Ambulatory blood pressure monitoring and biomarkers of renal damage in early detection of diabetic nephropathy in children

Uvod. Dijabetička nefropatija (DN) definirana je kao mikrovaskularna komplikacija u bolesnika sa ŠB koja bitno povećava rizik kardiovaskularnog morbiditeta i mortaliteta. Iako se unazad nekoliko desetljeća kod djece dijagnosticira znatno rjeđe, važno ju je otkriti što ranije s ciljem dugoročnog očuvanja bubrežne funkcije. Osim albuminurije kao opće prihvaćenoga biljega DN, ustanovljeno je da bi i rane promjene arterijskoga tlaka (AT) te biljezi tubularnoga oštećenja također mogli biti pokazatelji razvoja DN, čak i prije pojave trajne albuminurije. Stoga su ciljevi našega istraživanja bili odrediti karakteristike kontinuiranog mjerenja arterijskoga tlaka (KMAT) u djece sa šećernom bolešću (ŠB) tipa 1 te utvrditi njihov odnos s biljegom tubularnog oštećenja neutrophil gelatinase-associated lipocalin-a (NGAL) i albuminurijom te ustanoviti čimbenike karakteristične za ŠB koji su povezani s albuminurijom i biljegom tubularnog oštećenja NGAL-om. ----- Ispitanici i metode. U istraživanje je uključeno 201 dijete i adolescent sa ŠB tip 1 u dobi 5 – 20 godina s trajanjem bolesti od najmanje godinu dana. Svi ispitanici bili su pacijenti endokrinološkog odjela Klinike za pedijatriju KBC Sestre milosrdnice. Određivane su serumske vrijednosti HbA1c, kreatinin i lipidogram, kao i 3 uzorka prvog jutarnjeg urina za omjer albumin/kreatinin (ACR) u razmaku od tri mjeseca. Svakom ispitaniku sa ŠB izmjeren je ordinacijski AT i učinjen je KMAT. Kontrolnu skupinu činilo je 100 somatski zdrave djece. ----- Rezultati. Dokazali smo više dnevne vrijednosti SAT-a (sistolički arterijski tlak) te noćnog SAT-a i DAT-a (dijastolički arterijski tlak) u djece sa ŠB u odnosu na zdravu populaciju uz visok udio izostanka noćnog pada AT i urednu varijabilnost AT. S obzirom na razinu albuminurije varijabilnost noćnog DAT-a, mlađa dob i loša metabolička kontrola bolesti bile su prediktori visoko normalne albuminurije, dok su statistički značajni prediktori mikroalbuminurije bili 24 - satni, dnevni i noćni DAT, jutarnji skok AT i metabolička kontrola bolesti. Nije bilo razlike u uNGAL-u između djece sa ŠB i kontrola. Također, razlika u uNGAL- u nije bilo niti između djece s normoalbuminurijom i mikroalbuminurijom, kao niti između djece s nisko normalnom i visoko normalnom albuminurijom. Iako nije nađena povezanost uNGAL-a sa standardnim parametrima KMAT-a, bolesnici s povišenim uNGAL-om imali su višu varijabilnost dnevnog SAT-a. Varijabilnost AT i loša metabolička kontrola bolesti izdvojili su se kao zajednički čimbenici koji su imali utjecaja i na ACR i na uNGAL. ----- Zaključak. Analizom dobivenih podataka nije potvrđena hipoteza o oštećenju tubula kao najranijem znaku DN u djece sa ŠB tip 1, niti je potvrđena povezanost parametara KMAT-a s biljegom tubularnog oštećenja uNGAL-om. Međutim, dokazali smo kako su manja odstupanja u AT, prvenstveno promjene varijabilnosti AT, prisutne i bez mikroalbuminurije. Povećana varijabilnost AT i loša metabolička kontrola bolesti prediktori su glomerularnog i tubularnog oštećenja.Introduction. Diabetic nephropathy (DN) is one of the microvascular complications in diabetic patients which significantly increases the risk of cardiovascular morbidity and mortality. Although recent reports demonstrate a lower frequency of DN in children for several decades, the early recognition remains important in order to preserve renal function. Microalbuminuria has been established as a standard marker of kidney disease in diabetes, but early changes in blood pressure as well as signs of tubular damage could be present even before development of sustained microalbuminuria. The aims of our study were to analyse the characteristics of ambulatory blood pressure monitoring (ABPM) in children with type 1 diabetes and to determine the relationship between ABPM, urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a marker of tubular damage and albuminuria. Our aim was also to establish the diabetic indices related to albuminuria and tubular marker NGAL. ----- Patients and methods. The study group consisted of 201 children and adolescents aged 5 to 20 years with diabetes duration of at least one year. All patients were regulary followed at Department of Pediatrics, Sestre milosrdnice University Hospital Center in Zagreb. Serum concentrations of HbA1c, creatinine and lipids were determined along with 3 consecutive samples of first morning urine for albumin/creatinine ratio (ACR) over a 6 – month period . In all children with diabetes an office blood pressure was measured and ABPM performed. The control group consisted of 100 healthy children. ----- Results: Diabetic children had elevated daytime systolic and nighttime systolic and diastolic blood pressure compared to reference values of the healthy population along with high percentage of non-dippers but normal blood pressure variability. Nighttime diastolic blood pressure variability, younger age and poor glycaemic control were found as predictors of high – normal albuminuria. The predictors of microalbuminuria were 24 – hour, daytime and nighttime diastolic blood pressure, morning blood pressure surge and glycaemic control. No difference in uNGAL between diabetic and control group was observed. Also, there was no difference in uNGAL between the normoalbuminuric and microalbuminuric children as well as between those with low normal and high normal albuminuria. Although there was no correlation of uNGAL with standard parameters of ABPM, the subjects with elevated uNGAL had higher daytime blood pressure variability. Blood pressure variability and poor glycaemic control were common predictors of both ACR and uNGAL. ----- Conclusion: The results of our research didn't confirm neither the hypothesis on tubular damage as the earliest sign of DN in children with type 1 diabetes nor the correlation between ABPM variables and tubular damage marker NGAL. However, we have demonstrated that minor elevations in blood presssure, particulary in blood pressure variability, are already present without established microalbuminuria. Furthermore, an elevated blood pressure variabilty and poor glycaemic control were found as the predictors of both glomerular and tubular damage