Čimbenici rizika i etiologija kronične bubrežne bolesti nakon transplantacije jetre [Chronic kidney disease afther liver transplantation - risk factor and etiology]

Mrzljak, Anna (2010) Čimbenici rizika i etiologija kronične bubrežne bolesti nakon transplantacije jetre [Chronic kidney disease afther liver transplantation - risk factor and etiology]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Background: Chronic kidney disease (CKD) is a significant complication after liver transplantation (LT) which affects patients’ survival. Therefore it is important to identify and influence risk factors that negatively affect kidney function. Hypothesis of the thesis is that CKD is frequent after LT and that calcineurin inhibitors (CNIs) are the major leading cause. The goals of this study were to determine incidence of newly developed CKD, to identify the risk factors, to investigate clinical course and to determine the etiology of CKD after LT. Methods: Hundred and ninety seven liver recipients without preexisting CKD transplanted in KB Merkur between 2005. and 2010. were analyzed. CKD after LT was defined as decreased estimated glomerular filtration rate (eGFR) <60 ml/min/1,73m2 for at least three consecutive months using Modification in Renal Disease (MDRD) formula. Results: Majority of recipients (50,3%) were transplanted due to alcoholic liver cirrhosis. The level of eGFR before LT correlated positively with the eGFR decline after LT, where the decline was more pronounced in patients with higher eGFR prior to LT. The mean eGFR of all recipients significantly deteriorated after LT. Cumulative incidence of newly developed CKD for 12, 24, 36 and 48 months after LT was 54,5%, 58,9%, 63,6 % and 69,7%, respectively. A multivariate Cox regression analysis revealed that overall risk of CKD development was associated with old age of recipients, hepatitis C virus infection, the level of kidney function before LT and the level of kidney function at 1 month after LT. Pathohistological analysis of 33 kidney samples revealed in majority of patients (57,5%) CNI nephrotoxicity, in 24,2% primary glomerular disease and in 15,2% hypertensive nephropathy. No correlation was established between the eGFR and the stage of interstitial fibrosis and tubular atrophy (IF/TA) in all patients with CKD, as well as patients with CNI nephrotoxicity. Conclusion: CKD is frequent after LT, and CNI nephrotoxicity is its leading cause. Considering the lack of correlation between eGFR and IF/TA, a significant component of kidney dysfunction is functional (possible vasoconstrictive effect of CNI). With prolonged observation, it is likely to expect the increased incidence of advanced stages of CKD after LT and the application of renal replacement therapies in significant number of patients. Kidney biopsy is an irreplaceable diagnostic method for determining the etiology of CKD after LT. It should be considered in the early phase of diagnostic algorithm for the kidney dysfunction to enable proper etiological therapy before the development of irreversible histological changes in kidneys. Considering CNIs nephrotoxicity as the major leading cause of CKD after LT, it is necessary to evaluate immunosuppressive protocols with lower CNI exposition.

Abstract in Croatian

Uvod: Kroniĉna bubreţna bolest (KBB) znaĉajna je komplikacija transplantacije jetre (TJ), koja utjeĉe na morbiditet i mortalitet bolesnika nakon transplantacije. Stoga je vaţno identificirati i modificirati faktore rizika koji negativno utjeĉu na bubreţnu funkciju. Hipoteza disertacije bila je da je KBB ĉesta nakon TJ i da je vodeći uzroĉni ĉimbenik nefrotoksiĉnost kalcineurinskih inhibitora. Ciljevi ovog rada bili su odrediti incidenciju novonastale KBB, identificirati faktore rizike, istraţiti kliniĉki tijek, te odrediti etiologiju novonastale KBB kod bolesnika nakon TJ. Metode: Analizirano je 197 bolesnika kojima je u KB Merkur transplantirana jetra u razdoblju od 2005. do 2010. godine, koji nisu imali KBB prije TJ. KBB nakon TJ definirana je procijenjenom glomerularnom filtracijom (eGFR) <60 ml/min/1,73 m2 u trajanju od najmanje 3 mjeseca, koristeći Modification in Renal Disease (MDRD) formulu. Rezultati: Većina bolesnika (50,3%) transplantirana je zbog alkoholne bolesti jetre. Veliĉina eGFR prije TJ pozitivno je korelirala s veliĉinom pada eGFR nakon TJ, tako da su veći pad doţivjeli bolesnici s višom eGFR prije transplantacije. Prosjeĉna eGFR svih bolesnika pogoršala se nakon transplantacije. Kumulativna incidencija novonastale KBB nakon TJ iznosila je 54,5% nakon 12 mj., 58,9% nakon 24 mj., 63,6 % nakon 36 mj. i 69,7%.nakon 48 mj. Multivarijatna analiza pokazala je da su neovisni ĉimbenici rizika za razvoj KBB nakon TJ: starija dob bolesnika, infekcija virusom hepatitisa C, stupanj bubreţne funkcije prije TJ i stupanj bubreţne funkcije u 1. mj. nakon TJ. Patohistološkom analizom 33 bioptiĉka uzorka bubrega bolesnika s KBB nakon TJ, više od polovice bolesnika (57,5%) imalo je kalcineurinsku (CNI) nefrotoksiĉnost, 24,2% primarnu bolest glomerula, a 15,2% hipertenzivnu nefropatiju. Kod bolesnika s KBB općenito, kao ni kod bolesnika s CNI nefrotoksiĉnošću nije naĊena korelacija izmeĊu eGFR i stupnja intersticijske fibroze i tubularne atrofije (IF/TA). Zakljuĉak: KBB je ĉesta nakon TJ, a CNI nefrotoksiĉnost je njezin vodeći uzrok. S obzirom na izostanak korelacije izmeĊu IF/TA i eGFR, znaĉajna komponenta bubreţne disfunkcije je funkcionalna (vjerojatno vazokonstrikcijski uĉinak CNI). Duţim razdobljem praćenja moţe se oĉekivati daljnje povećanje uĉestalosti uznapredovalih stadija KBB nakon TJ, odnosno potreba za bubreţnim nadomjesnim lijeĉenjem u znaĉajnog broja bolesnika. Biopsija bubrega je nezamjenjivi alat u rasvjetljavanju etiologije KBB nakon TJ. Potrebno ju je rano uvrstiti u dijagnostiĉke algoritme bubreţne disfunkcije nakon TJ, jer se time omogućuje etiološka terapija, dok još kroniĉne histološke promjene u bubrezima nisu uznapredovale. S obzirom na CNI nefrotoksiĉnost kao vodeći uzrok KBB nakon TJ, potrebno je evaluirati imunosupresivne protokole s niţom ekspozicijom CNI-a.

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