Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice

Practical guidelines for diagnosing arterial hypertension of the Croatian Society of Hypertension of Croatian Medical Association and the Working Group on Hypertension of the Croatian Cardiac Society.

Arterijska je hipertenzija glavni neovisni čimbenik rizika za kardiovaskularni pobol i smrtnost. Prevalencija hipertenzije u većini zemalja pokazuje tendenciju rasta. Unatoč dostupnosti svih razreda antihipertenziva, kontrola liječenih hipertoničara nije zadovoljavajuća, za što postoji niz razloga i objašnjenja. Jedan od razloga jest i jaz između smjernica koje se temelje na činjenicama te mogućnostima njihova provođenja u stvarnome životu, što kao posljedicu ima lošu kontrolu hipertenzije i velik broj prijevremenih kardiovaskularnih događaja i smrti. Prvi korak u zbrinjavanju hipertoničara jest racionalna dijagnostika, što znači da pri tako masovnoj kroničnoj bolesti nepotrebnim pretragama ne povećavamo troškove, a s druge strane da pristupom na najmanju mjeru smanjimo propuste. Svrha je ovih smjernica za dijagnosticiranje arterijske hipertenzije da budu praktične i korisne u svakodnevnome radu. U njima je naglasak na konkretnim postupcima i podatcima s točno navedenim graničnim vrijednostima. Budući da je cilj smjernica ne samo usmjeriti i olakšati razmišljanja u svakodnevnome kliničkome radu nego i educirati, uz postupnike podsjećamo na neka temeljna znanja. U smjernicama ima nekoliko posve novih elemenata (upute o frekvenciji srca, mjesto i uloga mjerenja centralnoga arterijskoga tlaka i brzine pulsnoga vala, procjena bubrežne funkcije, zatim informatička tehnologija, tj. telemonitoriranje, primjena aplikacija za „pametne mobitele“). Na kraju smjernica uvršteno je nekoliko dodataka koji mogu biti korisni u svakodnevnome kliničkome radu, kao što su npr. upitnici za sindrom apneje u snu, upitnik o erektilnoj i seksualnoj disfunkciji, upitnik o kognitivnoj disfunkciji i drugi. U ovim smo smjernicama željeli biti praktični, precizni i realni s obzirom na mogućnosti koje nam pruža sredina u kojoj živimo. Svrha je bila na jednome mjestu obuhvatiti i prikazati što više konkretnih postupaka i podataka koji će biti korisni u radu, tako da liječnik ne mora gubiti vrijeme tražeći podatke bilo u samim smjernicama bilo u literaturi.Arterial hypertension is the main independent risk factor for cardiovascular morbidity and mortality. The prevalence of hypertension is increasing in most countries. Despite the availability of all classes of antihypertensive drugs, the rate control in hypertension treatment is insufficient, for which there are abundant explanations. One of the main reasons is the gap between evidence-based guidelines and their applicability in practice, a gap which leads to poor rate control in hypertension and increases the number of premature cardiovascular events and death. The first step in the management of a hypertensive patient is rational diagnosis, i.e., to avoid increasing the expenses of treating this mass chronic disease by unnecessary tests and to minimize errors. The aim of these practical guidelines for diagnosis of hypertension is for them to be practical and useful in everyday practice. There is an emphasis on particular procedures and data with exact cut-off values. The aim of these guidelines is not only to guide and simplify our decision-making process in everyday work, but also to educate. We thus provide reminders on some fundamental knowledge. There are some novel elements (instructions of heart rate, place and role of central blood pressure and pulse wave velocity measurement, estimation of renal function, IT e.g. telemonitoring, and the use of smartphone apps). At the end of the guidelines, we provide several appendices which could be useful in everyday clinical work, such as questionnaires for sleep apnea syndrome, questionnaires for erectile and sexual dysfunction, cognitive dysfunction questionnaires, and others. In these guidelines, we wanted to be practical, precise, and realistic given the options available in our work setting. The objective was to show and cover as many specific facts and procedures as possible that we find useful in everyday work, so that the clinician does not have to waste time searching the guidelines or literature

The importance of serum hepatocyte growth factor concentration in prehypertension

Istraživanje „Endemska nefropatija u Hrvatskoj – epidemiologija, etiologija i patofiziologija” provodila se u okolici Slavonskoga Broda tijekom 7 godina. Ispitanici su bili praćeni 5 ili 7 godina, ovisno o godini kada su uključeni u istraživanje. U ovo istraživanje uključene su osobe iz endemskih sela bez endemske nefropatije te stanovnici neendemskih sela. Ukupno 880 ispitanika (57,8 % žena i 42,2 % muškaraca) podijeljeno je prema arterijskomu tlaku (AT) u tri skupine. 295 ispitanika (33,5 %) klasificirano je u skupinu s optimalnim arterijskim tlakom (OAT), 317 ispitanika (36 %) kao predhipertoničari (PHT), a 268 ispitanika (30,5 %) kao neliječeni hipertoničari (HT). Učinjen je fizikalni pregled, uzeta opsežna anamneza te prikupljeni uzorci krvi i urina za laboratorijske pretrage. Arterijski tlak i srčana frekvencija mjereni su šest puta tlakomjerom OMRON. Ispitanici s OAT-om su najmlađi, PHT su značajno stariji, dok su najstariji HT. PHT ispitanici također imaju veću tjelesnu masu, opseg struka, indeks tjelesne mase (BMI), serumsku glukozu, ukupni kolesterol i razinu triglicerida u usporedbi s OAT-om. U skupini PHT uočeno je značajno više osoba s metaboličkim sindromom u odnosu na OAT. Nije nađena statistički značajna razlika u serumskoj koncentraciji čimbenika rasta hepatocita (HGF) među skupinama, iako postoji trend porasta koncentracije HGF-a s rastom AT-a. Nađena je značajna pozitivna korelacija između vrijednosti sistoličkoga i dijastoličkoga AT-a s koncentracijom HGF-a za sve ispitanike te u skupini predhipertoničara. Postoji značajna pozitivna korelacija između vrijednosti HGF-a i TGF-a bete za sve ispitanike te značajna korelacija za HGF i albuminuriju za sve ispitanike. Nije nađena značajna razlika za koncentraciju HGF-a u odnosu na prisutnost metaboličkoga sindroma. U multivarijantnoj linearnoj regresijskoj analizi su sistolički tlak i koncentracija HGF-a bili nezavisni prediktori albuminurije, a dob i TGF-beta nezavisni prediktori porasta koncentracije HGF-a. Na kraju praćenja značajno je više ispitanika razvilo arterijsku hipertenziju u skupini PHT u odnosu na OAT.The study "Endemic Nephropathy in Croatia - Epidemiology, Etiology and Pathophysiology" was conducted in the villages near Slavonski Brod throughout a period of seven years. Subjects were divided into three groups according to the value of their blood pressure (BP): 295 subjects (33.5 %) were classified into the group with optimal blood pressure (OAT), 317 subjects (36 %) were classified as prehypertensive (PHT), and 268 subjects (30.5 %) as untreated hypertensives (HT). All subjects underwent a physical examination, and provided blood and urine samples for laboratory tests. Blood pressure and heart rate were measured six times with an OMRON device using appropriate cuff size. Mean values were used for analysis. Subjects with the OAT were the youngest, the PHTs are significantly older, and the HTs were the oldest. Subjects with the PHT also had significantly higher body weight, waist circumference, BMI, fasting serum glucose, total cholesterol, and triglyceride levels compared to the OATs. There was significantly higher number of subjects with the metabolic syndrome in the PHT group than in the OAT group. There were no significant differences between the concentration of the HGFin the PHT and HT groups compared to the OAT group. A significantly positive correlation was found between systolic and diastolic blood pressure values and HGF concentration for all subjects. The correlation was higher for diastolic AT. There was a significantly positive correlation between HGF and TGF beta values for all subjects, while there was no significant difference between the HGF concentration and blood leukocyte count or CRP. There was also a significant correlation between HGF and albuminuria for all subjects. No significant difference was found in HGF concentration in relation to the presence of metabolic syndrome in all subjects Multivariant linear regression showed that systolic BP and HGF concentration are independent predictors of albuminuria elevation, whereas age and TGF beta are independent predictors of HGF concentration elevation. At the end of the seven- or five-year follow-up, significantly higher number of subjects developed arterial hypertension in the PHT group compared to the OAT group

The importance of serum hepatocyte growth factor concentration in prehypertension

Istraživanje „Endemska nefropatija u Hrvatskoj – epidemiologija, etiologija i patofiziologija” provodila se u okolici Slavonskoga Broda tijekom 7 godina. Ispitanici su bili praćeni 5 ili 7 godina, ovisno o godini kada su uključeni u istraživanje. U ovo istraživanje uključene su osobe iz endemskih sela bez endemske nefropatije te stanovnici neendemskih sela. Ukupno 880 ispitanika (57,8 % žena i 42,2 % muškaraca) podijeljeno je prema arterijskomu tlaku (AT) u tri skupine. 295 ispitanika (33,5 %) klasificirano je u skupinu s optimalnim arterijskim tlakom (OAT), 317 ispitanika (36 %) kao predhipertoničari (PHT), a 268 ispitanika (30,5 %) kao neliječeni hipertoničari (HT). Učinjen je fizikalni pregled, uzeta opsežna anamneza te prikupljeni uzorci krvi i urina za laboratorijske pretrage. Arterijski tlak i srčana frekvencija mjereni su šest puta tlakomjerom OMRON. Ispitanici s OAT-om su najmlađi, PHT su značajno stariji, dok su najstariji HT. PHT ispitanici također imaju veću tjelesnu masu, opseg struka, indeks tjelesne mase (BMI), serumsku glukozu, ukupni kolesterol i razinu triglicerida u usporedbi s OAT-om. U skupini PHT uočeno je značajno više osoba s metaboličkim sindromom u odnosu na OAT. Nije nađena statistički značajna razlika u serumskoj koncentraciji čimbenika rasta hepatocita (HGF) među skupinama, iako postoji trend porasta koncentracije HGF-a s rastom AT-a. Nađena je značajna pozitivna korelacija između vrijednosti sistoličkoga i dijastoličkoga AT-a s koncentracijom HGF-a za sve ispitanike te u skupini predhipertoničara. Postoji značajna pozitivna korelacija između vrijednosti HGF-a i TGF-a bete za sve ispitanike te značajna korelacija za HGF i albuminuriju za sve ispitanike. Nije nađena značajna razlika za koncentraciju HGF-a u odnosu na prisutnost metaboličkoga sindroma. U multivarijantnoj linearnoj regresijskoj analizi su sistolički tlak i koncentracija HGF-a bili nezavisni prediktori albuminurije, a dob i TGF-beta nezavisni prediktori porasta koncentracije HGF-a. Na kraju praćenja značajno je više ispitanika razvilo arterijsku hipertenziju u skupini PHT u odnosu na OAT.The study "Endemic Nephropathy in Croatia - Epidemiology, Etiology and Pathophysiology" was conducted in the villages near Slavonski Brod throughout a period of seven years. Subjects were divided into three groups according to the value of their blood pressure (BP): 295 subjects (33.5 %) were classified into the group with optimal blood pressure (OAT), 317 subjects (36 %) were classified as prehypertensive (PHT), and 268 subjects (30.5 %) as untreated hypertensives (HT). All subjects underwent a physical examination, and provided blood and urine samples for laboratory tests. Blood pressure and heart rate were measured six times with an OMRON device using appropriate cuff size. Mean values were used for analysis. Subjects with the OAT were the youngest, the PHTs are significantly older, and the HTs were the oldest. Subjects with the PHT also had significantly higher body weight, waist circumference, BMI, fasting serum glucose, total cholesterol, and triglyceride levels compared to the OATs. There was significantly higher number of subjects with the metabolic syndrome in the PHT group than in the OAT group. There were no significant differences between the concentration of the HGFin the PHT and HT groups compared to the OAT group. A significantly positive correlation was found between systolic and diastolic blood pressure values and HGF concentration for all subjects. The correlation was higher for diastolic AT. There was a significantly positive correlation between HGF and TGF beta values for all subjects, while there was no significant difference between the HGF concentration and blood leukocyte count or CRP. There was also a significant correlation between HGF and albuminuria for all subjects. No significant difference was found in HGF concentration in relation to the presence of metabolic syndrome in all subjects Multivariant linear regression showed that systolic BP and HGF concentration are independent predictors of albuminuria elevation, whereas age and TGF beta are independent predictors of HGF concentration elevation. At the end of the seven- or five-year follow-up, significantly higher number of subjects developed arterial hypertension in the PHT group compared to the OAT group

The importance of serum hepatocyte growth factor concentration in prehypertension

Istraživanje „Endemska nefropatija u Hrvatskoj – epidemiologija, etiologija i patofiziologija” provodila se u okolici Slavonskoga Broda tijekom 7 godina. Ispitanici su bili praćeni 5 ili 7 godina, ovisno o godini kada su uključeni u istraživanje. U ovo istraživanje uključene su osobe iz endemskih sela bez endemske nefropatije te stanovnici neendemskih sela. Ukupno 880 ispitanika (57,8 % žena i 42,2 % muškaraca) podijeljeno je prema arterijskomu tlaku (AT) u tri skupine. 295 ispitanika (33,5 %) klasificirano je u skupinu s optimalnim arterijskim tlakom (OAT), 317 ispitanika (36 %) kao predhipertoničari (PHT), a 268 ispitanika (30,5 %) kao neliječeni hipertoničari (HT). Učinjen je fizikalni pregled, uzeta opsežna anamneza te prikupljeni uzorci krvi i urina za laboratorijske pretrage. Arterijski tlak i srčana frekvencija mjereni su šest puta tlakomjerom OMRON. Ispitanici s OAT-om su najmlađi, PHT su značajno stariji, dok su najstariji HT. PHT ispitanici također imaju veću tjelesnu masu, opseg struka, indeks tjelesne mase (BMI), serumsku glukozu, ukupni kolesterol i razinu triglicerida u usporedbi s OAT-om. U skupini PHT uočeno je značajno više osoba s metaboličkim sindromom u odnosu na OAT. Nije nađena statistički značajna razlika u serumskoj koncentraciji čimbenika rasta hepatocita (HGF) među skupinama, iako postoji trend porasta koncentracije HGF-a s rastom AT-a. Nađena je značajna pozitivna korelacija između vrijednosti sistoličkoga i dijastoličkoga AT-a s koncentracijom HGF-a za sve ispitanike te u skupini predhipertoničara. Postoji značajna pozitivna korelacija između vrijednosti HGF-a i TGF-a bete za sve ispitanike te značajna korelacija za HGF i albuminuriju za sve ispitanike. Nije nađena značajna razlika za koncentraciju HGF-a u odnosu na prisutnost metaboličkoga sindroma. U multivarijantnoj linearnoj regresijskoj analizi su sistolički tlak i koncentracija HGF-a bili nezavisni prediktori albuminurije, a dob i TGF-beta nezavisni prediktori porasta koncentracije HGF-a. Na kraju praćenja značajno je više ispitanika razvilo arterijsku hipertenziju u skupini PHT u odnosu na OAT.The study "Endemic Nephropathy in Croatia - Epidemiology, Etiology and Pathophysiology" was conducted in the villages near Slavonski Brod throughout a period of seven years. Subjects were divided into three groups according to the value of their blood pressure (BP): 295 subjects (33.5 %) were classified into the group with optimal blood pressure (OAT), 317 subjects (36 %) were classified as prehypertensive (PHT), and 268 subjects (30.5 %) as untreated hypertensives (HT). All subjects underwent a physical examination, and provided blood and urine samples for laboratory tests. Blood pressure and heart rate were measured six times with an OMRON device using appropriate cuff size. Mean values were used for analysis. Subjects with the OAT were the youngest, the PHTs are significantly older, and the HTs were the oldest. Subjects with the PHT also had significantly higher body weight, waist circumference, BMI, fasting serum glucose, total cholesterol, and triglyceride levels compared to the OATs. There was significantly higher number of subjects with the metabolic syndrome in the PHT group than in the OAT group. There were no significant differences between the concentration of the HGFin the PHT and HT groups compared to the OAT group. A significantly positive correlation was found between systolic and diastolic blood pressure values and HGF concentration for all subjects. The correlation was higher for diastolic AT. There was a significantly positive correlation between HGF and TGF beta values for all subjects, while there was no significant difference between the HGF concentration and blood leukocyte count or CRP. There was also a significant correlation between HGF and albuminuria for all subjects. No significant difference was found in HGF concentration in relation to the presence of metabolic syndrome in all subjects Multivariant linear regression showed that systolic BP and HGF concentration are independent predictors of albuminuria elevation, whereas age and TGF beta are independent predictors of HGF concentration elevation. At the end of the seven- or five-year follow-up, significantly higher number of subjects developed arterial hypertension in the PHT group compared to the OAT group

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice

Typical course of cystinuria leading to untypical complications in pregnancy: A case report and review of literature

Cystinuria is a rare genetic disorder inherited by an autosomal recessive pattern which affects the transmembrane transporter for the base amino acid cystine. It has a general prevalence of 1 in 7000 with demographic variations. Patients with cystinuria have excessive urinary excretion of cystine, which can lead to the formation of stones. Up to 70% of patients will develop chronic kidney disease that can progress even to end-stage renal disease. Symptoms usually start in the first two decades of life with a typical presentation consisting of flank pain and renal colic, usually accompanied by urinary tract infection and deterioration of kidney function. Men are typically affected twice as often as women and have a more severe clinical course. Diagnosis is made by spectrophotometric analysis of the stones that are collected after spontaneous expulsion or medical intervention. Genetic testing is not mandatory but is recommended in uncertain cases or as a part of genetic counseling. Treatment consists of diet modification, alkalization of urine, and thiol-based therapies if other measures fail to prevent stone formation. In pregnancy, cystinuria with the formation of cystine stones represents a therapeutic challenge and requires a multidisciplinary approach consisting of an uro-nephrology team and a gynecologist. We present the case of a 34-year-old woman with cystinuria on whom the diagnosis was made by analysis of the expulsed stone. While her previous pregnancies were without complications, her third pregnancy was accompanied by frequent urinary tract infections, acute worsening of kidney function, and urological interventions during pregnancy due to the formation of new stones. Despite the complicated course, the pregnancy was successfully carried to term with the delivery of a healthy female child

Case report: Sevelamer-associated colitis-a cause of pseudotumor formation with colon perforation and life-threatening bleeding

Chronic kidney disease (CKD) is a very common chronic non-communicable disease. Phosphate and calcium metabolism disorders are one of the most common features of CKD. Sevelamer carbonate is the most widely used non-calcium phosphate binder. Gastrointestinal (GI) injury associated with sevelamer use is a documented adverse effect but is underrecognized as a cause of gastrointestinal symptoms in patients with CKD. We report a case of a 74-year-old woman taking low-dose sevelamer with serious gastrointestinal adverse effects causing colon rupture and severe gastrointestinal bleeding