Heritability

The overall variance of the phenotype (V_P) is the sum of variation due to individual causes:

V_P=V_A+V_D+V_I+V _E

Here V_A is the variance due to additive genetic effects, V_D is the variance due to dominant genetic effects, V_I is the variance of interaction of the effect of genes at several loci, and V_E is the environmental variance.

Heritability (h²) is the extent to which genetic variation (V_G) between individuals explains the difference in the variation of phenotypic trait (V_P).³⁰Š—•ǡ‹–‹•†‡ϐ‹‡†ƒ•ǣ

h²=V_౲/V_P

Traditionally, this narrow-sense heritability was estimated on the basis of closely related individuals, but recently it has become possible to estimate single nucleotide polymorphism (SNP) -based heritability for a complex trait with the variance of unrelated individuals.³¹ Complex diseases arise due to several factors and dichotomizing variance into genetic and environmental has proven over simplistic.³⁰ No knowledge regarding heritability in AKI exists. Regarding complex traits, heritability was deemed missing because the bulk of causative variants were not found with genome wide association analyses.^32,33 Possible explanations for the missing heritability include: variants that are too rare to be detected in common variant genotyping arrays; structural variants; low power to detect gene-gene and gene-environment interactions; low power to detect very small effects of causal common variants; epigenetic effects;

and the underestimation of the heritability because of tagged SNPs used in association studies.^32,33 The effect of shared family environment and assortative mating may lead to overestimation of heritability, suggesting there is no missing heritability in complex diseases.^32,33

Ϯ͘Ϯ͘ϮŽŵƉůĞdžĚŝƐĞĂƐĞƐĂŶĚƚƌĂŝƚƐ

Human appearance and behavior is the result of hundreds of complex

2

thus appearing as missing heritability.³⁵ In Figure 2 the relation between allele frequencies and effect sizes is illustrated.

Most diseases are complex as opposed to Mendelian.²¹ Whereas a Mendelian disease is caused by a single genetic mutation in one or both of the alleles of a causative gene, complex diseases are products of a repertory of susceptibility factors with a small increase to the overall risk. Even if the effect of an individual genetic variant is small, combining the effects of several variants that associate with a trait may be used in a polygenic risk score.¹¹ The genetic variants may be detrimental or protective in relation to the disease. Patterns of inheritance for a variant sequence are regarded identically in both Mendelian and complex disease: in dominant inheritance a single risk allele causes the risk addition, whereas in recessive inheritance both alleles must be risk alleles in order for the risk to confer.

In codominant inheritance, the contribution of the alleles is additive.²¹ Evidence of genetic association in relation to complex diseases has existed for several decades.^8,38 Some established associations are with migraine^9,39,40 and diabetes.^8,41 Figure 3 describes the heritability of some investigated complex traits.

&ŝŐƵƌĞϯ͘ƐƟŵĂƚĞƐŽĨŚĞƌŝƚĂďŝůŝƚLJ;Ś²ͿƉĞƌĐĞŶƚĂŐĞĨŽƌĐŽŵƉůĞdžƚƌĂŝƚƐĂƐƉƌĞƐĞŶƚĞĚ ŝŶƉƌĞǀŝŽƵƐƐƚƵĚŝĞƐĂďŽƵƚĂŐĞͲƌĞůĂƚĞĚŵĂĐƵůĂƌĚĞŐĞŶĞƌĂƟŽŶ͕⁴²ƐLJƐƚĞŵŝĐůƵƉƵƐ ĞƌLJƚŚĞŵĂƚŽƐƵƐ͕⁴³ƚLJƉĞϮĚŝĂďĞƚĞƐ͕⁴⁴ĂŶĚ,>ĐŚŽůĞƐƚĞƌŽů͘^ϰϱ

,>͕ŚŝŐŚĚĞŶƐŝƚLJůŝƉŽƉƌŽƚĞŝŶ͘

Ϯ͘Ϯ͘ϯ'ĞŶĞƟĐƐƚƵĚLJĚĞƐŝŐŶƐ

Ϯ͘Ϯ͘ϯ͘ϭ>ŝŶŬĂŐĞƐƚƵĚŝĞƐ

In linkage analyses, the genetic markers are followed on their passage down the generations of a pedigree. Rather large families in which the

–”ƒ‹–‹••‡‰”‡‰ƒ–‡†ƒ”‡”‡“—‹”‡†ˆ‘”Ž‹ƒ‰‡ƒƒŽ›•‹•ǤŠ‡˜‡”›ϐ‹”•–†‹•‡ƒ•‡Ǧ causing genes were located with linkage design. The aim is to create a map of genetic signposts that are in close proximity to the disease-causing defect.²¹Š‡’”‘„ƒ„‹Ž‹–›‘ˆ”‡…‘„‹ƒ–‹‘„‡–™‡‡–™‘Ž‘…‹‹•“—ƒ–‹ϐ‹‡†

by their proximity and a logarithm of the odds (LOD) score is derived. When large, the LOD score indicates that the two loci are linked.²¹ Nonetheless, identifying susceptibility factors for complex diseases by using linkage analysis has shown little success.³³ Nowadays linkage analyses are less frequently used.

Ϯ͘Ϯ͘ϯ͘ϮƐƐŽĐŝĂƟŽŶƐƚƵĚŝĞƐ

In association studies, the hypothesis prevails that the genetic variant of 60

50 40 30 20 10

0 ŐĞͲƌĞůĂƚĞĚŵĂĐƵůĂƌ ĚĞŐĞŶĞƌĂƟŽŶ

^LJƐƚĞŵŝĐůƵƉƵƐ ĞƌLJƚŚĞŵĂƚŽƐƵƐ

dLJƉĞϮ diabetes

HDL cholesterol Heritability (h2, %)

2 in a sample of cases and controls for a given trait.²¹ The hypothesis can

be formulated according to experimental data and theory; however, even in the case of an evident association with the trait, causation cannot be assumed.²¹ It is of vital importance to replicate these kinds of results in an independent sample.²¹ The typical effect size of a risk allele detected to have an association with a trait is 1.1 for heterozygote genotypes and 1.5-1.6 for homozygote genotypes³⁴. However, with larger sample sizes and the ability to combine the datasets in a meta-analysis, even the variants that confer a very small risk can be detected.

Genome wide association studies (GWAS) screen a plethora of known variants within the genome in association to a trait, and thus provide data about associated variants without a preset hypothesis. The published GWAS studies can be searched by using a GWAS Catalog created by the National Human Genome Research Institute and the European Bioinformatics Institute (https://www.ebi.ac.uk/gwas/).⁴⁶ In April 2019, the catalog …‘–ƒ‹‡†͵Ԝͻʹ͵’—„Ž‹…ƒ–‹‘•™‹–ŠͺͺԜͲͻͷ•ƒ†ͳ͵ͶԜ͹Ͳͷƒ••‘…‹ƒ–‹‘•Ǥ The enabling resource behind hundreds of GWAS studies has been the UK biobank that offers open access to the genomic and health data of more

–ŠƒͷͲͲԜͲͲͲ‹†‹˜‹†—ƒŽ•Ǥ^47,48

Ϯ͘Ϯ͘ϯ͘ϯEŽǀĞůƐĞƋƵĞŶĐŝŶŐƚĞĐŚŶŽůŽŐŝĞƐ

In addition to revolutionizing developments in sequencing techniques, it

Šƒ• „‡…‘‡ ’‘••‹„Ž‡ –‘ ’”‘†—…‡ †ƒ–ƒ ‘”‡ ‡ˆϐ‹…‹‡–Ž› ƒ† ˆ‘” ƒ •ƒŽŽ‡”

cost than previously, hence the scale of sequencing has grown. Novel high-throughput sequencing methods are utilized in, for example, whole-genome, targeted-DNA, whole-transcriptome, and DNA-methylation-site sequencing.⁴⁹ The applications include the comparison of genomes of individuals globally and across human history, as well as targeted according to tissues or individual cells.⁴⁹ The usefulness of exome sequencing for diagnostic purposes has been supported,⁵⁰ moreover in association to kidney disease.⁵¹

Ϯ͘ϯhd</Ez/E:hZz;</Ϳ

Ϯ͘ϯ͘ϭZĞŶĂůĨƵŶĐƟŽŶ

The kidneys are organs with multiple functions of vital importance. In order to achieve body homeostasis, the kidneys must remove uremic retention solutes and foreign substances, regulate the balance of electrolytes and water in respect to plasma osmolality, and maintain acid-base balance.⁵² In addition, kidneys participate in regulating systemic blood pressure, stimulation of red blood cell production, gluconeogenesis, and synthesis of the active form of vitamin D.⁵²

‹†‡›•”‡…‡‹˜‡ʹͲΨ‘ˆ–Š‡”‡•–‹‰…ƒ”†‹ƒ…‘—–’—–ˆ‘”ϐ‹Ž–”ƒ–‹‘Ǥ⁵³ For a healthy individual with two kidneys, the functional capacity of the kidneys is adequate in most situations. Each kidney contains approximately 1 million functional units — nephrons.⁵² The ability of the kidneys to remove

™ƒ•–‡’”‘†—…–•‹•‘–…‘’”‘‹•‡†—–‹Žƒ•‹‰‹ϐ‹…ƒ–Ž‘••‘ˆ‡’Š”‘•†—‡

to injury.^54,55

Ž‘‡”—Žƒ”ϐ‹Ž–”ƒ–‹‘”ƒ–‡ȋ Ȍ†‡•…”‹„‡•–Š‡ϐ‹Ž–”ƒ–‡˜‘Ž—‡…”‡ƒ–‡†‹

a nephron over time.⁵² It is usually expressed as the rate in proportion to standardized body surface area.⁵⁶ Measuring GFR in an individual requires techniques that are invasive and sometimes cumbersome.^56,57 Creatinine is produced in the body from muscle creatine phosphate.⁵⁸‹†‡›•ϐ‹Ž–‡”

and secrete creatinine. In clinical use, serum creatinine is utilized for a computational estimate of GFR (eGFR). Such estimation according to an endogenous marker is feasible in a steady state^54,59 and is affected by factors besides GFR, such as tubular secretion and extrarenal elimination.⁵⁹ Formulas developed for this purpose are created and validated.^59–64 In addition to using serum creatinine as a surrogate marker for renal function, they account for variables such as age, gender, and race.^62,63 In AKI, neither the production nor elimination of creatinine are in steady state, and, thus, computational creatinine based eGFR formulas are not feasible.

Urine output has an indirect relation to GFR and thus cannot be regarded as an indicative measure of kidney function.^1,65 However, oliguria is frequent among the critically ill.^65,66 Using merely plasma creatinine for AKI diagnosis decreases the sensitivity for detecting AKI⁶⁵ and underestimates the severity of outcomes.⁶⁶

Ϯ͘ϯ͘Ϯ</ĚĞĮŶŝƟŽŶ

AKI syndrome encompasses the multiple etiologies that cause renal function to deteriorate over short period of time.¹ Patients with AKI present with accumulation of waste products, such as creatinine, and reduction in urine output.⁶⁷ Whether this is a sign of injury of the kidney tissue or impairment of the function in relation to the demand at hand, AKI is associated with decreased survival in mild to severe stages.^68,69

Š‡Žƒ–‡•–…‘•‡•—•†‡ϐ‹‹–‹‘ˆ‘”™ƒ•’—„Ž‹•Š‡†‹ʹͲͳʹ„›–Š‡

Acute Kidney Injury Work Group,¹ and was based on the previously validated Risk, Injury, Failure, Loss, End-stage disease (RIFLE) criteria⁷⁰ by the Acute Dialysis Quality Initiative (ADQI), and Acute Kidney Injury Network (AKIN) …Žƒ••‹ϐ‹…ƒ–‹‘Ǥ⁷¹ ‡ˆ‘”‡ –Š‡ •›•–‡ ˆ‘” †‹ƒ‰‘•‹• ƒ† …Žƒ••‹ϐ‹…ƒ–‹‘

2

‹…‡–Š‡™‘”‘ˆ–Š‡ǡ–Š‡…Žƒ••‹ϐ‹…ƒ–‹‘™ƒ•’—„Ž‹•Š‡†„›–Š‡

Acute Kidney Injury Network in an attempt to better discover the very

•ƒŽŽ…Šƒ‰‡•‹…”‡ƒ–‹‹‡ǡƒ†–‘‰‡‡”ƒ–‡ƒ‘”‹‰‹ƒŽ†‡ϐ‹‹–‹‘ˆ‘”–Š‡

syndrome with a spectrum wider than mere renal failure.⁷¹ However, both of these existing criteria were proven inadequate as they disregarded relevant patients.⁷⁵ By creating the clinical practice guideline for evaluation and management of AKI, the Acute Kidney Injury Work Group generated

ƒ —‹ˆ‘” †‡ϐ‹‹–‹‘ ƒ† ‰”ƒ†‹‰ •›•–‡ –‘ •—„•–‹–—–‡ –Š‡ ’”‡˜‹‘—•

†‡ϐ‹‹–‹‘•Ǥ¹

‹•…Žƒ••‹ϐ‹‡†‹–‘•‡˜‡”‹–›•–ƒ‰‡•ƒ……‘”†‹‰–‘…”‹–‡”‹ƒǤ¹ This …Žƒ••‹ϐ‹…ƒ–‹‘”ƒ‰‡•ˆ”‘•–ƒ‰‡ͳ–‘͵Ǥ‘”‡•‡˜‡”‡‹•ƒ••‘…‹ƒ–‡†™‹–Šƒ

worse outcome.^14,15,76 However, clinical judgement and interest towards the cause of AKI are warranted in addition to preset thresholds of diagnosis and stage of severity.¹

Ϯ͘ϯ͘ϯWĂƚŚŽƉŚLJƐŝŽůŽŐLJŽĨ</

As AKI is a complex syndrome presenting in differing clinical scenarios, no uniform pathophysiology exists.^6,7 Investigation of the pathology in

ƒ‹ƒŽ‘†‡Ž•Šƒ•—†‡”Ž‹‡†–Š‡†‹ˆϐ‹…—Ž–‹‡•‹‹‹…‹‰–Š‡ƒŽ–‡”ƒ–‹‘

in physiology in a different species.^55,77,78 However, common underlying injury processes of cellular depolarization, apoptosis, and necrosis,⁵⁵ as

™‡ŽŽ ƒ• ‹ϐŽƒƒ–‹‘⁷⁸ have been found to follow all forms of insult. In depolarization, the cells of the tubular endothelium lose their ability to function, but recovery is possible.⁵⁵ When more severe damage is encountered, the cells die either by energy consuming apoptosis or necrosis.⁵⁵

Sepsis is the most common underlying condition of acute deterioration of renal function in the ICU setting.^15,79,80 In a Finnish cohort of critically ill patients, the AKI incidence in septic patients was 53%.¹⁶ Sepsis-associated AKI (SA-AKI) is unique from AKI without sepsis in pathophysiology, timing, and outcomes.⁸⁰ However, our understanding of the SA-AKI pathophysiology is perpetually evolving.^7,80,81

The assumption of global renal hypoperfusion preceding septic AKI has been invalidated.^82,83 Moreover, renal circulation appears to be uncoupled form systemic hemodynamics and, thus, cannot be reliably predicted from it.⁸⁴ In addition, oxygen-dependent metabolism is globally preserved in animals with septic shock and AKI.⁸⁵ ‘’Ž‡š ‹–”ƒǦ”‡ƒŽ „Ž‘‘† ϐŽ‘™

changes suggests that regional distribution in microcirculation, along with patency and caliber of renal vessels, plays a role in AKI development.^86–88 Renal vascular resistance and interstitial edema due to vascular permeability, as well as vasoconstriction, vasodilation, and oxidative stress -induced endothelial dysfunction are regarded as possible contributors to the development of SA-AKI.⁸⁷

As sepsis entails a dysregulated host response,⁸⁹ the emergence of

ƒŽ–‡”ƒ–‹‘•‹‹ϐŽƒƒ–‹‘’ƒ–Š™ƒ›•ƒ†‹—‘Ž‘‰‹…’”‘ϐ‹Ž‡•ƒŽ‘‰–Š‡

spectrum are plausible.^87,90 In sepsis, the pathogen-associated molecules, and occasionally endogenous molecules from injured cells, are recognized

„› ’ƒ––‡”Ǧ”‡…‘‰‹–‹‘ ”‡…‡’–‘”•ǡ ƒ† ‹ϐŽƒƒ–‘”› ‰‡‡ –”ƒ•…”‹’–‹‘

is up-regulated.^87,91 A storm of cytokines follows, during which

pro-‹ϐŽƒƒ–‘”› ‡†‹ƒ–‘”• ƒ…–‹˜ƒ–‡ ‡†‘–Š‡Ž‹ƒŽ …‡ŽŽ• ƒ† ‹…”‡ƒ•‡ ˜ƒ•…—Žƒ”

permeability.⁸⁷ More leucocytes are recruited to the kidney by adhesion molecules on the endothelium.^87,88 The function of neutrophilic leucocytes

ˆ—”–Š‡” ’”‘‘–‡• –Š‡ ‹ϐŽƒƒ–‹‘ ”‡ƒ…–‹‘ǡ ™Š‹…Š ‹• ”‡•’‘•‹„Ž‡ ˆ‘”

some tissue damage.⁸⁷Š‡‹ϐŽƒƒ–‘”›‹Œ—”‹‡•‹‡†‘–Š‡Ž‹ƒŽƒ†”‡ƒŽ

tubular cells are considered key in the initiation of AKI.⁹²

Apoptosis is one suggested consequence of cellular injury in SA-AKI.^80,93 However, the histologic changes in SA-AKI have been heterogeneously distributed and without marked signs of apoptosis or necrosis.77,87,88,94,95 In addition, vacuolization is evident in these tubular cells that are subjected to oxidative stress, which is infrequent in SA-AKI.⁸⁷ They adapt to the lack of ATP (adenosine triphosphate) by entering cell-cycle arrest with orchestration from the mitochondria.^87,88 Subsequently, energy is withheld from futile functions, rendering renal function reduced.^87,88 Once injured, the tubular endothelium is dysfunctional for sodium reabsorption, thus triggering tubuloglomerular feedback, which by decreasing hydrostatic pressure in the glomerulus decreases GFR.⁸⁸

Major surgery is another substantial cause of AKI in hospitalized patients with varying incidence according to type of procedure.^7,96–98 The underlying etiological factors vary accordingly, including alterations in hemodynamics, exposure to toxins, ischemia-reperfusion injury, embolization of the renal artery, neurohormonal responses to hypotension

ƒ†–‹••—‡‹Œ—”›ǡ‹ϐŽƒƒ–‹‘ǡƒ†‘š‹†ƒ–‹˜‡•–”‡••Ǥ⁷ A designated entity is cardiac surgery-associated AKI (CSA-AKI), which is the second most common type of AKI in the ICU setting.⁹⁹ The pathophysiology of CSA-AKI is multifactorial and incompletely understood.⁹⁹ When cardiopulmonary bypass (CPB) is used, the perfusion is non-pulsatile, there is hemodilution and temperature changes.⁹⁹ Intravascular hemolysis can develop because of CPB and cause tubular epithelial cell injury when free hemoglobin is present.⁹⁹ After CPB, there is a risk of ischemia-reperfusion injury, with

’”‘†—…–‹‘‘ˆ”‡ƒ…–‹˜‡‘š›‰‡•’‡…‹‡•ƒ†‹ϐŽƒƒ–‹‘Ǥ⁹⁹

Nephrotoxic exposure is the predisposing factor in 15% to 19% of ICU patients with AKI.^15,79 Biological effects vary between nephrotoxins, which can be both exogenous and endogenous.⁷ In cisplatin-induced injury the

2 media.¹⁰¹ The pathophysiology of CI-AKI is recognized to include both toxic

effects on tubular cells and hemodynamic alterations, resulting in reduced renal perfusion.¹⁰¹ Excess accumulation of endogenous substances, such as myoglobin which is released to bloodstream in rhabdomyolysis, contribute to AKI formation in mechanisms that may include oxidative stress and vascular alterations.^102,103

The necessity of classifying AKI into clinical sub-phenotypes has been claimed.⁷•—„Ǧ’Š‡‘–›’‡•™‹–Š†‹•–‹…–‘—–…‘‡•Šƒ˜‡„‡‡‹†‡–‹ϐ‹‡†

using a latent class-analysis approach that modelled predetermined baseline clinical data and circulating plasma biomarkers involved in

‡†‘–Š‡Ž‹ƒŽ†›•ˆ—…–‹‘ǡƒ†‹ϐŽƒƒ–‹‘ƒ†ƒ’‘’–‘•‹•’ƒ–Š™ƒ›•Ǥ¹⁰⁴ Of note, the potentially reversible causes of AKI, such as renal artery

‘……Ž—•‹‘ǡ ‹ϐŽƒƒ–‘”› ‹†‡› ’ƒ”‡…Š›ƒŽ †‹•‡ƒ•‡•ǡ ‘” ‘„•–”—…–‹‘ ‹

the urinary tract, should be determined and treated to avoid irreversible damage to the kidneys.¹

2.3.4 Risk factors for AKI

Multiple predisposing factors for AKI are recognized, and these frequently occur coincidentally. The most common underlying insults resulting in ‹ Š‘•’‹–ƒŽǦƒ†‹––‡† ’ƒ–‹‡–• ƒ”‡ •‡’•‹•ǡ ‹ϐŽ—‡…‡ ‘ˆ ƒ ‡’Š”‘–‘š‹…

agent, and reduced circulation to the kidneys in situations such as major surgery.¹⁵ In addition, several susceptibilities can increase the risk of AKI.

Chronic comorbidities are associated with increased risk of developing AKI. The most evidence to this extent is in relation to chronic kidney disease (CKD), which is an independent risk factor for AKI.^1,14,105 Patients with diabetes have an increased risk of AKI.^1,106,107 AKI is more common in patients with liver failure¹⁰⁸ or heart failure.¹⁰⁷ Patients with cancer are at increased risk for AKI, partially because of tumor lysis syndrome in association with a high tumor burden or cell turnover.¹⁰⁹

Advanced age is associated with higher risk of AKI.15,106,107,110 In addition, AKI is more prevalent in people of African descent.^106,111 Pre-ICU hypovolemia has been presented to independently increase risk for AKI.^1,14

‘™‡˜‡”ǡ…‘‰‡•–‹‘†—‡–‘‡š…‡••‹˜‡ϐŽ—‹†ƒ†‹‹•–”ƒ–‹‘Šƒ•ƒŽ•‘„‡‡

highlighted.¹¹² High risk surgery and emergency surgery increase the risk of AKI.¹⁰⁷ Nephrotoxicity by drugs such as antibiotics and diuretics,14,106,107,110

and pre-ICU use of colloids¹⁴ have been found to predispose to AKI. Female

‰‡†‡”Šƒ•„‡‡‹†‡–‹ϐ‹‡†ƒ•ƒ”‹•ˆƒ…–‘”ˆ‘”ǡ¹ however recently this

Šƒ•„‡‡†‡„ƒ–‡†‹”‡Žƒ–‹‘–‘…‘ϐŽ‹…–‹‰”‡•—Ž–•‹‡š’‡”‹‡–ƒŽƒ‹ƒŽ

models.¹¹³

Early recognition of AKI risk is advantageous in possibly preventing the onset of the condition. Thus, risk prediction tools that combine clinical data have been researched.¹¹⁴ In developing a risk prediction model, the challenges lie in choosing the predictors and evaluating how the model

performs.¹⁰ The models developed thus far^115–117 have provided average performance (positive predictive value range from 23% to 38%) and the chosen predictors are heterogeneous.¹¹⁴

Ϯ͘ϯ͘ϱ</ĞƉŝĚĞŵŝŽůŽŐLJ

AKI syndrome is a frequent complication to other conditions, especially in critically ill patients.¹¹⁸ In critically ill patients the AKI incidence is 36-67%.14,15,69,73,106 The global incidence of AKI has been steadily increasing.¹¹⁹ In hospitalized adult patients, the pooled incidence is approximately 20%.^12,13 In low-to-middle-income countries, the patients are generally younger and AKI is the result of a single noxa, whereas in high-income countries the patients are older and commonly have an underlying severe illness.^118,120 In addition, the treatment modalities and delay to their onset frequently hampers the care of AKI in low-to-middle-income countries.^118,121

AKI is associated with adverse outcomes, both short and long term, in regard to patients and the kidneys.¹¹⁸ AKI is an independent predictor of in-hospital mortality,15,69,73,108 as well as mortality at 90 days^14,122,123 and at 1 year.14,106,122,124 The long term survival after AKI has been deemed poor,¹²⁵ as the patients are at increased risk for death after discharge from ICU and hospital.¹⁰⁵ This risk is, however, mostly determined by age and pre-existing comorbidities,¹²⁶ and even a dialysis-requiring AKI episode may not independently hamper long-term survival.¹²⁷ For AKI survivors, the perceived health-related quality-of-life (HRQL) is acceptable or similar in comparison to survivors without AKI,^105,128 and renal recovery happens in the majority of the cases.¹⁰⁵ Although the HRQL decreases in relation to the general population, most AKI survivors would undergo similar treatment again if needed.¹²⁸

In order to recover from AKI, kidney tubular epithelium is mandated to undergo proliferation, in which stem cells and growth factors are denoted in animal models.⁵⁵ The degree of renal recovery can be assessed by determining renal functional reserve, which describes the capacity of

–Š‡‹†‡›•–‘‹…”‡ƒ•‡ ƒ•‡‡†‡†„›Š›’‡”ϐ‹Ž–”ƒ–‹‘‹–Š‡”‡ƒ–

nephrons.⁵⁴ When renal recovery is not achieved, patients remain dialysis dependent. In addition, distinct recovery phenotypes are associated with long term outcomes.⁵ Risk of requiring maintenance dialysis is increased when renal replacement therapy (RRT) is necessitated in the acute phase.¹²⁷ Moreover, AKI is associated with increased risk of chronic kidney disease and end-stage renal failure.^122,129

2 2 Ϯ͘ϯ͘ϲ</ƚƌĞĂƚŵĞŶƚŵŽĚĂůŝƟĞƐ

No known curative treatment for AKI exists.¹³³ Hence, prevention is of vital importance. Known risk factors confer a major proportion, especially in the younger age groups of the critically ill.¹⁰⁶ Avoidance of nephrotoxic agents

„›‹†‹˜‹†—ƒŽǦŽ‡˜‡Ž•–”ƒ–‹ϐ‹…ƒ–‹‘ƒ†—–‹Ž‹œƒ–‹‘‘ˆ’”‡˜‡–‹˜‡•–”ƒ–‡‰‹‡•‹•

suggested.¹⁰¹

Optimizing hemodynamics and volume status is a well-intentioned

‰‘ƒŽǡ Š‘™‡˜‡” Šƒ”† –‘ ƒ……‘’Ž‹•Š ™‹–Š –Š‡ †‹ˆϐ‹…—Ž– –ƒ• ‘ˆ †‡–‡”‹‹‰

optimal for existing kidney circumstance. Fluid overload is potentially harmful for critically ill patients, as is untreated hypovolemia.^134,135 The optimal solution to replenish the volume shortage has been under debate, with the strongest evidence for the majority of patients in favor of buffered salt solutions, and against synthetic colloids, that have been proven unsafe and not superior to crystalloids.^134,135

For established AKI, the pharmacological interventions have generally proven otiose. Diuretics are not recommended in prevention or treatment of AKI.^1,133 Alkaline phosphatase has been experimentally administered

–‘ •‡’–‹… ’ƒ–‹‡–• ™‹–Š …‘ϐŽ‹…–‹‰ ‡ˆˆ‡…–• ‘ ”‡ƒŽ ˆ—…–‹‘Ǥ^87,136,137 No medication is accepted for clinical use in AKI treatment. Elimination of

‡†‘–‘š‹ƒ†‹ϐŽƒƒ–‘”›‡†‹ƒ–‘”•‹Ǧ„›Š‡‘Ǧƒ†•‘”’–‹‘Šƒ•

been experimentally established.⁸⁷

The use of renal replacement therapy (RRT) in the critically ill is common.¹⁵ Several uncertainties remain, nonetheless, about the optimal administration and timing of RRT in AKI.¹³⁸ The conventional indications of initiating RRT include acidosis, hyperkalemia, uremic symptoms, oliguria or anuria, and volume overload; however, it is suggested that initiation of

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3 AIMS OF THE STUDY

The objective of this study was to investigate whether selected genetic variants associate with the risk to develop acute kidney injury in adult patients in an intensive care unit setting.

Š‡•’‡…‹ϐ‹…ƒ‹•‘ˆ–Š‹••–—†›™‡”‡ǣ

1. To systematically review the current literature for genetic predisposition to AKI (I)

2. To evaluate the quality of published studies (I)

3. ‘…‘ϐ‹”‘””‡ˆ—–‡–Š‡’”‡˜‹‘—•ϐ‹†‹‰•”‡‰ƒ”†‹‰•‡Ž‡…–‡†

variants in genes related to 3.1. apoptosis (II)

3.2. iron metabolism (III) 3.3. ‹ϐŽƒƒ–‹‘ȋȌǤ

3, 4

4 MATERIALS AND METHODS

4.1 PATIENTS

Patients in Studies II–IV were from the prospective, observational Finnish Acute Kidney Injury (FINNAKI) study. Seventeen Finnish ICUs took part in this multicenter study between September 1^st, 2011 and February 1^st, 2012. In addition to the main cohort, an extended cohort was enrolled until April 30^th to achieve the desired number of patients with sepsis. For the genetic study, 2968 patients gave their consent. After 122 DNA samples failed in isolation, 2846 patients were included for genetic association analyses. In addition, there were some samples with low success rate in each assay, which led to exclusion of these patients from the analysis.

Patients with emergency ICU admission of any duration or elective admission with an expected stay of more than 24 hours were included in the FINNAKI study. Conversely, patients were excluded from the study if they were under 18 years-of-age, re-admitted with RRT in previous admission, on maintenance dialysis, organ donors, without permanent

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another ICU after full (5 days) participation, or in intermediate care. For patients with multiple admissions during the study period, the admission with the highest KDIGO stage was chosen for the study.

For Studies II and III, the patients with known or suspected CKD and KDIGO Stage 1 AKI were excluded; for Study III, only patients with sepsis were included; and for Study IV, the entire cohort was included.

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patient characteristics for the entire FINNAKI genetic study as well as for Studies II–IV.

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4

ϰ͘ϭ͘ϭŝĂŐŶŽƐƟĐĚĞĮŶŝƟŽŶƐ

ϰ͘ϭ͘ϭ͘ϭĐƵƚĞŬŝĚŶĞLJŝŶũƵƌLJ

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ϐ‹Ž–”ƒ–‹‘ǡƒ•‡˜‹†‡–„›ƒ……——Žƒ–‹‘‘ˆ™ƒ•–‡’”‘†—…–•ƒ††‡…”‡ƒ•‡‹

urine output, according to KDIGO criteria.¹ Plasma creatinine was measured

urine output, according to KDIGO criteria.¹ Plasma creatinine was measured

In document Genetic predisposition to acute kidney injury in critically ill adults (sivua 18-0)