Multidisciplinary management of a typical case of acute kidney failure in the course of COVID-19 infection

Abstract

We report the case of a 68-year-old patient who arrived at the hospital with a fever and a cough for 7 days, a history of high blood pressure and chronic kidney failure stage 2 according to CKD-EPI (GFR: 62 ml/minute with creatinine: 1.2 mg/dl). Home therapy included lercanidipine and clonidine. A chest radiograph performed in the emergency department immediately showed images suggestive of pneumonia from COVID-19, confirmed in the following days by a positive swab for coronavirus. Kidney function parameters progressively deteriorated towards a severe acute kidney failure on the 15th day, with creatinine values of 6.6 mg/dl and urea of 210 mg/dl. The situation was managed first in the intensive care unit with CRRT cycles (continuous renal replacement therapy) and then in a “yellow area” devoted to COVID patients, where the patient was dialyzed by us nephrologists through short cycles of CRRT. In our short experience we have used continuous techniques (CRRT) in positive patients hemodynamically unstable and intermittent dialysis (IRRT) in our stable chronic patients with asymptomatic COVID -19. We found CRRT to be superior in hemodynamically unstable patients hospitalized in resuscitation and in the “yellow area”. Dialysis continued with high cut-off filters until the normalization of kidney function; the supportive medical therapy has also improved the course of the pathology and contributed to the favorable outcome for our patient. During the COVID-19 pandemic, our Nephrology Group at Savona’s San Paul Hospital has reorganized the department to better manage both chronic dialyzed patients and acute patients affected by the new coronavirus.

 

Keywords: COVID-19, “yellow area”, AKI, ACE2, viral particles, nephrology, CRRT

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Introduzione

Il danno renale acuto (Acute Kidney Injury, AKI) è una condizione patologica possibile tra i pazienti con Covid-19. Colpendo il 20-40 % dei pazienti ammessi in rianimazione, secondo l’esperienza in Europa e in USA, è considerato un marker di severità della patologia e un fattore prognostico negativo per la sopravvivenza [1].

Studi recenti riportano una più alta frequenza di anomalie urinarie nei pazienti con Covid-19. Nello studio cinese di Cheng et al. su 710 pazienti ospedalizzati con Covid-19, il 44% aveva proteinuria e ematuria ed il 27% aveva ematuria all’ingresso in ospedale. La prevalenza di elevati valori di creatinina sierica e di urea all’ingresso erano del 15,5% e del 14.1% [2,3]. La gran parte dei pazienti presentava quindi anomalie urinarie in assenza di dati clinici e laboratoristici di insufficienza renale acuta, presentando dunque un danno subclinico.

Secondo un altro studio cinese, l’incidenza di AKI in Covid-19 variava tra 0,9% e 29% in diversi centri [4], mostrando la minor frequenza di coinvolgimento renale nelle popolazioni orientali.

Lo stesso studio ci rivela vari quadri istopatologici renali dall’osservazione e studio di 26 autopsie di pazienti con Covid-19. I pazienti, 19 maschi e 7 femmine, alla morte avevano un’età media di 69 anni. La causa di morte era insufficienza respiratoria con sindrome da disfunzione multiorgano. Nove dei 26 pazienti mostravano segni di danno renale acuto, quali incremento della creatinina sierica o comparsa di proteinuria.

I quadri osservati furono i seguenti:

  1. Con microscopia ottica: danno diffuso del tubulo prossimale con degenerazione vacuolare, necrosi franca, dilatazione del lume tubulare con detriti cellulari. In due pazienti, erano osservati segni di pielonefrite acuta con batteri e polimorfonucleati nel lume dei tubuli. I tubuli distali e dotti collettori mostravano solo occasionale rigonfiamento cellulare ed espansione edematosa dell’interstizio senza grande infiammazione.
  2. Con microscopia elettronica, particelle simil-coronavirus sono state osservate nell’epitelio dei tubuli prossimali renali, nei podociti, e meno anche nei dotti distali, di diametro tra 65 e 136 nm con spike distintivi che assumevano l’aspetto di una corona. Aggregati di eritrociti sono stati osservati nel lume dei capillari peritubulari e anche nei capillari glomerulari. Depositi di emosiderina, danno endoteliale con trombi determinanti collasso ischemico e altri pigmenti relativi ad una rabdomiolisi sono stati rilevati.
  3. L’immunofluorescenza diretta o indiretta ha mostrato la presenza di IgM e C3. In particolare, una biopsia ha mostrato IgG granulari lungo la parete capillare e in un caso sono state osservate IgA in area mesangiale e sulla parete capillare, associati a corrispondenti depositi mesangiali e sottoendoteliali alla microscopia elettronica.

Lo stato di ipercoagulabilità presente nei pazienti con SARS-COV2 potrebbe essere responsabile in alcuni casi del passaggio da necrosi tubulare acuta a necrosi corticale acuta, determinando un danno renale irreversibile [5].

Circa il 20% dei pazienti positivi al Covid-19 ricoverati in rianimazione necessitava di tecniche CRRT (Terapia Sostitutiva Renale Continua) a una media di 15 giorni dall’inizio della malattia per l’insorgenza di AKI non rispondente alla terapia medica.

L’AKI viene definita da un incremento dei valori di creatinina sierica di 0.3 mg/dl in 48 ore e del 50% rispetto al valore basale entro 7 giorni [6]. Il valore basale è il valore della creatinina all’ingresso del paziente in ospedale.

Il danno renale acuto è classificabile in vari stadi:

  1. AKI stadio 1: la creatinina è 1,5-1,9 volte il valore iniziale. La produzione di urina è <0,5 ml/kg/h per 6-12 ore.
  2. AKI stadio 2: la creatinina è 2-2,9 volte il valore iniziale. La produzione di urina è <0,5 ml/kg/h per >12 ore.
  3. AKI stadio 3: la creatinina è 3 volte il valore iniziale oppure c’è un aumento di creatinina fino a valori >4 mg/dl. La produzione di urina è <0,3 ml/kg/h per >24h o c’è anuria per >24h.

I meccanismi fisiopatologici alla base dell’AKI in Covid-19 sono molteplici. Alcuni dati autoptici [7] indicano che viene colpito sia l’endotelio dei polmoni che quello del rene. SARS-CoV-2, inoltre, può direttamente infettare le cellule dell’epitelio tubulare e i podociti attraverso il legame con ACE2 (Angiotensin Converting Enzyme 2), causando disfunzione mitocondriale, necrosi tubulare acuta, glomerulopatia collassante. L’espressione di ACE2 è stata riportata in diversi organi, tra cui rene, cuore e intestino [8].

Le ultime ricerche indicano che l’AKI, il danno cardiaco e il dolore addominale sono le più comuni comorbidità di Covid-19, suggerendo che SARS-CoV-2 può avere un tropismo per questi organi.

 

Ingresso del Covid-19 nella cellula

Il SARS-CoV-2 entra nelle cellule del nostro organismo attraverso i recettori ACE2. Il recettore ACE2 è pressoché ubiquitario: è stato isolato sulla mucosa orale e nasale, nel nasofaringe, polmoni, stomaco, intestino tenue, colon, linfonodi, timo, midollo osseo, milza, fegato, reni e cervello, vasi, cuore. Tuttavia, l’83% delle cellule che esprimono ACE2 sembrano essere pneumociti di tipo 2. Il recettore ACE2 è anche espresso sul versante luminale dell’epitelio intestinale. Gli pneumociti di tipo 2 sono cellule cilindriche che rivestono gli alveoli occupando solo il 5% della superficie alveolare. Le infezioni severe causate dal virus Covid-19 interessano principalmente i polmoni, nonostante l’ubiquitarietà dei recettori ACE2. È vero però che i pazienti con infezione grave da SARS-CoV-2 presentano spesso anche danni miocardici, o anche lesioni multiorgano; comunque sia, i danni principali sembrano avvenire a livello polmonare.

È stato studiato che una mutazione della proteina Spike di SARS-CoV2 (proteina S situata sulla superficie esterna del virus) conferisce al virus affinità per una sequenza proteica complementare localizzata sulla regione carbossipeptidasica del recettore umano ACE2, un recettore che metabolizza l’angiotensina II per generare angiotensina 1-7. Il legame con il recettore è necessario affinché un altro enzima, TMPRSS2 (Transmembrane Protease Serine 2, un membro della sottofamiglia Hepsin-TMPRSS), separi la sequenza S1 da S2 di Spike. La porzione S2 della proteina, una volta esposta, aggancia la membrana cellulare dell’ospite dando inizio al meccanismo molecolare di ingresso del virus. In particolare, la proteina S si lega al recettore ACE2. Il legame sembra avvenire tra i residui 272 e 537 della proteina S virale 16. La proteina S del virus SARS-CoV-2 è strutturalmente identica alla proteina S dei virus SARS-CoV e MERS-CoV per la maggior parte. Questi dati potrebbero giustificare il fatto che una precedente esposizione ai coronavirus possa essere almeno in parte protettiva verso l’attuale SARS-CoV-2.

L’ingresso del virus nella cellula attraverso il recettore ACE2 viene mediato da alcune proteasi situate sulla superficie cellulare, in stretta vicinanza con il recettore ACE2, facilitando l’ingresso del virus nella cellula. Altre proteasi facilitano la diffusione del virus una volta che questo è penetrato all’interno della cellula. In particolare, la serin-proteasi TMPRSS2 è un enzima proteolitico transmembrana, che strutturalmente e funzionalmente fa parte del recettore ACE2. È proprio il TMPRSS2 che “attacca” l’unità S1 della proteina S virale e, grazie alla sua attività enzimatica, la distacca dall’unità S2. A distacco avvenuto, l’unità S2 virale si fonde con la cellula e, attraverso tale fusione, avviene il trasferimento del contenuto virale all’interno della cellula [9,10]. Tale attività enzimatica (distacco dell’unità S1) aumenta di quasi 100 volte l’ingresso del virus nella cellula attraverso il recettore ACE2.

Oltre alla spike protein hanno un ruolo nell’ingresso di SARS-COV2 nelle cellule:

  • Proteina M: la proteina di membrana (M) attraversa il rivestimento (envelope) interagendo all’interno del virione con il complesso RNA-proteina.
  • Dimero emagglutinina-esterasi (HE): questa proteina del rivestimento, più piccola della glicoproteina S, svolge una funzione importante durante la fase di rilascio del virus all’interno della cellula ospite.
  • Proteina E: l’espressione di questa proteina aiuta la glicoproteina S (e quindi il virus) ad attaccarsi alla membrana della cellula bersaglio.
  • Envelope: è il rivestimento del virus, costituito da una membrana che il virus “eredita” dalla cellula ospite dopo averla infettata.

Gli inibitori delle proteasi di superficie e di altri tipi di proteasi sono in grado di frenare l’ingresso dei coronavirus nella cellula. Non è dunque stato dimostrato che la maggiore espressione dei recettori ACE2 specificamente indotta da ACE-inibitori e sartani sia un fattore determinante, indipendente di maggiore penetranza e diffusione locale del virus.

Paradossalmente alcuni studi recenti evidenziano che l’up-regulation degli ACE2 indotta da ARB (recettori bloccanti dell’angiotensina) sarebbe protettiva durante l’infezione da SARS-CoV-2 [9]. L’espressione incrementata di ACE2 da ARB potrebbe indurre il sequestro di SARS-CoV-2 sulla membrana cellulare, senza incremento di TMPRSS2, limitando l’infezione virale [10].

Altre cause di Danno renale acuto:

Causa alternativa del danno renale acuto potrebbe essere una congestione renale e successiva AKI secondaria a insufficienza ventricolare destra da polmonite. Parallelamente, l’insufficienza ventricolare sinistra potrebbe portare a riduzione della gittata cardiaca e ipoperfusione renale.

Altri potenziali meccanismi di AKI sono: la disregolazione della risposta immunitaria con linfopenia e sindrome da rilascio di citochine, la rabdomiolisi, la sindrome da attivazione di macrofagi, lo sviluppo di microemboli e microtrombi e, quindi, una microangiopatia trombotica.

 

Figura 1: Struttura di SARS COV 2 della glicoproteina S. (A) La virulenza di SARS COV-2 dipende dall’attività di 16 proteine non strutturali e di 4 proteine strutturali (M, E, N e S). La proteina M regola il trasporto dei nutrienti attraverso la membrana e interagisce con il complesso RNA-proteine.La proteina E aiuta la proteina S ad ancorarsi alla cellula ospite. La proteina N aumenta la stabilità del singolo filamento a RNA. (B) La glicoproteina S è composta da due subunità S1 e S2. S1 svolge una funzione di legame al recettore mentre S2 svolge le funzioni di fusione tra virus e cellula e l’internalizzazione del virus. Gli omotrimeri della proteina S formano le spike che si attivano grazie alla presenza di una proteasi TMPRSSD2 sulla superfice della cellula ospite, e poi, tramite il dominio di legame per il recettore (RBD) si legano al dominio peptidasico sul recettore ACE2. Fonte: Basta G, Del Turco S, Caselli C, Meloni L, Vianello A. “È guerra Mondiale al Covid-19. Decisiva la prima battaglia sul fronte dell’invasione virale contro l’exitus per polmonite interstiziale”. Recenti Prog Med 2020 111(4):238-252.

 

Terapie sostitutive nel danno renale da Covid-19

Per prevenire e curare l’AKI in pazienti con Covid-19, sono state prese in considerazione la terapia medica conservativa e la terapia sostitutiva: CRRT o IRRT (terapia sostitutiva renale intermittente).

La terapia medica conservativa è importante per tenere in equilibrio il bilancio idrico, evitare il sovraccarico di volume e ridurre il rischio di edema polmonare e successivo sovraccarico ventricolare destro, congestione e danno renale acuto [11]. D’altra parte, i pazienti con Covid-19 spesso presentano febbre e ipovolemia per diversi giorni prima dell’ingresso in ospedale e, all’inizio della degenza, tale deplezione di volume dovrebbe essere corretta per prevenire l’AKI da ipoperfusione renale.

La CRRT è la modalità di dialisi preferita in pazienti emodinamicamente instabili colpiti da Covid-19. La CRRT si divide a sua volta in tecniche diverse:

  1. CVVHD (Continuous Haemodialisis). Utilizza membrane a bassa permeabilità con un flusso di dialisato in controcorrente. La clearance delle molecole avviene per diffusione ed è efficace per la rimozione delle piccole molecole.
  2. CVVHDF (Continuous Haemodiafiltration). Utilizza membrane ad alta permeabilità con flusso di dialisato in controcorrente. La clearance delle molecole viene ottenuta per convezione e diffusione con efficacia sulle molecole più grandi.
  3. CPFA (Continuous Plasma Filtration Coupled with Adsorption). Utilizza un plasmafiltro e il plasmafiltrato ottenuto è spinto in una cartuccia con sostanze assorbenti (resine o carboni); utile per la rimozione di citochine proinfiammatorie. Il plasma rigenerato viene reinfuso.
  4. Pex (Plasma Exchange). Separa la parte corpuscolata del sangue dal plasma, con sua rimozione (di solito il 15%) e sostituzione con plasma da donatore o albumina. Lo scopo è la rimozione di sostanze a peso molecolare elevato, liposolubili o legate a proteine.

Nella nostra breve esperienza abbiamo utilizzato le tecniche continue di CRRT nei pazienti con Covid-19 emodinamicamente instabili e la IRRT nei nostri pazienti cronici affetti da Covid-19 ma stabili e asintomatici o paucisintomatici. Abbiamo riscontrato la superiorità della CRRT sull’IRRT nei pazienti emodinamicamente instabili ricoverati in rianimazione o in area gialla Covid. Probabilmente, ci sono diverse ragioni che fanno preferire le tecniche continue:

  • L’emodialisi intermittente determina più facilmente ipotensione con danno ischemico e ritardo nel recupero funzionale renale.
  • Le membrane cellulosiche usate in dialisi convenzionale sono meno biocompatibili e possono attivare i mediatori dell’infiammazione e i neutrofili.
  • Le tecniche continue permettono un miglior controllo dell’azotemia e quindi una migliore terapia nutrizionale (introito proteico >2g/kg/die).
  • Le tecniche continue permettono un miglior controllo ionico e acido-base.
  • La CRRT permette una migliore perfusione cerebrale e coronarica.

La nostra esperienza ha evidenziato che il precoce inizio di CRRT in pazienti in rianimazione con Covid-19 e AKI previene la progressione della severità della malattia. Questo perché esiste una “finestra di opportunità” per pazienti con grave compromissione da Covid-19. La combinazione di alti livelli di IL-6 (>24,3 pg/ml) e di D-dimero (>0,28 mcg/l) sono stati predittivi di una polmonite severa in pazienti con Covid-19 con una sensibilità del 93% e una specificità del 96%. Il tempo medio dall’inizio della malattia all’entrata in rianimazione è stato di circa 10,5 giorni dopo una media di 1,5 giorni dalla diagnosi di ARDS (Sindrome da Distress Respiratorio Acuto). La vita media dei fattori dell’infiammazione nel sangue è di pochi minuti. Questo suggerisce che i trattamenti di purificazione del sangue devono essere iniziati precocemente: se si innesca la cascata dei mediatori dell’infiammazione, l’efficienza nella rimozione può essere limitata [12].

Il razionale nel trattamento extracorporeo è l’uso di membrane ad alto o medio cut-off per aumentare la rimozione di citochine e quindi ridurre l’infiammazione, oltre a migliorare lo stato di sovraccarico idrico [13]. Le membrane ad alto cut-off possono rimuovere efficacemente molecole di 20-60 KD [14]. Alcune membrane riescono a rimuovere molecole a medio e alto peso molecolare attraverso l’interazione di cariche ioniche. Un esempio è il filtro oXiris, quello utilizzato per eseguire la dialisi continua al paziente protagonista del caso clinico descritto nella prossima sezione.

La membrana oXiris è strutturata in 3 strati:

  1. Una membrana AN69, costituita da una struttura hydrogel idrofilica capace di rimuovere le citochine per convezione attraverso i pori delle membrane (cut-off 40 KD).
  2. Più strati di PEI che è un polimero cationico di polietilenimina capace di assorbire quelle citochine che hanno cariche negative sulla superficie.
  3. Rivestimento di eparina che riduce la trombogenicità e fa in modo che la membrana possa essere usata senza anticoagulazione in pazienti con incrementato rischio di sanguinamento [15].

Uno studio multicentrico francese retrospettivo, in cui erano stati arruolati 31 pazienti con AKI e sepsi, ha dimostrato che dopo il trattamento con la membrana oXiris, la mortalità ospedaliera era ridotta del 30% [16].

 

Figura 2: Struttura del filtro oXiris. Fonte: Monard C, Rimmelè T, Ronco C. “Extracorporeal Blood Purification Therapies for Sepsis”. Blood Purif 2019; 47(suppl 3):2-15.

Un’altra membrana utilizzata da vari centri di rianimazione e dalle Nefrologie nel massimo periodo di pandemia da Covid-19 è stato il cytosorb: cartuccia sorbente a struttura porosa, formato da sfere di polisirene-divinilbenzene e polivinilpirrolidone, assorbe citochine, mioglobina, bilirubina, e altri fattori dell’infiammazione. Può essere usato nell’emodialisi standard, nelle CRRT, nell’ECMO e altre metodiche [17].

 

Metodologia e presentazione caso clinico

Presentiamo e discutiamo in questo manoscritto un caso di AKI insorta in un paziente ricoverato nella nostra rianimazione con polmonite da Covid-19.

Premettiamo che nel nostro ospedale c’è stata, all’inizio dell’epidemia, una riorganizzazione dei reparti, che sono stati organizzati in aree di degenza medica per pazienti Covid: “aree gialle” distribuite dal quarto all’ottavo piano e “aree rosse” comprendenti la rianimazione; ancora tra le aree gialle c’era la medicina d’urgenza, mentre il pronto soccorso è stato suddiviso in un percorso Covid e un altro Covid-free. I reparti rimanenti erano tutti Covid-free.

La nostra Nefrologia si è organizzata per dializzare i pazienti ricoverati positivi al Covid-19 in area gialla attraverso un rene artificiale prismaflex con metodica di CRRT o anche attraverso una mono-osmosina portatile con metodica di dialisi intermittente. Per i nostri pazienti cronici asintomatici positivi abbiamo allestito un’area gialla dialitica al piano -1, vicino alla Rianimazione e al Pronto soccorso e lontana dal Reparto di Dialisi del nostro ospedale, che è sempre rimasto Covid-free.

Tra l’inizio di marzo e l’inizio di giugno 2020, abbiamo osservato un unico caso di insufficienza renale acuta severa, tale da richiedere l’intervento con CRRT, in un paziente ricoverato in rianimazione per severa polmonite da Covid-19.

Il nostro paziente ha 68 anni, anamnesi di ipertensione arteriosa, in duplice terapia con lercanidipina e clonidina, un valore di creatinina di 1,2 mg/dl da almeno 10 anni in assenza di proteinuria, dunque insufficienza renale cronica stadio G2A1. Non c’è menzione che il paziente abbia avuto contatti con altre persone positive al Covid-19 precedentemente al suo arrivo in pronto soccorso, né che abbia fatto viaggi in zone rosse.

Viene ricoverato per febbre e tosse da 7 giorni con un quadro clinico che è apparso quasi subito aggressivo e rapidamente peggiorativo. In pronto soccorso il paziente giunge il 09/03/2020: l’ecoscopia mostra subito un pattern polmonare a linee b diffuso bilateralmente; in parallelo la Tac torace HR mostra estesi addensamenti parenchimali con aspetto “a vetro smerigliato ” in corrispondenza del lobo inferiore, bilateralmente, a prevalente distribuzione declive e di maggiore entità a destra, con associato broncogramma aereo, e ispessimento dei setti inter- intralobulari (crazy-paving). Ulteriori sfumate aree di consolidazione parenchimale “a vetro smerigliato “si rilevano a livello segmentario apicale del lobo superiore di sinistra a disposizione basale parascissurale, ed in corrispondenza del lobo superiore di destra in sede anteriore basale sottocostale.

 

Figura 3: Linee B all’ecoscopia

 

Figura 4: Tac Torace del nostro paziente agli inizi di marzo

 

Il quadro TC appare suggestivo per polmonite interstiziale, di verosimile espressione Covid-19. Tale quadro è stato poi in seguito confermato dalla positività al tampone.

Dunque, il paziente viene ricoverato e inizia terapia medica con farmaci antivirali (norvir, darunavir, tamiflu, plaquenil) e antibatterici e terapia ventilatoria con CPAP (peep:10 cm H20 e FiO2:0,6). Dopo 24 ore, per intolleranza alla CPAP, viene ventilato con reservoir ma di nuovo, dopo poche ore, per desaturazione e un rapporto all’EGA P02/FiO2 di 69, viene intubato e trasferito in rianimazione.

Gli esami ematici al 12/03 evidenziano: rialzo della PCR e della procalcitonina (392mg/L; 2,8ng/mL), creatininemia 1,2 mg/dl e urea 51 mg/dl, linfocitopenia, aumento di LDH, aumento di fibrinogeno. L’ecografia renale mostra reni normali con dimensioni e spessore parenchimale nei range, assenza di dilatazione calico-pielica, buona vascolarizzazione parenchimale e IR (Indici di Resistenza) intrarenali di 0.65 circa in media. Nei giorni successivi si palesa alla misurazione delle 24h una proteinuria di circa 1g. Diversi reports hanno segnalato l’alta incidenza di proteinuria nefritica e ematuria nei pazienti affetti da SARS-CoV-2 [18].

Nei primi dieci giorni di degenza in rianimazione i parametri di funzione renale subiscono un progressivo peggioramento sino a valori di creatinina di 6.6 mg/dl e urea 209 mg/dl; il bilancio idrico si positivizza e insorge oligoanuria. Viene così avviato il primo ciclo di CRRT il 19/03, dopo 10 giorni dall’ingresso del paziente. Il ciclo ha una durata di 72 ore, viene utilizzato il filtro oXiris e le impostazioni iniziali sono le seguenti: Qb: 120ml/min, PBP: 1200ml/h, dialisato: 1200 ml/h, reinfusione: 500 ml/h, UF: 150 ml/h. Come anticoagulante viene utilizzato il citrato.

In tale data ripetiamo una radiografia del torace che mostra un peggioramento del quadro con incremento delle aree di disventilazione a carattere interstiziale. Tale quadro polmonare, ad una Tac di controllo successiva, risulterà ancora peggiorato, con incremento dell’estensione degli addensamenti parenchimali interstiziali a vetro smerigliato. Viene poi chiesta dai colleghi rianimatori una consulenza nefrologica, in cui riconosciamo una situazione abbastanza in linea con un quadro di danno renale acuto strettamente correlato al Novel Coronavirus.

Vengono eseguiti altri due cicli di CRRT il 24/03 e il 27/03; il 31/03 il paziente viene estubato e riventilato con CPAP. A questo punto viene trasferito in area gialla, dove noi nefrologi prendiamo in carico il paziente per proseguire la terapia sostitutiva con cicli di CRRT ad un Qb più alto, in media 250 ml/min. Dopo qualche giorno, il 04/04, il paziente viene colpito da una crisi epilettica e va in carbonarcosi a seguito di stato di male epilettico per cui viene ritrasferito in rianimazione, intubato e sottoposto a due cicli di CRRT di 72 ore, il 05/04 e il 15/04. Durante la degenza, inoltre, il paziente presenta emocolture positive per cocchi Gram positivi e miceti, per cui viene modificata la terapia antibiotica e aggiunta una terapia antimicotica. Il 07/04 il paziente viene nuovamente estubato e il 22/04 viene definitivamente trasferito in area gialla. A questo punto, l’evoluzione favorevole della malattia renale ci permette di non dializzare più il paziente; modulando la terapia diuretica e le infusioni elettrolitiche, gli indici di funzione renale subiscono un progressivo miglioramento sino ad ottenere un valore di 1,2 mg/dl di creatinina alla dimissione, sovrapponibile al valore precedente al ricovero (Tabella I).

Una Tac Torace eseguita qualche giorno prima della dimissione, ad inizi maggio, evidenzia una completa detersione dei noti multipli disomogenei addensamenti parenchimali a carattere prevalentemente ground-glass precedentemente localizzati nel contesto di entrambi i lobi superiori, del lobo medio e della lingula. Consensualmente, si apprezza una sostanziale risoluzione degli estesi consolidamenti con immagini di broncogramma aereo nel contesto localizzati ai lobi inferiori, nella sede dei quali sono presenti attualmente esclusivamente plurime bande dense di natura fibrotica, cui si associano multiple bronchiectasie da trazione. In considerazione anche dell’assenza di versamento pleurico, consegue una relativa riespansione del parenchima dei lobi inferiori stessi.

 

Figura 5: Tac torace del nostro paziente agli inizi di maggio

 

Sangue Range di riferimento 1°giorno ospedaliero 30°giorno ospedaliero Giorno della dimissione
Emoglobina(g/dl) 12-16 12,2 9,2 11,5
Globuli Bianchi (per ml) 4500-11000 11000 13000 8000
Neutrofili 1800-7700 9500 9800 6000
Linfociti 1000-4800 500 700 1200
Urea (mg/dl) 8-25 60 280 65
Creatinina (mg/dl) 0,6-1,2 1,2 6,8 1,2
D-dimero (ng/ml) <500 1200 6000 1600
Ferritina (mg/l) 20-300 400 930 214
Proteina C reattiva (mg/L) <5 163 300 1,7
LDH (U/l) 110-210 500 350 300
Sodio (mEq/l) 135-143 135 142 138
Potassio (mEq/l) 3,5-5 5,2 3,6 4,5
Glucosio (mg/dl) 70-110 100 155 90
Urine
Proteinuria (g/24h) <150 mg 200 mg/24h 1,2 g/24h 250 mg/24h
Tampone rino-faringeo Covid-19 POSITIVO INCONCLUSIVO NON RILEVATO
Tabella I: Evoluzione dei principali dati laboratoristici del paziente nel corso della degenza.

 

Discussione

Il nostro paziente ha presentato un’insufficienza renale acuta nel contesto di una sindrome respiratoria acuta severa da SARS-CoV-2. Tale danno renale ha raggiunto la massima espressione alla seconda settimana di infezione, come riscontrato già in diversi altri studi [19].

La gestione complessiva del nostro paziente, prima in rianimazione e poi in area gialla, ha preso in considerazione diversi aspetti:

  1. Garantire un’adeguata pressione arteriosa necessaria alla perfusione degli organi, in particolare del rene.
  2. Mantenere un bilancio idrico adeguato a consentire un buon compenso respiratorio e, parallelamente, una sufficiente perfusione ematica renale. Spesso nei pazienti con SARS-CoV-2 diversi fattori contribuiscono a mantenere un bilancio idrico negativo:
    • Scarso introito di liquidi in quanto il paziente è ventilato con C-PAP o addirittura intubato.
    • Perdita di fluidi associata a febbre.
    • Viene somministrata una quantità modesta di liquidi dai colleghi rianimatori per il rischio di scompenso respiratorio.
    • La ventilazione con alta pressione espiratoria positiva può ridurre il ritorno venoso e dunque la perfusione renale, condizionando il blocco della diuresi.
    • La lunga dipendenza da un ventilatore peggiora i fattori sopra descritti che condizionano un bilancio negativo e una scarsa risposta renale.

    Il ruolo del nefrologo è stato anche quello di bilanciare la giusta infusione dei liquidi da dare al paziente con la somministrazione di un’adeguata quantità di diuretico, che hanno consentito da un lato la ripresa della funzione renale e dall’altro un’adeguata pressione venosa centrale, tra 4 e 8 mmHg, necessaria per non incorrere in uno scompenso respiratorio.

  3. Aggiustare di volta in volta la posologia dei farmaci antivirali e antibatterici per il filtrato renale.
  4. Eseguire precocemente sedute di CRRT che hanno permesso di gestire la fase critica dell’AKI grazie all’utilizzo di filtri capaci di rimuovere frammenti di endotossina e citochine per assorbimento, o filtri a base di acrilonitrile e policarbonato ad alto cut-off. L’utilizzo del filtro oXiris, dell’eparina a basso peso molecolare per via sistemica e del citrato hanno permesso inoltre di ridurre al massimo il problema tecnico della coagulazione del filtro. Tale problema, riscontrato di frequente nei pazienti Covid-19, era stato responsabile della riduzione dei tempi di trattamento dialitico, di uno spreco di risorse per la frequente sostituzione dei filtri coagulati, e sovente dell’anemizzazione del paziente in CRRT.

 

Conclusioni

La pandemia da Covid-19 ha posto ai nefrologi una serie di domande sulla fisiopatologia, prognosi e trattamento dell’insufficienza renale acuta dovuta a Covid-19, alcune in parte chiarite, altre ancora non risolte.

Ad esempio, non è noto se la terapia antivirale (idrossiclorochina, remdesivir, lopinavir ecc) antiinfiammatoria o con anticorpi monoclonali, tipo il tocilizumab, possa ridurre l’insorgenza o mitigare la severità dell’insufficienza renale acuta che si manifesta nei pazienti con SARS-CoV-2.

I dati sembrano dar per certo che il danno renale acuto non si è manifestato frequentemente nei pazienti ospedalizzati per Covid-19. L’AKI si manifestava di più nei pazienti ricoverati in rianimazione, soprattutto nei più anziani e con anamnesi di ipertensione e diabete, e comunque in percentuale bassa.

Nella nostra rianimazione, su 30 pazienti ricoverati, 2 hanno manifestato AKI, ossia il 6,6%; di questi, 1 ha necessitato di tecniche di CRRT.

Le tecniche di CRRT, d’altra parte, sono state utilizzate in rianimazione, a scopo antiinfettivo e ultrafiltrativo, in almeno 5 pazienti che non erano stati colpiti da insufficienza renale acuta.

La comparsa di AKI ha peggiorato la prognosi e la mortalità dei ricoverati per Covid-19. Nel caso clinico discusso, l’inizio precoce della terapia sostitutiva renale e la prosecuzione delle sedute di CVVHDF anche al di fuori della rianimazione, in area clinica Covid, a carico dei nefrologi, sino a completa normalizzazione dei valori di funzione renale e insieme alla terapia medica di supporto, hanno consentito la risoluzione della patologia. L’attenzione ad evitare farmaci nefrotossici, a modulare la posologia dei vari antibiotici e antivirali per il valore di GFR, ad evitare l’utilizzo di mezzi di contrasto iodato ha contribuito a proteggere da un ulteriore danno renale indipendente.

Di grande impatto è stata, nell’emergenza, la collaborazione tra diverse figure professionali (rianimatori, nefrologi, infettivologi, infermieri della dialisi, della rianimazione ecc.) che hanno dovuto affrontare sfide emotive, gestionali, etiche e anche fisiche comprendenti la riorganizzazione dei reparti, dei turni, reperibilità e turni aggiuntivi, la scelta dell’autoisolamento dalle proprie famiglie, la condivisione di conoscenze e percorsi terapeutici.

 

 

Bibliografia

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An account of the first hours of the Covid-19 epidemic at the Nephrology Unit in Lodi (Lombardy)

Abstract

Marco Farina and colleagues give us their account of the first days of the Covid-19 epidemic in the Nephrology Unit of the Ospedale Maggiore in Lodi. From the news trickling through from Codogno on the 20th of February to the hospitalization, the following day, of the first dialytic patient with signs of pneumonia, who later tested positive to the virus.

They tell us of how the hospital has been completely restructured in the wake of the epidemic, at remarkable speed and providing an example for others to follow, and the great sense self-sacrifice displayed by all medical personnel. After an overview of the clinical conditions of the 7 patients positive to the virus hospitalised in the following few days, they describe in some detail how symptomatic Covid+ patients are currently managed at the Ospedale Maggiore in Lodi.

Keywords: Covid-19, Ospedale Maggiore di Lodi, nephrology, dialysis

Introduction

The Covid-19 epidemic suddenly hit us on the 20th of February, the day the news started trickling through that the first case of SARS-CoV-2 had been isolated in Codogno, far out in the province. After being all over the news because of a nasty high-speed train accident only a few days before, the Lodi area was once again in the spotlight as the theatre, this time, of a health emergency.

In those first confusing hours we spent plenty of time and energy trying to find the case 1 and case 0, and doing all we could to pinpoint the starting point of the epidemic — apparently a dinner between co-workers, one of which had just returned from China. Both patient 1 and his pregnant wife, for whom we were all particularly worried, had just been hospitalised. It was then clear that the virus had arrived in Italy, in all likelihood destined to spread from our own region to the rest of the country, and that there was no point in trying to find links between infected people and China any longer. We have since been witnessing an exponential growth that, up to this day, has not shown any signs of a slowdown.

 

The first case

When I got to work on the 21st I was told that our Nephrology department had just received a 62-year-old hemodialysis patient showing signs of pneumonia at a chest X-rays. Showing a commendable insight, our local Health Care System had published on the 5th of February a detailed plan on how to identify, signal and manage either potential, probable or confirmed cases of Covid-19. This is not to say we were ready for what was to come – who could have been? – but at least we had criteria in place to recognise and assess the problem. The patient described above, who had arrived from the small town that would soon become the main cluster of cases in the country, was immediately isolated and we all started using the protective equipment described in detail in the management plan. We sent blood samples and a nasopharyngeal swab to the Microbiology Lab at the Sacco Hospital in Milan and we waited the results with apprehension; as it was still early days, we received them the same evening: positive. We alerted the Crisis Unit created by the Region for this purpose and, in the night between the 21st and the 22nd, the patient was transferred to the Infective Disease Unit at S. Anna Hospital in Como. He was then transferred to the Intensive Care Unit not because of any worsening of his conditions (he did not need a ventilator during transfer) but because he needed dialysis, which cannot be administered in Infective Disease wards. However, within a day, we witnessed a sudden worsening of the patient’s respiratory conditions (something we have grown accustomed to seeing in this type of patients), followed by death. This announcement, that reached our Nephrology Unit through mainstream news channels, was met with bewilderment: we all knew that the patient, albeit young, had several comorbidities but we were nonetheless greatly distressed to learn of his death; as a pre-emptive measure we had to quarantine the entire medical personnel, as the very first contacts with the patient had, quite understandably, taken place without the necessary protections.

 

Re-structuring the Hospital

This is our account of the first hours of this ordeal; the rest, the local and national directives that have been published in quick succession and that keep being fine-tuned hour by hour, is well known to all of us. From the creation of the “red zone” in Lodi, later extended to the entire Lombardy area, to the strict quarantine measures required across the entire Region (DPCM 21 February, 8 March and 11 March, respectively).

Since the spike in the infection rate has started (as we write there has been no inversion in this trend, and we wait for it anxiously) our Hospital in Lodi has undergone a complete overhaul and its re-structuring has been used as a model by other institutes. On the 26th of February the “blue area” was created, with 18 hospital beds previously belonging to Neurology, to hold Covid+ patients necessitating ventilation; on the 28th the “yellow area” was opened, allowing for 37 additional beds for Covid+ patients without the need for ventilation or simply requiring oxygen therapy. On the 4th of March we opened an “orange area” (previously General Medicine) with 38 more beds; on the same date we started setting up a hemodialysis room devoted to patients positive to Covid+. On the 6th we opened, within Nephrology, a “red area” with 13 beds and a drywall-delimited space devoted exclusively to the dressing and undressing of healthcare personnel. On the 7th of March Covid+ pneumonia cases started being hospitalised in the Orthopedics Unit, under supervision of the surgeon.

Doctors and nurses have been assigned to any type of duty according to pressing and ever-changing needs, impossible to predict. At the helm, a multi-disciplinary team composed by the Directors of critical care, resuscitation, pneumology and infectiology and by a number of nurses; working closely with the Biochemical and Microbiology Labs, they constituted the Hospital’s Crisis Unit, gathered in a virtually permanent assembly. Everybody has been displaying a great sense self-sacrifice, working incredibly long shifts, often in silence. This same situation seems to repeat in most of Lombardy, but also in Veneto and in many other places.

 

Other cases

By looking at preliminary data, we clearly have yet to see the huge wave of hospitalizations described by initial projections (this, however, may change or might have already changed since I wrote this piece). Patients arriving from the “red zone” have been immediately treated with the utmost care and attention, and all necessary protections have been used both in local health care facilities and in hospitals. Those of them needing dialysis have been treated in a separate room, used exclusively to this purpose, and they have been closely monitored through anamnesis and the measuring of saturation and body temperature. Of the 18 tests administered to all patients who had been in contact with the first Covid+ case deceased at S. Anna Hospital only 3 turned out positive (about 15%); the rate is actually unexpectedly good, although in the present situation it is very difficult to make any statements with an acceptable degree of confidence.

As I write, there are 7 dialytic patients who resulted positive to SARS-CoV-2, although this number is certainly destined to go up; as we have a total of 162 patients in hemodialysis or peritoneal dialysis, the current number of infections accounts for around 4%. In addition to the case described above, where the patient was initially in good conditions but presented several comorbidities, 2 more have died. An 84-year-old patient, also with many underlying conditions, that had been hospitalized for other reasons but started testing positive during his hospital stay; X-rays showed signs of pneumonia, to be added to a recent diagnosis of pulmonary neoplasms. Then a female patient with stage 5 kidney disease who was not in dialysis but presented severe cardiac problems. She also caught the infection during the hospital stay; palliative care was the only viable option, as general conditions were already heavily compromised.

In the table below we try to summarise the clinical characteristics and outcomes of the patients who tested positive to the virus, while we wait to be able to collect and publish more precise data.

 

Table I: Clinical characteristics and outcomes of patients positive to the virus

 

Addendum and conclusions

We have been the first to be hit by the epidemic and, as such, we have also been the first to put in place stringent protocols and regulations. Although we have been doing our absolute best, there is sometimes a mismatch between the regulations and the actual situation on the ground. Until now, all nurses have been using FFP2 masks, counted and distributed at the beginning of the shift. Nurses assisting the dialysis of patients that are not confirmed cases wear single use garments and, in one of the two centers in the “red area”, also a waterproof vest. All nurses wear a hat and, since the FFP2 mask can be an obstacle to the use of the visor, we have equipped each room with goggles that are sanitized with 70% alcohol at the end of each shift. Leaving aside the FFP2 mask and the waterproof vest, these are for the most part standard sanitary measures.

Patients, on the other hand, wear a chirurgical mask that is changed at the beginning of each new shift. Most of them also use it during transportation, although it is probably the same one they were given the night before. While waiting, all patients are invited to stand at least a meter apart from each other and wash thoroughly their hands and the arm where the vascular access is located.

To date, at our Hospital in Lodi, patients testing positive to the virus and showing symptoms are treated in one of the following ways (as decided by the multidisciplinary team we have previously described):

  1. If invasive ventilation is needed, they are transferred to Intensive Care, where CRRT or hemodialysis is started immediately; a portable osmosis filtration system is also available.
  2. If non-invasive ventilation is needed, they are transferred to the “yellow area”, where CPAP is available, as well as water filtration systems.
  3. Regardless of ventilation needs they can also be assigned to the “red area” created within our Nephrology, where we have 3 rooms with 3 beds each that have also been fitted with systems to filtrate water.

We have very recently implemented a new water management system that allows for two patients to undergo dialysis at the same time. Together with the system available in the yellow area, which caters for one patient at the time, is therefore possible to dialyse 3 patients at the time, maintaining the ratio between nurses and patients to 1:3.

If the patient is a suspected case but has no symptoms, the hemodialysis can be carried out in a hospital room specifically set up for this purpose. It now has 2 beds that could easily become 6 with very minor changes to the set-up.

All considered, the system we have put in place seems currently up to the task. However, as the epidemiological landscape keeps changing, this evaluation could suddenly turn out to be wrong.

Managing patients in dialysis and with kidney transplant infected with Covid-19

Abstract

We are in the midst of a health emergency that is totally new for us all and that requires a concerted effort, especially when it comes to safeguarding patients on hemodialysis, and kidney transplant recipients. Brescia is currently a very active cluster of infections (2918 cases on the 17/03/2020), second only to Bergamo. The way our structure is organised has allowed us to treat nephropathic patients directly within the Nephrology Unit, following of course a great deal of reshuffling; at the moment, we are treating 21 transplanted patients and 17 on hemodialysis. This has led us to adopt a systematic approach to handling this emergency, not only in managing inpatients, but also in researching the
new disease. Our approach is mirrored in the guidelines attached to this article, originally intended for internal use only but potentially very useful to our colleagues, as they face the same exact problems.
We have also started collecting data on our positive patients with the aim of understanding better the functioning of this disease and how best to manage it. If anyone is interested, we ask you to please get in touch with us, so we can coordinate our efforts.

 

Keywords: Covid-19, Brescia, nephrology, dialysis, transplants, guidelines

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Introduzione

L’epidemia da Covid-19 in Lombardia richiede la messa a punto di un protocollo nei pazienti nefropatici, in particolare nei pazienti in trattamento dialitico e in quelli portatori di trapianto renale.

Recentemente, il China CDC ha pubblicato la più ampia casistica di Covid-19, che includeva 44672 casi; da questo studio emerge una mortalità totale del 2.3%. I fattori di rischio principali sembrano essere, oltre all’età (mortalità dell’1.3% nella fascia 50-59, 3.6% nella fascia 60-69, 8% nella fascia 70-79 e 14.8% nella fascia ≥80 anni), la presenza di malattie cardiovascolari (mortalità 10.5%), diabete (mortalità 7.3%), malattie respiratorie croniche (mortalità 6.3%), ipertensione arteriosa (mortalità 6%) e neoplasie (mortalità 5.6%) [1,2]. Nella regione Lombardia, tuttavia, la malattia sembra avere una mortalità decisamente maggiore di quella riportata in Cina, e questo deve indurci a studiare con attenzione tutti i fattori potenzialmente responsabili di questo andamento.

Le comorbidità associate ad aumentata mortalità in corso d’infezione da Covid-19 sono molto frequenti nei pazienti affetti da Insufficienza Renale Cronica (IRC) e nei pazienti in corso di terapia sostitutiva della funzione renale mediante emodialisi. Non esistono inoltre, al momento, dati solidi sui pazienti Covid-19 positivi in trattamento dialitico e nei portatori di trapianto di rene in cui, oltre ai vari fattori di rischio cardiovascolare, esiste una condizione di ridotta immunocompetenza.

Al momento della prima stesura di questo documento (17/03/2020) abbiamo seguito presso la nostra struttura di Brescia e l’annessa rete territoriale 20 pazienti trapiantati e 17 pazienti dializzati; la nostra preliminare esperienza suggerisce che la malattia ha un decorso severo, con outcome potenzialmente fatale, soprattutto nel sottogruppo di pazienti portatore di trapianto renale. Inoltre, un numero consistente di pazienti nefropatici con Covid-19 sono stati seguiti preso i centri di Lodi, Cremona, Manerbio, Montichiari e Chiari, che aderiscono alla task force di Brescia. L’esperienza cinese suggerisce che la malattia abbia un andamento meno severo nei pazienti dializzati, non solo rispetto ai pazienti con trapianto renale, ma anche ai pazienti non nefropatici. Questa è anche l’esperienza iniziale di Brescia, ma non è confermata da tutti i centri partecipanti alla nostra task force. Ovviamente, in assenza di dati adeguati sia nella popolazione generale (percentuale di asintomatici) che nei pazienti nefropatici, non è possibile formulare riflessioni conclusive. Proprio per questo, stiamo raccogliendo in dettaglio dati clinici e di laboratorio nei nostri pazienti, per poter condividere con la comunità nefrologica le caratteristiche cliniche e di outcome della malattia nei nefropatici.

In generale, l’ottimale gestione della patologia è ancora dibattuta e l’approccio terapeutico è privo di significative evidenze. L’indicazione alla terapia anti-retrovirale è dubbia e, ad oggi, non esiste alcun farmaco registrato per il trattamento di infezioni da Covid-19 [3]. Tuttavia, ci si può avvalere dell’esperienza derivante dall’uso di agenti anti-virali su virus appartenenti alla medesima famiglia di Beta-coronavirus (SARS e MERS); bisogna comunque considerare come la condizione di emergenza fornisca una buona ragione per l’utilizzo di antivirali, nonostante la mancanza di evidenze scientifiche preliminari. Nei pazienti affetti da IRC avanzata si pone inoltre la problematica dell’aggiustamento della terapia per il grado di funzione renale e, nei pazienti portatori di trapianto renale, la necessità di un’attenta modulazione della terapia immunosoppressiva; al momento non esistono chiare linee guida per la gestione di questi pazienti [4].

Al momento, Brescia rappresenta il secondo focolaio in Italia dopo Bergamo (2918 casi al 17/03/2019). Un gruppo di lavoro formato da infettivologi e intensivisti lombardi ha messo a punto un protocollo di terapia nei pazienti con Covid-19, sulla base della severità di malattia: le Linee guida sulla gestione terapeutica e di supporto per pazienti con infezione da coronavirus COVID-19. Edizione 2.0, del 12 marzo 2020. Mutuando in parte il background infettivologico ed intensivista del protocollo, abbiamo adattato questo approccio ai nostri pazienti in trattamento dialitico e con trapianto di rene, creando questa Proposta di schema di gestione terapeutica di pazienti emodializzati e trapiantati affetti da Covid-19 (cliccando questo link è possibile scaricare il documento in questione). Di seguito, forniremo inoltre alcune considerazioni logistiche derivanti dalla nostra esperienza diretta sulla gestione dei flussi di pazienti in corso di epidemia da Covid-19.

 

Trattamento farmacologico

Clorochina e idrossiclorochina: evidenze sperimentali supporterebbero un ruolo anti-virale in vitro e nel modello animale per la clorochina nei confronti del virus SARS e dell’influenza aviaria. Un panel di esperti cinesi supporta l’utilizzo del farmaco in ragione di un beneficio in termini di ospedalizzazione e outcome generale del paziente [5].

Lopinavir/ritonavir: evidenze aneddotiche supporterebbo un possibile ruolo di questo antiretrovirale di seconda generazione in corso di infezione da Covid-19.

Darunavir/ritonavir e darunavir/cobicistat: potenziali alternative al Lopinavir/ritonavir in ragione del meccanismo d’azione analogo.

Remdesivir: è un analogo nucleotidico il cui meccanismo d’azione consiste nell’incorporazione del farmaco nelle catene di RNA neosintetizzate. Viene proposto, in modelli animali e in vitro, un suo possibile ruolo nel ridurre la carica virale e nel migliorare i parametri di funzionalità polmonare [6,7]. Due trials clinici sono attualmente in corso in Cina.

Corticosteroidi: l’utilizzo dei corticosteroidi sarebbe controindicato nelle fasi iniziali della patologia. Dati suggeriscono tuttavia un loro ruolo nella gestione della sindrome da distress respiratorio acuto (ARDS), con un impatto significativo sulle curve di sopravvivenza dei pazienti trattati [8].

Tocilizumab: sulla scorta del ruolo centrale che l’IL6, in associazione ad altre citochine pro-infiammatorie, sembrerebbe avere nello sviluppo di ARDS indotta da Covid-19, il Tocilizumab potrebbe aver un ruolo nella gestione di casi selezionati, in assenza di controindicazioni maggiori.

 

Considerazioni logistiche

Riteniamo assolutamente necessaria un’adeguata pianificazione logistica nella gestione di questa emergenza sanitaria. Nel trattare questi pazienti si devono conciliare protocolli infettivologici (es. isolamento) con necessità intrinseche alla nostra specialità, come quella di movimentare i pazienti per l’emodialisi. La nostra esperienza, se pur ancora limitata, sembra suggerire un outcome migliore nei pazienti trapiantati gestiti direttamente in un reparto nefrologico rispetto al gruppo gestito in altre aree Covid generali e valutati dal nefrologo solo in consulenza.

La peculiare organizzazione logistica della nostra struttura ci ha in questo senso consentito un modello organizzativo efficiente. Riportiamo qui uno schema della nostra struttura:

 

Piano 1:

Piano 2:

A partire dal 27-28 febbraio abbiamo impostato una riduzione dei posti letto del Reparto femminile e un aumento delle dimissioni nel reparto maschile con successivo trasferimento delle pazienti donna non dimissibili nel lato maschile. Nella notte tra il 27 e 28 febbraio abbiamo ricoverata la prima paziente portatrice di trapianto di rene e positiva al virus, successivamente trasferita in terapia intensiva per deterioramento clinico. Al 28 febbraio, la situazione logistica era la seguente; da notare che nell’area COVID erano disponibili attrezzature ed impianti per l’eventuale effettuazione di emodialisi.

 

Piano 1:

Piano 2:

Tra il 2 e il 4 marzo abbiamo ricoverato i primi pazienti positivi nell’area COVID; in questa fase, la necessità era rivolta quasi esclusivamente ai pazienti trapiantati, avendo il nostro centro un grosso bacino d’utenza che include anche le aree di Lodi e Codogno. Il progressivo afflusso di pazienti positivi presso il nostro ospedale, unito alla necessità di accogliere pazienti emodializzati, ha quindi portato allo spostamento del reparto maschile e femminile al piano 2, alla chiusura del centro trapianti e alla rimodulazione degli spazi centrali del reparto in sale da emodialisi, in parte destinate a pazienti Covid positivi, in parte destinate a pazienti negativi.

 

Piano 1:

Piano 2:

In conclusione, ricordiamo nuovamente che le nostre linee guida per la gestione terapeutica dei pazienti emodializzati e trapiantati può essere scaricata qui.

 

La “Brescia Renal Covid Task Force”

Federico Alberici, Università degli Studi di Brescia, Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica; ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Elisa Del Barba, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Chiara Manenti, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Laura Econimo, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Francesca Valerio, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Alessandra Pola, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Camilla Maffei, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Possenti Stefano, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Nicole Zambetti, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Margherita Venturini, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Stefania Affatato, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Paola Piarulli, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Mattia Zappa, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Guerini Alice, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Fabio Viola, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Ezio Movilli, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Paola Gaggia, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Sergio Bove, ASST Brescia, Unità Operativa di Nefrologia, Montichiari (BS), Italia

Marina Foramitti, ASST Cremona, Unità Operativa di Nefrologia, Cremona, Italia

Paola Pecchini, ASST Cremona, Unità Operativa di Nefrologia, Cremona, Italia

Raffaella Bucci, ASST Lodi, Unità Operativa di Nefrologia, Lodi, Italia

Marco Farina, ASST Lodi, Unità Operativa di Nefrologia, Lodi, Italia

Martina Bracchi, ASST Franciacorta, Unità Operativa di Nefrologia, Chiari (BS), Italia

Ester Maria Costantino, ASST del Garda, Unità Operativa di Nefrologia, Manerbio (BS), Italia

Fabio Malberti, ASST Cremona, Unità Operativa di Nefrologia, Cremona, Italia

Nicola Bossini, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Mario Gaggiotti, ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

Francesco Scolari, Università degli Studi di Brescia, Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica; ASST Spedali Civili di Brescia, Unità Operativa di Nefrologia, Brescia, Italia

 

Bibliografia

  1. The Novel Coronavirus Pneumoniae emergency Response Epidemiology Team. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Disease (COVID-19) – China. 2020. Chinese Center for Disease control and Prevention 2020; 2(8).
  2. Huang C, Wang Y, Li X, Ren L, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497-506.
  3. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. WHO reference number: WHO/2019-nCoV/clinical/2020.4 (13 March 2020).
  4. Naicker S, Yang C-W, Hwang S-J, Liu B-C, et al. The Novel Coronavirus 2019 Epidemic and Kidneys. Kidney Int 2020; in press. https://doi.org/10.1016/j.kint.2020.03.001
  5. Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020;43(0):E019.
  6. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020; 11:222.
  7. de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci USA 2020; pii: 201922083.
  8. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020; online first. https://doi.org/10.1001/jamainternmed.2020.0994

Water immersion model in nephrology: from hydrotherapy to weightlessness

Abstract

The term immersion connotes a wide range of different procedures ranging from whole body immersion to head-out water immersion carried out utilizing diverse body postures and water temperatures. Though hydrotherapy has been used for centuries, it was the space program in the sixties of the twentieth century, which gave a new impetus to this procedure as an nonaggressive investigative tool, which has been used in studding the influence of weightlessness on hemodynamic, metabolic, hormonal and nervous system. It was possible because water immersion mimics the weightless state on earth.

During the next years head-out immersion model was used by scientists to investigate function and pathophysiology of cardiovascular system, liver and kidneys. After recognition that water immersion induces diuresis and natriuresis, the procedure has been used to study and to treat the disorders characterized by impaired volume homeostasis, as decompensated liver disease, nephrotic syndrome, essential hypertension, cardiac transplantation, diabetes, primary aldosteronism and pheochromocytoma.

Between investigative groups, which contributed the most in studies with using head-out water immersion model there are teams of M. Epstein (Miami, USA), J.E. Greenleaf (USA), P. Norsk (Denmark), A. Koomans (Utrecht, The Netherlands) and F. Kokot (Katowice, Poland).

Keywords: water immersion, nephrology, hydrotherapy

Introduction

Hydrotherapy is probably as old as mankind. It is one of the basic methods of treatment widely used in natural medicine, and has also been referred to as water therapy, aquatic therapy, pool therapy and balneotherapy.

Hydrotherapy dates back as far as ancient Egyptian, Greek and Roman times, when Egyptian royalty bathed in oils and Roman bath were frequently visited by its citizens. There is also historical evidence of such therapies having been used in the Far East, e.g. China and Japan – where hot springs were frequently used by people to bathe in. However, in those times people used hydrotherapy exclusively for relaxing and indulging themselves and it was only in the 19th century, that hydrotherapy started to resemble the therapy that it has become in today’s society. Heinrich Friedrich Francke (1766-1838), Vincent Priessnitz (1799-1851) and Sebastian Kneipp are supposed to be the pioneers of hydrotherapy.

 

Water immersion as a type of hydrotherapy

Nowadays hydrotherapy procedures can be divided to:

  1. Surface hydrotherapy with absorbent materials (e.g. washes, friction rubs, wraps packs and compresses);
  2. Hydrotherapy showers with variations in water striking pressure (douches, showers);
  3. Procedures based on the effects of hydrostatic pressures (under massage, whirlpool bath, exercise in water, full and partial immersion bath).

Among partial immersion modalities, head-out water immersion is of particular importance. Its effect on different body organs depends on water temperature. Therefore immersion in water at temperature e.g. 14, 20 and > 360C is commonly referred to as thermotherapy.

In the next part of the paper the head-out water immersion in neutral bath, ie. at temperature approximately 32-360C will be discussed and referred to as WI.

 

Differences between WI and saline administration

The most important effects of WI in humans are (1):

  • prompt redistribution of circulating blood from the periphery to the heart and great vessels of the chest and the neck, especially in the areas with volume-, baro- and chemo- receptors with a relative central hypervolemia,
  • increase in cardiac output by 25-33% and central blood volume by ~ 700 ml,
  • progressive diuresis and natriuresis equally in magnitude to those induced by acute NaCl administration (2 l/2 h).

Despite of many similarities, there are some significant differences between WI and saline administration (1).

  1. WI is associated with decrease in body weight rather than the increase that occurs after saline infusion.
  2. Majority of studies have indicated that systematic blood pressure is unaltered during immersion in normotensive studies and can decrease in patients with hypertension. Saline infusion always causes increase in blood pressure.
  3. WI doesn’t cause any changes in plasma compositions, while saline infusion does.
  4. WI entails a central hypervolemia without concomitant peripheral hypervolemia, whereas saline administration involves both a central and peripheral hypervolemia (in majority of studies).
  5. And, what is also important, action of WI is promptly reversible, while saline infusion doesn’t.

 

Head out WI as an investigative tool

Thought many from mentioned facts were already acknowledged in the second half of the 19th century but, unfortunately, there were no practical implications until about 100 years later. There are two applications of water immersion: as an investigative tool and as a therapeutic maneuver. Both applications and based on the above mentioned redistribution of blood volume.

Research studies of Henry Gauer et al carried out in the 50s and 60s 20th century are considered the true beginning of water immersion as an investigative tool. It is ironic that the recent widespread interest in WI as an investigative tool received its impetus not from centuries of hydrotherapeutic practice but from the modern space program. It turned out that, due to the buoyant property of water, head-out water immersion mimics the weightless state. It has therefore been used in studying the influence of weightlessness on human body (2). Norsk et al emphasized the similarities between these two conditions with respect to renal excretion of sodium and water (3).

The number of research studies significantly increased in the 70s and 80s of 20 century, including studies on the effects of WI on renal function. Table 1 presents the number of papers listed in Pub Med that had been prepared by each of the mentioned research teams. All these papers discussed WI as an investigative tool.

In his excellent review Murray Epstein described the mechanisms by which head-out water immersion causes increase in urinary sodium excretion and therefore increase diuresis and decrease blood pressure. The main mechanisms are: inhibition of RAA system, increase of renal prostaglandins production and increase of natriuretic peptides (3).

He also proved, that the rise in urinary sodium excretion occurred no matter how big was sodium contents in diet. On the 10 mmol sodium excretion were of course smaller, than on the 150 mmol, but in compare to controls, in bath cases increase was significantly higher. This increase in urinary sodium excretion decreased after giving steroid, but was still significantly higher than in controls.

In healthy subjects WI induced enhanced diuresis and natriuresis at last partly by suppression of the RAA system, vasopressin secretion, the pituitary adrenal axis and by enhanced of natriuretic factors (4).

In hypertensive patients WI induced a significant decline in plasma renin activity, aldosteron and AVP which is quantitatively different from that observed in normals. As WI induced reduction of blood pressure was not significantly related to endocrine alterations, it seems, that factors other than PRA, Aldo and AVP are of importance in the maintenance of the particular types of hypertension (5).

In contrast to non-pregnant women, healthy pregnant women and women with EPH gestosis showed a significantly reduced increase in ANP secretion induced by WI (6). In diabetes type 1 and type 2 WI induced ANP secretion was significantly reduced as compared with normals. Despite a reduced response of ANP Secretion, the WI induced enhanced diuresis was a comparable magnitude both in normals and diabetics (7). In heart transplant patients ANP plasma levels were significantly higher than in normals  and heart transplant patients. These results suggest presence of an infect physiological regulatory mechanism of ANP secretion in heart transplant patients (8).

To summarize the outcomes of the Kokot group, it can be concluded, that the importance of ANP secretion in the WI induced increase of diuresis may vary in different pathological states. However, first of all WI may be used as an nonaggressive investigative tool in patients with disturbances of the water electrolyte homeostasis, supplying information of endocrine organs, kidneys or nervous system in their pathogenesis.

Research studies into the WI model have been continued in the 21st century. Schou et al demonstrated, that suppression of generation of angiotensin 2 plays an important role in the natriuresis during WI (10). Valenti et al found that WI is associated with a reversible increase in urinary aquaporin 2 excretion (11). Recently Wang et al investigated the influence of WI on human motions and demonstrated that both the wrist and trunk activities were significantly decreased (12).

 

WI as a therapeutic maneuver

As mentioned before, WI was also used as a therapeutic maneuver in patients with excessive sodium and water retention.

The research has revealed the efficacy of WI as a therapeutic intervention for the variety of disease including essential hypertension (48 items in Pub Med), nephritic syndrome (9 items in Pub Med), decompensated liver cirrhosis (4 items in Pub Med), preeclampsia (7 items in Pub Med) and heart failure (38 items in Pub Med).

 

Conclusion

Presented in the article facts let to conclude, that WI was of great importance in development of nephrology as an investigative tool and therapeutic maneuver.

References

  1. Epstein M: Studies of volume homeostasis in man utilizing the model of head-out water immersion. Nephron, 1978, 22: 9-19.
  2. Epstein M: Renal effects of head-out water immersion in humans: a 15-year update.
    Am J Physiol: Endocrinology and Metabol, 1992, 72: 563-621.
  3. Norsk P, Drummer C, Christensen NJ, Cirillo M, Heer M, Kramer HJ, Regnard J, De Santo NG: Revised hypothesis and future perspectives. Am J Kidney Dis, 2001, 38: 696-8.
  4. Epstein M: Water immersion and kidney. Undersea Biomedical Research, 1984, 11: 113-121.
  5. Kokot F, Wiecek A, Grzeszczak W, Zukowska-Szczechowska E, Dulawa J: The water immersion model in nephrology. Acta Med Pol, 1990, 1-4: 77-84.
  6. Kokot F, Jupowiecki J: Head out WI induced endocrine alterations in hypertensive patients, Przegl Lek, 1985, 42: 316-320.
  7. Doniec-Ulman I, Kokot F, Wambach G, Drab M: Water immersion-induced endocrine alterations in women with EPH gestosisClin Nephrol,1987, 28: 51-55.
  8. Dulawa J, Kokot F, Klin M, Bar A, Grzeszczak W, Darocha Z: Studies on the ANP, diuresiss and natriuresis under conditions of WI in patients with diabetes.
    Pol Arch Med Wewn, 1990, 83: 166-176.
  9. Kokot F, Religa Z, Pasyk S, Wiecek A, Frycz J, Grzeszczak W, Bochenek A, Dulawa J: ANP secretion in heart transplant patients.
    Int J Artif Organs, 1989, 12: 321-326.
  10. Schou M, Gabrielsen A, Bruun NE, Skøtt P, Pump B, Dige-Petersen H, Frandsen E, Bie P, Warberg J, Christensen NJ, Norsk P: Angiotensin II attenuates the natriuresis of water immersion in humans. Am J Physiol Regul Integr Comp Physiol, 2002, 283: R187-96.
  11. Valenti G, Fraszl W, Addabbo F, Tamma G, Procino G, Satta E, Cirillo M, De Santo NG, Drummer C, Bellini L, Kowoll R, Schlemmer M, Vogler S, Kirsch KA, Svelto M, Gunga HC: Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers. Biochim Biophys Acta, 2006, 1758:1111-6.
  12. Wang P, Wang Z, Wang D, Tian Y, Li F, Zhang S, Zhang L, Guo Y, Liu W, Wang C, Chen S, Guo J: Altered Gravity Simulated by Parabolic Flight and Water Immersion Leads to Decreased Trunk Motion. PLoS One, 2015 Jul 24; 10 (7): e0133398.

The contribution of Professor Karel Opatrný Jr., MD, DSc. (1954-2006) to nephrology

Abstract

Karel Opatrný Jr., finished his medical studies at the Charles University in Pilsen in 1979. After graduation he began to work at the 1st Department of Internal Medicine at then part of the District Health Authority, and Charles University School of Medicine in Pilsen until the end of 1989. From 1990 to 1992 he worked as an assistant professor in the Department of Internal Medicine at Strahov in Prague. During 1992-1994 he was the Head of this department. In 1994 he returned to Pilsen and became the Head of the 1st Department of Internal Medicine, Charles University Medical School and Teaching Hospital. He worked in this position until his premature death in 2006. The principal subjects of his scientific contributions were: hemostatic disorders in hemodialysis patients; biocompatibility of dialysis membranes; and the novel field of proteomics. He published more than 300 scientific papers, most of them in international journals, and delivered more than 280 lectures.

Key words: nephrology, Karel Opatrný Jr., uremia, biocompatibility of dialysis membrane, hemostatic disorders, proteomics

Professor Karel Opatrný Jr., MD, DSc., was born on July 4, 1954 in Prague and died on March 9, 2006 in Pilsen at the age of 51 (Figure 1).

Karel Opatrný Jr. graduated from the Medical Faculty of Charles University in Pilsen in 1979. He started his medical career at the 1stDepartment of Internal Medicine at then part of the District Health Authority, and Charles University School of Medicine in Pilsen. In 1985 he defended his doctoral thesis on “Haemostatic disorders in hemodialysis patients” at the Faculty of Medicine in Prague. In 1988 he passed the nephrology attestation, and in 1991 he was habilitated as an associate professor in internal medicine. The topic of his habilitation thesis was “Chronic Kidney Failure and Haemostatic Disorders”. He was appointed full Professor of Internal Medicine by President Václav Havel in 2000. He defended his academic title of “Doctor of Medical Sciences” at the Medical Faculty of Comenius University in Bratislava on the topic of “Biocompatibility of dialysis membranes” in 2002.

Professor Opatrný Jr., began working as an assistant professor at the Department of Internal Medicine at Strahov in Prague at the invitation of Professor Albert Válek, MD, DSc., in January 1990. From 1992 to 1994 he was the Head of this department. He returned to Pilsen in 1994 to take up the position of Head of the 1st Department of Internal Medicine, Charles University Medical School and Teaching Hospital replacing his father, Professor Karel Opatrný Sen, MD, DSc., after his retirement. He worked in this position until his premature death in 2006.

Professor Karel Opatrný Jr. scientific activity was manifested in more than 300 published papers, most of them in international journals, and over 280 lectures delivered various congresses around the world, especially in Europe, the USA, and Japan, often as an invited speaker. He held many positions at the university, faculty, international societies and other institutions; for example he was a Vice Dean for Science, Education and International Relations of Charles University in Prague; a Vice President of the Czech Nephrological Society; a Member of the Editorial Boards of international journals such as Blood Purification, Kidney and Blood Pressure Research and Nieren-und Hochdruckkrankheiten. In 1995 he was a founder and editor in chief of the journal “Aktuality v nefrologii (News in Nephrology) issued at his initiative that continues to be published to this day. For his outstanding research activities and achievements in the field of nephrology he received several awards, notably the “International Distinguished Medal” of the American National Kidney Foundation.

His scientific interests and the most important results of his research studies were as follows: At the beginning of the 1980s, K. Opatrný Jr. started his scientific work in the Laboratory for Hemostasis and Thrombosis Research at the 1st Department of Internal Medicine at then part of the District Health Authority, and Charles University School of Medicine in Pilsen, together with J. Dvorak, MD and later L. Vit MD, under the guidance of Professor Cepelak.

Diligent as he was, K. Opatrný studied the platelet adhesion and aggregation induced by adenosine diphosphate (ADP) and collagen, as well as the anticoagulatory activity of heparin and heparinoids (predecessors of today’s low molecular weight heparins) in vitro and in vivoIn vivo research was conducted in healthy volunteers and in patients with end-stage renal failure, who showed persistent strong inhibition of the collagen-induced platelet aggregation activity after administration of heparin even on days without hemodialysis (1).

In his continued research, he hypothesized improvement of the efficacy of 4 times re-used dialyzers (plate dialyzers Gambro Lundia) through administration of the antiplatelet drug ticlodipin (Ticlid) during hemodialysis alongside the standard heparin anticoagulation. The additional administration of 500 mg ticlodipin 2 times/day showed increased dialyzer urea and creatinine clearance. This was a placebo controlled study, i.e. a high-quality randomized controlled trial – especially considering it having taken place in the 1980s‘ Czechoslovakia during the communist era (2).

In subsequent studies he examined the relation between hemodialysis efficacy and hemostasis from a different point of view. It was a prospective study in ESRD patients on long-term maintenance hemodialysis treatment, as then was usually twice a week for 7 hours on a coil dialyzer with an effective surface area of 1 m2. Surviving patients were checked after three and a half and after five years. The study revealed serious defects of thrombocyte functions which deteriorated further during prolonged hemodialysis treatment. He concluded that the applied dialytic therapy was not adequate enough from the aspect of hemostasis and stressed the necessity to alter the technique and prescription the used in the country (3). Later, collaborating with Professors K. Šebeková and R. Dzúrik, they described the retention of a uremic toxin, 5-hydroxyindole-acetic-acid, in ESRD and its effect on platelet aggregation (4).

Subsequently he extended his studies to fibrinolysis, specifically on derangements of fibrinolytic activity in ESRD patients on maintenance hemodialysis or on conservative treatment as compared to healthy volunteers; after a standard fibrinolytic stimulus of i.v. administration of 1-deamino-8-D-arginine-vasopressin (DDAVP). There was a significant reduction of the fibrinolytic activity in hemodialysis patients, which was considered significant in relation to the frequent incidence and an early onset of atherosclerosis in this patient population (5).

Opatrný Jr. continued to study this issue after joining the team of Professor Albert Válek in the Department of Internal Medicine in Strahov, Prague. With the availability of more sensitive and specific methods, which were far from easy to obtain then in Czechoslovakia, he was able to demonstrate that the decreased fibrinolytic response to DDAVP administration in dialysis patients is caused by inadequate rise in the plasma concentrations of tissue-type plasminogen activator (t-PA) released from vessel wall (6).

In subsequent studies, he tried to identify factors contributing to the changes in tissue-type plasminogen activator during haemodialysis (7). The design of this study was very complex and resulted in the finding that t-PA is released from vessel walls during hemodialysis. Thus the extracorporeal circulation system of hemodialysis apparatus was shown to be a contributory factor.

In the 1990s, erythropoietin (EPO) gradually became available to ESRD patients in the Czech Republic. By then, it was still administered in high doses and the treatment was not free of cardiovascular complications including tendency to arteriovenous fistula thrombosis and to blood clotting in the extracorporeal circuit. Karel Opatrny Jr., and his team sought to assess, by means of the changes in thrombin-antithrombin III complex (TAT III), the effect of EPO on coagulation activation during hemodialysis. Surprisingly enough, there was no increase in predialytic nor intradialytic TAT III concentrations (8, 9). Subsequent studies confirmed that EPO therapy does not enhance coagulation activation during hemodialysis, does not have an effect on thrombocyte activation, and does not influence complement activation, provided the hematocrit does not exceed a value of 31% (10). Even when sensitive and specific fibrinolysis markers were used, he did not find fibrinolysis changes during EPO treatment, again when increasing the hematocrit slowly to values not higher than 34% (10). Later he demonstrated a dependance between the severity of anemia and the effectiveness of blood purification in peritoneal dialysis patients as assessed by the Kt/V index, whereas correlation between the renal component of Kt/V was much closer and at a higher level of significance than peritoneal component of Kt/V (11).

In vitro studies had shown that some dialysis membranes significantly adsorb EPO, a fact that might have an effect on anemia in long-term hemodialysis patients and on anemia treatment with recombinant human EPO. In a study designed to determine whether the ability of adsorption demonstrated in vitro also has an effect on EPO concentrations in vivo, he showed that under clinical conditions, AN69 and Cuprophan membranes do not differ in their effects on plasma EPO concentration (12).

Based on his original results from methodical and elaborate work, Karel Opatrný Jr. was invited to collaborate on testing biocompatibility of dialysis membranes developed by the AKZO company, when it became possible to cooperate with Western Europe again. These were well designed methodically challenging, flawlessly conducted and comprehensive trials whose outcome laid the foundation for composition changes of the dialysis membranes under development. These complex trials included activation testing of complement, platelets and fibrinolysis (13). This cooperation resulted not only in a professional collaboration, but also in a lifelong friendship with J. Vienken, of whom Karel Opatrný Jr. thought very highly. The procedures already established were extended and enriched with others, which were used in further studies testing high-flux membranes (14), where, among others, C5a (complement 5a) transfer into dialysate was described.

Another international team Karel Opatrný Jr. started a cooperation with was based at Grosshadern Clinic in Munich, Germany, under the leadership of Prof. Gurland and S. Mujais from Northwestern University in Chicago. Together, they examined the influence of polyacrylonitrile (PAN) membrane modification on its biocompatibility. Modification of this membrane was necessary, as otherwise, it led to disturbing interaction with bradykinin generation system particularly in the presence of angiotensin converting enzyme inhibitors (15).

In another study, K. Opatrný Jr. proved that heparin used to rinse polysulphone dialyzers before hemodialysis (HD) had no effect on blood coagulation or on the need for heparin during the procedure (16).

Professor Opatrný Jr. considered it an honour to be able, together with prof. H. Klinkmann and D. Falkenhagen, to edit a monograph titled “Blood-material interaction” released in 1998 and to contribute to it a chapter on ‘The fibrinolytic system in blood/material interaction‘  (17).

In science, there is considerable need for the exchange of information. To that end, Professor K. Opatrný Jr. started organizing high quality scientific meetings in Pilsen, focused predominantly on uremic toxicity and subsequent metabolic abnormalities in chronic kidney disease. On this occasions, he collaborated not only with above mentioned colleagues, but also with Professors M. Mydlík and K. Derzsiová from Kosice, Slovakia, Professors N.G. De Santo, G. Bellinghieri, V. Bonomini from Italy, Professors Grabensee, Debussmann, Ostenand from Germany, Professor Kokot from Poland, Professors Shaul G. Massry, JD Kopple, G. Eknoyan from the United States as well as many others.

The scientific work of Professor Opatrný Jr. and his team included also the field of peritoneal dialysis, continuous renal replacement therapies and plasmapheresis (18). Further detailed analysis of his contribution to this field would however exceed this article’s framehold.

As a next step, alongside with new technological developments, Professor K. Opatrný Jr. intended to advance his biocompatibility research to the next level through proteomics. Thanks to his scientific work, his enthusiasm and determination and the prospect of introducing proteomics in Pilsen, he succeeded in obtaining a large grant, for The Main Research Project (No MSM 0021620819), of almost 12 millions Euros (approximately 300 millions Czech crowns) for the School of Medicine in Pilsen. He studied proteomics at the Department of Nephrology (head: Professor John Klein) at the Louisville University, Kentucky. During his stay of several months, he collaborated especially with Prof. Visith Thongboonkerd, whom he enjoyed greatly and with Prof. Thongboonkerd, whom he held in high esteem. Regrettably , the unfortunate premature death of Professor Opatrný Jr. put a sad end to all these plans.

However, Prof. Thongboonkerd proved to be not only a brilliant scientist but also an outstanding friend, who helped the Pilsner School of Medicine to introduce and develop proteomic methods even after Prof. Opatrny’s death. This has moved this department to a different level not only within the Charles University and the Czech Republic, but also at the international level. For a whole next generation of scientists in Pilsen, the hard and tremendously diligent work of Professor Karel Opatrný Jr., MD, DSc., thereby became a spring board to work under entirely new and never-thought-of possible circumstances.

In the death of Professor Opatrný the Medical Society in Pilsen as well as the whole Czech Society of Nephrology as well as the International Society of Nephrology have lost a professionally outstanding personality.

This study was supported by the National Sustainability Program I (NPU I) Nr. LO 1503 (Opatrná Sylvie).

References:

  1. Čepelák V, Roubal Z, Zemanová I, Opatrný K Jr. Effect of heparin and heparinoids on platelet aggregation. Folia Haematol 1984;6:750-760.
  2. Opatrný K Jr, Čepelák V, Opatrný K et al. Influence of effectivness of re-use dialyzers after administration of ticlopidin (Ticlid). Vnitř Lék 1986; 4: 356-361.
  3. Opatrný K Jr, Čepelák V, Opatrný K et al. Influence of long-term hemodialysis therapy on some parameters of hemostasis. Vnitř Lék 1986; 7: 667-672.
  4. Šebeková K, Opatrný K Jr, Dzúrik R. Plasma levels of 5-hydroxyindole-acetic acid in chronic Renal insufficiency and their effect on platelet aggregation. Nephron 1991; 2: 253-254.
  5. Opatrný K Jr, Čepelák V, Opatrný K et al. Impairment of fibrinolytic capacity in patients with chronic renal failure. Čas Lék čes 1988; 15: 461-463.
  6. Opatrný K Jr, Vít L, Opatrný K Sen. et al. Fibrinolysis in patients with chronic Renal failure after 1-deamino-8-D-arginine vasopressin. J Nephrol 1991; 4: 233-238.
  7. Opatrný K Jr, Opatrný K Sen, Vít L et al. What are the factors contributing to the changes in tissue-type plasminogen activator during haemodialysis? Nephrol Dial Transplant 1991; S3: 26-30.
  8. Opatrný K Jr, Opatrná S, Vít L et al. Plasma concentrations of the thrombin-antithrombin complex in dialysis patients during erythropoietin therapy. Nephrol Dial Transplant 1992;10:1072-1073.
  9. Opatrný K Jr, Vít L, Opatrná S et al. Hemocompatibility in hemodialysis and erythropoietin therapy. Artif Organs 1995; 8: 814-820.
  10. Opatrný K Jr, Vít L, Opatrná S et al. Hypofibrinolyse nach stimulation durch venose Stauung bei haemodialysierten Kranken und der Einfluss von Erythropoetin. Niern- und Hoch druckkrenkheiten 1995; 7: 324-328.
  11. Opatrná S, Opatrný K Jr, Čejková P et al. Relationship between anemia and adequacy of continuous ambulatory peritoneal dialysis. Nephron 1977; 3: 359-360.
  12. Opatrný K Jr, Kroužecký A, Wirth J et al. The effects of a polyacrylonitrile membrane and a membrane of regenerated cellulose on the plasma concentrations of erythropoietin during hemodialysis. Artif Organs 1998; 22: 816-820.
  13. Opatrný K Jr, Sulková S, Vít L et al. Clinical study of biocompatibility of dialysis membranes from unsubstituted and substituted cellulose. Čas Lék čes 1992;15:457-461.
  14. Opatrný K Jr, Sulková S, Lopot F et al. A Clinical study on high-flux cuprammonium rayon haemodialysis membranes. Artif Organs 1993;12: 971-976.
  15. Mujais S K, Schmidt B, Hacker H, Opatrný K Jr et al. Synthetic modification of PAN membrane: biocompatiblity and functional characterization. Nephrol Dial Transplant 1995; S 3: 46-51
  16. Opatrný K Jr, Bouda M, Kohoutková L et al. A Clinical study to assess the effect of heparin in dialyzer rinsing solution Int J Artif Organs 1997;20:112-118.
  17. Opatrný K Jr, Vít L, Opatrný K Sen. The fibrinolytic systém in blood/materiál interaction,s.65-68. In: Blood-material interactoin. A basic guide from polymer science to Clinical application. D Falkenhagen, H. Klinkmann, E. Piskin, K. Opatrný Jr. (eds). Krems, Glasgow, INFA, 1998, p 156.
  18. Mydlík M, Derzsiová K, Válek A, Opatrný K Jr et al. Influence of continuous ambulatory peritoneal dialysis on some plasma and erythrocyte vitamins – retrospective study. Prague Med Rep 2009; 3: 231-238.

History of the Polish Society of Nephrology

Abstract

Polish Society of Nephrology (PSN) was born during the Founding Congress organized in September 1983 in Bydgoszcz. The main propagator of this idea was prof. Franciszek Kokot (Katowice) – widely recognized in whole nephrological community. In Bydgoszcz the PSN by-laws was approved and first Executive Council of the Society was elected. First PSN president was elected Tadeusz Orłowski (Warszawa) and vicepresident Andrzej Manitius (Gdańsk) respectively. Subsequent Congresses were organizes each three years in following cities: Kraków (1986), Gdańsk (1989), Katowice (1992), Lublin (1995), Poznań (1998), Kraków (2001), Białystok (2004), Wisła (2007), Bydgoszcz (2010), Wrocław (2013) and Łódź (2016). During these meetings and annual conferences organized between congresses actual topics dedicated to pathophysiology, clinical nephrology, dialysis therapy and kidney transplantation were presented and discussed. Prof. Tadeusz Orłowski was the PSN president till 1986 and subsequently other known Polish nephrology leaders hold this function: Kazimierz Bączyk (Poznań: 1986-1989), Franciszek Kokot (Katowice: 1989-1998), Bolesław Rutkowski (Gdańsk: 1998-2004), Michał Myśliwiec (Białystok: 2004-2007), Andrzej Więcek (Katowice: 2007-2010), Jacek Manitius (Bydgoszcz: 2010-2013), Magdalena Durlik (Warszawa: 2013-2016) and Michał Nowicki (Łódź: 2016 – present). Number of PSN members has risen from 150 at the beginning to over 1000 nowadays. During this 34 years regional structure of PSN was established and today 9 regional divisions are actively working. In 2014 Young Nephrologists’ Club was organized in PSN which is collaborating with Young Nephrologists’ Platform existing in the ERA-EDTA structure. PSN is collaborating closely with international (ISN, ERA-EDTA, IAHN) and Polish (Polish Transplantation Society) scientific societies. Many well known scientists from whole the world were recognized as Honorary Members of PSN. Coming to the end of this short presentation of the PSN activity it is worth to mention also that two journals are officially recognized by our society: Nefrologia I Dializoterapia Polska (Polish Nephrology and Dialysis Therapy) edited from 1997 in Kraków and Forum Nefrologiczne (Nephrological Forum) edited from 2004 in Gdańsk.

Keywords: Poland, nephrology, society, history

Introduction

Polish Society of Nephrology (PSN) was founded during its First Founding Congress organized in September 1983 in Bydgoszcz. At this time two structures connected with nephrology existed in Poland: Nephrological Committee of the Polish Academy of Science chaired by prof. Tadeusz Orłowski (Warsaw) and Nephrological Section of the Polish Society of Internal Medicine chaired by prof. Kazimierz Trznadel (Łódź). The main initiator and propagator of the PSN was prof. Franciszek Kokot (Katowice) who was then member of the European Dialysis and Transplant Association Board (1, 2). One has to remember that it was time when other National Nephrological Societies were founded in whole Europe. Prof. Kokot was supported strongly by the group of other known Polish nephrologists like prof. Kazimierz Bączyk (Poznań), prof. Zenon Szewczyk (Wrocław) and prof. Zygmunt Hanicki (Kraków) and great part of the younger colleagues. All of them worked hard to persuade this idea to other nephrological leaders. In Bydgoszcz last official Conference of the Nephrological Section of Polish Society of Internal Medicine was transformed to the PSN Founding Congress. It is necessary to mention that local organizer of this event was prof. Edmund Nartowicz, Head of Nephrology Department in Bydgoszcz and all necessary documents were prepared by prof. Kazimierz Trznadel (Head of Nephrology Department in Military Hospital in Łódź). During this Founding Congress rules and regulations of the new Society were established and first Executive Council was elected. First PSN president for three years term prof. Tadeusz Orłowski (Figure 1) prominent nephrologist form Warsaw was elected and Vicepresident prof. Andrzej Manitius – Head of Nephrology Department in Gdańsk Medical University (3, 4). Prof. Tadeusz Orłowski was the PSN president till 1986 and subsequently other known Polish nephrology leaders hold this function. Prof. Kazimierz Bączyk from Poznań (Figure 2) was the second and prof. Franciszek Kokot from Katowice (Figure 3) the third PSN president. Whole list of PSN presidents and period of their activity on this position was presented in Table 1, Figure 4, Figure 5 and Figure 6. Subsequent Congresses were organized every three years in following cities: Kraków (1986), Gdańsk (1989), Katowice (1992), Lublin (1995), Poznań (1998), Kraków (2001), Białystok (2004), Wisła (2007), Bydgoszcz (2010), Wrocław (2013) and Łódź (2016). There were also annual scientific and educational conferences organized under the auspices of PSN like:

  1. “Advances in peritoneal dialysis” organized from 1996 in different nephrological centers – prof. B. Rutkowski and currently prof. M. Lichodziejewska-Niemierko (Gdańsk).
  2. “Advances in Nephrology and Hypertension” Polish-German-Czech conferences organized from 1994 by turns in Poland (mainly in Wisła – prof. F. Kokot and Wrocław – prof. M. Klinger), Germany (mainly Gorlitz) and Czech Republic (mainly Liberec).
  3. Post ASN Meetings – Gdańsk Repetitory in Nephrology organized from 2002 by prof. B. Rutkowski
  4. Katowice Seminar – Advances in Nephrology and Hypertension organized from 2001 by prof. A. Więcek
  5. Top Nephrological Trends organized in Poznań currently by prof. A. Oko, earlier from 2002 as Great Poland Spring Nephrological Actualities by prof. S. Czekalski
  6. Nephrocardiology – conference organized from 2005 in Białowieża by prof. M. Myśliwiec (Białystok) and currently by his successor prof. B. Naumnik (Białystok)
  7. Płock Nephrology Days organized between 1995 and 2005 by dr M. Świtalski in Płock
  8. Cracovian Dialysis Days – very special meeting organized on the biennial mode from 1994 until 2014 this meetings which is uniting all parties involved in dialysis – physicians, nurses, technicians, dietitians and patients was organized by prof. O. Smoleński. After his sudden death in 2015 this important meeting is organized by his successors dr A. Smoleńska, mgr M. Liber and prof. J. Pietrzyk.
  9. Nephrological Conference in Włocławek organized from 1992 by doc. J. Ostrowski.

It is worth to mention that also Regional PSN divisions are organizing educational conferences at least 2–3 times during a year. Lectures during all these events were delivered not only by Polish speakers but also very often by eminent nephrologists from Europe and United States. It is worth to mention that many well-known scientists from whole the world were recognized as Honorary Members of PSN. Whole list of foreign PSN Honorary Members is shown in Table 2. One may recognize that among them are also active IAHN members like: G. Richet, S. Massry, G. Eknoyan, R. Ardaillou, A. Heidland and M. Mydlik. There are also twenty six eminent Polish nephrologists who were recognized as PSN Honorary Members (Table 3). Number of PSN members has risen from 150 at the beginning to over 1000 nowadays (Figure 6). During this 34 years regional structure of PSN was established and today 9 regional divisions are actively working. There are also several sections in the PSN central structure eg. historical, rehabilitation in chronic kidney disease, Polish Renal Registry and Polish Registry of Kidney Biopsy. In 2014 Young Nephrologists’ Club was organized in PSN which is collaborating with Young Nephrologists’ Platform existing in the ERA-EDTA structure. PSN is collaborating closely with international (ISN, ERA-EDTA, IAHN) and Polish (Polish Transplantation Society) scientific societies. It is worth to mention that Polish nephrologists played active role in these organizations. Prof. J. Roguski (Poznań) and prof. Stefan Angielski were members of the ISN Board in sixties and seventies. Later on prof. F. Kokot was a member of Nominating Committee and prof. A. Więcek – Head of the section organizing COMGAN CME courses and prof. B. Rutkowski member of the Historical Committee. Even closer is collaboration with ERA-EDTA where several Polish representatives were elected as members of the Council like: prof. T. Orłowski, prof. F. Kokot (3 times), prof. A. Więcek, prof. M. Klinger, prof. J. Małyszko. One have to remember that prof. A. Więcek after accomplishing his second term as Council member was elected as a Secretary-Treasurer and later hold most important position of ERA-EDTA President during last three years (2014-2017). Additionally prof. B. Rutkowski was a member of the Scientific Board of ERA-EDTA Registry and prof. R. Gellert director of the Registry Office. It is worth to mention that three Polish nephrologists were among founders of the International Society of Peritoneal Dialysis: prof. K. Bączyk (Poznań), prof. Z. Twardowski (Lublin), prof. P. Hirszel (Kraków) (4). Currently prof. M. Lichodziejewska-Niemierko is member of the Council in this Society. Very successful EuroPD Meeting was organised in 2015 in Kraków coordinated by prof. W. Sułowicz (Kraków) and prof. Lichodziejewska-Niemierko (Gdańsk). Another scientific collaboration was maintained between PSN and International Society of Uremic Research and Toxicity (ISURT). B. Rutkowski was member of the Council, president elect, president and past president in this Society. He organized also very successful ISURT Congress in Sopot in 2007. Special attention has to be paid to collaboration with the International Association for the History of Nephrology (IAHN). Prof. B. Rutkowski spent in the IAHN Council four terms as member, president elect, president and past president of the Association. Doc. Janusz Ostrowski from Włocławek was Council member, president elect and currently he is holding position of IAHN president. Dr Marek Muszytowski from Toruń was Council member and currently is secretary treasurer. Three IAHN Congresses were organized in Poland: in 2004 in Gdańsk in 2010 in Toruń and in 2016 in Wieniec near Włocławek. All these events were organized in collaboration with PSN.

Coming to the end of this short presentation of the PSN activity it is worth to mention also that two journals are officially recognized by our society: Nefrologia i Dializoterapia Polska (Polish Nephrology and Dialysis Therapy) edited from 1997 in Kraków (Chief editor – prof. W. Sułowicz) and Forum Nefrologiczne (Nephrological Forum) edited from 2004 in Gdańsk (Chief editor – prof. B. Rutkowski).

In summary we like to underline that during almost 35 years of PSN activity our Society help to establish high position of Polish nephrology among European countries both from scientific and practical point of view (5). This fact is the result of hard work of many people mentioned in this article and many other anonymous PSN members. We do hope that young generations of Polish nephrologists will keep this high level and also will remember about their mentors who established and developed PSN.

 

References:

  1. Rutkowski B.: Professor Franciszek Kokot – his contribution in the development of Polish nephrology: Pol Arch Med Wewn 1994, 9: 1 11-13.
  2. Rutkowski B.: Leader and promotor of the of the polish nephrology. In: Franciszek Kokot, Ed. Medical University of Silesia, Main Library, Katowice 1999.
  3. Heidland A., Pączek L. Professor Tadeusz Orłowski – in memory of a pioneer in European Nephrology and Transplantation. Kidney Blood Press. Res. 2009; 32: 304-306.
  4. Ostrowski J., Rutkowski B.: Honorary member of the Polish Society of Nephrology. Part One: Tadeusz Orłowski. Forum Nefrol. 2013; 1: 71-75.
  5. Czekalski S. Kazimierz Bączyk, Poznań, Poland. Nephrol. Dial. Transplant. 1996; 11:1656.
  6. Czekalski S., Rutkowski B. The History of nephrology in Poland. J. Nephrol. 2006; 19 (supl. 10): S150-S158.