‑d‑arginine
vasopressin (DDAVP; also known as desmopressin)
to these rats recapitulates the phenotype of the paren-
tal Pkhd1‑knockout rat15. Additional insults, including
ischaemia–reperfusion injury, might also contribute to
accelerated cystogenesis16. Finally, cyst formation and
expansion itself is accompanied by inflammation, macro­
phage activation, ischaemia, cytokine production and
renal tubular obstruction, which might further promote
an environment of increased cyst formation and growth
in what has been referred to as a ‘snowball’ effect17.
Phenotypic variability of ADPKD
The phenotype of ADPKD can be characterized using
clinical, biochemical, imaging, environmental exposure
and biomarker data18,19 (FIG. 2). Cysts vary in size, distri-
bution and growth rate between patients, with resulting
variations in the rate of TKV increase20. The rate of TKV
increase is the sum of the volumes of newly formed cysts
and the growth of existing cysts20. Without intervention,
the rate of TKV increase remains remarkably constant
in an individual, yielding an exponential increase in
TKV20,21. In individuals with ADPKD, kidney function
is typically in the normal range (estimated glomerular
filtration rate (eGFR) >90 ml/min/1.73 m2) throughout
the first three decades of life. Decreases in eGFR to ­levels
of established renal insufficiency or stage 3 chronic kid-
ney disease (CKD) occur long after the accumulation
of a substantial cyst burden (FIG. 3). Importantly, a cli-
nician might recognize a downward trend in the eGFR
of an individual patient while serum creatinine level
and eGFR remain in the ‘normal’ range, which should
raise concerns22. Diagnosis and initiation of therapies to
prevent progression of ADPKD should be started early,
when the renal parenchyma is intact and long before
clinically significant impairment in kidney function is
detected23. By shifting from a simple ADPKD diagnosis
to the assessment of a continuous network of interrelated
quantitative traits, clinical heterogeneity can be quanti-
fied, disease status can be characterized and phenotypes
can be measured that reflect the underlying molecular
and genetic defects that cause ADPKD18,19.
Clinical evaluation of ADPKD. ADPKD can have a wide
range of clinical presentations: severe cases are diag-
nosed in utero or neonatally, whereas mild cases can go
unrecognized until 60–70 years of age and ESRD might
be avoided altogether1. Collection of a detailed family
history is essential for ADPKD diagnosis and to assess
the severity of ADPKD. ADPKD is typically diagnosed
following an ultrasound scan that reveals numerous
renal cysts, kidney enlargement and liver cysts, which
 REVIEWS

Somatic mutations Impaired trafficking

Decreased production Altered post-translational

• Haploinsufficiency Deficiency of PC1 or PC2 modification
• Hypomorphic alleles (e.g. glycosylation)

Loss of intracellular inhibitory signalling

↓Ca2+, ↑cAMP, ↑mTOR, ↓AMPK, ↑ERK, ↑JAK–STAT

↑Aerobic glycolysis Cystogenesis ↑AVP

Inflammation, ischaemia, ↑cytokines, tubular obstruction

Figure 1 | Pathogenic mechanisms and pathways in ADPKD. Loss of polycystin 1 (PC1) and/or polycystin 2 (PC2) activity
leads to measurable biochemical changes in several cellular signalling pathways, including elevated cAMP levels and
Nature Reviews | Nephrology
increased activation of mechanistic target of rapamycin (mTOR) complex 1, extracellular signal-regulated kinase (ERK),
and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling pathways with reductions in
intracellular calcium levels and 5ʹ‑AMP-activated protein kinase (AMPK) activation. These alterations lead to subsequent
cyst formation, cellular proliferation and metabolic dysregulation, including alterations in the level of arginine vasopressin
(AVP). Each of the above mechanisms has been observed with loss of PC1 or PC2 function, although the relative
contribution of each mechanism probably varies from patient to patient.

are associated with haematuria, abdominal pain and
early-onset hypertension. Alternatively, ADPKD can
be diagnosed in the absence of symptoms in individu-
als with a family history of ADPKD, or coincidentally
during medical evaluation of unrelated issues. Renal
complications, such as hypertension or proteinuria, cyst
pain, infection or gross haematuria, especially occurring
before 35 years of age, are predictors of increased disease
severity and are the major components of the retrospec-
tively developed predicting renal outcomes in ADPKD
(PROPKD) prognostic model24,25. All patients should be
asked about symptoms, including discomfort, nocturia,
polydipsia, dyspareunia or early satiety, as they might not
volunteer such details, despite the possibility of a substan-
tial adverse effect on quality of life. Information on num-
ber of pregnancies, complications during pregnancy and
previous episodes of acute kidney injury (AKI) should
also be sought25. Environmental exposures, including
caffeine intake, smoking and low birth weight, are often
difficult to quantify and lack rigorous evidence of a
considerable role in ADPKD, but should be clarified25.
Dietary patterns are important in the management of
patients with ADPKD and intake of sodium, protein and
fluids should be evaluated and reviewed with the patient.
Genetic testing for ADPKD. Patients with ADPKD can
have mutations in either PKD1 or PKD2, which account
for disease in approximately 78% and 13% of all patients,
respectively10. Significant allelic heterogeneity exists in
both PKD1 and PKD2, with >1,200 and >200 pathogenic
mutations reported, respectively (ADPKD Mutation
Database). Patients with truncating PKD1 mutations
typically have the most severe disease, with the largest
TKV and earliest-onset ESRD, followed by patients with
PKD1 non-truncating missense mutations, patients
with PKD2 mutations and, finally, patients in whom no
PKD1 or PKD2 mutation is detected (NMD)26. Further
stratification of disease severity according to muta-
tion strength based upon the predicted effect of mis-
sense mutations can provide additional information27.
Approximately 15% of patients with ADPKD present
without a family history of disease, and in such patients
the disease is most often caused by de novo mutations in
PKD1 or PKD2, whereas somatic PKD1 or PKD2 muta-
tions are occasionally responsible28,29. Genetic results are
incorporated into the prognostic PROPKD model, which
contains data collected from over 1,000 patients, includ-
ing retrospectively collected data on clinical features,
albeit without renal imaging or quantification of TKV24.
A high-risk PROPKD score has a positive predictive value
of 81% for the prediction of ESRD by 60 years of age24 .
Importantly, substantial heterogeneity in ADPKD pres-
entation exists, including age of diagnosis, rate of eGFR
decline, and extrarenal manifestations, even among fam-
ily members carrying the same mutation, suggesting that
additional genetic or environmental factors contribute to
disease severity26,30. Mutations in a third gene, GANAB
(encoding glucosidase II subunit‑α (GIIα)), have been
identified in a small subset of patients with ADPKD
(<2%), who typically have mild renal cyst involvement
but moderate-­to‑severe liver cysts12,29,31. GANAB was rec-
ognized as an ideal candidate for a role in cysto­genesis, as
mutations in PRKCSH (encoding glucosidase II s­ ubunit-β
(GIIβ)) cause polycystic liver disease (PLD)12.

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REVIEWS

Brain MRI imaging

Buccal saliva sample Presence and size of aneurysm
DNA studies including whole-genome, whole- Cerebral or arachnoid cysts
exome or gene panel-targeted resequencing aneurysm

Cardiac MRI and echocardiography

Blood sample Valvular function, left ventricular
Genomic, epigenomic, transcriptomic mass index and ejection fraction
and metabolomic analysis
Heart with LVH or valvulopathy
Arteries
Cystic liver Automated and ambulatory
blood pressure monitoring
Cyst fluid sample
Genomic, transcriptomic, proteomic,
metabolomic and microRNA analysis of Liver MRI and ultrasonography imaging
single cells, the cell-free fraction and Cyst number and distribution, total
exosomes liver volume, total liver cyst volume

Cystic kidney
Kidney MRI and ultrasonography
Urine sample imaging
Genomic, transcriptomic, proteomic, Cyst number and distribution, total kidney
peptidomic, metabolomic and microRNA volume, cyst volume, parenchymal volume
analysis of single cells, the cell-free fraction
and exosomes Bladder

Figure 2 | Sources of data to characterize the ADPKD clinical phenotype. Beyond vital information obtained from
analyses of a patient’s medical and family history, molecular genetic and imaging techniques Nature
can be used to further
Reviews | Nephrology
characterize the current disease status and prognosis of a patient. Other modalities that can provide clinically relevant
information include blood-pressure monitoring and analyses of bodily fluids for the presence of specific biomarkers.
LVH, left ventricular hypertrophy.

Other hereditary renal cystic conditions exist, for
which mutations in over 100 additional genes have
been identified (TABLE 1). Autosomal dominant cystic
diseases for which genetic mutations have been identi-
fied include: polycystic liver disease (PLD) with or with-
out renal cysts (mutations in PRKCSH, SEC63, LRP5,
GANAB, ALG8 and SEC61B); tuberous sclerosis com-
plex (TSC; mutations in TSC1 and TSC2), which also
includes a contiguous deletion syndrome involving both
TSC2 and PKD1, which accounts for approximately 2%
of patients with ADPKD; syndrome of renal cysts and
diabetes (RCAD; mutations in HNF1B); von Hippel–
Lindau syndrome (mutations in VHL); and medullary
cystic disorders associated with autosomal dominant
tubulointerstitial kidney disease (ADTKD; mutations
in UMOD, MUC1 and REN). The remaining cystic gene
disorders are rare, severe syndromic ciliopathies with
autosomal recessive patterns of inheritance or spontan­
eous occurrence, which account for a small percentage
of patients with cystic kidney disease32. The clinical
presentation, or phenotype, of patients with non-AD-
PKD cystic kidney diseases can be recognized by the
experienced clinician, but obtaining a molecular genetic
diagnosis can support identification and classification in
some patients.
With the cost of next-generation sequencing
(NGS) falling, targeted gene-panel, whole-exome and
whole-genome sequencing to identify the cause of
hereditary diseases is becoming increasingly accessible
for clinical diagnostics and will most likely contribute
to a precision medicine approach. Targeted candidate
gene panels enable the sequencing of selected groups
of genes (usually 10–50), which enables increased
read depth and reduces the per-patient costs, whereas
whole-exome sequencing involves the entire cod-
ing region of the genome. Owing to the presence of
sequence identity with six pseudogenes, the first half
of PKD1 has been poorly sequenced following cap-
ture for gene-panel or exome strategies, but is an area
of active research interest33. Locus-specific long-range
PCR is required to reliably and accurately sequence this
region of PKD1.34 Whole-genome sequencing does not
require sequence capture and enables the pseudogene
issue to be overcome using long paired-end reads, but

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 REVIEWS

a b c
Rate of TKV increase TKV eGFR
6 4,000 120

Increase in TKV/year (%)

eGFR (ml/min/1.73 m2
5 100
3,000
4 80

TKV (ml)
3 2,000 60
2 40
1,000
1 20
0 0 0
0 20 40 60 80 0 20 40 60 80 0 20 40 60 80
Age (years) Age (years) Age (years)

1% 3% 5%

Figure 3 | Theoretical relationship between total kidney volume (TKV) and kidney function. Rate of TKV increase
Nature Reviews | Nephrology
(part a), measured TKV (part b) and estimated glomerular filtration rate (eGFR; part c) over time in patients with either mild
(blue line, defined as a 1% increase in TKV per year), moderate (red line, defined as a 3% increase in TKV per year) or severe
(green line, defined as 5% TKV growth per year) autosomal dominant polycystic kidney disease (ADPKD). The model
assumes a TKV of 400 ml at 20 years of age, with a baseline eGFR of 120 ml/min/1.73 m2 and a calculated
eGFRt = eGFRt-1 – (TKVt/400). eGFRt is the eGFR at time t in years45.

remains technically challenging35. Detection of dele-
tions that can range from a few bases to many exons
can be difficult and often requires multiplex ligation-­
dependent probe amplification (MLPA) or quantitative
PCR. However, the detection of deletions will improve
with the use of NGS techniques35. NGS will also enable
the detection and quantification of somatic mutations
that create mosaicism in blood, urine and pathologi-
cal specimens and that are responsible for a small per-
centage of ADPKD cases29. In addition to a main effect
PKD1 or PKD2 mutation, modifier effect heterozygous
mutations in additional cystic kidney disease genes,
as described above (such as HNF1A and LRP5), have
been identified as potential contributors to the pheno­
type, representing digenic inheritance36,37. Families
with compound hetero­zygous or bilineal hypo­morphic
PKD1 alleles 38 and uniparental disomy of mutated
PKD2 alleles39 have also been identified with severe,
early-onset phenotypes. As a further example of the
evolving genetic complexity of ADPKD, homo­zygous
or compound heterozygous mutations in PKHD1,
which encodes fibrocystin, cause autosomal recessive
polycystic kidney disease (ARPKD), whereas hetero­
zygous PKHD1 mutation carriers can present with iso-
lated PLD12,40. The modifier effect of common alleles or
rare NGS-identified hypomorphic mutations in other
­cystogenic genes requires further investigation.
In our opinion, clinical genetic testing for ADPKD
is currently best utilized in patients with ADPKD who
have atypical presentations, including early-onset dis-
ease, in the context of variable presentations among fam-
ily members, or in those patients with a lack of family
history of ADPKD10,41 or, alternatively, young (<30 years
of age) at‑risk individuals with no evidence of cysts on
imaging but who require a definite diagnosis, including
potential kidney donors from known ADPKD families.
Genetic testing might also be helpful for pre-­conception
counselling. With the availability of additional geno-
type–phenotype information, the implementation of
genetic testing for molecular diagnosis of ADPKD is
likely to increase.
ADPKD risk stratification and monitoring with TKV.
Ultrasonography is the screening method of choice
for ADPKD, especially in those with a family history
of ADPKD and who are >40 years of age42. However,
TKV (adjusted for height and age), as measured using
MRI, provides a more precise evaluation of disease sta-
tus, prognosis and longitudinal risk assessment21,43,44.
The average increase in TKV in patients with ADPKD
is 5–7% per year, but ranges from little or no increase
to a >20% increase per year45. Measurement of TKV
enables the prediction of slope of eGFR decline, and
therefore the age of onset of ESRD5,46,47. Increased TKV
is also associated with renal complications including
hyper­tension, albuminuria, nephrolithiasis, renal cyst
infections, haematuria and worsening abdominal pain46.
Evaluation of the progression of ADPKD via sequen-
tial TKV measurements has been utilized as a primary
outcome in m ­ ultiple randomized controlled trials6,7,48–57.
Automated segmentation methods that enable cyst
burden to be calculated using the sum of the kidney area
in each MRI slice have been developed, and favourable
comparisons with methods such as MRI-based mid-
slice area and ellipsoid equation volume (ellipsoid vol-
ume = ∏/6 × length × width × depth), ultrasound-based
kidney length and volume, and manual segmentation
methods support their use for risk stratification, particu-
larly in patients with smaller kidneys, but are not yet
widely implemented44,58. Nevertheless, ellipsoid-based
measures of TKV using MRI seem to be sufficient and
clinically applicable for risk assessment owing to their
ease of use, speed of use and availability59.
The Mayo clinic ADPKD classification scheme, which
was developed to enable the identification of individuals
with ADPKD who have intact kidney function for inclu-
sion in clinical trials, classifies patients as having typi-
cal disease (class 1; bilateral and symmetrical disease,
found in >95% of patients) or atypical disease (class 2;
uni­lateral, segmental, or asymmetrical disease, found
in <5% of patients)21. Patients with class 1 disease are
sub­divided into five risk strata: A (low risk) through
to E (high risk), after adjustment for height and age21.

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REVIEWS

This schema does not include kidney function, gender
or ethnicity in its formulae. Both height-adjusted TKV
and the Mayo ADPKD classification can be simply
determined from measurements of kidney sagittal and
coronal length, and axial width and depth. In the Mayo
and the Consortium for Radiologic Imaging Studies of
Polycystic Kidney Disease (CRISP) cohorts, patients in
the highest risk stratum (1E) averaged a decline in eGFR
of nearly 5 ml/min/1.73 m2 per year, compared with a
decline of 2.5 ml/min/1.73 m2 per year in the middle
stratum (1C) and no reduction in the lowest risk stra-
tum (1A) over 10 years of follow‑up. The Mayo risk
classification (class 1A to 1E) remained fairly stable over
time for the majority of patients; however, as many as
20% of patients shifted up or down one stratum over
10 years of follow‑up21. The rate of TKV increase meas-
ured following serial imaging, as opposed to estimation
from a single scan, might also yield an improvement in
risk stratification and requires further study45. As out-
lined in a review published in 201645, the use of TKV

Table 1 | Cystic kidney diseases

Disease AD/ Gene Typical Characteristics Prevalence
AR decade of
diagnosis;
ESRD
Autosomal dominant AD PKD1 Childhood−30s; • Early age of cyst onset, hypertension, ESRD, innumerable • ~78% of ADPKD
polycystic kidney 50s small renal cortical cysts • ~1 in 2,000
disease (ADPKD), type 1

Autosomal dominant AD PKD2, 30s; 70s • Late age of cyst onset, hypertension, ESRD, fewer, larger • ~13% of ADPKD
polycystic kidney GANAB renal cysts and liver cysts very common • ~1 in 7,000
disease, type 2
Autosomal recessive AR PKHD1 Birth; early • Neonatal death in 30% of patients, Potter phenotype, ~1 in 20,000
polycystic kidney childhood oligohydramnios
disease • Renal symptoms include early renal failure and severe
polycystic kidneys
• Biliary symptoms include dysgenesis, portal hypertension
and cholangitis
Renal cysts and AD HNF1B, TCF2 Teens; 15% • Renal cysts, diabetes, hypomagnesaemia, hyperuricaemia Unknown
diabetes syndrome ESRD in teens and genital tract malformations; also known as
mature-onset diabetes of youth 5 (MODY5)
Polycystic liver disease AD PRKCSH, 30s; NA • Massive liver volume expansion with numerous cysts, liver • Isolated: ~1 in
SEC63, LRP5, cysts were traditionally considered entirely isolated from 100,000
GANAB, polycystic kidneys, but phenotypic overlap with ADPKD • Liver cysts in up
ALG8, now recognized to 90% of patients
SEC61B with ADPKD
Tuberous sclerosis AD TSC1, TSC2 Childhood; 40s • Dermatomal symptoms include facial angiofibroma, ~1 in 10,000
shagreen patch and hypomelanotic macules
• Cerebral symptoms include cortical tubers, subependymal
giant cell astrocytoma, seizures and developmental delay
• Renal symptoms include polycystic kidneys and
angiomyolipoma
• Pulmonary symptoms include lymphangioleiomyomatosis
• Ophthalmic symptoms include retinal hamartomas
TSC2–PKD1 contiguous AD TSC2–PKD1 Childhood; 20s • Similar presentation to that of tuberous sclerosis with Rare
deletion syndrome more severe renal phenotype
Von Hippel–Lindau AD VHL 20s; NA • Neuroendocrine tumours of the pancreas, ~1 in 36,000
disease pheochromocytoma, renal cell carcinoma, serous
cystadenomas, cerebellar and spinal haemangioblastoma,
retinal angioma
Autosomal dominant AD UMOD, Teens−20s; • Slowly progressive kidney disease, medullary cysts, Unknown
tubulointerstitial kidney MUC1, REN 40s−60s hyperuricaemia and gout in ADTKD–MUC1; also known as
disease medullary cystic kidney disease
Medullary sponge NA Unknown; 30s; NA • Medullary nephrocalcinosis, nephrolithiasis ~1 in 5,000
kidney familial
clustering
Nephronophthisis AR >90 genes Childhood; • Paediatric-onset tubulointerstitial nephritis, large range Rare
teenage years of rare monogenic multisystem conditions (including
Joubert, Senior–Loken, Bardet–Biedl and Meckel–Gruber
syndromes)
Acquired cystic disease NA Unknown Variable • Associated with chronic renal failure, ESRD Common, up to 50%
• Normal or small-sized kidneys might have 1 cyst
AD, autosomal dominant; AR, autosomal recessive; ESRD, end-stage renal disease; NA, not applicable.

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as a surrogate outcome to evaluate the effectiveness of
a therapy or to monitor disease progression has been a
source of controversy. TKV is the strongest prognostic
term in predictive modelling of eGFR decline and pro-
gression to ESRD, and has been approved by both the
FDA and the European Medicines Agency (EMA) for use
as a biomarker for clinical trial enrichment, but TKV has
not been approved as a primary end point for use in ran-
domized controlled trials60. Nevertheless, in our opinion,
TKV is a useful prognostic tool for predicting the future
rate of decline in kidney function, is a sufficient surrogate
outcome for evaluating the effectiveness of interventions
in randomized controlled trials and is a useful method to
evaluate the extent of longitudinal disease progression.
Serum and urinary biomarkers, metabolomics,
­ roteomics and exosomes. Predictive biomarkers enable
p trolled trials, and includes TKV, with adjustments for age
the quantitative identification of patients with greatest
disease activity and the highest risk of disease progres-
sion, and the potential differentiation of patients who
might respond to therapy from those who would not.
Ideally, biomarkers should not only associate with eGFR
or TKV cross-sectionally, but should also be predictive
of longitudinal changes in TKV and/or decline in eGFR.
Evaluation of a biomarker in interventional trials can
implicate a causal role of a biomarker in disease patho-
genesis. The clinical value of over a dozen biomarkers
as prognostic indicators for the severity and progression
of ADPKD has been evaluated (TABLE 2). The severity of
ADPKD is associated with an increasingly impaired
urine-concentrating ability and lower urinary osmo-
lality; therefore, maximum urine-­concentrating ability
after water deprivation has been used to assess disease
severity61–63. Copeptin, which is the stable portion of
the precursor of AVP, is an easily measured surrogate
indicator of AVP production that can be measured in
urine or serum. Higher AVP levels are associated with
a worse renal prognosis in patients with ADPKD61,63–68.
Mass spectrometry analysis of urinary peptides impli-
cates proteins that are known to reside in cystic fluid
(such as apolipoprotein A1, antithrombin III, fibrinogen
and α1 antitrypsin), as well as novel peptides that require
further study in ADPKD (such as collagen degradation
products, cathepsin and matrix metalloproteinases)69.
Exosomes, which are vesicles that are released from the
plasma membrane of cells and are present in all bodily
fluids, contain cellular proteins, RNA and metabolites,
and are thought to have a role in cell‑to‑cell communi-
cation and transport70. The contents of urinary exosomes
can be identified, thus providing information about
the cells from which the exosomes originated71. Using
this approach, reduced levels of PC1 and PC2 have
been detected in urinary exosomes from patients with
ADPKD compared with those without ADPKD72, and an
overabundance of desmosome components (periplakin
and envoplakin), villin 1 and complement proteins have
been identified in the urinary exosomes of patients
with ADPKD70. Using a machine-learning classifier,
the effects of multiple biomarkers were combined into a
single, more-powerful test69,73. Biomarkers could poten-
tially have an important role in risk stratification, and
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REVIEWS
might also yield new insights into disease patho­genesis,
but they require further evaluation and ­validation before
application in clinical practice.
Cumulative risk stratification. As mentioned above,
the PROPKD score24 was developed from retrospective
clinical data to predict the onset of ESRD at <60 years of
age, and includes information on the main mutated gene
(PKD1, PKD2 or NMD), as well as other clinical factors
(sex, history of hypertension and/or urological adverse
events, such as haematuria, cyst infection or nephrolithi­
asis, before 35 years of age). However, this score does
not take into account the age, serum creatinine level or
the TKV of patients24. The Mayo Clinic ADPKD classi-
fication24 was developed for risk stratification in patients
with ADPKD to optimize enrolment in randomized con-
and height, but does not include other aspects such as
genotype, serum creatinine level or other clinical vari­
ables. Neither the PROPKD nor the Mayo classification
include current eGFR or the trajectory of previous eGFR
loss, which has been incorporated into the European
Renal Association–European Dialysis and Transplant
Association (ERA–EDTA) recommendations for identi­
fying patients with high-risk disease for initiation of tol-
vaptan treatment22. Ultimately, selection of treatments
for the management of ADPKD will be personalized and
will likely incorporate clinical, biochemical and genomic
factors in the context of current disease status, increase
in TKV to date and prediction of eGFR decline and onset
of ESRD (FIG. 4).
Management of hypertension
In patients with ADPKD, hypertension has an aver-
age age of onset of 31 years, before the emergence of a
measurable reduction in eGFR in 60% of patients with
ADPKD5,49,74,75. The presence, age of onset, and severity
of hypertension is associated with increased TKV5,21,74,
and is a risk factor for younger age at onset of ESRD24,76.
For every 100 ml increase in TKV, the relative risk of
development of hypertension increases by 1.4‑fold77.
Additionally, patients with ADPKD are at an increased
risk of both left ventricular hypertrophy and adverse
­cardiovascular events78–80.
An increase in cyst burden or TKV is thought to
result in bilateral intrarenal ischaemia and activation
of the renin–angiotensin–aldosterone system (RAAS),
resulting in vasoconstriction and sodium retention,
worsening hypertension and potential acceleration of
cyst growth74. Patients with ADPKD and hypertension
have elevated levels of plasma renin activity and serum
aldosterone concentrations compared with individu-
als with essential hypertension81. Importantly, ciliary
defects in endothelial cells and vascular smooth muscle
cells lead to altered intracellular calcium concentrations,
elevated cAMP levels and increased cellular prolifera-
tion, thus creating a primary vasculopathy82. Additional
mechanisms that contribute to the hypertensive state
include endothelial dysfunction, reduced nitric oxide
levels, increased levels of reactive oxygen species and
activation of the sympathetic nervous system74,83.
REVIEWS

Table 2 | Emerging serum and urinary biomarkers in ADPKD not yet in clinical practice
Biomarker Source Features Effect in ADPKD
Loss of polycystin
PC1, PC272 Urinary Reduced expression of PC1 and PC2 Expression reduced by 50% in exosomes
exosomes
Water handling
Osmolality61,63,100 Urine, serum Quantify loss of urine concentrating ability Maximum urine concentration reduced by 15%
Copeptin 61,63–68
Serum, urine Portion of AVP precursor peptide, a Higher copeptin concentration associates with higher
surrogate marker of AVP TKV and decline in eGFR
Apelin177,178 Serum Inverse relationship with AVP, also 39% lower level in non-progressors
associated with fibrosis
Metabolic
HDL‑C, apolipoprotein Serum, urine Anti-atherogenic, reverse cholesterol Lower HDL‑C associates with greater TKV and
A169,100 peptide transport, anti-inflammatory increased eGFR decline
Uric acid179,180 Serum, urine Reduced filtration, increased tubular Hyperuricaemia is associated with eGFR decline
reabsorption, endothelial dysfunction,
hypertension
Klotho, FGF23181–183 Serum Low Klotho appears to prevent phosphouric Higher FGF23, lower Klotho levels early in ADPKD
effect of high FGF23 progression
Inflammatory
MCP1184,185 Urine, blood Chemokine that regulates monocyte Higher MCP1 associated with greater TKV and decline
activity in eGFR
Complement (C3, C5, C4B, Urine Activation of complement cascade >2‑fold higher in urinary exosomes of patients with
C9, CfB, C1q)70 exosomes ADPKD than in patients with CKD
IL‑18185 Urine Pro-inflammatory cytokine Increased level in patients with ADPKD, but not
associated with TKV or eGFR
Proliferation
HB-EGF186 Blood, urine Growth, migration and proliferation of >2‑fold higher in patients with ADPKD than in
tubular cells patients with CKD, also associated with increased TKV
and lower eGFR
sFRP4187 Blood, urine Antagonist of canonical WNT signalling Predictive of eGFR decline, limited association with
TKV
Tubular injury
KIM1184 Urine Ectodomain of KIM1 is shed after tubular Increased, also associated with increased TKV and
injury eGFR decline
NGAL185 Urine Part of innate immunity, elevated in acute Increased, but not associated with TKV or eGFR
kidney injury decline
NAG184 Urine Proximal tubular lysosomal enzyme, marker Increased, also associated with increased TKV and
of tubular injury eGFR decline
H-FABP184,186 Urine Distal tubular cytosolic protein released Increased, also associated with eGFR decline, and a
with injury loss of renal blood flow
Cellular morphology
Villin 170 Urine Actin-modifying protein that affects >2‑fold higher in patients with ADPKD than in
exosomes morphology, motility patients with CKD
Periplakin, envoplakin70 Urine Part of desmosome needed for gap >2‑fold higher level in patients with ADPKD than in
exosomes junctions and cell polarity patients with CKD
Unknown
Peptides derived from Urine Pathway analysis-derived hypothesized Part of machine learning peptidomic classifier
collagen, antithrombin III, α1 peptides functions
antitrypsin and cathepsin69,73
ADPKD, autosomal dominant polycystic kidney disease; AVP, arginine vasopressin; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FGF23,
fibroblast growth factor 23; HB‑EGF, heparin-binding epidermal growth factor; HDL‑C, high density lipoprotein cholesterol; H-FABP, heart-type fatty acid-binding
protein; IL‑18, interleukin 18; KIM1, kidney injury molecule 1; MCP1, monocyte chemoattractant protein 1; NAG, N‑acetyl-β‑D glucosaminidase; NGAL, neutrophil
gelatinase-associated lipocalin; PC1, polycystin 1; sFRP4, secreted frizzle-related protein 4; TKV, total kidney volume.

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 REVIEWS

Treatment of hypertension in patients with ADPKD

should include nonpharmacological interventions, such
ESRD@ 50 years old

(% increase in TKV/year)
as weight reduction, exercise and dietary salt restriction. 5

Exclusion of additional secondary causes of hypertension,
such as primary hyperaldosteronism, pheochromo­cytoma
or obstructive sleep apnoea, should all be considered with
clinical suspicion of their existence84,85. Inhibition of the
RAAS using angiotensin-converting enzyme (ACE) inhib-
itors is favoured, as well as the use of angiotensin-­receptor
blockers (ARBs) and β‑blockers83. The findings of early
studies with small cohorts of patients demonstrated that
ACE inhibitors reduce the severity of proteinuria and
left ventricular mass compared to diuretics and calcium
channel blockers86, whereas ARBs resulted in a greater
reduction in proteinuria than calcium channel blockers87,
and data from two small-cohort studies suggest equipoise
between β‑blockers and ACE inhibitors with respect to
blood-pressure control, proteinuria, left ventricular mass
index and decline in eGFR88,89. Given RAAS activation,
stimulation of vasopressin release with dehydration, and
the potential untoward effects of AKI, concern regard-
ing the use of diuretics given concomitantly with RAAS
blockers, particularly ACE inhibitors, should be consid-
ered, though not supported by direct evidence83,90. The
findings of the HALT–PKD studies showed that most
patients can safely achieve rigorous blood pressure control
(<110/75 mmHg) with an ACE inhibitor as mono­therapy
and d ­ iuretics as second-line agent, without evidence
of worsening kidney function, AKI or a major risk of
adverse events6,51.
The most recent guidelines from Kidney Disease:
Improving Global Outcomes (KDIGO) on the control of
blood pressure in patients with CKD suggest a target
of ≤140/90 mmHg for patients without albuminuria and
≤130/80 mmHg for those with albuminuria of ≥30 mg
per day91. The randomized, controlled, HALT–PKD
trial included 558 patients with ADPKD <50 years of
age with an eGFR >60 ml/min/1.73 m2, and revealed a
reduced rate of increase in TKV (5.6% versus 6.6% per
year; P = 0.006), a decrease in urinary albumin excretion
(−3.77% versus 2.43%; P <0.001), and a reduced left-­
ventricular mass index (−1.17 g/m2 versus −0.57 g/m2
per year; P <0.001), but no overall difference in the rate
of eGFR decline between aggressive (<110/75 mmHg)
and standard (<130/80 mmHg) blood pressure targets
over 5 years of follow‑up6. As expected from haemo­
dynamic effects, patients with aggressive blood pres-
sure-reduction targets had an initial decline in eGFR in
the first 4 months of study compared to those on stand-
ard blood pressure control (−3.1 ml/min/1.73 m2 versus
0.5 ml/min/1.73  m2; P <0.001), but less decline in eGFR
over the remainder of the study (−2.7 ml/min/1.73 m2
per year versus −3.1 ml/min/1.73 m2 per year; P = 0.05),
resulting in no significant overall difference in eGFR over
5 years of follow‑up (−2.9 ml/min/1.73 m2 per year versus
−3.0 ml/min/1.73 m2 per year; P = 0.55)6. At the time the
HALT–PKD study was designed, the Mayo Clinic classi-
fication of risk stratification had not been developed. In a
post hoc analysis of the HALT–PKD study, patients with
a higher baseline TKV (class 1C, 1D or 1E) had the greatest
level of benefit from blood pressure reduction (P = 0.001)6.
Rate of progression
ESRD@ 70
years old
3
1
Patient 1 Patient 2 Patient 3 Patient 4
Main genetic effect: Somatic genetic
mutation of PKD1 vs changes, epigenetic
PKD2; missense vs modifications
truncating mutations
Environmental effects:
Other genetic effects hypertension,
(common or rare): nephrolithiasis, acute
genes involved in kidney injury, drugs,
cystic, signalling and trauma, vasopressin,
trafficking pathways; tubular obstruction,
genes altering capsular pressure,
metabolic risk factors blood flow
Figure 4 | The theoretical contribution of genetic and
Nature Reviews
environmental factors to polycystin protein| Nephrology
dosage
explains the rate of cyst progression in patients with
autosomal dominant polycystic kidney disease
(ADPKD). Bars represent the relative loss of functional
polycystin protein dosage and contribution of genetic
and environmental factors to subsequent cyst growth and
increase in total kidney volume (TKV). The upper
horizontal orange line indicates a growth rate consistent
with reaching end-stage renal disease (ESRD) at 50 years
of age, whereas the lower horizontal red line indicates a
growth rate consistent with ESRD at 70 years of age.
Patient 1 has a missense mutation in PKD2 (encoding
polycystin 2), which has less severe consequences for
disease progression than other mutations, but has had
environmental exposures that increase the rate of cyst
growth. Patients 2 and 3 have similar main genetic effects,
a missense mutation in PKD1, but patient 2 has also had a
‘second-hit’ somatic mutation, whereas patient 3 also has
other genetic modifiers. Patient 4 has a nonsense mutation
in PKD1, resulting in early-onset ESRD.
The HALT–PKD study B randomized controlled trial
included 486 patients with eGFR of 25–60 ml/min/1.73 m2
who were randomly assigned to receive either ACE
inhibitors or ACE inhibitors plus ARBs, but did not
evaluate blood pressure targets directly, as a target of
<130/80 mmHg was set for both groups; a similar decline in
eGFR (−3.91 ml/min/1.73 m2 versus −3.87 ml/min/1.73 m2
per year; P = 0.86) was observed in the two groups51. An
earlier study, the two-year Modification of Diet in Renal
Disease (MDRD) study involving patients with moder-
ate to advanced CKD (eGFR 25–55 ml/min/1.73 m2),
which included 220 patients with ADPKD, revealed
no significant difference in eGFR (inulin clearance;
−6.0 ml/min/1.73 m 2 versus −5.7 ml/min/1.73 m 2
per year, P = not significant) between use of aggres-
sive (mean arterial pressure (MAP) ≤92 mmHg) and

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REVIEWS
standard (MAP ≤107 mmHg) blood p ­ ressure targets, and
potential harm of aggressive blood pressure targets in
patients with eGFR <24 ml/min/1.73 m2 (eGFR decline
−4.9 ml/min/1.73 m2 per year versus −3.9 ml/min/1.73 m2
per year, P = 0.03)92. Importantly, these rates of decline are
significantly greater than those observed in the similar
HALT–PKD study B trial, and following the conclusion of
the MDRD study, long-term follow‑up of the participants
revealed a potential benefit of aggressive blood pressure
reduction in those with protein-to‑­creatinine ratios >0.22
and a reduced risk of mortality once ESRD was reached93,94.
The SPRINT trial has led to a re‑­evaluation of blood-­
pressure targets in patients >50 years of age with a high
level of cardiovascular risk, including those with CKD but
without diabetes, although this trial specifically excluded
patients with ADPKD95. The findings of the SPRINT trial
revealed fewer cardiovascular adverse events and reduced
­levels of mortality, with no difference in renal outcomes
in patients with CKD, when targeting a systolic blood
pressure of <120 mmHg compared to <140 mmHg95,96.
Overall, these data suggest, either directly (HALT–PKD
study A) or through inference (MDRD and SPRINT), that
a lower, rather than a moderate blood pressure reduction
target is advantageous in patients with ADPKD who
have hypertension.
We encourage home blood pressure monitoring and
utilization of an automated digital blood pressure monitor
for both improved patient ease and satisfaction. A sched-
ule of at least 10 measurements over a 3 month period
during drug trough periods, including both weekday
and weekend measurements, is considered an inform-
ative approach to managing patients that also engages
them in self-care. For clinic-based blood pressure meas-
urements, we recommend the use of three automated
measurements after a 5 minute rest in a seated position95.
Stringent control of dietary sodium intake is advised for
the management of hypertension, as well as for reduction
of cyst growth, as outlined below. In our opinion, blood
pressure targets need to be tailored to the needs of each
patient based on their age, extent of ADPKD progression,
prognosis, current eGFR, comorbid­ities and tolerance of
treatment. Given the greater lifetime cardiovascular risk
of patients with ADPKD and the potential benefit of
low blood pressure targets in slowing the progression
of renal disease that was demonstrated in the HALT–
PKD (study A) trial, we target blood pressures below
110/75 mmHg in patients <50 years of age with preserved
kidney function. The remaining patients are treated in
accordance with the KDIGO guidelines91.
Management of proteinuria
The KDIGO guidelines recommend the annual assess-
ment of albuminuria and proteinuria in all patients with
CKD in order to evaluate disease severity, progression
and prognosis91. Among patients with ADPKD with a
creatinine clearance >60 ml/min that were enrolled in
the TEMPO3:4 trial, >50% had moderately increased
albuminuria (3–30 mg/mmol or 30–300 mg/g)7,91,97.
Glomerular-range proteinuria (>1 mg per day) is
rarely seen in patients with ADPKD and an alternative
glomerular-­based diagnosis should be sought98,99. The
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CRISP cohort provided longitudinal evidence for associ­
ations between elevated albumin-to‑creatinine ratio
(ACR), increased TKV and decreased eGFR100. Baseline
characteristics in the HALT–PKD and TEMPO 3:4 trials
demonstrated statistically significant independent associ-
ations between urinary albumin excretion, hypertension,
higher TKV and lower eGFR97,101. In the early HALT–
PKD (study A) trial, aggressive blood pressure lowering
(<110/75 mmHg) was associated with a 3.77% reduction
in ACR compared with a 2.43% increase in the standard
blood pressure target group (<130/80 mmHg; P <0.001)6.
In the TEMPO 3:4 trial, baseline ACR was also associ-
ated with a more rapid eGFR reduction over the course
of the study (P <0.0001), and tolvaptan treatment was
associated with a 0.4 mg/mmol reduction in ACR com-
pared with a 0.23 mg/mmol increase in the placebo group
(P <0.001), independent of changes in blood pressure or
concomitant use of ACE inhibitors97. Direct evidence that
reducing albuminuria in ADPKD affects progression to
ESRD is not currently available, but we believe that an
elevated ACR is a risk factor for progressive disease and
should be included in the decision to target lower blood
pressures and increase the dose of RAAS inhibitors.
Slowing the increase in cyst burden
Ten distinct types of medication have been or are cur-
rently being tested in randomized controlled trials, with
the goal of reducing the rate of increase in TKV or cyst
burden over time and maintaining eGFR (TABLE 3).
Vasopressin V2 receptor antagonists. Tolvaptan is a
highly selective vasopressin V2 receptor antagonist
that was assessed for ADPKD in the TEMPO 3:4 trial7.
In a total of 1,445 patients with estimated creatinine
clearance >60 ml/min and TKV >750 ml, tolvaptan
decreased the rate of TKV increase by almost 40%
(2.8% versus 5.5% per year; P <0.001), and slowed the
rate of decline in eGFR (2.72 ml/min/1.73 m2 versus
3.70 ml/min/1.73 m2 per year; P <0.001) compared with
placebo after 3 years of follow‑up. Patients who received
tolvaptan had fewer complications, including clinically
significant renal pain requiring hospitalization or nar-
cotic intervention (27% versus 35%), urinary tract infec-
tions (8.3% versus 12.6%) and episodes of haematuria
(7.8% versus 14.1%), than patients who received placebo.
However, increased thirst (55.3% versus 20.5%), poly­
uria (38.3% versus 17.2%) and polydipsia (10.4% versus
3.5%) were more frequent in patients in the tolvaptan
group than in those in the placebo group. An alanine
aminotransferase level >2.5‑fold above the upper normal
levels was also more frequently observed in patients who
received tolvaptan than in patients who received placebo
(4.9% versus 1.2%), which resolved following drug dis-
continuation. Post-hoc analyses demonstrated that tol-
vaptan had simi—lar beneficial effects in patients with
stage 1–3 CKD102, that patients with the greatest decline
in urine osmolality displayed the greatest therapeutic
benefit103, that tolvaptan treatment resulted in a reduc-
tion in ACR independent of RAAS blockade and blood
pressure97 and that tolvaptan reduced acute kidney pain
events in patients with CKD of any stage104.

TEMPO 4:4 was a 2‑year open-label observational
extension study involving patients from the TEMPO 3:4
cohort. This study compared the outcomes of an ‘early-­
treatment’ group comprising patients from the tolvaptan
group of TEMPO 3:4 with a ‘delayed-treatment’ group
comprising patients from the placebo group of TEMPO
3:4 who started on tolvaptan treatment following the
conclusion of the original trial8. The primary outcome
was negative (29.9% increase in TKV in the patients in
the early-treated group versus 31.6% among patients
in the delayed-treatment group from TEMPO 3:4 base-
line to TEMPO 4:4 closure; P = 0.38). After excluding
Japanese participants, who were undertaking a sepa-
rate follow‑up extension trial, and those who dropped
out of TEMPO 3:4, 91.9% of patients who were eligible
for TEMPO 4:4 enrolled in this study (60.3% of total
TEMPO 3:4 enrolment). Interpretation of the study
results is complicated by prognostic imbalance result-
ing from loss of the ran­domization, with the delayed-­
treatment group including more men, and more patients
with higher TKV and ACR at the start of TEMPO 4:4.
Owing to the onset of new aquaretic adverse effects in
TEMPO 4:4 when switching from placebo to tolvaptan,
the delayed-treatment group had twice the dropout
rate of the early-treatment group (early-treated n = 50
(9.0%) versus delayed-treatment n = 58 (18.5%)), which
is consistent with the expected incidence of first-time
aquaretic adverse effects when starting tolvaptan treat-
ment. Nevertheless, the results of TEMPO 4:4 showed
sustained beneficial effects of tolvaptan on eGFR decline
(a difference of 3.15 ml/min/1.73 m2 between patients
in the early-treated versus delayed-treatment groups;
P <0.001) and after correction for covariates, beneficial
effects on TKV (−4.15% between the early versus delayed
treatment groups; P = 0.04). Moreover, no differences in
safety profile were observed, and patients with the great-
est level of risk (Mayo class 1C−1E, or those with PKD1
truncating mutations) had the greatest level of benefit in
TEMPO 4:4, similar to the findings of TEMPO 3:4.7,102
Tolvaptan is now approved for the treatment of
ADPKD in Japan, Canada, South Korea, Switzerland
and Europe, and the ERA–EDTA and Canadian guide-
lines for the use of this agent have been published22,41.
Current recommendations for use are based upon the
inclusion criteria of TEMPO 3:4, and on identifying
patients with high-risk disease (18–50 years of age,
eGFR >45 ml/min/1.73 m2, with rapid decline in eGFR
or Mayo class 1C−1E)22,41. FDA approval of tolvaptan
for patients with ADPKD is currently awaiting results
of the upcoming REPRISE clinical trial105. A precision
medicine strategy might help to identify patients who
are appropriate for therapy by enabling the selection of
patients with maintained renal function but who are
at risk of disease progression, as demonstrated by risk
­evaluation and stratification outlined above.
Statins. Statins have a role in reducing cardiovascular
risk in patients with CKD who are not on dialysis and
are either >50 years of age or have a level of 10‑year
cardiovascular risk exceeding 10%91. Supported by
animal studies, statins have been proposed to have
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REVIEWS
pleiotropic beneficial effects in patients with ADPKD,
albeit via mechanisms that are currently poorly under-
stood, including enhanced renal blood flow, reduced
inflammation and increased vascular and glomerular
nitric oxide production48. Data from small short-term
studies examining surrogate outcomes suggest that
treatment with statins early in the course of ADPKD
could potentially lead to improvements in inflamma-
tory biomarkers, renal plasma flow and endothelial
cell dysfunction106–108. The findings of a 3‑year ran-
domized controlled trial involving 110 children and
young adults with ADPKD (mean age of 16 years),
indicate that pravastatin significantly reduces the rate
of TKV increase, after correction for age, gender and
blood pressure, compared with placebo (23% ± 3%
versus 31% ± 3% over 3 years; P = 0.02)48. By contrast,
a 2‑year open-label trial involving 49 patients with
ADPKD (mean eGFR 54 ml/min/1.73 m2) identified
no difference in rate of eGFR decline or proteinuria
with pravastatin treatment compared with placebo109.
Furthermore, a post hoc propensity score-based analysis
of the effectiveness of statins as a co‑intervention in par-
ticipants in the HALT–PKD trial found no evidence for
benefit of pravastatin treatment in early stage (study A)
or late stage (study B) ADPKD110. These observations
suggest that early intervention with statin therapy might
be bene­ficial in patients with ADPKD, but additional
evidence is required before widespread prescription of
statins to patients with ADPKD. However, given the low
level of risk and the likelihood of beneficial vascular
effects, we have a low threshold for initiation of statin
therapy in patients with ADPKD who have either a high
risk of disease progression or an elevated cardiovascu-
lar risk, after appropriate counselling, especially in the
context of dyslipidaemia.
Somatostatin analogues, mTOR inhibitors and others.
Somatostatin analogues, including octreotide, lanreotide
and pasireotide, have demonstrated promise as treat-
ments for ADPKD, especially in patients with associated
PLD. A systematic review of three small randomized
controlled trials investigating the efficacy of somato­
statin analogues in patients with ADPKD or PLD showed
a 9% reduction in TKV increase over 3 years (95% CI
−10.33 to −7.58; P <0.001; total n = 136), with no change
in eGFR52,54,111,112. Total liver volumes also decreased by
5% per year54,112,113. Concerns regarding somatostatin
analogue-associated hepatic cyst infections currently
exist, as an interim analysis of the ongoing DIPAK trial
reported eight hepatic cyst infections in seven patients
over 342 patient-years of lanreotide use, compared with
no cyst infections in patients receiving placebo114,115. Until
the results of further studies are available, somatostatin
analogues are not recommended for use in patients with
ADPKD without substantial hepatic involvement as the
primary indication.
The efficacy of inhibitors of mTOR complex 1
(mTORC1), including sirolimus and everolimus, has
been tested in five randomized controlled trials involv-
ing patients with ADPKD. Despite a strong mechanistic
foundation and impressive results in model organisms,
REVIEWS

Table 3 | Randomized controlled trials testing therapies for reducing kidney cyst burden
Therapy Trial name, lead Sample Effect on eGFR or TKV*
author or trial no. size (n)
Vasopressin V2 receptor antagonists
Tolvaptan TEMPO7 1,445 • eGFR: −2.61 versus −3.81 mg/ml per year (P <0.001)
• TKV growth: 2.8% versus 5.5% per year (P <0.001)
REPRISE105 1,337 • Not yet reported
ACE inhibitors and/or ARBs
Lisinopril +  HALT-PKD6,51 Early: 558 • eGFR: −2.9 versus −3.0 ml/min/1.73 m2 per year (P = 0.55) with
telmesartan versus low BP target or combination of ACE inhibitor and ARB
lisinopril alone • TKV increase: 5.6% per year in low BP target versus 6.6% per
year in standard BP target (P = 0.006). No differences with
combination of ACE inhibitor and ARB
Late: 486 • No difference in TKV or eGFR
Somatostatin analogues
Octreotide Hogan et al.54,113 34 • iGFR: −5.1 versus −7.2 ml/min in 1 year (P = 0.6)
• TKV increase: 0.3% versus 8.6% per year (P = 0.05)
Ruggenenti et al.57 12 • eGFR: −2.5 versus −3.2 ml/min/1.73 m2 (P = NS)
• TKV increase: 2.2% versus 5.9% in 6 months (P <0.05)
ALADIN52 75 • eGFR: −3.9 versus −5.0 ml/min/1.73 m2 in 3 years (P = NS)
• TKV increase: 46.2 ml versus 143.7 ml per year (P = 0.03)
Lanreotide van Keimpema 54 • Creatinine: −2 versus 4 μmol/l (P = NS)
et al.112 • TKV increase: –1.5% versus 3.4% per 24 weeks (P = 0.02)
DIPAK114,115 309 • Phase III, ongoing, not yet reported
Pasireotide NCT01670110 48 • Phase II, ongoing
mTORC1 inhibitors
Everolimus Walz et al.50 433 • eGFR: −8.9 versus −7.7 ml/min/1.73 m2 at 2 years (P = 0.15)
• TKV increase at 1 year: 102 ml versus 157 ml (P = 0.02)
• TKV increase at 2 years: 230 ml versus 301 ml (P = 0.06)
Sirolimus RAPYD53 55 • Ramipril versus ramipril + high dose versus ramipril + low dose
• GFR: −2.8 versus 4.5 versus 0.8 at 2 years (P = NS)
SUISSE49 100 • eGFR: 0.2 versus −3.5 ml/min/1.73 m2 (P = 0.07)
• TKV increase: 36 versus 15 versus 14 ml at 2 years (P = NS)
Braun et al.55 30 • Low-dose versus high-dose versus standard care in 1 year
• iGFR: 7.7 versus 1.6 versus −11.2 ml/min/1.73 m2 (P <0.01)
• TKV increase: 99 cm3 versus 97 cm3 at 18 months (P = 0.26)
SIRENA-II188 40 • TKV increase: 9.3% versus 4.8% versus 7.8% (P = 0.29)
• Stopped owing to safety concerns
Statin
Pravastatin Cadnapaphornchai 110 • Creatinine clearance: 126 versus 126 ml/min (P = 0.98)
et al.48 • >20% height-corrected TKV increase: 46% versus 68%
(P = 0.03)
Fassett et al.109 49 • eGFR: −1.34 versus −0.31 ml/min/1.73 m2 at 2 years (P = 0.78)
• TKV: not assessed
Tyrosine kinase inhibitors
Bosutinib NCT01233869 172 • Ongoing, phase II
Tesevatinib NCT03096080 18 • Ongoing, phase I
(KD019)
Other approaches
Niacinamide NCT02140814 10 • Completed, not yet reported
(Vitamin B3)
NCT02558595 36 • Ongoing, phase II
Metformin NCT02656017 96 • Ongoing, phase II
NCT02903511 50 • Ongoing, phase II

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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Table 3 (cont.) | Randomized controlled trials testing therapies for reducing kidney cyst burden
Therapy Trial name, lead Sample
author or trial no. size (n)
Other approaches (cont.)
PPARγ agonist: NCT02697617 28
pioglitazone
Aldosterone NCT01853553 60
antagonist:
spironolactone
Water intake NCT00784030 13
NCT02776241 32
NCT03102632 60
*Comparisons are treatment versus placebo unless otherwise noted. ACE, angiotensin-converting enzyme; ARB, angiotensin 2
receptor blocker; BP, blood pressure; eGFR, estimated glomerular filtration rate; iGFR, 125I-iothalamate GFR; mTORC1, mechanistic
target of rapamycin complex 1; NS, not significant; PPARγ, peroxisome proliferator-activated receptor‑γ; TKV, total kidney volume.
the findings of a systematic review demonstrated no
beneficial effects of mTORC1 inhibition on the rate
of change of TKV or the rate of decline in eGFR111.
Adverse effect profiles, including stomatitis, podo­cyto­
pathy, protein­uria and renal toxicity, as well as wide var-
iations in doses used in different studies, which either
were subtherapeutic or resulted in high levels of adverse
effects, make full interpretation of the potential benefits
of mTORC1 inhibition difficult. The lack of efficacy of
these inhibitors has been hypothesized to reflect lower
cyst-specific drug concentrations in patients, compared
to the concentrations that are effective in preventing
ADPKD progression in mouse models116. Nonetheless,
mTORC1 inhibitors are not currently recommended for
the treatment of patients with ADPKD.
Several randomized controlled trials involving inhib-
itors that specifically target the proliferative nature of
ADPKD, based on growing insights into cyst biology
from cellular and animal studies, are currently o ­ ngoing.
These agents include the tyrosine-kinase inhib­itors
bosutinib and tesevatinib, as well as metformin, piogli-
tazone, spironolactone and niacinamide. Finally, oligo-
nucleotides targeting microRNAs are a new therapeutic
strategy that could be employed in the treatment of
ADPKD. An oligonucleotide directed against miR‑17
is currently moving through preclinical studies and an
oligo­nucleotide directed against miR‑21, which was
tested in a phase I trial for Alport syndrome, could be
helpful in the treatment of ADPKD117,118.
Managing renal complications in ADPKD
Patients with ADPKD can be fairly asymptomatic, especi­
ally early in the course of disease, but chronic vague
abdominal discomfort, early satiety, polyuria and poly-
dipsia remain common. Acute adverse events, such as
gross haematuria, infections, acute pain syndromes and
nephrolithiasis, often require medical attention and lead
to increased medical resource utilization and ­hospital
visits compared with that of the general population119.
Haematuria and cyst haemorrhage. The initial manage-
ment of haematuria is reliant on identifying the under-
lying aetiology, which can include cyst rupture and/or
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 13
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REVIEWS
Effect on eGFR or TKV*
• Ongoing, phase II
• Completed, not yet reported
• Completed, not yet reported
• Recruiting
• Recruiting
haemorrhage, infection, nephrolithiasis or an under-
lying malignancy. Cyst haemorrhage can be asymp-
tomatic and occur with or without gross haematuria,
fever and/or pain120,121. Haemorrhage might be the
result of trauma, and is a common cause of presenta-
tion in affected children and adolescents following
contact sports or falls. Isolated haematuria is usually
self-­limiting and resolves within a week in the absence
of specific treatment122. Unenhanced CT should reveal
increased density (>25 Hounsfield units) and an irregu-
lar haematoma and wall thickening within the haemor-
rhagic cyst123. Administration of ACE inhibitors should
be delayed until bleeding resolves, owing to a risk
of AKI124. The risks and benefits of delaying the use of
anticoagulant or antiplatelet therapies should be deter-
mined based upon the specific indication. Patients with
non-resolving haemorrhages might develop substantial
subcapsular or retroperitoneal haematomas or require
blood transfusions, haemostatic agents, interventional
embolization, or surgical procedures123.
Cyst infections. The presence of numerous cysts can
create areas of non-laminar tubular flow, and pockets
of urinary stasis and obstruction can serve as a nidus
for infection, or act as an infectious reservoir. Cysts
can become disconnected from tubules and thus, when
infected, effectively become an abscess. Both ascending
urinary and haematogenous spread have been identified
as sources of kidney cyst infections120. In addition, liver
cysts can also become infected. Diagnosing kidney and
liver cyst infections can be difficult and should be sus-
pected in any patient with ADPKD who has fever and/or
abdominal pain, especially those with elevated serum
white blood cell counts and C‑reactive protein levels,
and in the absence of an alternative diagnosis120,125. The
identification of infected cyst aspirate remains the gold
standard for diagnosis, but aspiration is uncommon in
practice owing to the invasive nature of the procedure,
the risk of complications and the difficulty in identifying
and accessing the infected cyst126. Urine and blood cul-
tures should be obtained, as they might guide the selec-
tion of antibiotics, but their usefulness is limited as >50%
of such cultures are sterile, including those from patients
REVIEWS
with positive cyst-aspirate cultures126. Ultrasonography
and non-contrast CT are of limited utility, and although
contrast-enhanced CT might be helpful, its use is limi­
ted by concerns about the use of contrast in those with
impaired kidney function126. Advanced imaging studies,
including MRI and fluorodeoxyglucose positron emis-
sion tomography/CT (FDG–PET/CT), seem better
approaches for the diagnosis of cyst infections, but are
limited by costs and availability126–129.
The frequency of kidney and liver cyst infections in
patients with ADPKD is difficult to estimate, but such
infections are not a common event. In a 10‑year (2005–
2015) single-centre retrospective analysis including 173
patients with ADPKD, 16 patients had a total of 23 cyst
infections120. In a meta-analysis, investigators collected
a published case series describing a total of 85 patients
with ADPKD that had renal cyst infections130. Cyst
infections appear more frequently in older patients with
later stage disease (mean age of 51 years; 79% of patients
had eGFR <60 ml/min/1.73 m2, and 40% of patients had
ESRD)130. Persistent infections that are resistant to
antibiotic eradication were reported in 61% of patients
following initial treatment, and were more common
in patients with large (>5 cm in diameter) cysts, when
urolithiasis and atypical pathogens (organisms other
than Escherichia coli, such as Staphylococcus aureus,
Enterococcus faecium, Clostridium perfringens and
Candida krusei, among others) were present, and when
shorter (<2‑week) durations of empiric treatment were
used130. Positive cyst aspirates were obtained in half of all
patients and E. coli was the most common organism in
cyst aspirates (in 51% of patients)130. Fluoroquinolones
and trimethoprim-sulfamethoxazole are generally the
preferred first-line treatments of cyst infections owing
to their lipid solubility and therefore increased likeli-
hood of cyst penetration131. In the meta-analysis, the
average duration of antibiotic treatment was 14 days130,
and given the abscessed nature of cyst infections, treat-
ment without drainage required a longer duration of
antibiotic therapy131. Without ­invasive cyst fluid col-
lection, the selection of an appropriate antimicrobial
agent remains empirical, and the risk of antimicrobial
resistance must be considered when patients do not
recuperate on an appropriate trajectory. Evidence to
guide the timing of advanced imaging studies is scant,
but, in our opinion, such studies should be sought in
patients with refractory symptoms that do not improve
after 1 week of empirically selected cyst-penetrating
treatment. Even when antimicrobial therapy is under-
taken, invasive procedures are typically required when
cyst diameters exceed 5 cm, and were required in a sig-
nificant proportion of patients included in the above-
mentioned meta-analysis (percutaneous cyst drainage
(31%); surgical drainage (8%); and partial (1%) and
total (33%) nephrectomy)130.
Nephrolithiasis. Metabolic and structural abnormal-
ities predispose patients with ADPKD to nephrolithi­
asis, and reports suggest that up to a quarter of patients
with ADPKD will have a kidney stone at some point
in their disease course132. ADPKD-related metabolic
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abnormalities that predispose to urinary crystal formation
include low urinary pH, hypocitraturia, hypomagnesuria,
hyperuricaemia and hyperuricosuria, hyperoxaluria
and, occasionally, hypercalciuria and secondary hyper-
parathyroidism132,133. Compared with patients with
ADPKD with no previous nephrolithi­asis, patients with
stone-forming ADPKD have a greater number of cysts
and an increased cyst size and TKV, and lower eGFR and
24 h urine volumes132,134. Phenotypic overlap or coexist-
ence with medullary sponge kidney can occur in patients
with ADPKD133. Uric acid stones are the most commonly
reported stone composition in patients with ADPKD,
although calcium-containing and struvite stones both
also occur frequently133. Ultrasonography might enable
the detection of larger stones, although altered anatomy
and the presence of parenchymal and cyst wall calcifi-
cations can reduce the sensitivity and specificity of this
imaging technique, which makes non-contrast CT the
preferred modality for diagnosis132.
Urological treatments of patients with ADPKD and
symptomatic stones might include percutaneous nephro­
lithotomy135, extracorporeal shockwave lithotripsy or
uretero­scopy with laser lithotripsy136. Increased fluid
intake is the mainstay of stone prevention, which is help-
ful for patients with ADPKD, regardless of the presence
of stones. Screening for concomitant hypercalcaemia and
hyperparathyroidism, and standard dietary counselling
for stone prevention, including high fluid intake, high
fruit and vegetable intake, and a low-salt, protein and
oxalate containing diet, is advisable137. Correcting meta­
bolic abnormalities by prescribing potassium citrate,
sodium bicarbonate or vitamin D, where appropriate
is also a reasonable approach. Thiazide diuretics might
be useful for recurrent nephrolithiasis in the context
of hypercalciuria138.
Pain. Acute abdominal pain secondary to cyst rupture,
cyst infection or the presence of kidney stones should be
treated with analgesics, including acetaminophen and
opioids. The judicious use of short courses of NSAIDs
might also be considered in patients with an eGFR in the
normal range139. Patients with ADPKD might also have
chronic pain, which has been attributed to the compres-
sion of adjacent structures, capsular distension, traction
of the renal pedicle and aberrant activation of the sen-
sory or autonomic nervous system121. Pain sensations
in these patients can be either sharp and stabbing or
dull and aching, and fluctuating in intensity, and might
affect a wide dermatomal distribution121. The high level
of variability in symptoms at presentation makes a diag-
nosis difficult, especially as patients with ADPKD are
not precluded from having chronic pain of other aetiol-
ogies, including fibromyalgia, gynaecological pain and
inflammatory or irritable bowel disease, among others.
Pain is more common in the later stages of ADPKD, but
is not proportional to TKV at early disease stages (eGFR
>60 ml/min/1.73 m2)104,140.
The management of chronic pain begins with use
of nonpharmacological interventions, including phys-
ical interventions (for example, massage, physical
therapy, ice and heating pads) and psycho-educational

interventions, although the effectiveness of these inter-
ventions has not been specifically studied in patients
with ADPKD141. Further interventions can be divided
into pharmacological and procedural modalities, and
are best delivered by a multidisciplinary team including
nephrologists, urologists, interventional radiologists and
pain physicians.
Pharmacological analgesia should be prescribed
according to the WHO three-step analgesic ladder,
which was originally developed for cancer-related
pain142. The steps of the ladder include: firstly, aceta-
minophen; secondly, NSAIDs, with the caveat of lim-
iting their use in patients with impaired renal function,
or mild opioids (such as tramadol); and thirdly, strong
opioids (such as morphine or hydromorphone)142.
Patients must be counselled about the possible substan-
tial adverse effects of opioids, which include constipa-
tion, nausea, sedation and a risk of dependence and/or
overdose142. Impaired clearance of opioids in patients
with renal dysfunction is a problem. Furthermore, con-
cerns have been raised about the excessive use of opioids
for chronic non-cancer-related pain, and the presence
of unrecognized harms that can occur with their pre-
scription143. Adjuvant analgesics that are intended for
patients with neuropathic pain, including pregabalin
or gabapentin, and antidepressants, including amitrip-
tyline, nortriptyline or duloxetine, have been proposed
for the treatment of pain in patients with ADPKD,
but have not been studied in this context121,141,144. Patients
have anecdotally reported beneficial effects of using
medicinal marijuana145, but its use has not been studied
or reported in the formal literature. In the TEMPO 3:4
trial, patients receiving tolvaptan had fewer kidney pain
events than those in the placebo group (10.1% versus
16.7%; P <0.001). The number needed to treat in order
to prevent any pain event was 35, and to prevent a severe
event requiring clinician-prescribed intervention with
narcotics or hospitalization was 94.104
Following the failure of conservative and pharma-
cological strategies, the stepwise use of minimally inva-
sive, followed by more-invasive procedures has been
proposed141,146, and has been evaluated in a 44‑patient
prospective cohort study139. The underlying theory is
that pain originating from pressure on adjacent organs
is transmitted via the coeliac plexus and the major
splanchnic nerves, whereas pain from renal capsule
pressure is transmitted via the aorticorenal plexus and
the minor and least splanchnic nerves139,141,147. A diagnos-
tic coeliac or splanchnic nerve block with short-­acting
local anaesthetic can be used to indicate the source of
pain141. Renal denervation, either surgically or using
percutaneous transluminal catheter-based radioablation,
might help to relieve renal-capsule-related pain148–150.
Sympathetic nerve ablation is the same procedure as
that used in the negative SYMPLICITY-HTN trials for
refractory hypertension151. Minimally invasive liver
or kidney cyst aspiration, with sclerotherapy or fenes-
tration, especially for large cysts (>5 cm in diameter),
is also a potential treatment option141. Laparoscopic
or surgical interventions aimed at cyst decortication or
deroofing have been reported to improve pain outcomes
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 15
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REVIEWS
and can be considered following a failure of minimally
invasive strategies; however, such interventions do not
improve blood pressure control and might be associated
with worsening renal function144,152,153. Partial, or total
nephrectomy should be considered as an absolute last
resort, in order to avoid the loss of any residual renal
function. No gold-standard modality for pain relief
exists in patients with ADPKD; therefore, the selection
of treatment options is at least partially dictated by local
expertise and practice patterns.
Dietary counselling
Patients with ADPKD are often motivated to comply
with therapeutic recommendations, and questions
regarding dietary recommendations are frequently
among the first asked by patients. Modifications to diet
are difficult to adopt and maintain — in consequence,
most patients regress to their baseline dietary pattern,
driven by intrinsic taste, thirst and habit100. However,
data from clinical trials have demonstrated that major,
sustainable dietary alterations are possible with repeated
use of counselling interventions154–156.
Salt restriction. Dietary sodium intake is best evaluated
using 24 h urine collection157. Despite heated contro-
versy, and the possible presence of a J‑shaped relationship
between dietary sodium intake and both CKD and cardio­
vascular disease risk, most clinicians agree that patients
should avoid a high-sodium diet (>5 g per day)158–163. The
current KDIGO recommendation is a daily intake tar-
get of <2 g of sodium (corresponding to <5 g of sodium
chlor­ide or table salt) in all patients with CKD without
contraindications, especially in those with hypertension
or proteinuria91. The results of two randomized controlled
trials involving patients with diabetic and non-diabetic
CKD suggest that increased sodium intake reduces the
effectiveness of RAAS blockade164,165. Salt avoidance is
important in patients with ADPKD owing to a high preva­
lence of salt-sensitive hypertension and a requirement for
optimal RAAS blockade. The CRISP trial provided lon-
gitudinal evidence of an association between higher uri-
nary sodium excretion, which is a surrogate indicator of
dietary sodium intake, and both an increased rate of TKV
increase and a fall in GFR100.
The best evidence for the efficacy of reducing sodium
intake in ADPKD comes from a post-hoc analysis of
data from the early (study A) and late (study B) HALT–
PKD trials6,51,155. Study A revealed a significant associ-
ation between each 18 mEq (414 mg) urinary sodium
excretion per 24 h increase and increased TKV (0.43%
per year, P <0.001), and a nonsignificant fall in eGFR
(−0.07 ml/min/1.73 m2; P = 0.094), whereas in Study B,
each 18 mEq (414 mg) urinary sodium excretion per 24 h
increase was associated with more-rapid eGFR decline
(−0.09 ml/min/1.73 m2; P <0.001) and an increased risk
of the composite outcome (a 50% reduction in eGFR, and
ESRD or death, HR 1.08; P = 0.01)155. The lack of a sig-
nificant association between sodium intake and eGFR in
study A was attributed to the slow decline in eGFR
in patients with early stage ADPKD and the inclusion of
patients with mild disease who are unlikely to experience
REVIEWS
a decline in eGFR during the study period155. At enrol-
ment, study participants were counselled to reduce their
sodium intake below 100 mEq per day (2.3 g per day),
and modest reductions in intake were achieved over the
course of the study (baseline mean intake was 178 mEq
per day (4.1 g of sodium per day), mean reduction was
12 mEq per day (276 mg per day) in study A and 26 mEq
per day (598 mg per day) in study B)155.
Studies of the effect of dietary protein restriction in
patients with ADPKD are lacking, but the KDIGO guide-
lines recommend reducing protein intake to 0.8 g/kg per
day for adults with an eGFR <30 ml/min/1.73 m2 and
avoiding high protein intake (>1.3 g/kg per day) in all
patients with CKD who are at risk of disease progres-
sion91. Dietary protein intake can be estimated from
measurements of 24 h urinary urea nitrate excretion166.
Excessive protein intake is thought to result in glomer-
ular hyperfiltration and the accumulation of nitrogen­
ous wastes, especially in the context of reduced GFR167.
In  North America, high-protein, low-­carbohydrate
diets are common168, especially with the popularity of
diets such as the ‘South Beach diet’ and the ‘Atkins diet’169.
Despite equivocal results of the MDRD study, which only
included patients with ADPKD170, a meta-analysis of
data from 10 randomized controlled trials investigating
restriction of protein intake in patients with non-diabetic
CKD, about a quarter of whom had ADPKD, supports
the restriction of dietary protein171. The number needed
to treat for 1 year to prevent one renal death ranged from
as few as two, and up to 56.171
We employ 24 h urine collections in conjunction with
multidisciplinary education, food records and motiva-
tional interviewing to encourage patients to reduce their
salt and protein intake in accordance with the KDIGO
guidelines. We advocate a balanced diet of complex car-
bohydrates, fruits and vegetables, with a low sodium
(<2.3 mg per day) and modest protein (<0.8 g/kg per
day) content.
Water intake. Humans have basal levels of AVP, which
assist in urine concentration and avoid the need for
excess fluid intake62. The renal concentrating defects in
patients with ADPKD can lead to mild hypovolaemia,
and a higher concentration of circulating AVP. Increased
AVP levels, and levels of its surrogate copeptin, are
associated with progression of ADPKD and increased
TKV64,65,67,68. Fluid intake reduces the concentration of
circulating AVP via a negative feedback loop, whereas
AVP concentrations increase in response to V2 recep-
tor antagonism62,172. Given the role of AVP in the patho-
genesis of ADPKD, suppression of AVP concentrations
by excess water ingestion seems a reasonable treatment
approach173. In individuals without kidney disease, low
levels of urinary osmolality are strongly correlated with
low AVP activity64,65. However, owing to impaired uri-
nary concentrating deficits, patients with ADPKD might
have low levels of urinary osmolality despite the pres-
ence of AVP, especially in those with advanced-stage
disease61. Patients in whom the use of water prescription
is limited include those with impaired GFR and with a
relative excess or inappropriate AVP secretion, which
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can result in failed free water excretion and subsequent
hyponatraemia62. Additionally, individuals with severely
reduced salt and protein intake, or those using diuretics
might be at an increased risk of hyponatraemia62.
The findings of observational studies including a total
of 18 patients with ADPKD demonstrated the safety and
tolerability of a water prescription, as well as a reduction
in urine osmolality and decreased circulating AVP con-
centrations174,175. A 1-year observational study failed to
reveal any differences in TKV or eGFR slopes between
those with high (2.6 l per day) and those with free (1.4 l
per day) patterns of water intake in 34 patients with
ADPKD176. Other randomized controlled trials investi-
gating the efficacy of water intake as a prescription in
patients with ADPKD are currently underway (TABLE 2).
In patients with eGFR >30 ml/min/1.73 m2 who are
not using diuretics, do not have a condition or take a
drug that alters AVP (that is, a possible contributor to
the syndrome of inappropriate antidiuretic hormone),
and have no urological abnormalities, we prescribe an
increase in free water intake targeting a urinary osmo-
lality of <250 mosm/kg H20. This prescription typically
consists of a daily water intake of >3 l per day173,175.
Conclusions
ADPKD can be a devastating disease that leads to consid-
erable morbidity and mortality in affected families. Owing
to the marked variability in the severity and progression
of ADPKD, a detailed personalized evaluation can assist
in differentiating between patients who can be reassured
regarding their mild disease and those who require closer
monitoring and early therapeutic intervention. Genetic
testing has an important role in diagnosis and precon-
ception counselling in patients with ADPKD, especially
in complex or unusual cases of ADPKD or involving
young (<30 years old) patients. MRI-based measurement
of TKV is a powerful imaging biomarker that enables
accurate ADPKD-related risk assessment. Risk stratifi-
cation is required before the prescription of treatments
targeting cyst reduction to ensure that the therapeutic
burden of costs and adverse effects is outweighed by
the benefits of treatment. Data from randomized con-
trolled trials provide evidence to direct the management
of hypertension and proteinuria, based upon risk strata.
Dietary interventions, including increasing water intake
and limiting salt and protein intake, are likely to be bene­
ficial and empower patients — supporting evidence for
these recommendations come from post hoc analyses of
randomized controlled trials involving other therapeutics.
The establishment of centres of excellence will enable the
development of expertise for accurate risk assessment,
and the diagnosis and treatment of the complications
of ADPKD. Ultimately, continued patient participation
in studies is needed to generate sufficient evidence for a
full precision medicine approach. Currently, strong evi-
dence exists suggesting that early assessment and treat-
ment of patients with high-risk ADPKD improves the
outcomes of these patients. This approach is associated
with a therapeutic burden, but seems worth the effort to
slow the deteri­oration of kidney function and cyst growth,
­ultimately delaying the onset of ESRD.

1. Gabow, P. A. Autosomal dominant polycystic kidney
disease. N. Engl. J. Med. 329, 332–342 (1993).
2. Reule, S. et al. ESRD from autosomal dominant
polycystic kidney disease in the United States,
2001–2010. Am. J. Kidney Dis. 64, 592–599
(2014).
3. Spithoven, E. M. et al. Renal replacement therapy
for autosomal dominant polycystic kidney disease
(ADPKD) in Europe: prevalence and survival —
an analysis of data from the ERA-EDTA Registry.
Nephrol. Dial. Transplant. 29, iv15–iv25 (2014).
4. Fernando, M. R., Dent, H., McDonald, S. P. &
Rangan, G. K. Incidence and survival of end-stage
kidney disease due to polycystic kidney disease in
Australia and New Zealand. Popul. Health Metr. 15,
7 (2017).
5. Chapman, A. B. et al. Renal structure in early
autosomal-dominant polycystic kidney disease
(ADPKD): The Consortium for Radiologic Imaging
Studies of Polycystic Kidney Disease (CRISP) cohort.
Kidney Int. 64, 1035–1045 (2003).
6. Schrier, R. W. et al. Blood pressure in early autosomal
dominant polycystic kidney disease. N. Engl. J. Med.
371, 2255–2266 (2014).
7. Torres, V. E. et al. Tolvaptan in patients with autosomal
dominant polycystic kidney disease. N. Engl. J. Med.
367, 2407–2418 (2012).
8. Torres, V. E. et al. Multicenter, open-label, extension
trial to evaluate the long-term efficacy and safety of
early versus delayed treatment with tolvaptan in
autosomal dominant polycystic kidney disease: the
TEMPO 4:4 Trial. Nephrol. Dial. Transplant.
http://dx.doi.org/10.1093/ndt/gfx043 (2017).
9. Committee on A Framework for Developing a New
Taxonomy of Disease. Toward Precision Medicine:
Building a Knowledge Network for Biomedical
Research and a New Taxonomy of Disease.
(The National Academies Press, 2011).
10. Harris, P. C. & Torres, V. E. Genetic mechanisms and
signaling pathways in autosomal dominant polycystic
kidney disease. J. Clin. Invest. 124, 2315–2324
(2014).
11. Cornec‑Le Gall, E., Audrezet, M. P., Le Meur, Y.,
Chen, J. M. & Ferec, C. Genetics and pathogenesis
of autosomal dominant polycystic kidney disease:
20 years on. Hum. Mutat. 35, 1393–1406 (2014).
12. Besse, W. et al. Isolated polycystic liver disease genes
define effectors of polycystin‑1 function. J. Clin. Invest.
127,1772–1785 (2017).
13. Lantinga-van Leeuwen, I. S. et al. Lowering of Pkd1
expression is sufficient to cause polycystic kidney
disease. Hum. Mol. Genet. 13, 3069–3077 (2004).
14. Rowe, I. et al. Defective glucose metabolism in
polycystic kidney disease identifies a new therapeutic
strategy. Nat. Med. 19, 488–493 (2013).
15. Wang, X., Wu, Y., Ward, C. J., Harris, P. C. &
Torres, V. E. Vasopressin directly regulates cyst growth
in polycystic kidney disease. J. Am. Soc. Nephrol. 19,
102–108 (2008).
16. Takakura, A. et al. Renal injury is a third hit promoting
rapid development of adult polycystic kidney disease.
Hum. Mol. Genet. 18, 2523–2531 (2009).
17. Leonhard, W. N. et al. Scattered deletion of PKD1
in kidneys causes a cystic snowball effect and
recapitulates polycystic kidney disease. J. Am. Soc.
Nephrol. 26, 1322–1333 (2015).
18. Houle, D., Govindaraju, D. R. & Omholt, S. Phenomics:
the next challenge. Nat. Rev. Genet. 11, 855–866
(2010).
19. Lanktree, M. B., Hassell, R. G., Lahiry, P. &
Hegele, R. A. Phenomics: expanding the role of clinical
evaluation in genomic studies. J. Investig. Med. 58,
700–706 (2010).
20. Grantham, J. J. et al. Determinants of renal volume
in autosomal-dominant polycystic kidney disease.
Kidney Int. 73, 108–116 (2008).
21. Irazabal, M. V. et al. Imaging classification of
autosomal dominant polycystic kidney disease:
a simple model for selecting patients for clinical trials.
J. Am. Soc. Nephrol. 26, 160–172 (2015).
22. Gansevoort, R. T. et al. Recommendations for the use
of tolvaptan in autosomal dominant polycystic kidney
disease: a position statement on behalf of the ERA-
EDTA Working Groups on Inherited Kidney Disorders
and European Renal Best Practice. Nephrol. Dial.
Transplant. 31, 337–348 (2016).
23. Grantham, J. J. Rationale for early treatment of
polycystic kidney disease. Pediatr. Nephrol. 30,
1053–1062 (2015).
24. Cornec‑Le Gall, E. et al. The PROPKD score: a new
algorithm to predict renal survival in autosomal
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 17
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
dominant polycystic kidney disease. J. Am. Soc.
Nephrol. 27, 942–951 (2016).
25. Schrier, R. W. et al. Predictors of autosomal dominant
polycystic kidney disease progression. J. Am. Soc.
Nephrol. 25, 2399–2418 (2014).
26. Hwang, Y. H. et al. Refining genotype-phenotype
correlation in autosomal dominant polycystic kidney
disease. J. Am. Soc. Nephrol. 27, 1861–1868 (2016).
27. Heyer, C. M. et al. Predicted mutation strength of
nontruncating PKD1 mutations aids genotype-
phenotype correlations in autosomal dominant
polycystic kidney disease. J. Am. Soc. Nephrol. 27,
2872–2884 (2016).
28. Cornec‑Le Gall, E. et al. Type of PKD1 mutation
influences renal outcome in ADPKD. J. Am. Soc.
Nephrol. 24, 1006–1013 (2013).
29. Iliuta, I. A. et al. Polycystic kidney disease without
an apparent family history. J. Am. Soc. Nephrol. 28,
2768–2776 (2017).
30. Barua, M. et al. Family history of renal disease
severity predicts the mutated gene in ADPKD.
J. Am. Soc. Nephrol. 20, 1833–1838 (2009).
31. Porath, B. et al. Mutations in GANAB, encoding the
glucosidase IIα subunit, cause autosomal-dominant
polycystic kidney and liver disease. Am. J. Hum. Genet.
98, 1193–1207 (2016).
32. Braun, D. A. & Hildebrandt, F. Ciliopathies.
Cold Spring Harb. Perspect. Biol. 9, a028191 (2017).
33. Song, X., Haghighi, A., Iliuta, I. A. & Pei, Y. Molecular
diagnosis of autosomal dominant polycystic kidney
disease. Expert Rev. Mol. Diagn. 13, 1–11 (2017).
34. Kinoshita, M. et al. Technical evaluation: identification
of pathogenic mutations in PKD1 and PKD2 in
patients with autosomal dominant polycystic kidney
disease by next-generation sequencing and use of a
comprehensive new classification system. PLoS ONE
11, e0166288 (2016).
35. Mallawaarachchi, A. C. et al. Whole-genome
sequencing overcomes pseudogene homology to
diagnose autosomal dominant polycystic kidney
disease. Eur. J. Hum. Genet. 24, 1584–1590 (2016).
36. Bergmann, C. et al. Mutations in multiple PKD genes
may explain early and severe polycystic kidney
disease. J. Am. Soc. Nephrol. 22, 2047–2056 (2011).
37. Cnossen, W. R. et al. LRP5 variants may contribute to
ADPKD. Eur. J. Hum. Genet. 24, 237–242 (2016).
38. Rossetti, S. et al. Incompletely penetrant PKD1 alleles
suggest a role for gene dosage in cyst initiation in
polycystic kidney disease. Kidney Int. 75, 848–855
(2009).
39. Losekoot, M. et al. Neonatal onset autosomal
dominant polycystic kidney disease (ADPKD) in a
patient homozygous for a PKD2 missense mutation
due to uniparental disomy. J. Med. Genet. 49, 37–40
(2012).
40. Ward, C. J. et al. The gene mutated in autosomal
recessive polycystic kidney disease encodes a large,
receptor-like protein. Nat. Genet. 30, 259–269
(2002).
41. Soroka, S. et al. Assessing risk of disease progression
and pharmacological management of autosomal
dominant polycystic kidney disease: a canadian expert
consensus. Can. J. Kidney Health Dis. 4,
2054358117695784 (2017).
42. Pei, Y. et al. Unified criteria for ultrasonographic
diagnosis of ADPKD. J. Am. Soc. Nephrol. 20,
205–212 (2009).
43. Tangri, N. et al. Total kidney volume as a biomarker of
disease progression in autosomal dominant polycystic
kidney disease. Can. J. Kidney Health Dis. 4,
2054358117693355 (2017).
44. Turco, D., Busutti, M., Mignani, R., Magistroni, R.
& Corsi, C. Comparison of total kidney volume
quantification methods in autosomal dominant
polycystic disease for a comprehensive disease
assessment. Am. J. Nephrol. 45, 373–379 (2017).
45. Grantham, J. J. & Torres, V. E. The importance of total
kidney volume in evaluating progression of polycystic
kidney disease. Nat. Rev. Nephrol. 12, 667–677
(2016).
46. Grantham, J. J., Chapman, A. B. & Torres, V. E. Volume
progression in autosomal dominant polycystic kidney
disease: the major factor determining clinical
outcomes. Clin. J. Am. Soc. Nephrol. 1, 148–157
(2006).
47. Grantham, J. J. et al. Volume progression in polycystic
kidney disease. N. Engl. J. Med. 354, 2122–2130
(2006).
48. Cadnapaphornchai, M. A. et al. Effect of pravastatin
on total kidney volume, left ventricular mass index,
and microalbuminuria in pediatric autosomal
REVIEWS
dominant polycystic kidney disease. Clin. J. Am. Soc.
Nephrol. 9, 889–896 (2014).
49. Serra, A. L. et al. Sirolimus and kidney growth in
autosomal dominant polycystic kidney disease.
N. Engl. J. Med. 363, 820–829 (2010).
50. Walz, G. et al. Everolimus in patients with autosomal
dominant polycystic kidney disease. N. Engl. J. Med.
363, 830–840 (2010).
51. Torres, V. E. et al. Angiotensin blockade in late
autosomal dominant polycystic kidney disease.
N. Engl. J. Med. 371, 2267–2276 (2014).
52. Caroli, A. et al. Effect of longacting somatostatin
analogue on kidney and cyst growth in autosomal
dominant polycystic kidney disease (ALADIN):
a randomised, placebo-controlled, multicentre trial.
Lancet 382, 1485–1495 (2013).
53. Stallone, G. et al. Rapamycin for treatment of type I
autosomal dominant polycystic kidney disease (RAPYD-
study): a randomized, controlled study. Nephrol. Dial.
Transplant. 27, 3560–3567 (2012).
54. Hogan, M. C. et al. Randomized clinical trial of long-
acting somatostatin for autosomal dominant polycystic
kidney and liver disease. J. Am. Soc. Nephrol. 21,
1052–1061 (2010).
55. Braun, W. E., Schold, J. D., Stephany, B. R.,
Spirko, R. A. & Herts, B. R. Low-dose rapamycin
(sirolimus) effects in autosomal dominant polycystic
kidney disease: an open-label randomized controlled
pilot study. Clin. J. Am. Soc. Nephrol. 9, 881–888
(2014).
56. Perico, N. et al. Sirolimus therapy to halt the
progression of ADPKD. J. Am. Soc. Nephrol. 21,
1031–1040 (2010).
57. Ruggenenti, P. et al. Safety and efficacy of long-acting
somatostatin treatment in autosomal-dominant
polycystic kidney disease. Kidney Int. 68, 206–216
(2005).
58. Kim, Y. et al. Automated segmentation of kidneys from
MR images in patients with autosomal dominant
polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 11,
576–584 (2016).
59. Spithoven, E. M. et al. Estimation of total kidney
volume in autosomal dominant polycystic kidney
disease. Am. J. Kidney Dis. 66, 792–801 (2015).
60. Perrone, R. D. et al. Total kidney volume is a prognostic
biomarker of renal function decline and progression to
end-stage renal disease in patients with autosomal
dominant polycystic kidney disease. Kidney Int.Rep. 2,
442–450 (2017).
61. Casteleijn, N. F. et al. Urine and plasma osmolality in
patients with autosomal dominant polycystic kidney
disease: reliable indicators of vasopressin activity and
disease prognosis? Am. J. Nephrol. 41, 248–256
(2015).
62. Torres, V. E., Bankir, L. & Grantham, J. J. A case for
water in the treatment of polycystic kidney disease.
Clin. J. Am. Soc. Nephrol. 4, 1140–1150 (2009).
63. Zittema, D. et al. Kidney function and plasma copeptin
levels in healthy kidney donors and autosomal
dominant polycystic kidney disease patients.
Clin. J. Am. Soc. Nephrol. 9, 1553–1562 (2014).
64. Boertien, W. E. et al. Relationship of copeptin, a
surrogate marker for arginine vasopressin, with change
in total kidney volume and GFR decline in autosomal
dominant polycystic kidney disease: results from the
CRISP cohort. Am. J. Kidney Dis. 61, 420–429 (2013).
65. Boertien, W. E. et al. Copeptin, a surrogate marker for
vasopressin, is associated with kidney function decline
in subjects with autosomal dominant polycystic kidney
disease. Nephrol. Dial. Transplant. 27, 4131–4137
(2012).
66. Corradi, V. et al. Copeptin levels and kidney function
in ADPKD: case-control study. Clin. Nephrol. 86,
147–153 (2016).
67. Meijer, E. et al. Copeptin, a surrogate marker of
vasopressin, is associated with disease severity in
autosomal dominant polycystic kidney disease.
Clin. J. Am. Soc. Nephrol. 6, 361–368 (2011).
68. Nakajima, A., Lu, Y., Kawano, H., Horie, S. & Muto, S.
Association of arginine vasopressin surrogate marker
urinary copeptin with severity of autosomal dominant
polycystic kidney disease (ADPKD). Clin. Exp. Nephrol.
19, 1199–1205 (2015).
69. Pejchinovski, M. et al. Urine peptidome analysis
predicts risk of end-stage renal disease and reveals
proteolytic pathways involved in autosomal dominant
polycystic kidney disease progression. Nephrol. Dial.
Transplant. 32, 487–497 (2017).
70. Salih, M. et al. Proteomics of urinary vesicles links
plakins and complement to polycystic kidney disease.
J. Am. Soc. Nephrol. 27, 3079–3092 (2016).
REVIEWS
71. Street, J. M., Koritzinsky, E. H., Glispie, D. M. &
Yuen, P. S. T. Urine exosome isolation and
characterization. Methods Mol. Biol. 1641, 413–423
(2017).
72. Hogan, M. C. et al. Identification of biomarkers for
PKD1 using urinary exosomes. J. Am. Soc. Nephrol.
26, 1661–1670 (2015).
73. Kistler, A. D. et al. Urinary proteomic biomarkers for
diagnosis and risk stratification of autosomal dominant
polycystic kidney disease: a multicentric study.
PLoS ONE 8, e53016 (2013).
74. Chapman, A. B., Stepniakowski, K. & Rahbari-Oskoui, F.
Hypertension in autosomal dominant polycystic kidney
disease. Adv. Chron. Kidney Dis. 17, 153–163 (2010).
75. Chapman, A. B. & Gabow, P. A. Hypertension in
autosomal dominant polycystic kidney disease.
Kidney Int. Suppl. 61, S71–S73 (1997).
76. Johnson, A. M. & Gabow, P. A. Identification of
patients with autosomal dominant polycystic kidney
disease at highest risk for end-stage renal disease.
J. Am. Soc. Nephrol. 8, 1560–1567 (1997).
77. Yu, A. S. et al. Trajectory of the GFR in autosomal
dominant polycystic kidney disease. J. Am. Soc.
Nephrol. 27, abstr., FR‑OR006 (2016).
78. Schrier, R. W. Hypertension and autosomal dominant
polycystic kidney disease. Am. J. Kidney Dis. 57,
811–813 (2011).
79. Ecder, T. Cardiovascular complications in autosomal
dominant polycystic kidney disease. Curr. Hypertens.
Rev. 9, 2–11 (2013).
80. Chapman, A. B. et al. Left ventricular hypertrophy in
autosomal dominant polycystic kidney disease.
J. Am. Soc. Nephrol. 8, 1292–1297 (1997).
81. Chapman, A. B., Johnson, A., Gabow, P. A. &
Schrier, R. W. The renin-angiotensin-aldosterone
system and autosomal dominant polycystic kidney
disease. N. Engl. J. Med. 323, 1091–1096 (1990).
82. Kip, S. N. et al. [Ca2+]i reduction increases cellular
proliferation and apoptosis in vascular smooth muscle
cells: relevance to the ADPKD phenotype. Circ. Res.
96, 873–880 (2005).
83. Rahbari-Oskoui, F., Williams, O. & Chapman, A.
Mechanisms and management of hypertension in
autosomal dominant polycystic kidney disease.
Nephrol. Dial. Transplant. 29, 2194–2201 (2014).
84. Hessheimer, A. J., Vidal, O., Valentini, M. & Garcia-
Valdecasas, J. C. Pheochromocytoma as a rare cause
of arterial hypertension in a patient with autosomal
dominant polycystic kidney disease: a diagnostic and
therapeutic dilemma. Int. J. Surg. Case Rep. 14,
85–88 (2015).
85. Hoorn, E. J. et al. A case of primary aldosteronism
revealed after renal transplantation. Nat. Rev. Nephrol.
7, 55–60 (2011).
86. Schrier, R. W. ACE inhibitors, left ventricular mass and
renal cyst growth in ADPKD. Pharmacol Res. 114,
166–168 (2016).
87. Nutahara, K. et al. Calcium channel blocker versus
angiotensin II receptor blocker in autosomal dominant
polycystic kidney disease. Nephron Clin. Pract. 99,
c18–c23 (2005).
88. Zeltner, R., Poliak, R., Stiasny, B., Schmieder, R. E.
& Schulze, B. D. Renal and cardiac effects of
antihypertensive treatment with ramipril versus
metoprolol in autosomal dominant polycystic kidney
disease. Nephrol. Dial. Transplant. 23, 573–579
(2008).
89. van Dijk, M. A., Breuning, M. H., Duiser, R.,
van Es, L. A. & Westendorp, R. G. No effect of enalapril
on progression in autosomal dominant polycystic
kidney disease. Nephrol. Dial. Transplant. 18,
2314–2320 (2003).
90. Ecder, T. et al. Diuretics versus angiotensin-converting
enzyme inhibitors in autosomal dominant polycystic
kidney disease. Am. J. Nephrol. 21, 98–103 (2001).
91. Kidney Disease: Improving Global Outcomes (KDIGO)
Chronic Kidney Disease Work Group. KDIGO 2012
clinical practice guideline for the evaluation and
management of chronic kidney disease. Kidney Int.
Suppl. 3, 1–150 (2013).
92. Klahr, S. et al. Dietary protein restriction, blood
pressure control, and the progression of polycystic
kidney disease. J. Am. Soc. Nephrol. 5, 2037–2047
(1995).
93. Appel, L. J. et al. Intensive blood-pressure control in
hypertensive chronic kidney disease. N. Engl. J. Med.
363, 918–929 (2010).
94. Ku, E. et al. Association between strict blood pressure
control during chronic kidney disease and lower
mortality after onset of end-stage renal disease.
Kidney Int. 87, 1055–1060 (2015).
18 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
95. Group, S. R. et al. A randomized trial of intensive
versus standard blood-pressure control. N. Engl.
J. Med. 373, 2103–2116 (2015).
96. Ruzicka, M., Burns, K. D. & Hiremath, S. Precision
medicine for hypertension management in chronic
kidney disease: relevance of SPRINT for therapeutic
targets in nondiabetic renal disease. Can. J. Cardiol.
33, 611–618 (2017).
97. Gansevoort, R. T. et al. Albuminuria and tolvaptan in
autosomal-dominant polycystic kidney disease: results
of the TEMPO 3:4 Trial. Nephrol. Dial.Transplant. 31,
1887–1894 (2016).
98. Akinbodewa, A. A., Adejumo, O. A.,
Ogunsemoyin, A. O., Osasan, S. A. & Adefolalu, O. A.
Co‑existing autosomal dominant polycystic kidney
disease and nephrotic syndrome in a Nigerian patient
with lupus nephritis. Ann. Afr. Med. 15, 83–86
(2016).
99. Yenigun, E. C. et al. Coexistence of autosomal
dominant polycystic kidney disease and amyloidosis
in a patient with nephrotic-range proteinuria.
Iran. J. Kidney Dis. 8, 243–245 (2014).
100. Torres, V. E. et al. Potentially modifiable factors
affecting the progression of autosomal dominant
polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 6,
640–647 (2011).
101. Torres, V. E. et al. Analysis of baseline parameters in
the HALT polycystic kidney disease trials. Kidney Int.
81, 577–585 (2012).
102. Torres, V. E. et al. Effect of tolvaptan in autosomal
dominant polycystic kidney disease by CKD stage:
results from the TEMPO 3:4 Trial. Clin. J. Am. Soc.
Nephrol. 11, 803–811 (2016).
103. Devuyst, O. et al. Urine osmolality, response to
tolvaptan, and outcome in autosomal dominant
polycystic kidney disease: results from the TEMPO 3:4
Trial. J. Am. Soc. Nephrol. 28, 1592–1602 (2017).
104. Casteleijn, N. F. et al. Tolvaptan and kidney pain in
patients with autosomal dominant polycystic kidney
disease: secondary analysis from a randomized
controlled trial. Am. J. Kidney Dis. 69, 210–219
(2017).
105. Torres, V. E. et al. Rationale and design of a clinical
trial investigating tolvaptan safety and efficacy in
autosomal dominant polycystic kidney disease.
Am. J. Nephrol. 45, 257–266 (2017).
106. Zand, L. et al. Renal hemodynamic effects of the
HMG-CoA reductase inhibitors in autosomal dominant
polycystic kidney disease. Nephrol. Dial. Transplant.
31, 1290–1295 (2016).
107. Namli, S. et al. Improvement of endothelial
dysfunction with simvastatin in patients with
autosomal dominant polycystic kidney disease.
Ren Fail 29, 55–59 (2007).
108. van Dijk, M. A., Kamper, A. M., van Veen, S.,
Souverijn, J. H. & Blauw, G. J. Effect of simvastatin
on renal function in autosomal dominant polycystic
kidney disease. Nephrol. Dial. Transplant. 16,
2152–2157 (2001).
109. Fassett, R. G., Coombes, J. S., Packham, D.,
Fairley, K. F. & Kincaid-Smith, P. Effect of pravastatin
on kidney function and urinary protein excretion in
autosomal dominant polycystic kidney disease.
Scand. J. Urol. Nephrol. 44, 56–61 (2010).
110. Brosnahan, G. et al. Effect of statin therapy on the
progression of autosomal dominant polycystic kidney
disease. A secondary analysis of the HALT PKD trials.
Curr. Hypertens. Rev. http://dx.doi.org/10.2174/1573
402113666170427142815 (2017).
111. Myint, T. M., Rangan, G. K. & Webster, A. C.
Treatments to slow progression of autosomal
dominant polycystic kidney disease: systematic review
and meta-analysis of randomized trials. Nephrology
19, 217–226 (2014).
112. van Keimpema, L. et al. Lanreotide reduces the
volume of polycystic liver: a randomized, double-blind,
placebo-controlled trial. Gastroenterology 137,
1661–1668.e2 (2009).
113. Hogan, M. C. et al. Somatostatin analog therapy for
severe polycystic liver disease: results after 2 years.
Nephrol. Dial. Transplant. 27, 3532–3539 (2012).
114. Meijer, E. et al. Rationale and design of the DIPAK 1
study: a randomized controlled clinical trial assessing
the efficacy of lanreotide to Halt disease progression
in autosomal dominant polycystic kidney disease.
Am. J. Kidney Dis. 63, 446–455 (2014).
115. Lantinga, M. A. et al. Hepatic cyst infection during use
of the somatostatin analog lanreotide in autosomal
dominant polycystic kidney disease: an interim
analysis of the randomized open-label multicenter
DIPAK‑1 study. Drug Saf. 40, 153–167 (2017).
116. Novalic, Z. et al. Dose-dependent effects of sirolimus
on mTOR signaling and polycystic kidney disease.
J. Am. Soc. Nephrol. 23, 842–853 (2012).
117. Hajarnis, S. et al. microRNA‑17 family promotes
polycystic kidney disease progression through
modulation of mitochondrial metabolism.
Nat. Commun. 8, 14395 (2017).
118. Yheskel, M. & Patel, V. Therapeutic microRNAs
in polycystic kidney disease. Curr. Opin. Nephrol.
Hypertens. 26, 282–289 (2017).
119. Knight, T. et al. Medical resource utilization and costs
associated with autosomal dominant polycystic kidney
disease in the USA: a retrospective matched cohort
analysis of private insurer data. Clinicoecon.
Outcomes Res. 7, 123–132 (2015).
120. Neuville, M., Hustinx, R., Jacques, J., Krzesinski, J. M.
& Jouret, F. Diagnostic algorithm in the management
of acute febrile abdomen in patients with autosomal
dominant polycystic kidney disease. PLoS ONE 11,
e0161277 (2016).
121. Hogan, M. C. & Norby, S. M. Evaluation and
management of pain in autosomal dominant polycystic
kidney disease. Adv. Chron. Kidney Dis. 17, e1–e16
(2010).
122. Chapman, A. B. et al. Autosomal-dominant polycystic
kidney disease (ADPKD): executive summary from a
Kidney Disease: Improving Global Outcomes (KDIGO)
Controversies Conference. Kidney Int. 88, 17–27
(2015).
123. Suwabe, T. et al. Clinical features of cyst infection and
hemorrhage in ADPKD: new diagnostic criteria.
Clin. Exp. Nephrol. 16, 892–902 (2012).
124. Chapman, A. B., Gabow, P. A. & Schrier, R. W.
Reversible renal failure associated with angiotensin-
converting enzyme inhibitors in polycystic kidney
disease. Ann. Intern. Med. 115, 769–773 (1991).
125. Lantinga, M. A. et al. International multi-specialty
delphi survey: identification of diagnostic criteria for
hepatic and renal cyst infection. Nephron 134,
205–214 (2016).
126. Lantinga, M. A., Drenth, J. P. & Gevers, T. J.
Diagnostic criteria in renal and hepatic cyst infection.
Nephrol. Dial. Transplant. 30, 744–751 (2015).
127. Lantinga, M. A., de Sevaux, R. G. & Drenth, J. P.
18F‑FDG PET/CT during diagnosis and follow‑up of
recurrent hepatic cyst infection in autosomal dominant
polycystic kidney disease. Clin. Nephrol. 84, 61–64
(2015).
128. Suwabe, T. et al. Intracystic magnetic resonance
imaging in patients with autosomal dominant
polycystic kidney disease: features of severe cyst
infection in a case-control study. BMC Nephrol. 17,
170 (2016).
129. Piccoli, G. B. et al. Positron emission tomography in the
diagnostic pathway for intracystic infection in adpkd
and “cystic” kidneys. a case series. BMC Nephrol. 12,
48 (2011).
130. Lantinga, M. A. et al. Management of renal cyst
infection in patients with autosomal dominant
polycystic kidney disease: a systematic review.
Nephrol. Dial. Transplant. 32, 144–150 (2017).
131. Suwabe, T. et al. Cyst infection in autosomal dominant
polycystic kidney disease: causative microorganisms
and susceptibility to lipid-soluble antibiotics.
Eur. J. Clin. Microbiol. Infect. Dis. 34, 1369–1379
(2015).
132. Nishiura, J. L. et al. Evaluation of nephrolithiasis in
autosomal dominant polycystic kidney disease
patients. Clin. J. Am. Soc. Nephrol. 4, 838–844
(2009).
133. Torres, V. E., Wilson, D. M., Hattery, R. R. &
Segura, J. W. Renal stone disease in autosomal
dominant polycystic kidney disease. Am. J. Kidney Dis.
22, 513–519 (1993).
134. Grampsas, S. A. et al. Anatomic and metabolic risk
factors for nephrolithiasis in patients with autosomal
dominant polycystic kidney disease. Am. J. Kidney Dis.
36, 53–57 (2000).
135. Umbreit, E. C. et al. Percutaneous nephrolithotomy for
large or multiple upper tract calculi and autosomal
dominant polycystic kidney disease. J. Urol. 183,
183–187 (2010).
136. Mallett, A., Patel, M., Tunnicliffe, D. J. & Rangan, G. K.
KHA-CARI autosomal dominant polycystic kidney
disease guideline: management of renal stone disease.
Semin. Nephrol. 35, 603–606.e3 (2015).
137. Penniston, K. L., Wertheim, M. L., Nakada, S. Y. &
Jhagroo, R. A. Factors associated with patient recall
of individualized dietary recommendations for kidney
stone prevention. Eur. J. Clin. Nutr. 70, 1062–1067
(2016).

138. Fink, H. A. et al. Medical management to prevent
recurrent nephrolithiasis in adults: a systematic review
for an American College of Physicians Clinical
Guideline. Ann. Intern. Med. 158, 535–543 (2013).
139. Casteleijn, N. F. et al. Novel treatment protocol for
ameliorating refractory, chronic pain in patients with
autosomal dominant polycystic kidney disease.
Kidney Int. 91, 972–981 (2017).
140. Miskulin, D. C. et al. Health-related quality of life in
patients with autosomal dominant polycystic kidney
disease and CKD stages 1‑4: a cross-sectional study.
Am. J. Kidney Dis. 63, 214–226 (2014).
141. Casteleijn, N. F. et al. A stepwise approach for effective
management of chronic pain in autosomal-dominant
polycystic kidney disease. Nephrol. Dial. Transplant. 29
(Suppl. 4), iv142–iv153 (2014).
142. World Health Organisation. Cancer pain relief: with a
guide to opiod availability — 2nd ed. (WHO, 1996).
143. Ballantyne, J. C., Kalso, E. & Stannard, C. WHO
analgesic ladder: a good concept gone astray. BMJ
352, i20 (2016).
144. Tellman, M. W., Bahler, C. D., Shumate, A. M.,
Bacallao, R. L. & Sundaram, C. P. Management of
pain in autosomal dominant polycystic kidney disease
and anatomy of renal innervation. J. Urol. 193,
1470–1478 (2015).
145. PKD Foundation forum. Living with PKD: pain relief and
medical marijuana. PKD Foundation http://forums.
pkdconnection.org/viewtopic.php?f=3&t=109 (2017).
146. Walsh, N. & Sarria, J. E. Management of chronic pain
in a patient with autosomal dominant polycystic kidney
disease by sequential celiac plexus blockade,
radiofrequency ablation, and spinal cord stimulation.
Am. J. Kidney Dis. 59, 858–861 (2012).
147. Loukas, M. et al. A review of the thoracic splanchnic
nerves and celiac ganglia. Clin. Anat. 23, 512–522
(2010).
148. Casteleijn, N. F., de Jager, R. L., Neeleman, M. P.,
Blankestijn, P. J. & Gansevoort, R. T. Chronic kidney
pain in autosomal dominant polycystic kidney disease:
a case report of successful treatment by catheter-
based renal denervation. Am. J. Kidney Dis. 63,
1019–1021 (2014).
149. Valente, J. F., Dreyer, D. R., Breda, M. A. &
Bennett, W. M. Laparoscopic renal denervation for
intractable ADPKD-related pain. Nephrol. Dial.
Transplant. 16, 160 (2001).
150. Chapuis, O., Sockeel, P., Pallas, G., Pons, F. &
Jancovici, R. Thoracoscopic renal denervation for
intractable autosomal dominant polycystic kidney
disease-related pain. Am. J. Kidney Dis. 43, 161–163
(2004).
151. Bhatt, D. L. et al. A controlled trial of renal denervation
for resistant hypertension. N. Engl. J. Med. 370,
1393–1401 (2014).
152. Haseebuddin, M. et al. Long-term impact of
laparoscopic cyst decortication on renal function,
hypertension and pain control in patients with
autosomal dominant polycystic kidney disease. J. Urol.
188, 1239–1244 (2012).
153. Millar, M. et al. Surgical cyst decortication in
autosomal dominant polycystic kidney disease.
J. Endourol. 27, 528–534 (2013).
154. Cook, N. R. et al. Long term effects of dietary sodium
reduction on cardiovascular disease outcomes:
observational follow‑up of the trials of hypertension
prevention (TOHP). BMJ 334, 885–888 (2007).
155. Torres, V. E. et al. Dietary salt restriction is beneficial
to the management of autosomal dominant polycystic
kidney disease. Kidney Int. 91, 493–500 (2017).
156. McMahon, E. J., Campbell, K. L., Bauer, J. D. &
Mudge, D. W. Altered dietary salt intake for people
with chronic kidney disease. Cochrane Database Syst.
Rev., CD010070 (2015).
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 19
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
157. Dougher, C. E. et al. Spot urine sodium measurements
do not accurately estimate dietary sodium intake in
chronic kidney disease. Am. J. Clin. Nutr. 104,
298–305 (2016).
158. Thomas, M. C. et al. The association between dietary
sodium intake, ESRD, and all-cause mortality in
patients with type 1 diabetes. Diabetes Care 34,
861–866 (2011).
159. Mente, A., O’Donnell, M. J. & Yusuf, S. Sodium and
cardiovascular disease — Authors’ reply. Lancet 388,
2113–2114 (2016).
160. O’Donnell, M. et al. Dietary sodium and
cardiovascular disease risk. N. Engl. J. Med. 375,
2404–2406 (2016).
161. O’Donnell, M., Mente, A. & Yusuf, S. Commentary:
Accepting what we don’t know will lead to progress.
Int. J. Epidemiol. 45, 260–262 (2016).
162. Campbell, N. R. Dissidents & dietary sodium:
concerns about the commentary by O’Donnell et al.
Int. J. Epidemiol. 46, 362–366 (2017).
163. Graudal, N., Jurgens, G., Baslund, B. &
Alderman, M. H. Compared with usual sodium intake,
low- and excessive-sodium diets are associated with
increased mortality: a meta-analysis. Am. J. Hypertens.
27, 1129–1137 (2014).
164. Vegter, S. et al. Sodium intake, ACE inhibition, and
progression to ESRD. J. Am. Soc. Nephrol. 23,
165–173 (2012).
165. Lambers Heerspink, H. J. et al. Moderation of dietary
sodium potentiates the renal and cardiovascular
protective effects of angiotensin receptor blockers.
Kidney Int. 82, 330–337 (2012).
166. Maroni, B. J., Steinman, T. I. & Mitch, W. E. A method
for estimating nitrogen intake of patients with chronic
renal failure. Kidney Int. 27, 58–65 (1985).
167. Ko, G. J., Obi, Y., Tortorici, A. R. & Kalantar-Zadeh, K.
Dietary protein intake and chronic kidney disease.
Curr. Opin. Clin. Nutr. Metab. Care 20, 77–85
(2017).
168. Kalantar-Zadeh, K. et al. North American experience
with low protein diet for non-dialysis-dependent
chronic kidney disease. BMC Nephrol. 17, 90 (2016).
169. Ma, Y. et al. A dietary quality comparison of popular
weight-loss plans. J. Am. Diet Assoc. 107, 1786–1791
(2007).
170. Levey, A. S. et al. Effect of dietary protein restriction
on the progression of kidney disease: long-term
follow‑up of the Modification of Diet in Renal Disease
(MDRD) Study. Am. J. Kidney Dis. 48, 879–888
(2006).
171. Fouque, D. & Laville, M. Low protein diets for chronic
kidney disease in non diabetic adults. Cochrane
Database Syst Rev, CD001892 (2009).
172. Boertien, W. E. et al. Short-term effects of tolvaptan
in individuals with autosomal dominant polycystic
kidney disease at various levels of kidney function.
Am. J. Kidney Dis. 65, 833–841 (2015).
173. Wang, C. J., Grantham, J. J. & Wetmore, J. B. The
medicinal use of water in renal disease. Kidney Int. 84,
45–53 (2013).
174. Barash, I., Ponda, M. P., Goldfarb, D. S. & Skolnik, E. Y.
A pilot clinical study to evaluate changes in urine
osmolality and urine cAMP in response to acute
and chronic water loading in autosomal dominant
polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 5,
693–697 (2010).
175. Wang, C. J., Creed, C., Winklhofer, F. T. &
Grantham, J. J. Water prescription in autosomal
dominant polycystic kidney disease: a pilot study.
Clin. J. Am. Soc. Nephrol. 6, 192–197 (2011).
176. Higashihara, E. et al. Does increased water intake
prevent disease progression in autosomal dominant
polycystic kidney disease? Nephrol. Dial. Transplant.
29, 1710–1719 (2014).
REVIEWS
177. Lacquaniti, A. et al. Apelin and copeptin: two opposite
biomarkers associated with kidney function decline
and cyst growth in autosomal dominant polycystic
kidney disease. Peptides 49, 1–8 (2013).
178. Kocer, D., Karakukcu, C., Ozturk, F., Eroglu, E. &
Kocyigit, I. Evaluation of fibrosis markers: apelin and
transforming growth factor‑β1 in autosomal dominant
polycystic kidney disease patients. Ther. Apher. Dial.
20, 517–522 (2016).
179. Helal, I. et al. Serum uric acid, kidney volume and
progression in autosomal-dominant polycystic kidney
disease. Nephrol. Dial. Transplant. 28, 380–385
(2013).
180. Kocyigit, I. et al. Serum uric acid levels and endothelial
dysfunction in patients with autosomal dominant
polycystic kidney disease. Nephron Clin. Pract. 123,
157–164 (2013).
181. Akiyama, K., Mochizuki, T., Kataoka, H., Tsuchiya, K.
& Nitta, K. Fibroblast growth factor 23 and soluble
Klotho in patients with autosomal dominant polycystic
kidney disease. Nephrology http://dx.doi.org/10.1111/
nep.12862 (2016).
182. Pavik, I. et al. Soluble klotho and autosomal dominant
polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 7,
248–257 (2012).
183. Pavik, I. et al. Secreted Klotho and FGF23 in chronic
kidney disease Stage 1 to 5: a sequence suggested
from a cross-sectional study. Nephrol. Dial. Transplant.
28, 352–359 (2013).
184. Meijer, E. et al. Association of urinary biomarkers with
disease severity in patients with autosomal dominant
polycystic kidney disease: a cross-sectional analysis.
Am. J. Kidney Dis. 56, 883–895 (2010).
185. Parikh, C. R. et al. Evaluation of urine biomarkers of
kidney injury in polycystic kidney disease. Kidney Int.
81, 784–790 (2012).
186. Harskamp, L. R. et al. Urinary EGF receptor ligand
excretion in patients with autosomal dominant
polycystic kidney disease and response to tolvaptan.
Clin. J. Am. Soc. Nephrol. 10, 1749–1756 (2015).
187. Zschiedrich, S. et al. Secreted frizzled-related protein
4 predicts progression of autosomal dominant
polycystic kidney disease. Nephrol. Dial Transplant 31,
284–289 (2016).
188. Ruggenenti, P. et al. Effect of sirolimus on disease
progression in patients with autosomal dominant
polycystic kidney disease and CKD stages 3b‑4.
Clin. J. Am. Soc. Nephrol. 11, 785–794 (2016).
Acknowledgements
M.B.L. is supported by the American Society of Nephrology
Jared J. Grantham fellowship.
Author contributions
Both authors contributed to all aspects of the preparation of
this manuscript.
Competing interests statement
A.B.C. declares an association with Otsuka Pharmaceutical
Group through membership of the TEMPO steering ­committee.
M.B.L. declares no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
DATABASES
ADPKD Mutation Database (PKDB): http://pkdb.mayo.edu/
Mayo Clinic ADPKD classification: http://www.mayo.edu/
research/documents/pkd-center-adpkd-classification/
doc-20094754
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