First Documented Case of BK Nephropathy in Kidney Transplant Recipient in Croatia: Usage of Urine Cytology in Evaluation Process

BK virus associated nephropathy (BKVAN) in transplanted kidney, although recognized as a distinct entity in the 1970-es, continues to represent a challenge in kidney transplantation, mainly because the optimal treatment approach has not been determined yet. The fact that about 10–20% of patients have simultaneously some stage of acute rejection, complicate the treatment even more. Herein we present a case of BK nephropathy in the patient, one year after combined liver and kidney transplantation, complicated by episode of acute T-cell mediated rejection. Identification of decoy cells by cytology urine exam in patient with acute kidney graft function deterioration, raised suspicion of BKVAN. Diagnosis has been made by histological examination and confirmed with immunohistochemical staining for BK virus in kidney graft biopsy. One month after he had been treated for BKVAN with intravenous immunoglobulin, leflunomide and overall immunosuppression therapy reduction, there was further deterioration of graft function due to an episode of acute T-cell mediated rejection (Banff classification IA). He received 500 mg of metilprednisolon intravenously and mycophenolate mofetil had been reintroduced, which resulted in slow partial recovery of the graft function, but never to the baseline values. For the past two years his renal graft function has been stable, maintaining lower levels of immunosupressive therapy. According to our knowledge this is the first documented case of BK virus associated nephropathy, diagnosed and confirmed with immunohistochemical staining of tissue from kidney biopsy in Croatia

First Documented Case of BK Nephropathy in Kidney Transplant Recipient in Croatia: Usage of Urine Cytology in Evaluation Process

BK virus associated nephropathy (BKVAN) in transplanted kidney, although recognized as a distinct entity in the 1970-es, continues to represent a challenge in kidney transplantation, mainly because the optimal treatment approach has not been determined yet. The fact that about 10–20% of patients have simultaneously some stage of acute rejection, complicate the treatment even more. Herein we present a case of BK nephropathy in the patient, one year after combined liver and kidney transplantation, complicated by episode of acute T-cell mediated rejection. Identification of decoy cells by cytology urine exam in patient with acute kidney graft function deterioration, raised suspicion of BKVAN. Diagnosis has been made by histological examination and confirmed with immunohistochemical staining for BK virus in kidney graft biopsy. One month after he had been treated for BKVAN with intravenous immunoglobulin, leflunomide and overall immunosuppression therapy reduction, there was further deterioration of graft function due to an episode of acute T-cell mediated rejection (Banff classification IA). He received 500 mg of metilprednisolon intravenously and mycophenolate mofetil had been reintroduced, which resulted in slow partial recovery of the graft function, but never to the baseline values. For the past two years his renal graft function has been stable, maintaining lower levels of immunosupressive therapy. According to our knowledge this is the first documented case of BK virus associated nephropathy, diagnosed and confirmed with immunohistochemical staining of tissue from kidney biopsy in Croatia

Polyomavirus Associated Nephropathy after Kidney and Pancreas Transplantation: Case Report

Polyomavirus virus associated nephropathy (PVAN) is an important cause of graft failure in the renal transplant population. The prevalence of PVAN has increased from 1% to 10% in the past decade, leading to loss of transplanted organ in 30% to 80% of cases. In the absence of specific antiviral drugs, early detection of disease and modification/reduction of immunosuppressive regimen is currently the cornerstone of therapy. In the setting of multiorgan transplantation, like simultaneous pancreas and kidney transplantation (SPKT), diagnosis and therapy of PVAN can be even more challenging problem. We report a first described case of PVAN in patient after SPKT in Croatia. Patient is a 32 years old Caucasian male with type 1 diabetes mellitus and end stage renal failure, diagnosed for PVAN 6 month after SPKT. Patient was treated with reduced immunosuppressive regimen. At 32 month follow up, patient has preserved kidney and pancreas function with estimated glomerular filtration (eGFR) rate of 91 mL/min and no signs of PVAN on his 2 year protocol kidney biopsy

Protein ADAMTS-4 as a novel biomarker in chronic kidney disease

Provedeno je istraživanje pojavnosti ADAMTS-4 proteina u KBB u cilju utvrđivanja ove molekule kao novog biološkog biljega KBB. Uključeno je 150 ispitanika podijeljenih u 9 skupina: 5 (stupnjevi KBB1-5), 1 hemodijaliza, 1 peritonejska dijaliza, 1 nakon transplantacije bubrega te 1 skupina zdravih ispitanika. Metode su uključivale: (1) tekućinsku kromatografiju sa spektrometrijom masa za proteomsku analizu ekspresije proteina u združenim uzorcima plazme svake pojedine skupine te dodatnom analizom signalnih bioloških puteva obogaćivanjem gena; (2) ELISA analizu pojedinačnih uzoraka krvi i mokraće 79 ispitanika iz navedenih 9 skupina; (3) imunohistokemijsku analizu (IHK) ADAMTS-4 na biopsijskim tkivima 19 nativnih i 34 transplantirana bubrega s KBB te 8 bubrega bez KBB. Parna analiza je uključila 15 postransplantacijskih biopsija i njihovih parnih biopsija učinjenih tijekom postupka transplantacije. Proteomska analiza pokazala je da se značajna promjena trenda ekspresije različitih skupina proteina događa u stupnju KBB2. ADAMTS-4 nije utvrđen proteomskom analizom, ali je njegova prisutnost potvrđena ELISA analizom. Njegova koncentracija nije korelirala s napredovanjem KBB. Najviše prosječne koncentracije u plazmi utvrđene su u stupnjevima KBB2 i KBB3. Frekvencija pojavljivanja IHK ekspresije ADAMTS-4 u području intersticija, peritubularnih i glomerularnih kapilara bila je viša u skupinama s KBB u odnosu na kontrole. Ekspresija proteina ADAMTS-4 u području peritubularnih kapilara bila je značajno češća u bubrezima s razvijenom (KBB3-5) u odnosu na početnu (KBB1-2) fazu bolesti. Viši stupanj intersticijske fibroze bio je povezan s ekspresijom ADAMTS-4 u području bubrežnog intersticija. U analizi parova ADAMTS-4 značajno je češće izražen u skupini s nižom glomerulskom filtracijom i višim stupnjem fibroze u odnosu na skupinu biopsija učinjenih tijekom postupka transplantacije. Zaključno, ADAMTS-4 mogao bi biti novi biološki biljeg KBB, povezan sa stupnjem progresije bolesti i pokazateljima bubrežne fibroze te su potrebna daljnja istraživanja.Aim of the study was to investigate ADAMTS-4 molecule as a novel biomarker of CKD. ADAMTS-4 were determined in plasma and urine of 150 participants from 9 investigational groups: 5 (CKD stages 1-5), 1 haemodialysis, 1 peritoneal dialysis, 1 kidney transplant recipients and 1 healthy control. Methods included high-liquid performance chromatography accompanied by mass spectrometry of pooled group samples and ELISA of 79 individual samples. Gene enrichment analysis for significant biological pathways was performed afterwards. Immunohistochemistry (IHC) analysis included biopsy samples from 19 native and 34 transplanted kidneys with CKD and controls without CKD. Paired analysis included 15 posttransplant and their biopsy pairs, taken at transplantation. Expression of considerable number of proteins changed their trend significantly in stage 2 of CKD. ADAMTS-4 was not detected by proteomic analysis, but confirmed by ELISA. The highest plasma concentrations were detected in stages CKD2 and CKD3 but correlated poorly with CKD progression. Biopsy samples with CKD expressed ADAMTS-4 significantly more frequent than controls. Frequencies of IHC staining were significantly higher in biopsies with higher stages of fibrosis. In paired analysis expression was significantly higher in group with lower eGFR and higher fibrosis score. ADAMTS-4 could be a novel biomarker for chronic kidney disease but further validation is needed

Protein ADAMTS-4 as a novel biomarker in chronic kidney disease

Provedeno je istraživanje pojavnosti ADAMTS-4 proteina u KBB u cilju utvrđivanja ove molekule kao novog biološkog biljega KBB. Uključeno je 150 ispitanika podijeljenih u 9 skupina: 5 (stupnjevi KBB1-5), 1 hemodijaliza, 1 peritonejska dijaliza, 1 nakon transplantacije bubrega te 1 skupina zdravih ispitanika. Metode su uključivale: (1) tekućinsku kromatografiju sa spektrometrijom masa za proteomsku analizu ekspresije proteina u združenim uzorcima plazme svake pojedine skupine te dodatnom analizom signalnih bioloških puteva obogaćivanjem gena; (2) ELISA analizu pojedinačnih uzoraka krvi i mokraće 79 ispitanika iz navedenih 9 skupina; (3) imunohistokemijsku analizu (IHK) ADAMTS-4 na biopsijskim tkivima 19 nativnih i 34 transplantirana bubrega s KBB te 8 bubrega bez KBB. Parna analiza je uključila 15 postransplantacijskih biopsija i njihovih parnih biopsija učinjenih tijekom postupka transplantacije. Proteomska analiza pokazala je da se značajna promjena trenda ekspresije različitih skupina proteina događa u stupnju KBB2. ADAMTS-4 nije utvrđen proteomskom analizom, ali je njegova prisutnost potvrđena ELISA analizom. Njegova koncentracija nije korelirala s napredovanjem KBB. Najviše prosječne koncentracije u plazmi utvrđene su u stupnjevima KBB2 i KBB3. Frekvencija pojavljivanja IHK ekspresije ADAMTS-4 u području intersticija, peritubularnih i glomerularnih kapilara bila je viša u skupinama s KBB u odnosu na kontrole. Ekspresija proteina ADAMTS-4 u području peritubularnih kapilara bila je značajno češća u bubrezima s razvijenom (KBB3-5) u odnosu na početnu (KBB1-2) fazu bolesti. Viši stupanj intersticijske fibroze bio je povezan s ekspresijom ADAMTS-4 u području bubrežnog intersticija. U analizi parova ADAMTS-4 značajno je češće izražen u skupini s nižom glomerulskom filtracijom i višim stupnjem fibroze u odnosu na skupinu biopsija učinjenih tijekom postupka transplantacije. Zaključno, ADAMTS-4 mogao bi biti novi biološki biljeg KBB, povezan sa stupnjem progresije bolesti i pokazateljima bubrežne fibroze te su potrebna daljnja istraživanja.Aim of the study was to investigate ADAMTS-4 molecule as a novel biomarker of CKD. ADAMTS-4 were determined in plasma and urine of 150 participants from 9 investigational groups: 5 (CKD stages 1-5), 1 haemodialysis, 1 peritoneal dialysis, 1 kidney transplant recipients and 1 healthy control. Methods included high-liquid performance chromatography accompanied by mass spectrometry of pooled group samples and ELISA of 79 individual samples. Gene enrichment analysis for significant biological pathways was performed afterwards. Immunohistochemistry (IHC) analysis included biopsy samples from 19 native and 34 transplanted kidneys with CKD and controls without CKD. Paired analysis included 15 posttransplant and their biopsy pairs, taken at transplantation. Expression of considerable number of proteins changed their trend significantly in stage 2 of CKD. ADAMTS-4 was not detected by proteomic analysis, but confirmed by ELISA. The highest plasma concentrations were detected in stages CKD2 and CKD3 but correlated poorly with CKD progression. Biopsy samples with CKD expressed ADAMTS-4 significantly more frequent than controls. Frequencies of IHC staining were significantly higher in biopsies with higher stages of fibrosis. In paired analysis expression was significantly higher in group with lower eGFR and higher fibrosis score. ADAMTS-4 could be a novel biomarker for chronic kidney disease but further validation is needed

Protein ADAMTS-4 as a novel biomarker in chronic kidney disease

Provedeno je istraživanje pojavnosti ADAMTS-4 proteina u KBB u cilju utvrđivanja ove molekule kao novog biološkog biljega KBB. Uključeno je 150 ispitanika podijeljenih u 9 skupina: 5 (stupnjevi KBB1-5), 1 hemodijaliza, 1 peritonejska dijaliza, 1 nakon transplantacije bubrega te 1 skupina zdravih ispitanika. Metode su uključivale: (1) tekućinsku kromatografiju sa spektrometrijom masa za proteomsku analizu ekspresije proteina u združenim uzorcima plazme svake pojedine skupine te dodatnom analizom signalnih bioloških puteva obogaćivanjem gena; (2) ELISA analizu pojedinačnih uzoraka krvi i mokraće 79 ispitanika iz navedenih 9 skupina; (3) imunohistokemijsku analizu (IHK) ADAMTS-4 na biopsijskim tkivima 19 nativnih i 34 transplantirana bubrega s KBB te 8 bubrega bez KBB. Parna analiza je uključila 15 postransplantacijskih biopsija i njihovih parnih biopsija učinjenih tijekom postupka transplantacije. Proteomska analiza pokazala je da se značajna promjena trenda ekspresije različitih skupina proteina događa u stupnju KBB2. ADAMTS-4 nije utvrđen proteomskom analizom, ali je njegova prisutnost potvrđena ELISA analizom. Njegova koncentracija nije korelirala s napredovanjem KBB. Najviše prosječne koncentracije u plazmi utvrđene su u stupnjevima KBB2 i KBB3. Frekvencija pojavljivanja IHK ekspresije ADAMTS-4 u području intersticija, peritubularnih i glomerularnih kapilara bila je viša u skupinama s KBB u odnosu na kontrole. Ekspresija proteina ADAMTS-4 u području peritubularnih kapilara bila je značajno češća u bubrezima s razvijenom (KBB3-5) u odnosu na početnu (KBB1-2) fazu bolesti. Viši stupanj intersticijske fibroze bio je povezan s ekspresijom ADAMTS-4 u području bubrežnog intersticija. U analizi parova ADAMTS-4 značajno je češće izražen u skupini s nižom glomerulskom filtracijom i višim stupnjem fibroze u odnosu na skupinu biopsija učinjenih tijekom postupka transplantacije. Zaključno, ADAMTS-4 mogao bi biti novi biološki biljeg KBB, povezan sa stupnjem progresije bolesti i pokazateljima bubrežne fibroze te su potrebna daljnja istraživanja.Aim of the study was to investigate ADAMTS-4 molecule as a novel biomarker of CKD. ADAMTS-4 were determined in plasma and urine of 150 participants from 9 investigational groups: 5 (CKD stages 1-5), 1 haemodialysis, 1 peritoneal dialysis, 1 kidney transplant recipients and 1 healthy control. Methods included high-liquid performance chromatography accompanied by mass spectrometry of pooled group samples and ELISA of 79 individual samples. Gene enrichment analysis for significant biological pathways was performed afterwards. Immunohistochemistry (IHC) analysis included biopsy samples from 19 native and 34 transplanted kidneys with CKD and controls without CKD. Paired analysis included 15 posttransplant and their biopsy pairs, taken at transplantation. Expression of considerable number of proteins changed their trend significantly in stage 2 of CKD. ADAMTS-4 was not detected by proteomic analysis, but confirmed by ELISA. The highest plasma concentrations were detected in stages CKD2 and CKD3 but correlated poorly with CKD progression. Biopsy samples with CKD expressed ADAMTS-4 significantly more frequent than controls. Frequencies of IHC staining were significantly higher in biopsies with higher stages of fibrosis. In paired analysis expression was significantly higher in group with lower eGFR and higher fibrosis score. ADAMTS-4 could be a novel biomarker for chronic kidney disease but further validation is needed

Polyomavirus associated nephropathy after kidney and pancreas transplantation: case report [Polomavirusom uzrokovana nefropatija nakon simultane transplantacije bubrega i gušterače: prikaz slučajeva]

Polyomavirus virus associated nephropathy (PVAN) is an important cause of graft failure in the renal transplant population. The prevalence of PVAN has increased from 1% to 10% in the past decade, leading to loss of transplanted organ in 30% to 80% of cases. In the absence of specific antiviral drugs, early detection of disease and modification/reduction of immunosuppressive regimen is currently the cornerstone of therapy. In the setting of multiorgan transplantation, like simultaneous pancreas and kidney transplantation (SPKT), diagnosis and therapy of PVAN can be even more challenging problem. We report a first described case of PVAN in patient after SPKT in Croatia. Patient is a 32 years old Caucasian male with type 1 diabetes mellitus and end stage renal failure, diagnosed for PVAN 6 month after SPKT. Patient was treated with reduced immunosuppressive regimen. At 32 month follow up, patient has preserved kidney and pancreas function with estimated glomerular filtration (eGFR) rate of 91 mL/min and no signs of PVAN on his 2 year protocol kidney biopsy

First documented case of BK nephropathy in kidney transplant recipient in Croatia: usage of urine cytology in evaluation process [Prvi potvrđeni slučaj BK virusne nefropatije u bolesnika sa transplantiranim bubregom u Hrvatskoj: korištenje citološke analize urina u otkrivanju bolesti]

BK virus associated nephropathy (BKVAN) in transplanted kidney, although recognized as a distinct entity in the 1970-es, continues to represent a challenge in kidney transplantation, mainly because the optimal treatment approach has not been determined yet. The fact that about 10–20% of patients have simultaneously some stage of acute rejection, complicate the treatment even more. Herein we present a case of BK nephropathy in the patient, one year after combined liver and kidney transplantation, complicated by episode of acute T-cell mediated rejection. Identification of decoy cells by cytology urine exam in patient with acute kidney graft function deterioration, raised suspicion of BKVAN. Diagnosis has been made by histological examination and confirmed with immunohistochemical staining for BK virus in kidney graft biopsy. One month after he had been treated for BKVAN with intravenous immunoglobulin, leflunomide and overall immunosuppression therapy reduction, there was further deterioration of graft function due to an episode of acute T-cell mediated rejection (Banff classification IA). He received 500 mg of metilprednisolon intravenously and mycophenolate mofetil had been reintroduced, which resulted in slow partial recovery of the graft function, but never to the baseline values. For the past two years his renal graft function has been stable, maintaining lower levels of immunosupressive therapy. According to our knowledge this is the first documented case of BK virus associated nephropathy, diagnosed and confirmed with immunohistochemical staining of tissue from kidney biopsy in Croatia

Inkapsulirajuća peritonealna skleroza - uspješno medicinsko/kirurško liječenje i transplantancija bubrega: prikaz slučaja

The patient was born in 1967. In 2004 the patient started renal replacement therapy with peritoneal dialysis. In 2010, after the first episode of peritonitis caused by Staphylococcus aureus, due to poor response to antibiotic therapy, the peritoneal catheter was removed. A month after this episode, pain accompanied by fever and an increase in inflammatory parameters occurred. Initial computed tomography scans did not show any specific abnormalities and the second CT two months later diagnosed sclerosing peritonitis. Corticosteroid and tamoxifen therapy with enteral nutrition was initiated. Five months after the symptoms started, the patient developed intestinal obstruction, so a nasogastric tube was placed and total parenteral nutrition was introduced. After four months, the patient was surgically treated at the Manchester Royal Infirmary, resection of the terminal ileum and caecum was performed, and an ileocecal anastomosis with enterolysis was performed. Then, in 2012, a successful kidney transplant was performed. The patient has since remained without clinical signs of obstruction. Tamoxifen and corticosteroid therapy with adequate nutritional support, surgical treatment, and transplantation with long-term immunosuppressive therapy may be reasons for long-term remission and survival ten years after EPS diagnosis.Bolesnici rođenoj 1967. godine, 2004. godine započeto je nadomještanje bubrežne funkcije peritonejskom dijalizom. 2010. godine bolesnica je imala prvu epizodu peritonitisa uzrokovanu Staphylococcus aureusom. Zbog nepostizanja adekvatnog odgovora na ciljanu antibiotsku terapiju, izvađen je peritonejski kateter i bolesnica je transferirana na hemodijalizu. Nakon kliničkog i laboratorijskog poboljšanja, mjesec dana kasnije javila se bol nakon jela uz povišenu temperaturu i porast upalnih parametera. Inicijalno učinjen CT abdomena nije bio specifičan, tek na ponovljenom CT-u dva mjeseca kasnije nađeni su znaci sklerozirajućeg peritonitisa. Započeta je terapija kortikosteroidom i tamoksifenom uz enteralnu prehranu. Pet mjeseci od pojave sklerozirajućeg peritonitisa bolesnica je razvila sliku intestinalne opstrukcije, pa je plasirana nazogastrična sonda i uvedena je totalna parenteralna prehrana. Nakon četiri mjeseca bolesnica je operativno liječna u Manchester Royal Infirmary, učinjena je resekcija terminalnog ileuma i cekuma i formirana je ileocekalna anastomoza, te enteroliza preostalih crijeva. Potom je 2012. godine učinjena uspješna transplantacija bubrega. Bolesnica od operativnog liječenja je bez kliničkih znakova opstrukcije. Terapija tamoksifenom i kortikosteroidima uz odgovarajuću prehrambenu podršku unatoč ileusu, kirurško liječenje u centru koji ima iskustva u liječenju EPS-om (enkapsulirajuća peritonealna skleroza) i transplantacija s dugotrajnom imunosupresivnom terapijom mogu biti razlozi dugotrajne remisije i preživljenja deset godina od dijagnoze EPS-a

Prvi potvrđeni slučaj BK virusne nefropatije u bolesnika sa transplantiranim bubregom u Hrvatskoj: korištenje citološke analize urina u otkrivanju bolesti

BK virus associated nephropathy (BKVAN) in transplanted kidney, although recognized as a distinct entity in the 1970-es, continues to represent a challenge in kidney transplantation, mainly because the optimal treatment approach has not been determined yet. The fact that about 10–20% of patients have simultaneously some stage of acute rejection, complicate the treatment even more. Herein we present a case of BK nephropathy in the patient, one year after combined liver and kidney transplantation, complicated by episode of acute T-cell mediated rejection. Identification of decoy cells by cytology urine exam in patient with acute kidney graft function deterioration, raised suspicion of BKVAN. Diagnosis has been made by histological examination and confirmed with immunohistochemical staining for BK virus in kidney graft biopsy. One month after he had been treated for BKVAN with intravenous immunoglobulin, leflunomide and overall immunosuppression therapy reduction, there was further deterioration of graft function due to an episode of acute T-cell mediated rejection (Banff classification IA). He received 500 mg of metilprednisolon intravenously and mycophenolate mofetil had been reintroduced, which resulted in slow partial recovery of the graft function, but never to the baseline values. For the past two years his renal graft function has been stable, maintaining lower levels of immunosupressive therapy. According to our knowledge this is the first documented case of BK virus associated nephropathy, diagnosed and confirmed with immunohistochemical staining of tissue from kidney biopsy in Croatia.BK virusna nefropatija, koja je prepoznata kao posebni entitet u transplantiranom bubregu još tijekom 1970-tih godina, i dalje predstavlja dijagnostički i terapijski izazov u transplantacijskoj medicine. Otprilike 10–20% bolesnika istovremeno razvije određeni stupanj akutnog odbacivanja grafta bubrega, što dodatno komplicira pristup liječenju. Prikazujemo slučaj nefropatije uzrokovane BK virusom u bolesnika, godinu dana nakon istovremene transplantacije bubrega i jetre, čije liječenje je dodatno komplicirala epizoda akutnog odbacivanja bubrega. Temeljem citološke analize i nalaza tzv. »decoy« stanica u urinu bolesnika sa akutnim pogoršanjem funkcije grafta bubrega, postavljena je sumnja na BK virusnu nefropatiju, a dijagnoza je postavljena temeljem patohistološke analize bioptata tkiva bubrega i specifičnog imunohistokemijskog bojenja tkiva na BK virus. Bolesnika smo liječili smanjenjem ukupne doze imunosupresivne terapije, uz adjuvantnu intravensku primjenu humanog imunoglobulina, te zamjenom mikofenolat mofetila sa leflunomidom. Mjesec dana nakon početka liječenja dolazi do daljnjeg pogoršanja bubrežne funkcije, uzrokovane patohistološki dokazanom epizodom akutnog odbacivanja posredovanog T-limfocitima. Bolesnik je liječen parenteralno Solumedrolom, uz ponovo uvođenje mikofenolat mofetila, čime se funkcija grafta bubrega djelomično oporavlja i ostaje stabilna tijekom posljednje dvije godine, uz trajno nižu razinu ukupne imunosupresivne terapije. Temeljem našeg saznanja, radi se o prvom potvrđenom slučaju BK nefropatije u bolesnika s transplantiranim bubregom u Hrvatskoj, čija je dijagnoza postavljena temeljem specifičnog imunohistokemijskog bojenja tkiva bubrega na BK virus