Međudjelovanje dijagnostičkih biljega endemske nefropatije [Interaction of markers endemic nephropathy]

Cvitković, Ante (2012) Međudjelovanje dijagnostičkih biljega endemske nefropatije [Interaction of markers endemic nephropathy]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Endemic nephropathy (EN) is a chronic tubulointerstitial disease. Different hypothesis and possible etiologic agents for development of EN have been investigated. Recent results from Croatia suggest that aristolochic acid (AA) is a major risk factor for EN. According to Ivić hypothesis, the most likely route of human exposure to AA is via-ingestion of home-baked bread prepared from flour contaminated by seeds of Aristolochia clematitis. One of the specifics of EN is that different countries use different diagnostic criteria. There is no specific diagnostic marker for EN. EN is a rare disease considering its prevalence and there is a problem of questionable diagnostics. The postulate for standardization of diagnostic markers is the analysis of its relationships. In 2005. a field survey was conducted in 3 endemic villages and 1 control village, which comprised 1081 examinees. They respondents were given the questionnaire. The clinical examination and anamnesis were done also. According to WHO criteria, the examinees were classified in 4 groups: diseased, suspected, at the risk and the others. The diagnosis of EN was confirmed in 23 examinees after surveillance from 2005-2010. Demographic and epidemiological characteristics of examinees, considering their exposure to AA, as well as identification of possible markers of EN, were analyzed by logistical regression (odds ratio) and by their 95% interval of reliability between positive and negative groups. The negative group was the one with examinees without EN. The positive group was defined by 2 models. According to the 1st model, the diseased and the suspected were in positive group, and according to the 2nd model, the diseased, the suspected and those under the risk were in positive group. Multidimensional relations among diagnostic markers were analyzed by CoPlot method. The ratio between the diseased and the others, the diseased and those under the risk, the diseased and suspected was demonstrated. In those CoPlot maps, WHO criteria were used (7 variables) and all available epidemiological and clinical-diagnostic criteria (18 variables). The prevalence of the diseased in the examined specimen is 1,32%, suspected – 3,6%, those at the risk – 8,88%. The results show that, considering the exposure to AA, the chance (probability) that examinees encountered AA on their fields 20-30 years ago was 2,5x (1st model), and 2x (2nd model) higher among examinees in positive group than in negative group. According to the 1st model, the chance that they sometimes encountered AA on their fields 20-30 years ago was 2x higher among examinees in positive group than in negative group. The chance that they always encountered AA seeds amongst the seeds intended for flour 20-30 years ago, was 2,6x (1st model) and 2x (2and model) higher among examinees in positive group than in negative group. CoPlot map shows the accepted goodness of fit measure tresholds in both reports (with exception of the diseased and suspected with 18 variables). This method identifies the examinees which with their characteristics, contrast the group they belong to. The best correlation in CoPlot presentation with WHO criteria, have alfa1microglobulin and creatinin, and the worst – age (CoPlot solution of the diseased and the others and the diseased and at risk) and positive family anamnesis (CoPlot solution of the diseased and suspected). The best correlation in CoPlot presentation with 18 variables have hemoglobin, hematocrit and eritrocites. The worst correlation in CoPlot solution have the diseased and the others – gender and systolic pressure, the diseased and those at the risk – systolic pressure and ratio of alfa1 microglobulinuria and albuminuria, the diseased and suspected – family anamnesis and gender. The following variables show redundancy: time spent in the family, in the village, in the region and age. They are negatively correlated with positive family anamnesis, which points the fact that certain genetic predisposition could implicate shorter time from exposure to the diseases. Eritrocites, hematocrit and hemoglobin also show redundancy. In CoPlot maps which show the diseased and the others, alfa1 microglobulinuria, creatinin, albuminuria, proteinuria and family anamnesis of EN show positive correlation with the diseased, hemoglobin, hematocrit, erotrocites, glomerular filtration calculated by Cockroft-Gault and MDRD formulas, systolic and diastolic pressure show negative correlation, and ratio of alfa1 microglobulinuria and albuminuria, time spent in the family, in the region, in the village, age and gender show dis-correlation. In CoPlot solution of the diseased and those at the risk, the diseased and suspected, alfa1 microglobulinuria, albuminuria, proteinuria and creatinin show positive correlation with the diseased. In all 3 presentations, time spent in the families, in the region, in the village, age, gender, alfa1 microglobulin/albumin are not correlated neither with the diseased nor with the rest of the groups according to WHO criteria. The 5 main diagnostic markers are: positive family anamnesis, glomerular filtration calculated by Cockroft-Gault, proteinuria, hematocrit i alfa1 microglobulinuria. Considering that hematocrit, hemoglobin, hematocrit and eritrocites give redundant information we can use one of them. According to WHO criteria glomerular filtration estimated by Cockroft-Gault formula has higher correlation then creatinin. These results show that CoPlot methodology for multidimensional relations is adequate for the analysis of rare diseases in heterogeneous groups, when it is not possible to have a large number of the examinees.

Abstract in Croatian

Endemska nefropatija je kronična tubulointersticijska bolest. Do sada su istraživane različite hipoteze i mogući etiološki agensi za nastanak EN. Recentni rezultati istraživanja u Hrvatskoj pokazuju da je aristolohična kiselina iz vučje stope najvažniji rizični čimbenik. Prema Ivićevoj hipotezi sjemenke vučje stope obzirom da ona raste sa žitom dospijevaju među žito namijenjeno za brašno, zatim mljevenjem do brašna i naposljetku preko kruha do ljudi. Osim brojnih do sada istraživanih hipoteza jedno od obilježja EN je da se u različitim zemljama primjenjuju različiti dijagnostički kriteriji. Specifičnog dijagnostičkog biljega za EN za sada nema. Obzirom na prevalenciju EN se smatra rijetkom bolesti. Time se otvara problem nepouzdano dijagnosticirane bolesti. Za standardizaciju dijagnostičkih biljega preduvjet je analiza njihovog međuoodnosa. U tri endemska sela i jednom kontrolnom 2005. godine provedeno je terensko istraživanje koje je obuhvatilo 1081 ispitanika. Oni su anketirani upitnikom. Izvršen je klinički pregled i uzeta detaljna anamneza. Prema WHO kriterijima ispitanici su svrstani u skupine oboljelih, sumnjivih, pod rizikom i ostali. Nakon praćenja ispitanika za koje se sumnjalo da boluju od EN u razdoblju od 2005. do 2010. godine dijagnoza EN je potvrđena kod njih 23. Demografske i epidemiološke karakteristike ispitanika obzirom na moguću izloženost aristolohičnoj kiselini, kao i identifikaciju mogućih biljega EN analizirani su logističkom regresijom, odnosno multivarijatnim omjerima izgleda (engl. odds ratio) i njihovim 95% intervalom pouzdanosti između pozitivne i negativne skupine. Negativna skupina je definirana ispitanicima koji nemaju EN. Pozitivna skupina je definirana dvama modelima. Prema prvom modelu pozitivnu skupinu čine oboljeli i sumnjivi, a prema drugom oboljeli, sumnjivi i ispitanici pod rizikom. Višedimenzionalni međuodnos dijagnostičkih biljega analiziran je Coplot metodom. Prikazan je odnos oboljelih i ostalih, oboljelih i pod rizikom, te oboljelih i sumnjivih. U tim CoPlot prikazima korišteni su WHO kriteriji (sedam varijabli) i svi dostupni epidemiološko kliničko dijagnostički kriteriji (osamnaest varijabli). Prevalencija oboljelih u ispitivanom uzorku iznosi 1,32 %, sumnjivih 3,6%, a ispitanika pod rizikom 8,88%. Rezultati obzirom na izloženost vučjoj stopi pokazuju da je vjerojatnost da su uvijek viđali vučju stopu na svojim poljima prije 20-30 godina 2,5 puta (prvi model), odnosno 2 puta (drugi model) veća među ispitanicima u pozitivnoj nego u negativnoj skupini. Vjerojatnost prema prvom modelu da su ponekad viđali vučju stopu na svojim poljima prije 20-30 godina je 2 puta veća među ispitanicima pozitivne nego među ispitanicima negativne skupine. Vjerojatnost da su prije 20-30 godina uvijek viđali sjemenke vučje stope među sjemenkama namijenjenim za brašno je 2,6 puta (prvi model) odnosno 2 puta (drugi model) veća među ispitanicima pozitivne nego među ispitanicima negativne skupine. CoPlot vizualizacija pokazuje dobar koeficijent otuđenja i srednju korelaciju kod oba prikaza (uz izuzetak oboljelih i sumnjivih sa osamnaest varijabli). Ova metoda identificira ispitanike koji svojim karakteristikama znatno odstupaju od skupine kojoj pripadaju. Najveću korelaciju kod CoPlot prikaza s WHO kriterijima donose alfa1mikroglobulin i kreatinin, a najmanju dob (CoPlot prikaz oboljelih i ostalih i oboljelih i pod rizikom) i pozitivna obiteljska anamneza (CoPlot prikaz oboljelih i sumnjivih). Najveću korelaciju kod CoPlot prikaza osamnaest varijabli donose hemoglobin, hematokrit i eritrociti. Najmanju korelaciju pokazuju kod CoPlot prikaza oboljeli i ostali spol i sistolički tlak, oboljeli i pod rizikom sistolički tlak i omjer alfa1 mikroglobulinurije i albuminurije, te kod oboljelih i sumnjivih obiteljska anamneza i spol. Redundanciju pokazuju slijedeće varijable: dužina boravka u obitelji, u selu, u regiji i dob. One su negativno povezane s pozitivnom obiteljskom anamnezom što nam ukazuje na činjenicu da bi određena genska predispozicija mogla utjecati da za pojedine ispitanike vrijeme izloženosti do oboljenja bude kraće. Redundanciju također pokazuju varijable: eritrociti, hematokrit i hemoglobin. U Coplot prikazima koji prikazuju oboljele i ostale pozitivnu povezanost s oboljelim pokazuju alfa1 mikroglobulinurija, kreatinin, albuminurija, proteinurija i obiteljska anamneza na EN, negativnu povezanost pokazuju hemoglobin, hematokrit, eritrociti, glomerularna filtracija procijenjena pomoću Cockroft-Gaultove i MDRD formule, te sistolički i dijastolički tlak, a nepovezanost omjer alfa 1 mikroglobulinurije i albuminurije, trajanje boravka u regiji, obitelji, selu, dob i spol. U CoPlot prikazu oboljelih i pod rizikom, te oboljelih i sumnjivih pozitivnu povezanost sa oboljelima pokazuju alfa 1 mikroglobulinurija, albuminurija, proteinurija i kreatinin. U sva tri prikaza boravak u obiteljima, u regijama, u selu, dob, spol, omjer alfa1 mikroglobulinurije i albuminurije nije povezana ni s oboljelima, ni s ostalim skupinama prema WHO kriterijima. Ključnih pet dijagnostičkih biljega različite orijentacije i s najvećom korelacijom uz navođenje samo jednog od redundantnih biljega (s najvećom korelacijom) su: pozitivna obiteljska anamneza, glomerularna filtracija procijenjena Cockroft Gaultovom formulom, proteinurija, hematokrit i alfa1 mikroglobulinurija. S obzirom na to da hemoglobin, hematokrit i eritrociti pružaju redundantnu informaciju možemo ih koristiti na način da koristimo samo jednog. U odnosu na WHO kriterije glomerularna filtracija procijenjena Cockroft Gaultovom formulom ima veću korelaciju od kreatinina.

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