IgA Nephropathy study according to the Oxford Classification: IgA Nephropathy clinical-morphological correlations, disease progression and the effect of renoprotective therapy

Abstract

Immuunoglobuliin A nefropaatia (IgAN) on kõige sagedasem glomerulonefriit maailmas. Diabeetilise nefropaatia kõrval on IgAN järgmine oluline nefroloogiavaldkonna probleem, kuna haigestuvad peamiselt noored inimesed ja aeglaselt progresseerudes tekib lõpp-staadiumi neerupuudulikkus ligikaudu pooltel patsientidel 25 aasta jooksul. Kuigi kahjustuse sihtmärk on neerud, pärineb esmane defekt süsteemsest aberrantsest O-seotud glükaanide glükosüleerimisest IgA1 ühenduspiirkonnas, mis põhjustab suurenenud galaktoosi-defitsiitset IgA1 taset vereseerumis. Efektiivne ja spetsiifiline ravi tänapäeval puudub. Uuringu eesmärgid: 1) leida erinevate glomerulopaatiate jaotuvus ja IgAN osakaal neerubiopsia materjalis; 2) analüüsida IgAN kliinilist leidu ja morfoloogiat vastavalt Oxfordi klassifikatsioonile; 3) hinnata kliiniliste ja morfoloogiliste andmete korrelatsioone ning soolisi erinevusi; 4) hinnata kliiniliste ja morfoloogiliste riskitegurite osatähtsust erinevat ravi saanutel. Retrospektiivsed kliinilis-morfoloogilised uuringud viidi läbi Tartu Ülikooli Kliinikumis. Aastatel 2001–2010 teostatud 547 adekvaatse neerubiopsia (340 mest, 238 naist; keskmine vanus 39.9 ± 17.9 aastat, nendest 5% lapsed) seas registreeriti 88 IgAN juhtu. Kliinilised ja laboratoorsed andmed koguti haiguslugudest. Uuringus leiti, et primaarsed glomerulopaatiad moodustasid peamise rühma (45,4%) kõikidest informatiivsetest neerubioptaatidest ja IgAN moodustas nendest põhiosa (35,5%). Võrreldes tulemusi 1991–1994 läbiviidud uuringuga täheldasime muutust mittepõletikuliste glomerulopaatiate esinemise suurenemise suunas. IgAN oli kõige sagedasem glomerulonefriit meie populatsioonis ja selle levimus ei ole muutunud. Asümptomaatiline mikrohematuuria ja asümptomaatiline mikrohematuuria proteinuuriaga olid peamised kliinilised sündroomid IgAN haigetel. Tüüpiline leid päsmakestes oli mesangiaalmaatriksi rohkenemine ja mesangiaalrakkude proliferatsioon. Mesangiaalne hüpertsellulaarsus, endokapillaaarne hüpertsellulaarsus, segmentaarne skleroos/adhesioon ja tuubulite atroofia/interstitsiaalne fibroos (MEST) korreleerusid kliiniliste andmetega ja MEST osade kõrgemad väärtused korreleerusid glomerulaarfiltratsiooniga (eGFR). Statistiliselt usutav korrelatsioon esines M1 ja eGFR-i vahel ainult meestel, kuid S1 korreleerus proteinuuriaga ja eGFR-iga nii naistel kui meestel. T1 korreleerus meestel eGFR-i ja proteinuuriaga ning E1 puhul leiti naistel korrelatsioon proteinuuriaga. Suurem eGFR taseme langus jälgimisperioodi lõpus oli patsientidel, kellel esinesid nii kliinilised kui morfoloogilised riskitegurid. Suurem eGFR taseme langus jälgimisperioodi jooksul oli meestel. IgAN progresseerumist ei olnud patsientidel ilma riskifaktoriteta ja ravita ning ka ilma riskifaktoriteta ja RASb raviga rühmades.IgA nephropathy (IgAN) remains the most common primary glomerulonephritis in the world. Other than diabetic nephropathy, IgAN is the next important health-care issue in nephrology as it often affects young adults and the nephropathy keeps a slow but relentless clinical course. The clinical progression in IgAN varies, and according to literature the consequent end-stage kidney disease (ESKD) occurs in about 50% of patients within 25 years after the diagnosis. The kidney is a target of injury in IgAN, yet the primary defect originates from a systemic aberrant glycosylation of O-linked glycans in the hinge region of IgA1, resulting in the increased serum levels of galactose-deficient IgA1 (Gd-IgA1). An effective and specific treatment for IgAN is still lacking. The aims of the study were: 1) to find the occurrence of various glomerulopathies, including IgAN, in the kidney biopsy material; 2) to identify the clinical presentation and the morphological patterns of IgAN at the time of biopsy according to the Oxford classification; 3) to assess the clinical and morphological data correlations in IgAN patients and to define their gender-related differences; 4) to evaluate the relative importance of clinical and morphological prognostic risk factors among patients with different treatments. The retrospective clinical-morphological study was carried out at the Tartu University Hospital during the period of 2001–2010. In total 547 of informative kidney biopsies were reviewed (340 men, 238 women; mean age 39.9 ± 17.9 years, 5% of patients were children), where 88 IgAN cases were registered. The clinical data for the study were collected from the medical history records. Primary glomerulopathies comprised the main part (45.4%) of all informative kidney biopsies and IgAN formed the main part of them (35.5%). Comparing this data with the data of the period of 1991–1994, the change towards non-inflammatory glo¬me¬rulo¬pathies was noticed. IgAN has been the most common primary glome¬ru¬lo¬nephritis in our population and it has not changed over the time. Asymptomatic microhematuria and asymptomatic microhematuria with proteinuria were the main presenting clinical syndromes in IgAN patients. The typical finding in glomeruli was the expanding of mesangial area and the mesangial cell proliferation. Mesangial and endocapillary hypercellularity, segmental sclerosis/adhesion and tubular atrophy/interstitial fibrosis (the MEST parts) have a correlation with the clinical data as their higher score was linked to the eGFR. We found a statistically significant correlation between the M1 and the eGFR in males. The other – S1 – was correlated with the proteinuria level and eGFR at the time of renal biopsy in both genders, T1 lesions with eGFR and proteinuria in males, E1 in females did not show correlation with eGFR, but showed correlation with proteinuria. The biggest eGFR decrease after the follow-up was found among the patients who had clinical and morphological risk factors. More rapid IgAN progression occurred in males. Progression of IgA nephropathy was not found in the patients groups without risk factors and without treatment, and without risk factors and with RASb treatment.