Improving treatment and imaging in ADPKD
van Gastel, Maatje Dirkje Adriana
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imaging in ADPKD
ISBN: 978-94-034-1505-5 (printed version)
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Financial support by the University Medical Center Groningen,
Graduate School of Medical Sciences and the University of Groningen
for the publication of this thesis is gratefully acknowledged.
Financial support for the printing of this thesis was also kindly provided
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Cover design: Gerard te Wierik
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Proefschrift
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 29 mei 2019 om 14.30 uur
door
Maatje Dirkje Adriana van Gastel
geboren op 21 november 1988
te Deventer
Prof. dr. R.T. Gansevoort Prof. dr. V.E. Torres
COPROMOTOR Dr. E. Meijer BEOORDELINGSCOMMISSIE Prof. dr. M.H. Breuning Prof. dr. R.H. Henning Prof. dr. S.P. Berger
PARANIMFEN
E. Cornec-le Gall, MD, PhD L.R. Harskamp, MDChapter 1 Introduction Part I. Treating ADPKD by influencing the vasopressin pathway
Chapter 2 PKD and the vasopressin pathway
Ann Nutr Metab 2017;70(suppl 1):43–50
Chapter 3 Modifiable factors associated with copeptin concentration:
a general population cohort
Am J Kidney Dis. 2015;65:719-727
Chapter 4 Modifiable factors associated with copeptin concentration
in ADPKD
Submitted
Chapter 5 Copeptin to predict disease progression and tolvaptan efficacy
in ADPKD
Kidney International. 2019, Epub ahead of print
Chapter 6 Case report: A thiazide diuretic to treat polyuria
induced by tolvaptan BMC Nephrol. 2018;19:157
Chapter 7 Sodium intake and vasopressin V2 receptor antagonism
versus disease progression in experimental PKD
In preparation 9 23 41 67 93 129 141
Chapter 8 T1 versus T2 weighted magnetic resonance imaging to assess total kidney volume in patients with ADPKD
Abdom Radiol (NY). 2018;43:1215-1222
Chapter 9 Estimation of total kidney volume in ADPKD
Am J Kidney Dis. 2015;66:792-801
Chapter 10 Automated segmentation of kidneys and liver in MR images of
patients affected by polycystic kidney and liver disease
J Am Soc Nephrol. Accepted for publication
Chapter 11 Summary, discussion and future perspectives
Addendum Nederlandse samenvatting / Dutch summary
Dankwoord / Acknowledgements List of publications 163 185 211 235 247 257 265
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary
kidney disease with a prevalence of 3 to 4 patients per 10,000 of the general population1.
The disease is characterized by cyst formation in both kidneys. Extra-renal symptoms include cardiac valve abnormalities and intracranial aneurysms, as well as cyst develop-ment in other organs, predominantly the liver with a prevalence of 94% in patients older
than 35 years2,3. Cyst formation is characterized by proliferation of tubular epithelial cells
and excessive fluid secretion4. This cyst formation leads to expansion of kidney size, and
leads to end-stage renal disease (ESRD) requiring renal replacement therapy in the ma-jority of patients. As shown in the magnetic resonance image (MRI) in Figure 1, kidney (and liver) growth can vary among patients, even within one family (patients C and D). Kidney volumes in healthy individuals are 202 ± 36 ml per kidney for men and 154 ± 33 ml
per kidney for women5.
ADPKD is most commonly caused by a mutation in the PKD1 and PKD2 gene, responsible
for approximately 85% and 15% of detected mutations. They encode for polycystin-1 (PC1) and polycystin-2 (PC2) respectively. The type of mutation is associated with prognosis. Patients with a mutation in the PKD1 gene generally have an earlier expression of disease and reach ESRD at a younger age than those with a mutation in the PKD2 gene, with
median ages of onset of ESRD of 58.1 and 79.7 years, respectively6. A truncating
muta-tion in the PKD1 gene causes a 12-year earlier onset of ESRD compared to patients with a non-truncating PKD1 mutation, with median ages of onset of ESRD of 55.6 versus 67.9
years, respectively6.
VASOPRESSIN AND ADPKD
The vasopressin pathway plays a pivotal role in the pathophysiology of ADPKD. Vaso-pressin is commonly known for its antidiuretic effects. This hormone binds to the vaso-pressin V2 receptor located in the kidney at the basolateral side of the principal cells in the collecting duct cells, leading to adenylyl cyclase 6 activation. This results in cyclic AMP-dependent protein kinase A activation that in turn phosphorylates aquaporin-2
(AQP2)4. Increased trafficking of AQP2 into the apical membrane results in water
reab-sorption in the kidney.
Vasopressin, measured by its surrogate marker copeptin, has shown to be associated
with disease severity and progression in ADPKD7-9. Treatment with a vasopressin V2
re-ceptor antagonist slowed disease progression in various animal models orthologous
to human cystic diseases10-12. In addition, the vasopressin V2-antagonist tolvaptan was
shown in the TEMPO 3:4 trial, which included 1,445 patients with ADPKD, to ameliorate
the rate of disease progression13. Tolvaptan lowered annual TKV growth from 5.5% to
10
pared to placebo, and is now approved by, among others, the European Medicines Agen-cy as fi rst drug that ameliorates the rate of disease progression in ADPKD.
During the TEMPO 3:4 trial aquaretic side-eff ects, like thirst (55.3%), polyuria (38.3%) and nocturia (29.1%) were more common in the tolvaptan treated group. These aquaretic side-eff ects led to treatment discontinuation in 8.3% of tolvaptan treated patients during this trial.
Figure 1. Variability of the disease progression. Patient A is a 26-year old male with a total kidney volume (TKV) of 7374 mL, total liver volume (TLV) of 1744 mL and an eGFR of 60 mL/ min/1.73m2, patient B is 36-year old female, with a TKV of 844 mL, TLV of 7660 mL and an
eGFR of 49 mL/min/1.73m2. Patient C and D show the variability within one family. These two sisters are 27 (C) and 33 (D) years of age, with a TKV of 1495 and 703 mL, TLV of 3171 mL and 2204 mL, and an eGFR of 117 and 118 mL/min/1.73m2, respectively.
11
12
The finding that tolvaptan ameliorated the rate of disease progression in ADPKD has con-firmed that the vasopressin pathway is detrimental in ADPKD. Given this line of evidence, it is of interest to study whether lowering vasopressin activity can also be achieved via lifestyle measures instead of tolvaptan, as this would imply that such lifestyle measures could potentially ameliorate the rate of disease progression in ADPKD. Furthermore, in-creasing tolerability of tolvaptan treatment by lowering its aquaretic side-effects as well as improvement of its treatment efficacy have become of interest now tolvaptan is mar-keted. Theoretically, lifestyle or drug interventions that lower the circulating vasopressin concentration could decrease tolvaptans aquaretic side-effects and potentially improve its efficacy. Other potential treatment modalities that could lower aquaretic side-effects of tolvaptan use are treatment options that have been proven to be effective in nephro-genic diabetes insipidus, where the vasopressin V2 receptor is dysfunctional, resulting in increased urine production as well.
RISK PREDICTION OF DISEASE PROGRESSION IN
ADPKD
Biomarkers that can identify patients with rapid disease progression in an early phase of the disease course have become increasingly important, especially now drug interven-tions that can ameliorate the rate of disease progression in ADPKD are available. This will enable selection of patients that have a rapid disease progression, and thus are most likely to benefit from drug intervention. Simultaneously, such markers may be of help to prevent unnecessary treatment of patients that will never reach ESRD in their life. As ADPKD leads to renal function decline, measurement of the glomerular filtration rate (GFR) appears to be a logical biomarker to assess disease severity and progression in ADPKD. However, measurements of GFR can be misleading to assess disease severity in ADPKD (Figure 2) as remaining glomeruli have a remarkable capacity to compensate for the loss of functioning nephrons, a phenomenon called hyperfiltration. Another can-didate biomarker would be total kidney volume (TKV). Cyst formation already starts in utero and continues throughout life. Importantly, TKV is already markedly increased by
the time the GFR decline becomes apparent14. A classification based on TKV adjusted
for height and age to predict the rate of disease progression has been introduced, and works reasonably well to select patients with a high likelihood of rapidly progressive disease.
Measurement of TKV is recognized by the American Food and Drug Administration and European Medicines Agency as an official biomarker for risk prediction in ADPKD. TKV meas-urement is most reliably done by manual tracing using magnetic resonance imag ing (MRI).
of TKV because of the short scanning time, low variations in image quality and higher contrast of the renal structures against the surrounding tissues compared to T1 weight-ed images without gadolinium15. When not using gadolinium contrast, T2 weightweight-ed im-ages might be preferred for the measurement of the TKV, because this technique shows high kidney tissue-contrast and hyperintense renal cysts in T2 weighted images and
would help to better delineate the kidney boundaries against background tissue16. MRI
techniques have developed over the last decades, and the single-shot turbo spin-echo technique was developed, being potentially more feasible to use for TKV assessment. This technique has a shorter examination time, fewer motion artifacts and ensures that all images are obtained from the same anatomic position regardless of the patients’
abil-ity to hold their breath17, making this technique potentially more feasible for manual TKV
measurement in ADPKD.
Figure 2. Natural history of PKD. A. Shows the natural growth of total kid-ney volume. B. Total kidkid-ney volume (red line) exhibits exponential growth at an average rate of 5% per year, presumably due to cyst epithelial cell proliferation and fl uid secretion, although this rate can vary widely from patient to patient19
13
14
1
Still, manual tracing of the kidneys is very laborious, limiting its applicability in clinicalcare. In case kidney volume could be estimated with sufficient accuracy and reliability, it would alleviate the time consuming process of kidney volume measurement. Recently, two kidney volume estimation methods have been developed: the mid-slice method by
the CRISP consortium18 and the ellipsoid method by the Mayo Clinic17. For both
meth-ods, measured and estimated kidney volumes appeared to be well correlated, but other groups have yet not validated these methods.
AIMS AND OUTLINE OF THIS THESIS
This thesis consists of two parts. In the first part of this thesis, the aim is to investigate whether the prognosis of ADPKD can be improved via lifestyle interventions that lower vasopressin concentration and via optimization of vasopressin antagonism. In the sec-ond part of this thesis the aim is to optimize total kidney and liver volume measurement in ADPKD to improve feasibility of this procedure in clinical practice.
Part I. Treating ADPKD by influencing the vasopressin pathway
Vasopressin plays a pivotal role in development and progression of ADPKD. Chapter 2 provides a comprehensive overview on the pathophysiological relation of vasopressin with ADPKD, as well as an overview of potential treatment options, by either antago-nizing the vasopressin V2 receptor using tolvaptan or lowering circulating vasopressin concentration by changing lifestyle factors that are known to physiologically influence vasopressin, like fluid and salt intake, but also other lifestyle factors.
Identification of modifiable factors that are associated with vasopressin concentration opens potential to treat patients with ADPKD by means of lifestyle changes. In Chapter 3 it is investigated which lifestyle factors are associated with vasopressin in a large gen-eral population cohort. Physiological stimuli of vasopressin release are factors that
influ-ence plasma osmolality20. Water and dietary sodium intake are the main determinants
of plasma osmolality20. It was therefore hypothesized that these two lifestyle factors
would be associated with vasopressin concentration. Vasopressin was assessed using its surrogate copeptin.
To verify whether these lifestyle factors also are associated with copeptin concentration in ADPKD patients, and to see whether there may be ADPKD specific associations of lifestyle factors with vasopressin, a similar study is performed specifically in this patient group in Chapter 4.
15
ed whether plasma copeptin levels, as marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy.
Exploring new treatment modalities for ADPKD and optimizing tolvaptan treatment are the scope of Chapters 6 and 7. Chapter 6 investigates whether lowering sodium intake,
as main stimulus for systemic vasopressin release20, could lower plasma vasopressin
concentration in two experimental models, of which one performed in the Mayo Clinic (Rochester, MN, USA). This would be of interest because a decrease in vasopressin con-centration could hypothetically ameliorate the rate of disease progression in ADPKD, as an increased vasopressin concentration is associated with disease severity and
pro-gression7-9. Furthermore, it can be hypothesized that lowering the agonist (vasopressin)
may increase the treatment efficacy of its antagonist, i.e. the vasopressin V2 receptor an-tagonist. In addition, a lower sodium intake (i.e. less osmolar intake) will lead to a lower plasma osmolality and consequently less thirst, leading to less fluid intake and thus less urine production. This may be of benefit for patients, as the excessive urine production during tolvaptan use is for most patients the most debilitating side-effect of this drug. The third hypothesis therefore is that combining a vasopressin V2 receptor antagonist with a low sodium diet will reduce aquaretic side-effects.
Blockade of the vasopressin V2 receptor physiologically resembles a situation in which the vasopressin V2 receptor is not functioning, such as in patients with nephrogenic dia-betes insipidus (NDI). In such patients hydrochlorothiazide (HCT) is known to reduce
polyuria by up to 50%21. Chapter 7 reports a patient that concomitantly used tolvaptan
and HCT in a patient with ADPKD. From this report interesting conclusions can be drawn with respect to the effectivity of CHT to lower tolvaptan induced polyuria, and whether this co-medication may have influence on the rate of eGFR decline.
Part II. Assessing ADPKD severity by MR imaging
TKV is an important parameter that enables detection of disease progression in ADPKD, even before GFR declines. New magnetic resonance imaging (MRI) techniques have been developed, leading to new imaging techniques with fewer artifacts that require less scanning time. The newer T2-single shot fast spin echo-technique has previously been suggested to be the preferred sequence for TKV assessment in ADPKD, as this technique shows high kidney tissue-contrast and hyperintense renal cysts, which may
help to better delineate the kidney boundaries against background tissue16. In Chapter 8
the hypothesis is studied that this new technique is preferable over the historically used T1-3D spoiled gradient echo-technique.
16
The gold standard for TKV measurement is manual segmentation of the whole kidney. Thus far, there is no validated alternative that performs equally to this laborious method. This limits the feasibility of TKV measurement in clinical care. Recently, two techniques
have been developed to estimate TKV in ADPKD patients17-18. In Chapter 9 these methods
are validated, hypothesizing that these techniques provide reasonably adequate TKV measurements that will not affect the risk prediction of disease progression in these patients.
However, there is still need for a more accurate methodology to assess TKV, especially for use in clinical trials. In Chapter 10, a validation study is described, that investigates the validity of the artificial deep neural network that was developed for fully automated assessment of TKV.
17 1. Willey CJ, Blais JD, Hall AK, et al. Prevalence of autosomal dominant polycystic kidney disease in the european
union. Nephrol Dial Transplant. 2017;32(8):1356-1363.
2. Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med. 1993;329(5):332-342.
3. Bae KT, Zhu F, Chapman AB, et al. Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: The consortium for radiologic imaging studies of polycystic kidney disease cohort. Clin J Am Soc Nephrol. 2006;1(1):64-69.
4. Torres VE, Harris PC. Mechanisms of disease: Autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol. 2006;2(1):40-55.
5. Cheong B, Muthupillai R, Rubin MF, et al. Normal values for renal length and volume as measured by magnetic resonance imaging. Clin J Am Soc Nephrol. 2007;2(1):38-45.
6. Cornec-Le Gall E, Audrezet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24(6):1006-1013.
7. Meijer E, Bakker SJ, van der Jagt EJ, et al. Copeptin, a surrogate marker of vasopressin, is associated with disease severity in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011;6(2):361-368.
8. Boertien W, Meijer E, Zittema D, et al. Copeptin, a surrogate marker for vasopressin, is associated with kid-ney function decline in subjects with autosomal dominant polycystic kidkid-ney disease. Nephrol Dial Transplant. 2012;27(11):4131-4137.
9. Boertien W, Meijer E, Li J, 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. 2013;61(3):420-429.
10. Gattone VH,2nd, Wang X, Harris PC, et al. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003;9(10):1323-1326.
11. Torres VE, Wang X, Qian Q, et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004;10(4):363-364.
12. Wang X, Gattone V,2nd, Harris PC, et al. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J Am Soc Nephrol. 2005;16(4):846-851. 13. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease.
N Engl J Med. 2012;367(25):2407-2418.
14. Grantham J, Chapman A, Torres V. Volume progression in autosomal dominant polycystic kidney disease: The major factor determining clinical outcomes. Clin J Am Soc Nephrol. 2006;1(1):148-157.
15. Bae KT, Tao C, Zhu F, et al. MRI-based kidney volume measurements in ADPKD: Reliability and effect of gadolinium enhancement. Clin J Am Soc Nephrol. 2009;4(4):719-725.
16. Bae KT, Grantham JJ. Imaging for the prognosis of autosomal dominant polycystic kidney disease. Nat Rev Neph-rol. 2010;6(2):96-106.
17. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of autosomal dominant polycystic kid-ney disease: A simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-172.
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18. Bae KT, Tao C, Wang J, et al. Novel approach to estimate kidney and cyst volumes using mid-slice magnetic reso-nance images in polycystic kidney disease. Am J Nephrol. 2013;38(4):333-341.
19. Antignac C, Calvet JP, Germino GG, et al. The future of polycystic kidney disease research--as seen by the 12 kaplan awardees. J Am Soc Nephrol. 2015;26(9):2081-2095.
20. Bourque CW. Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci. 2008;9(7):519-531.
21. Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol. 2015;11(10):576-588.
Lowering vasopressin concentration and
optimization of vasopressin antagonism in polycystic kidney disease treatment
Maatje D.A. van Gastel
Vicente E. Torres
ABSTRACT
Vasopressin, also known as AVP or antidiuretic hormone (ADH), plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease pro-gression in polycystic kidney disease (PKD), and in experimental studies vasopressin has shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2 receptor, or lower circulating vasopressin concentration, are poten-tial treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2 receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1445 patients with autosomal dominant polycystic kidney disease (ADP-KD), lowering total kidney volume growth from 5.5% to 2.8% and the slope of the recipro-cal of the serum creatinine level from -3.81 to -2.61 [mg per milliliter](-1)/year. Alterna-tively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake; other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. We also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, fluid intake in particular.
24
In this review, we summarize the current evidence about the pathophysiological rela-tion of vasopressin with the progression of polycystic kidney disease (PKD), and give a comprehensive overview of potential treatment options, by either blocking the effect of vasopressin using the kidney specific vasopressin V2 receptor antagonist tolvaptan or lowering circulating vasopressin concentration by changing lifestyle, fluid intake in particular. Due to the journal limitation regarding number of references allowed, we only included papers and reviews conducted in the last ten years.
PHYSOLOGICAL ACTIONS OF VASOPRESSIN
Arginine vasopressin or AVP is a hormone pivotal to maintain fluid homeostasis in the body, and is secreted after osmotic as well as hemodynamic stimuli. Vasopressin is well-known for its antidiuretic effects in the kidney, but also influences the vascular tonus and is involved in the regulation of the endocrine stress response. There are three pathways by which vasopressin is released. For this review the classical, and most well-known, pathway is relevant. Via this pathway, vasopressin is released directly into the circulation
in response to osmotic or hemodynamic stimuli1.
There are three different known receptors for vasopressin that are all part of the
sub-group rhodopsin, all G-protein-coupled receptors1. Via the V1a-receptor, present in many
tissues, vasopressin is known to influence hepatic glycogenolysis, platelet aggregation,
and vasoconstriction during hypovolemia1. The V1b-receptor is found in the
adenohypo-physis, where it influences ACTH secretion, which stimulates the synthesis and secretion of the adrenocortical hormones cortisol, androgens and aldosterone. The V2 receptor is mainly located in the collecting ducts and the thick ascending limbs of the loops of Henle
and plays a pivotal role in body homeostasis because of its antidiuretic effect1. Binding
of vasopressin to the V2 receptor in the collecting duct increases water permeability and sodium reabsorption, via activation of AQP-trafficking and the epithelial sodium channel
(ENaC) respectively2.
In 2006, copeptin was introduced as a biomarker for measurement of circulating vaso-pressin. At the time there was an unmet need to find a biomarker for vasopressin, since vasopressin is a small molecule that is unstable in plasma. Copeptin has been shown to be a reliable surrogate, and has been used in many studies in different fields, including
cardiovascular, renal and polycystic kidney disease3.
25
PATHOPHYSIOLOGICAL EFFECTS OF VASOPRESSIN
IN POLYCYSTIC KIDNEY DISEASE
Mutations in either the PKD1 and PKD2 gene cause autosomal dominant PKD (ADPKD),
whereas mutations in the PKHD1 gene cause autosomal recessive PKD (ARPKD). PKHD1
normally encodes the protein fibrocystin whereas PKD1 and PKD2 encode polycystin-1
(PC1) and polycystin-2 (PC2), respectively4. Both disorders are associated with cyst
for-mation in the kidney and are characterized by abnormal excessive fluid secretion, as well
as excessive proliferation and apoptosis of the tubular epithelial cells4.
Vasopressin is increased in patients with PKD, and the concentration of its surrogate
copeptin is associated with disease severity when analyzed cross-sectionally,5 as well
as disease progression measured longitudinally as kidney function decline and kidney
growth6,7. It has been shown that vasopressin directly regulates cyst growth in rats
orthologous to human ARPKD which phenotypically resembles human ADPKD. After breeding these rats with vasopressin deficient Brattleboro rats, it was shown that rats lacking vasopressin had lower levels of cAMP and that cystogenesis was inhibited almost completely. Administration of the vasopressin V2 receptor agonist DDAVP recovered the
full cystic phenotype in these Brattleboro rats8.
A urine concentrating defect is thought to be the cause of the increased vasopressin con-centration in PKD. Findings of a decreased urine concentrating capacity in an early phase
of ADPKD, before renal impairment occurs, strengthen this hypothesis9. When
analyzing this urine concentrating defect in more detail, Bankir et al. observed that this was a urea-selective concentrating defect by means of a lower urine/plasma (U/P)-urea ratio, whereas no difference in total U/P osmoles- or U/P sodium-ratios compared to healthy controls were observed. This defect is thought to originate in the disruption of the medullary architecture by cysts, which reduces the efficiency of countercurrent
ex-change of urea10.
Lowering the vasopressin effect on the kidney could potentially modify the disease course in ADPKD. This either could be accomplished by blocking the effects of vasopres-sin in the kidney uvasopres-sing a vasopresvasopres-sin V2 receptor specific antagonist like tolvaptan, or could be accomplished by lowering the circulating vasopressin concentration using life-style changes such as increased water intake. Recent preclinical studies suggest that additional drugs acting downstream from the vasopressin V2 receptor could enhance and possibly improve the tolerability of vasopressin V2 receptor antagonists and deserve further study. Evidence for these approaches is discussed in the following sections.
26
NEY DISEASE
The increased vasopressin and cAMP concentration associated with PKD formed the ra-tionale for exploring the effects of vasopressin V2 receptor antagonists (V2RA). Adminis-tration of V2RA OPC31260 led to a lowered renal cAMP, inhibited disease development, and either halted progression or caused regression of established disease in animal mod-els orthologous to the human ARPKD and nephronophthisis (NPH), as well as in mouse
models of ADPKD11.
In the TEMPO 3:4 Trial, a large randomized controlled study including 1,445 patients with ADPKD, tolvaptan slowed the disease progression of ADPKD after 3 years of treatment, by a lower total kidney volume growth of 2.8% annually versus 5.5% in placebo treated patients (P<0.001), as well as a decreased slope of the reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year, in
tolvap-tan versus placebo treated patients respectively12. Patients were eligible if they had an
estimated creatinine clearance of ≥60 ml/min. Recent post hoc analyses found similar
beneficial effects of tolvaptan in ADPKD across CKD stages 1-3,13 showed that
tolvap-tan use lowered albuminuria14 and monocyte chemotactic protein-1 (MCP-1) excretion,15
whereas it increased copeptin concentration,16 and that it significantly lowered the
inci-dence of kidney pain events from 16.8% to 10.1%, with a risk reduction of 36%17. A higher
albuminuria and a higher copeptin concentration at baseline both predicted renal func-tion decline in placebo- as well as tolvaptan-treated patients, and were both associated
with a stronger tolvaptan treatment effect14,16.
DRUGS WITH EFFECTS THAT ARE POTENTIALLY
SYN-ERGISTIC OR ADDITIVE TO THOSE OF TOLVAPTAN
Tolvaptan has been shown to slow disease progression in ADPKD by antagonizing the vasopressin V2 receptor in the kidney (Figure 1), lowering intracellular cAMP, and inhib-iting fluid secretion and cell proliferation. By interfering with aquaporin-2 (AQP2) traf-ficking, however, it induces aquaresis and enhances vasopressin release. Combining tolvaptan with treatments that lower cAMP or increase AQP2 in the apical membrane of principal cells could increase its efficacy and reduce the side effect of aquaresis (Figure 1). Long-acting somatostatin analogs acting on somatostatin receptors (SSTR) inhibit ade-nylyl cyclase and slow renal and hepatic cyst expansion in murine and small clinical trials of ADPKD. Hopp et al. found an additive efficacy of tolvaptan and pasireotide (a SSTR-1,
27
-2, -3 and -5 analogue) compared to either treatment alone, as well as less aquaresis in
the combination therapy compared to tolvaptan alone18.
Metformin inhibits complex 1 of the mitochondrial respiratory chain thus reducing ATP
production and increasing AMP19. AMP in turn directly inhibits adenylyl cyclase and
acti-vates AMPK. Inhibition of adenylyl cyclase20 and activation of phosphodiesterase 4B by
AMPK-mediated phosphorylation lower cAMP21. Furthermore, metformin via
AMPK-me-diated phosphorylation of AQP2 enhances its accumulation in the apical membrane and
reduces the aquaretic effect of tolvaptan22. Currently, two phase 2 studies are
investigat-ing the effect of metformin treatment on disease progression in ADPKD (Clinicaltrial.gov Identifiers: NCT02656017 and NCT02903511).
Statins and tetracycline antibiotics demeclocycline and doxycycline may also have syn-ergistic effects with tolvaptan. Statins may lower cAMP through downregulation of Gαs
protein23 and induce membrane accumulation of AQP2 via inhibition of endocytosis,24
thus reducing aquaresis. Demeclocycline decreases adenylate cyclase 5/6 expression
and, consequently, cAMP generation25. In animal studies doxycycline significantly
de-creased renal tubule cell proliferation and inhibited cystic disease progression in rats
or-thologous to human ARPKD26. However, the nephrotoxicity of these drugs when used at
high doses may limit their potential for the treatment of PKD; for example, doxycycline at a high dose was found to aggravate cyst growth and fibrosis in a mouse model of type
3 nephronophthisis27.
WATER INTAKE
Lowering vasopressin concentration and slowing disease progression in PKD by increas-ing water intake has been a topic of studies for many years. It should be noted that the effects of V2R antagonists and enhanced hydration are not identical (Table 1). Promising effects of increased water intake have been found by Nagao et al., who found in rats orthologous to human ARPKD that a high water intake decreased urinary vasopressin excretion by 68.3%, and the renal expression of vasopressin V2 receptors was decreased. High water intake slowed disease progression in both male and female rats, decreased kidney-to-body weight-ratio 29.8 and 27.0% respectively, and reduced serum urea
nitro-gen in the male rats from 38.7 to 26.3 mg/dl28. Similar results were obtained by Hopp
et al. in the same rat model,29 but not in a Pkd1 mouse model. In these rats, a fourfold
increase in urine output led to reductions in urine vasopressin and renal levels of cAMP, with a marked protective effect on the development of PKD, as reflected by lower kidney
weights, plasma urea, and cystic and fibrotic indexes29.
28
effects on disease progression have not yet been confirmed. In a pilot clinical study by Barash et al., 13 ADPKD patients were instructed to increase their water intake for seven days, resulting in average intake of 3.1 L/day. This caused a significant urine osmolality decline of 46% to 270 mOsm/L (P=0.04), lowering it below plasma osmolality, and thus
likely causing a decreased vasopressin concentration (not measured)30. Higashihara et al.
performed a study in 34 patients with ADPKD who received either a high or free water intake during one year, leading to mean 24-hour urine volumes of 2.6 versus 1.4 liter per day (P<0.001).
Table 1. Different effects of V2R antagonists and enhanced hydration (Bankir et al.2)
V1aR, vasopressin V1a receptor; V1bR, vasopressin V1b receptor
* Note that enhanced V1aR-mediated actions may not be harmful as is usually feared
Outcome Increase fluid intake V2R antagonists
Patient behavior Voluntary frequent drinking Taking a pill Adherence to treatment Poor (difficult to drink without
thirst)
Good (easy)
Plasma osmolality Decreased Increased
Vasopressin secretion and plasma level
Decreased Increased
Vasopressin effects mediated by other receptors (V1aR and
V1bR) *
Reduced Enhanced
Possible side effects Aversion to water, frequent need to urinate, risk of hyponatraemia
Thirst, frequent need to urinate, risk of dehydration
Financial costs None High
2
Figure 1.
Intracellular signaling in tubular cells of the collecting duct in ADPKD, and the role of vasopressin
2
(both P=0.02). However, non-significant trends towards faster eGFR decline (-5.6 mL/
min/1.73m2 vs. -1.1, P=0.06) and total kidney volume (TKV) growth (9.68 %/year vs. 5.28,
P=0.08), rather than a beneficial effect, were observed in the high compared to the free
water intake31. Finding no beneficial effects of an increased water intake in this study
might have been due to shortcomings of the study design. First, the study had only 34 participants, potentially leading to an underpowered statistical analysis. Second, for as-sessment of the primary endpoint, historical data was used. Third, participants were not randomized, but could enroll in the group they preferred, potentially leading to a selec-tion bias, as is reflected by a significantly higher 24-hour urine volume in the high water intake group at baseline. Finally, the high water intake group was instructed to drink - 50 mL water/kg body weight/day (2.5–3.0 L of water/day) or more, mostly during the first half of the day, which might not be enough to change the disease course and show a beneficial effect.
These inconclusive results suggest a need for future randomized controlled trials which study the effect of an increased fluid intake on disease progression in CKD and PKD in particular. Currently, there is an ongoing trial studying the effect of an increased fluid intake of 1-1.5L/day in CKD (Clinicaltrial.gov Identifier: NCT01766687), and another clinical trial in 180 ADPKD patients, of which half will have prescribed fluid intake to reduce urine
osmolality to ≤270 mOsm/kg32.
DIETARY FACTORS
Besides water intake, other lifestyle factors might influence the disease course of PKD by lowering the vasopressin concentration (Table 2). The recommendations in the KHA-CARI ADPKD Guideline for diet and lifestyle management are based on lifestyle modifica-tions that have proven to be effective in management of early CKD progression, as there is no evidence specific to ADPKD that would alter these recommendations. It includes a moderate protein diet (0.75-1.0 g/ kg/day), a restricted dietary sodium intake to 100 mmol/day (i.e. 2.3 g sodium or 6 g salt) or less, to drink fluid to satisfy thirst, and to stop
or not start smoking33.
In a large general population cohort, we previously found that a higher copeptin concen-tration was cross-sectionally associated with lower water intake (measured as 24-hour urine volume), higher 24-hour sodium and urea excretion (in steady state markers of sodium and protein intake), a lower 24-hour potassium excretion, higher number of
ciga-rettes smoked, as well as alcohol use and higher number of alcoholic consumptions34.
2
Non-linear relations between copeptin concentration and body mass index, as well as plasma glucose concentration, were observed.
In the CRISP study, involving 241 patients with ADPKD, high urine osmolality (a marker for AVP activity), high urine sodium excretion (a marker for sodium intake) and low
se-rum HDL-cholesterol were associated with the rates of TKV increase and eGFR decline35.
In a recent post hoc analysis of the HALT-PKD clinical trials, dietary sodium – measured as averaged sodium excretion – showed to be associated with the rate of TKV increase, but not with the rate of eGFR decline in ADPKD patients with an eGFR over 60 ml/min/1.73 m2. In patients with an eGFR 25-60 ml/min/1.73 m2 averaged sodium excretion was as-sociated with reaching a composite endpoint of 50% reduction of eGFR, ESRD or death,
and with a faster rate of eGFR decline36. Markers of vasopressin were not studied in the
HALT-PKD trials.
Protein intake, both a single meal and chronic high intake, is known to directly increase the circulating vasopressin concentration and simultaneously GFR. It changes the urea handling by the renal tubule, as the fractional excretion of urea is increased following a protein meal, and is thought to participate in glomerular hyperfiltration and kidney
hy-pertrophy37. As reviewed in the KHA-CARI Guideline, the only study investigating protein
intake in ADPKD was a secondary analysis of the MDRD Study analyzing 200 patients with ADPKD, where they found no clear benefit of low protein intake and decline in GFR. Meta-analyses in chronic kidney disease indicate either no effect or a modest benefit of
protein-restricted diets33.
Recently, a very promising pilot study treated 34 ADPKD patients with a low osmolar, water-adjusted diet and observed a lower copeptin concentration on this dietary regime. Patients received a low sodium (1,500 mg/d), low protein (daily protein dietary allow-ance, 0.8 g/kg body weight), and low urea (i.e., avoidance of preservatives, food addi-tives, bulking agents, and chewing gum) diet, combined with an individually-adjusted water intake, to ensure urine osmolality of 280 mOsm/kg or lower. After two weeks of treatment, patients had significantly lower plasma copeptin levels compared to non-treated patients (6.2±3.05 versus 5.3±2.5pmol/L, respectively; P=0.02). Total urinary sol-ute decreased in only the intervention group and significantly differed between groups
at week 1 (P=0.03)38.
2
Hypothetically, caffeine has a specific deleterious effect in PKD via phosphodiesterase (PDE) inhibition, but when analyzing the effects of caffeine intake in a case-control study in 102 ADPKD patients, no associations were found between coffee intake and eGFR or
TKV39. However, the majority of these patients (63%) had previously been advised to
low-er coffee consumption, and the mean coffee intake was significantly lowlow-er compared to
healthy controls (86±77 vs 134±116 mg/day, P≤0.001)39.
Nicotine is known to have an antidiuretic effect and causes an increased vasopressin con-centration. A history of smoking and pack-year of cigarettes smoked, were significantly
associated with rapid disease progression in ADPKD40. In ADPKD patients, smoking also
correlated with proteinuria and an increased risk of progression to end-stage renal
dis-ease (ESRD)41. A recent mouse study in Pkd1 mice revealed that smoking aggravated the
renal phenotype of these mice, thereby supporting the theoretical accelerating effect of
smoking on PKD-progression42.
Vasopressin was associated with obesity, metabolic syndrome and diabetes mellitus in
the Malmö Diet and Cancer Study cardiovascular cohort (n=2,064)43. In a separate, small
case-control study in subjects with preserved renal function, the presence of ADPKD was associated with components of metabolic syndrome such as hypertension, abdominal
obesity and higher fasting glycaemia44. Markers of vasopressin concentration were not
studied.
2
Study Model Lifestyle Study type Outcome measure(s) Main findings Nagao et al. (2006) 28 Rats ortholo -gous to human ARPKD W ater intake
Interventional animal study
Urinary A
VP excre
-tion, A
VP V2 receptor
expression, kidney-to- body-weight (%), SUN
Urinary A
VP excretion decreased 68.3%, A
VP V2 receptor expres
-sion normalized under high water intake, kidney-to-body-weight
decreased 29.8% and 27.0% in male and female rats, respectively, and
SUN decreased from 38.7 to 26.3 mg/dl in the male rats.
Hopp et al. (2015)
29
Rats ortholog. to human ARPKD and Pkd1
rc-mice
W
ater intake
Interventional animal study Urine output, plasma AVP, renal cAMP, kid
-ney weight, cyst and fibrosis, plasma urea
and creatinine
Urine output was increased by 4-fold and all studied parameters
were lower in rats on a high water intake. Despite a more than 7-fold increased urine output in
Pkd1
-mice, no significant differences on
any of the markers were observed.
Barash et al. (2010) 30 ADPKD patients W ater intake Interventional study
24-hour urine volume, urine osmolality
24-hour urine volume increased 64% (to 3.1 L), urine osmolality
decreased 46% (to 270±21 mOsm/L).
Higashi -hara et al. 2014) 31 ADPKD patients W ater intake Interventional study Plasma A VP and co
-peptin, eGFR decline,
TKV growth
Plasma A
VP and copeptin lower in high (HW) versus low water
(L
W) intake (both P=0.02), whereas no effect on eGFR decline (mL/
min/1.73m 2), being -5.6 HW vs. -1.1 L W (P=0.06) or TKV growth (9.68 HW vs. 5.28 L W; P=0.08) were observed. Torres et al. (2011) 35 ADPKD patients Sodium
and protein intake, HDL- chol., BSA,
BMI
Multicenter study, case series
TKV slope and eGFR
decline
excretion and low serum HDL-cholesterol were associated with TKV and eGFR slopes. Also baseline BSA, BMI, and estimated protein
intake were associated with TKV increase over time.
Torres et al. (2016)
36
ADPKD patients
Sodium intake (as sodium excretion) Post hoc analysis TKV growth, eGFR change and risk to reach composite
endpoints
Urine sodium excretion was significantly associated with TKV growth (P<0.001), and an non-significant trend for eGFR decline
(P=0.09). A
veraged urine sodium excretion was significantly associ
-ated with eGFR decline (P<0.001) with risk to reach the composite
end-point of 50% reduction in eGFR, ESRD or death.
Table 2.
Studies that suggest an association between lif
estyle f
actors and polycystic kidney disease progres
-2
Study Model Lifestyle Study type Outcome measure(s) Main findings Amro et al. (2016) 38 ADPKD patients
Low osmolar diet and ad
-justed water
intake
Randomized controlled trial
(pilot)
Plasma copeptin,
urine osmolality, and total urinary solute Mean plasma copeptin levels and urine osmolality declined from 6.2±3.05 to 5.3±2.5pmol/L (P=0.02) and from 426±193 to
258±117mOsm/kg water (P=0.01), respectively in the intervention group. T
otal urinary solute decreased in only the intervention group
and significantly differed between groups at week 1 (P=0.03).
Vendramini et al. (2012) 39 ADPKD patients Caffeine Cross-section -al study eGFR, TKV, hyperten -sion
Mean caffeine intake was significantly lower in ADPKD patients versus controls (86 vs 134 mg/day). No significant differences for
tertiles of coffee intake and eGFR, TKV or hypertension.
Ozkok et al. (2013)
40
ADPKD patients
Clinical char
-acteristics like smoking, hyperten
-sion and proteinuria Historical prospective study
Decline in GFR
Rapidly progressing patients had significantly higher history of
smoking (36 versus 18%, P=0.01) and pack years of smoking. A Cox regression did not confirm that smoking predicted progression of CKD in ADPKD patients (P=0.63), whereas age, presence of hepatic cysts, hypertension and proteinuria did (P=0.01, P=0.001, P=0.04 and
P=0.02, respectively). Orth et al. (1998) 41 ADPKD patients Smoking Case-control study Progression to ESRD
In smoking men (average pack years 16.9±20.2), a significant dose- dependent increase of the risk to progress to ESRD compared to
controls (average pack years 8.2±14.9) was found (p=0.001).
Veloso Sousa et al. (2016) 42 Pkd1 -deficient mice Smoking
Interventional animal study SUN, cystic index, renal fibrosis and cell proliferation
In
Pkd1
-mice, smoking increased SUN (57.2±32.4 vs 35.7±6.0 mg/dL,
p<0.05), the cystic index (17.4 vs 4.6%; P<0.05), renal fibrosis (1.1 vs 0.3%; P<0.0001) and cell proliferation in cystic epithelia (2.1 vs 1.1%;
P<0.05). Table 2. continued Abbreviations: ARPKD, Autosomal Recessive
Polycystic Kidney Disease;
AVP , Ar ginine Vasopressin; SUN, serum urea nitrogen; cAMP , cyclic adenosine monoph osphate; ADPKD, Autosomal Dominant Polycystic Kidney Disease; eGFR, estimated glome rular filtration rate; TKV , total kidney volume; HDL, high-density lipoproteins; BSA, body surf
ace area; BMI, body mass index; ESRD, end-stage renal disease
2
CONCLUSIONS
It is important that future studies focus on the relationship between increased fluid con-sumption and lowering osmolar intake on vasopressin concentration, and most impor-tantly the progression of PKD. If future research determines that reducing vasopressin concentration leads to slowed disease progression, other lifestyle factors, like smoking and obesity, should be studied because they are associated with increased vasopressin concentrations.
ACKNOWLEDGEMENTS
VET received from Danone Research the reimbursement of travel expenses and registra-tion fee to attend the H4H Scientific Conference.
2
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2
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38. Amro OW, Paulus JK, Noubary F, et al. Low-osmolar diet and adjusted water intake for vasopressin reduction in autosomal dominant polycystic kidney disease: A pilot randomized controlled trial. Am J Kidney Dis. 2016. 39. Vendramini LC, Nishiura JL, Baxmann AC, et al. Caffeine intake by patients with autosomal dominant polycystic
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2
a general population cohort
Maatje D.A. van Gastel
Esther Meijer
Lieneke E. Scheven
Joachim Struck
Stephan J.L. Bakker
Ron T. Gansevoort
Am J Kidney Dis. 2015;65(5):719-727ABSTRACT
Background: Vasopressin plays an important role in maintaining volume homeostasis.
Recent studies, however, suggest that vasopressin may also play a detrimental role in progression of chronic kidney disease. It is therefore of interest to identify factors that influence vasopressin concentration, particularly modifiable ones.
Methods: Data used are from participants in a large, general population cohort study
(PREVEND). Subjects with a missing copeptin value (n=888), a non-fasting blood sample (n=495), missing or assumed incorrect 24-hour urine collections (n=388) or with heart failure (n=20) were excluded, leaving 6,801 subjects for analysis. Copeptin concentration was measured by an immunoluminometric assay as a surrogate for vasopressin. Associa-tions were assessed in uni- and multivariable linear regression analyses.
Results: Median copeptin concentration was 4.7 (IQR 2.9-7.6) pmol/L. When copeptin
was studied as dependent variable, the final stepwise backward model revealed asso-ciations with higher copeptin concentration for: lower 24-hour urine volume (p<0.001), higher sodium excretion (p<0.001), higher systolic blood pressure (p<0.001), current smoking (p<0.001), higher alcohol use (p<0.001), higher urea excretion (p 0.003), lower potassium excretion (p 0.002), use of glucose lowering drugs (p 0.02), higher BMI and higher plasma glucose. No associations with copeptin concentration were found for C-reactive protein and use of diuretics or non-diuretic antihypertensives.
Conclusions: Important life style and diet related factors associated with copeptin
con-centration are current smoking, use of alcohol, protein and potassium intake, but par-ticularly fluid and sodium intake. These data form a rationale to investigate whether in-tervening on these factors results in lower vasopressin concentration with concomitant beneficial renal effects.
42
INTRODUCTION
Vasopressin plays an important role in the physiology of volume homeostasis. Recently, however, it became clear that vasopressin may also play a deleterious role in the
pro-gression of heart failure and particularly chronic kidney disease1-5. In cross-sectional
epi-demiological studies, performed in the general population and patients with diabetes, it has been shown that copeptin concentration (as a surrogate marker for vasopressin)
is associated with albuminuria and eGFR2,6-8. In addition to this epidemiological
evi-dence, it has been shown in intervention studies that infusion of synthetic vasopressin causes an increase in albuminuria, while lowering vasopressin activity by increasing
wa-ter intake or by vasopressin antagonists induced renoprotection in animal models3,9,10.
It is therefore of interest to determine which factors can influence plasma vasopressin concentrations, particularly modifiable ones, because by intervening on these factors it may be possible to ameliorate the detrimental effects associated with increased vaso-pressin concentration.
Vasopressin is secreted by the pituitary gland, primarily in response to increases in plas-ma osmolality. As a consequence, the kidney will retain water, which will result in a fall of plasma osmolality towards existing values. Plasma osmolality is dependent pre-dominantly on fluid and osmolar intake. In turn, the latter is determined by the intake of sodium and protein (as main determinant of plasma urea concentration). The acute effects of fluid, sodium and protein intake on vasopressin concentration have been well
studied9, 11-17. Less is, however, known of the effect of long-term stable sodium and
pro-tein intake on vasopressin concentrations. Besides these diet related factors, there are other life style factors, such as obesity, smoking, alcohol, and coffee use, of which it
has been suggested that they may influence vasopressin concentration18-22. The evidence
supporting a role of these factors is scarce and has generally been obtained in relatively small-scale studies, with a focus on single factors without adjustment for other factors,
and often with conflicting results18-21.
The measurement of vasopressin has been problematic for a long time because vaso-pressin is unstable in isolated plasma and most vasovaso-pressin assays have relatively limited sensitivity. Copeptin consists of the C-terminal portion of pro-vasopressin, the precursor of vasopressin, and is produced in equimolar amounts as vasopressin during precursor
processing23. Copeptin has been shown to be a relatively easily measurable, stable
sub-stitute for circulating vasopressin24-25.
43
Given the aforementioned considerations we investigated in an integrated manner in a large-scale observational, cross-sectional study which modifiable subject characteristics are associated with copeptin concentration.
MATERIAL AND METHODS
Study design and population
This investigation was conducted using data obtained in subjects who participate in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective cohort
study that started in 1997. Details of the study protocol have been published elsewhere26.
In summary, all inhabitants of the city of Groningen aged 28–75 years were sent a ques-tionnaire on demographics, disease history, smoking habits, use of medication and a vial to collect a first-morning-void urine sample. Of these subjects 40,856 responded (47.8%). From these subjects, the PREVEND cohort was selected with the aim to create a cohort enriched for subjects with higher albuminuria. After exclusion of patients with type 1 dia-betes mellitus (defined as requiring the use of insulin) and pregnant females (defined by self-report), all subjects with a urinary albumin concentration (UAC) of >10 mg/L (7,768) were invited, of which 6,000 participated. Furthermore, a randomly selected control group with a urinary albumin concentration of <10 mg/L (3,394) was invited, of which 2,592 participated. These 8,592 subjects constitute the PREVEND cohort and visited a re-search clinic for in-detail assessment of clinical characteristics, including blood and urine collection. For the present study, subjects from the PREVEND cohort with a missing co-peptin value (n=888), a non-fasting blood sample (n=495), missing or assumed incorrect 24-hour urine collections (n=388, see below) and with heart failure (n=20) were exclud-ed, leaving 6,801 subjects for the present analyses. Of these subjects 4,786 participants had at the initial screening a UAC >10 mg/L (70.4%) and 2,015 (29.6%) a UAC <10 mg/L. The PREVEND study was approved by the medical ethics committee of our institution and conducted in accordance with the International Conference of Harmonization Good Clinical Practice Guidelines and adheres to the ethical principles that have their origin in the Declaration of Helsinki.
Measurements and definitions
At baseline participants completed two visits at a screening facility for an extensive gen-eral work-up. They filled in a questionnaire on disease history, medication use and life style factors such as smoking, coffee and alcohol use. Height and weight were measured and body mass index (BMI) was calculated. Body surface area (BSA) was calculated
ac-cording to the Mosteller equation27. Blood pressure was measured on the right arm in
supine position, every minute for respectively 10 and 8 minutes on the first and second
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visit to our outpatient unit, with an automatic device (Dinamap XL Model 9300; Johnson-Johnson Medical, Tampa, FL., USA). Systolic blood pressure (SBP) was calculated as the mean of the last two measurements of each of the two visits. Two 24-hour urine samples were collected, after thorough oral and written instructions on how to perform such a urine collection, in which creatinine, sodium, urea and potassium were measured. Sub-jects were fasting from 12:00 pm onwards when they visited the PREVEND research clinic between 08:00 and 11:00 am where blood was drawn for measurement of copeptin, creatinine, cholesterol, glucose, albumin and high-sensitivity C-reactive protein. Thus, subjects had at least 8 hours not used coffee, alcohol or cigarettes.
We measured copeptin concentration in baseline samples of the PREVEND cohort us-ing a sandwich immunoassay (B.R.A.H.M.S. AG/ThermoFisher, Hennigsdorf, Germany), with a lower limit of detection of 0.4 pmol/l and a functional assay sensitivity (defined
as where the assay has a 20% inter-assay coefficient of variation) of less than 1 pmol28.
History of cardiovascular disease (CVD) was defined as self-reported myocardial infarc-tion, cardiac operainfarc-tion, percutaneous transluminal coronary angioplasty, or cerebrovas-cular accident. Information on specific drug use was obtained from the Inter-Action Da-ta-Base (IADB), which comprises pharmacy-dispensing data of community pharmacists
located in the northern regions of the Netherlands29. Included in our definition of diuretic
use were all agents mentioned under C03 of the Anatomical Therapeutic Chemical (ATC) classification system. The use of other antihypertensives was defined as all agents tioned under C02 of the ATC classification system, with the exception of agents men-tioned under C02L (antihypertensives and diuretics in combination). Subjects that used these latter agents were included in the diuretics group.
Serum creatinine concentration was used to calculate the estimated glomerular
filtra-tion rate (eGFR), using the CKD-EPI equafiltra-tion30.For the 24-hour urine volume, and sodium,
urea and potassium excretion, we used the mean volume or excretion of the aforemen-tioned analytes in the two 24-hour urine samples. We deliberately did not study overall urine osmolality because urine osmolality is determined by intake of fluid and osmoles, with intake of osmoles in turn being determined by intake of sodium, potassium and protein as source of urea. We studied these variables separately, to allow assessing their individual influence. For these food parameters the average of the two values at baseline was used. 24-hour urine collection was assumed to be incorrect in case the difference between expected and actually measured 24-hour urine volume was outside the 95% distribution range. The expected 24-hour urine volume was calculated by comparing cre-atinine clearance estimated by the Cockcroft-Gault (CG) formula and actual crecre-atinine clearance.
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