Impact of Angiotensin-Converting Enzyme Gene Polymorphism on Proteinuria and Arterial Hypertension

Proteinuria is the hallmark of renal disease. In essential hypertension the onset of de novo proteinuria is associated with faster rate of progression of disase. Some authors have suggested that the DD genotype of the angiotensin-convert- ing enzyme (ACE) gene would be an adverse renal prognosis factor. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. Observations on the association between the ACE gene poly- morphism and hypertension have been inconsistent, which might be due to ethnic and geographical variations. In this study was to investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (ramipril) and to evaluate the possible association between I/D polymorphism and hypertension. We recruited 66 hyper- tensive patients (male 42, female 24) with overt proteinuria (urinary protein excretion over 500 mg/day). Patients were classified into three groups in accordance with ACE genotypes (17 DD; 35 ID; 14 II). They were treated with ramipril and prospectively followed up for one year. Various clinical parameters including age, body mass index (BMI), 24-h urine protein, creatinine, creatinine clearance (Ccr), systolic and diastolic blood pressure (SBP and DBP), mean arterial pres- sure (MAP) were measured in the pre- and post-treatment periods. The ACE gene insertion/deletion(I/D) polymorphisms in intron 16 were determined by PCR. Results showed that there were no significant differences in the clinical parame- ters such as age, gender, serum creatinine, Ccr, SBP , DBP , MAP , and daily urinary excretion of protein among three groups (P>0.05). ID genotype patients were found to have lower BMI (p=0.031). ACE inhibition significantly reduced proteinuria in all genotype groups (p<0.05). The percentage reductions of 24-h urinary excretion of protein were signifi- cantly different between the genotype groups (p=0.042) and for DD genotype were significantly greater than in ID (79.2± 28.9% vs 49.2±64.8%, P=0.015). The slope of SBP was the main factor related to the slope of the percentage reduction of proteinuria, however, a significant negative correlation coefficient between these parameters was found (rs=–0.382, p= 0.002). We failed to find significant difference in outcomes of treatments with ACE inhibitor between male and female ac- cording the I/D polymorphism of the ACE gene. D allele in the ACE genotype could be a useful genetic marker with im- portant clinical, therapeutic and prognostic implications in recognizing patients with proteinuria that are at greater risk of renal damage

Liječenje vaskulitisa povezanih s antineutrofilnim citoplazmatskim protutijelima [Treatment of anti-neutrophil cytoplasmic antibody related vasculitis]

ANCA-associated vasculitides are a well-known clinico-pathological group of systemic diseases comprising microscopic poliangiitis, granulomatosis with poliangiitis and eosinophilic granulomatosis with poliangiitis. This article shows contemporary treatment of this diseases with extensive literature review. Stepwise treatment of ANCA-associated vasculitides is divided into induction therapy and remission maintenance therapy. Standard induction therapy is a combination of glucocorticoids and cyclophosphamide, and in maintenance therapy, combination of low-dose glucocorticoids and azathioprine or methotrexate is used. Leading rheumatology and nephrology associations developed treatment guidelines. Since ANCA-associated vasculitides are relatively rare diseases, there are only few randomized controlled studies to provide high level of evidence and treatment recommendations. Most patients achieve remission, but relapses often occur. The main treatment considerations, apart from frequently relapsing disease, are disease refractory to treatment and potentially harmful effects of immunosuppressants, especially cyclophosphamide. Future studies are needed to determine the effects of less toxic immunosuppressants, mainly biological agents

NONSTEROIDAL ANTIRHEUMATICS AND HYPERTENSION

Nesteroidni antireumatici (NSAR) skupina su lijekova koji se najčešće rabe u kliničkoj medicini, čine 4–9% svih propisanih lijekova, a bolesnici koji ih uzimaju izloženi su mogućim nuspojavama. Nesteroidni antireumatici: starija generacija NSAR, neselektivni inhibitori ciklooksigenaze (inhibitori COX-1 i COX-2) i novija generacija NSAR, selektivni inhibitori ciklooksigenaze, koksibi (inhibitori COX-2) mogu u nekih bolesnika povisiti krvni tlak i time povećati kardiovaskularni rizik. Velik broj randomiziranih studija pokazao je porast krvnog tlaka za 5–10 mmHg u bolesnika koji su uzimali NSAR. Budući da je primjena NSAR česta, povišenje krvnog tlaka koje uzrokuje ova skupina lijekova ima veliko značenje u javnom zdravstvu. Najvažniji mehanizam kojim NSAR povisuju krvni tlak jest retencija natrija i tekućine zbog smanjene sinteze prostaglandina. Velik broj randomiziranih studija pokazao je da nesteroidni antireumatici mogu povisiti krvni tlak, i u normotenzivnih osoba i u hipertenzivnih bolesnika. Hipertenzivni učinak indometacina, naproksena i drugih nesteroidnih antireumatika zabilježen je u bolesnika koji uzimaju b-blokatore, diuretike, metildopu, ACE-inhibitore i kombinaciju različitih antihipertenziva. Bolesnici koji su liječeni blokatorima kalcijevih kanala, nakon primjene NSAR nisu pokazali promjene krvnog tlaka. U većini studija niske doze aspirina nisu značajno povisile arterijski tlak. Neke su studije pokazale da i novija generacija NSAR (selektivni COX-2-inhibitori) povisuje krvni tlak kao i starija generacija NSAR, neselektivni inhibitori ciklooksigenaze (inhibitori COX-1 i COX-2).Nonsteroidal anti-inflammatory drugs (NSAID) are the most common prescribed drugs in clinical medicine (4–9% of all prescriptions), and their side-effects are very common. These drugs, the older group, nonselective ciclooxigenase inibitors (inhibitors of COX-1 and COX-2), may increase blood pressure and cardiovascular risk. Many studies have shown that NSAID could increase blood pressure for 5–10 mmHg. The use of NSAID is common and their side effects to increase blood pressure have a large impact on the public health. The main mechanism of the increased blood pressure by NSAID is blockage of prostaglandin synthesis. The results of blockage of prostaglandin synthesis are sodium and fluid retention. NSAID may increase blood pressure in normotensive and hypertensive persons. Indomethacin, naproxen, and other NSAID increase the blood pressure in patients treated with b-blockers, diuretics, metildopa, ACE-inhibitors and combination of various antihipertensive drugs, but there is no increase of blood pressure in patients treated with calcium blockers. In many studies, aspirin did not increase the blood pressure. The new group of NSAID, coxibes, selective ciclooxigenase inibitors (inhibitors of COX-2) could increase the blood pressure like older generation of NSAID

TREATMENT OF ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY RELATED VASCULITIS

Vaskulitisi vezani uz ANCA dobro su poznata kliničko-patološka skupina sustavnih bolesti koja obuhvaća mikroskopski poliangiitis, granulomatozni poliangiitis i eozinofilni granulomatozni poliangiitis. U ovome preglednom članku prikazano je suvremeno liječenje ovih bolesti s opširnim osvrtom na literaturne podatke. Liječenje ovih bolesti stupnjevito je i dijeli se na indukcijsko liječenje te terapiju održavanja. Standardno indukcijsko liječenje čini kombinacija glukokortikoida i ciklofosfamida, a terapiju održavanja kombinacija niske doze glukokortikoida i azatioprina ili metotreksata. Vodeća svjetska reumatološka i nefrološka društva imaju jasne smjernice za liječenje tih bolesti. S obzirom na to da je riječ o relativno rijetkim bolestima, malo je randomiziranih kliničkih istraživanja te posljedično tomu i visokih razina dokaza i preporuke glede liječenja. U većine bolesnika postigne se remisija bolesti, ali su relapsi česti. Osnovni problem u liječenju osim često relabirajuće bolesti jesu i refrakterni oblici bolesti te potencijalni štetni učinci liječenja, posebice ciklofosfamida. Buduća istraživanja bit će usmjerena na traženje manje toksičnih imunosupresiva, ponajprije bioloških lijekova.ANCA-associated vasculitides are a well-known clinico-pathological group of systemic diseases comprising microscopic poliangiitis, granulomatosis with poliangiitis and eosinophilic granulomatosis with poliangiitis. This article shows contemporary treatment of this diseases with extensive literature review. Stepwise treatment of ANCA-associated vasculitides is divided into induction therapy and remission maintenance therapy. Standard induction therapy is a combination of glucocorticoids and cyclophosphamide, and in maintenance therapy, combination of low-dose glucocorticoids and azathioprine or methotrexate is used. Leading rheumatology and nephrology associations developed treatment guidelines. Since ANCA-associated vasculitides are relatively rare diseases, there are only few randomized controlled studies to provide high level of evidence and treatment recommendations. Most patients achieve remission, but relapses often occur. The main treatment considerations, apart from frequently relapsing disease, are disease refractory to treatment and potentially harmful effects of immunosuppressants, especially cyclophosphamide. Future studies are needed to determine the effects of less toxic immunosuppressants, mainly biological agents

MEMBRANOUS GLOMERULONEPHRITIS – RECENT ADVANCES IN PATHOGENESIS AND TREATMENT

Membranski glomerulonefritis jedan je od najčešćih uzroka nefrotskog sindroma u odraslih osoba. Obilježen je varijabilnim kliničkim tijekom, u kojem se u nekih bolesnika sporo razvija zatajenje bubrega, dok drugi ulaze u spontanu remisiju. Cilj je ovoga preglednog članka osvrt na novosti koje su posljednjih godina nađene u patogenezi i liječenju ove bolesti u ljudi. Posljednjih godina otkriveni su ciljni podocitni autoantigeni koji su odgovorni za stvaranje autoprotutijela i imunih kompleksa in situ: neutralna endopeptidaza, M-tip receptora za fosfolipazu A2, superoksid-dismutaza 2, aldoza-reduktaza i a-enolaza. Pretpostavlja se da će otkrića ovih antigena pomoći u razlikovanju primarnog od sekundarnoga membranskoga glomerulonefritisa, predviđanju remisije i/ili relapsa bolesti, kao i specifičnijem liječenju bolesti. Posljednjih godina u liječenju bolesti provedene su pilot-studije u kojima su prvi put pokazani pozitivni terapijski učinci ACTH, rituksimaba i takrolimusa.Membranous glomerulonephritis is one of the leading causes of nephrotic syndrome in adults. It may have very variable course, with some patients slowly progressing to renal failure and some entering spontaneous remission. The aim of this article is to review recent advances in the pathogenesis and treatment of the disease in recent years. In recent years, first human podocyte autoantigens, responsible for autoantibodies and in situ immune complexes formation, were discovered: neutral endopeptidase, m-type phospholipase A2receptor, superoxide-dismutase 2, aldose-reductase, a-enolase. It is postulated that these discoveries will help in differentiation between primary and secondary membranous glomerulonephritis, in predicting remission and/or relapse and also in determining more specific therapy. There have been also some pilot studies recently, in which new drugs have been introduced in the treatment of membranous glomerulonephritis: ACTH, rituximab and tacrolimus

NONSTEROIDAL ANTIRHEUMATICS AND HYPERTENSION

Nesteroidni antireumatici (NSAR) skupina su lijekova koji se najčešće rabe u kliničkoj medicini, čine 4–9% svih propisanih lijekova, a bolesnici koji ih uzimaju izloženi su mogućim nuspojavama. Nesteroidni antireumatici: starija generacija NSAR, neselektivni inhibitori ciklooksigenaze (inhibitori COX-1 i COX-2) i novija generacija NSAR, selektivni inhibitori ciklooksigenaze, koksibi (inhibitori COX-2) mogu u nekih bolesnika povisiti krvni tlak i time povećati kardiovaskularni rizik. Velik broj randomiziranih studija pokazao je porast krvnog tlaka za 5–10 mmHg u bolesnika koji su uzimali NSAR. Budući da je primjena NSAR česta, povišenje krvnog tlaka koje uzrokuje ova skupina lijekova ima veliko značenje u javnom zdravstvu. Najvažniji mehanizam kojim NSAR povisuju krvni tlak jest retencija natrija i tekućine zbog smanjene sinteze prostaglandina. Velik broj randomiziranih studija pokazao je da nesteroidni antireumatici mogu povisiti krvni tlak, i u normotenzivnih osoba i u hipertenzivnih bolesnika. Hipertenzivni učinak indometacina, naproksena i drugih nesteroidnih antireumatika zabilježen je u bolesnika koji uzimaju b-blokatore, diuretike, metildopu, ACE-inhibitore i kombinaciju različitih antihipertenziva. Bolesnici koji su liječeni blokatorima kalcijevih kanala, nakon primjene NSAR nisu pokazali promjene krvnog tlaka. U većini studija niske doze aspirina nisu značajno povisile arterijski tlak. Neke su studije pokazale da i novija generacija NSAR (selektivni COX-2-inhibitori) povisuje krvni tlak kao i starija generacija NSAR, neselektivni inhibitori ciklooksigenaze (inhibitori COX-1 i COX-2).Nonsteroidal anti-inflammatory drugs (NSAID) are the most common prescribed drugs in clinical medicine (4–9% of all prescriptions), and their side-effects are very common. These drugs, the older group, nonselective ciclooxigenase inibitors (inhibitors of COX-1 and COX-2), may increase blood pressure and cardiovascular risk. Many studies have shown that NSAID could increase blood pressure for 5–10 mmHg. The use of NSAID is common and their side effects to increase blood pressure have a large impact on the public health. The main mechanism of the increased blood pressure by NSAID is blockage of prostaglandin synthesis. The results of blockage of prostaglandin synthesis are sodium and fluid retention. NSAID may increase blood pressure in normotensive and hypertensive persons. Indomethacin, naproxen, and other NSAID increase the blood pressure in patients treated with b-blockers, diuretics, metildopa, ACE-inhibitors and combination of various antihipertensive drugs, but there is no increase of blood pressure in patients treated with calcium blockers. In many studies, aspirin did not increase the blood pressure. The new group of NSAID, coxibes, selective ciclooxigenase inibitors (inhibitors of COX-2) could increase the blood pressure like older generation of NSAID

DRUG INDUCED ALLERGIC INTERSTITIAL NEPHRITIS

Alergijski intersticijski nefritis (AIN) uzrokovan lijekovima rijedak je oblik bubrežne bolesti koji se klinički primarno manifestira akutnom bubrežnom insuficijencijom. Najčešća etiopatogeneza AIN-a reakcija je preosjetljivosti na lijekove među kojima su najzastupljeniji antibiotici. Najvažnija dijagnostička metoda u bolesnika sa sumnjom na AIN jest biopsija bubrega. Uz ukidanje uzročnog lijeka, u liječenju AIN preporučuje se primjena glukokortikoida, u dozi od 1 mg/kg/dan s postepenim snižavanjem doze, u trajanju do 3 mjeseca. U ovom radu, prikazali smo 10 bolesnika kod kojih je nakon pregleda bubrežnog bioptata s nalazom AIN-a, retrospektivno učinjena analiza kliničkih i biokemijskih podataka. Definirane su četiri različite uzročne skupine lijekova AIN-a, a najčešći su bili antibiotici. U kliničkoj prezentaciji dominirala je akutna bubrežna insuficijencija s medijanom serumskog kreatinina od 497,5 µmol/L. Svi bolesnici osim jednoga liječeni su preporučenim dozama glukokortikoida. Troje bolesnika liječeno je i hemodijalizom. U svih bolesnika došlo je do oporavka bubrežne funkcije, uz medijan serumskog kreatinina nakon tromjesečnoga glukokortikoidnog liječenja (u sedmero bolesnika) od 152 µmol/L (p=0,018).The allergic interstitial nephritis (AIN) is a rare renal disorder which is commonly clinically presented with an acute renal failure. AIN is the most frequent result of the hypersensitivity related to drugs (most often antibiotics). In the patients with clinical suspicion to a drug related AIN, kidney biopsy is the most important diagnostic procedure. Except of causative drug discontinuation, AIN therapy is based on high dose glucocorticoids 1 mg/kg/day with dose tapering during consecutive 3 months. In the present work, we have shown 10 patients with drug induced AIN. We identified 4 causative drug groups among which most frequent were antibiotics. In clinical presentation of our patients acute renal failure was dominant and median of baseline serum creatinine was 497.5 µmol/L. In all patients the kidney biopsy was performed and nine patients (90%) have been treated with recommended glucocorticoid regimen, additionally, in 3 patients hemodialysis was introduced. In all patients, reduction in serum creatinine value was achieved with serum creatinine median of 152 µmol/L after a three-month glucocorticoid treatment (p=0.018)

Liječiti ili ne visoko normalan krvni tlak?

Vrijednosti sistoličkoga krvnog tlaka od 130 do 139 mmHg te dijastoličkog od 85 do 89 mmHg smatraju se visoko normalnim krvnim tlakom. Već se duže vrijeme raspravlja treba li bolesnike s visoko normalnim krvnim tlakom medikamentno liječiti. Odgovor su dali Europsko društvo za hipertenziju i Europsko kardiološko društvo 2007. godine kada su objavljene smjernice za dijagnosticiranje i liječenje arterijske hipertenzije. Po smjernicama, medikamentno liječenje visoko normalnoga krvnog tlaka ovisi o ukupnome kardiovaskularnom riziku (ostali rizični čimbenici, druge bolesti), pa se tako intervencija kod bolesnika s visoko normalnim krvnim tlakom kreće od promjene životnih navika do medikamentne terapije. Rezultati novih studija (TROPHY, PHARAO) govore u prilog medikamentnom liječenju bolesnika s visoko normalnim krvnim tlakom, ali su potrebna daljnja istraživanja

GOODPASTURE’S SYNDROME – CASE REPORTS

Goodpastureov sindrom rijedak je klinički entitet karakteriziran brzoprogresivnim glomerulonefritisom (BPGN), difuznim plućnim hemoragijama i prisutnošću cirkulirajućih autoprotutijela na glomerularnu bazalnu membranu (GBM). Autoprotutijela se vežu na reaktivne epitope nekolagene domene a-3 lanca kolagena tipa IV, sastavnog dijela alveolarne i glomerularne bazalne membrane, te aktiviraju kaskadu komplementa, što rezultira oštećenjem tkiva po tipu II reakcije preosjetljivosti prema Coombsu i Gellu. Prognostički faktori uključuju patohistološke promjene i promjene ekskrecijske funkcije bubrega te stupanj plućnog oštećenja u trenutku očitovanja bolesti. Brzo postavljena dijagnoza i što ranije provedeno adekvatno liječenje osobito su važni za bolesnike. Agresivno liječenje kombinacijom imunosupresivne terapije i plazmafereze ima najbolje izglede za uspjeh. U ovom radu prikazano je troje bolesnika koji su se klinički očitovali renopulmonalnim sindromom: bubrežnim zatajenjem, hematurijom, proteinurijom i hemoptizama. Histološki u tkivu bubrega dobivenom biopsijom u svih bolesnika radilo se o glomerulonefritisu s polumjesecima uzrokovanom protutijelima na GBM. U sve troje bolesnika provedeno je liječenje glukokortikoidima, ciklofosfamidom i plazmaferezom. Svi bolesnici preživjeli su uz remisiju plućne bolesti. U dva bolesnika koja su u trenutku kliničke prezentacije imala znatno sniženu ekskrecijsku bubrežnu funkciju i visok postotak polumjeseca u tkivu bubrega dobivenog biopsijom došlo je do trajnoga gubitka bubrežne funkcije. U jednog bolesnika koji je u trenutku očitovanja bolesti pokazivao lakše bubrežno oštećenje te manji postotak polumjeseca došlo je do potpunog oporavka bubrežne funkcije.Goodpasture’s syndrome is a rare clinical entity characterized by rapidly progressive glomerulonephritis, diffuse pulmonary hemorrhage and the presence of circulating autoantibodies to the glomerular basement membrane (GBM). Autoantibodies bind to reactive epitopes of noncollagenous domain of the collagen type IV a-3 chain in glomerular and alveolar basement membranes. Autoantibodies activate the complement cascade resulting in tissue injury by the type II hypersensitivity reaction according to the Coombs and Gell classification of antigen-antibody reactions. Prognostic factors include the renal excretory function and the degree of renal and lung damage at the time of presentation. Prompt diagnosis and early and adequate medical treatment is vital for patients. Clinical treatment must be aggressive in order of achieving better outcome. This article describes three patients who clinically presented with renopulmonary syndrome, renal failure, hematuria, proteinuria and hemoptysis. Kidney biopsy diagnosis was crescentic glomerulonephritis due to antibodies against GBM. In all three patients we started therapy with glucocorticoids and cyclophosphamide combined with plasma exchange therapy. In two patients who initially had severe impairment of renal function and high percentage of crescents in the renal biopsy, kidney function recovery was not achieved. In one patient, who at the time of clinical presentation showed milder renal failure and lower percentage of crescents in renal biopsy, the full recovery of renal function was obtaine

Tireotoksična periodična paraliza: prikaz slučaja

A case of thyrotoxic periodic paralysis in a 24-year-old male with hyperthyroidism is presented. Clinical manifestations included progressive symmetrical weakness that led to flaccid paralysis due to hypokalemia with concurrent thyrotoxicosis. Intravenous administration of potassium chloride resulted in complete regression of the symptoms of muscle weakness and paralysis. Hypokalemic periodic paralysis is an uncommon complication of thyrotoxicosis, which primarily occurs in Orientals, with a high male predominance, and has rarely been described in Caucasians.U radu je prikazan 24-godišnji muškarac s napadajem periodične paralize u hipertireozi. Prikazan je bolesnik s progresivnom simetričnom slabošću koja je dovela do mlohave paralize uslijed hipokalijemije tijekom tireotoksikoze. Nakon parenteralnog dodatka kalija (intravenskom primjenom kalijevog klorida) došlo je do potpunog povlačenja simptoma mišićne slabosti i paralize. Hipokalijemična periodična paraliza rijetka je komplikacija tireotoksikoze opisana u stanovnika Dalekog Istoka, i to prvenstveno u mlađih muškaraca, a iznimno se rijetko javlja u bijelaca