The Nephrology School in Bari

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Francesco Paolo Schena

Francesco Paolo Schena

Professore Emerito di Nefrologia nell’Università di Bari e Presidente della Fondazione Schena

Corresponding author:
Francesco Paolo Schena
Università degli Studi di Bari, Policlinico
Piazza G. Cesare 11,
70124 Bari
E-mai: francescopaolo.schena@uniba.it

 

Abstract

This article describes the origin and development of the Nephrology School in Bari, which has noble roots in the Italian Medical School. The narrative begins with the description of my initial interest in Internal Medicine, and later in Nephrology, highlighting the important role that a teacher has on their students during their university education.

The second section describes the creation and development of the Nephrology School in Bari, which was influenced by the knowledge gained abroad and by the international scientific relationships that have been developed over the years.

The third section describes the historical origins of the Nephrology School in Bari, which has grown considerably over the course of 30 years. Finally, after a brief mention of my family, I could not hide my passion for sports, particularly running and soccer. Cinema and theatre are also excellent means of reflection.

In conclusion, my heartfelt hope is that my students will always remember to pursue goals of scientific excellence and, when choosing someone to train as a potential young researcher in the future, to always observe the two founding principles of the School: professional and scientific reliability, respectively based on excellent clinical expertise and scientific production.

 

Keywords: Nephrology School, Nephrology, Dialysis, Transplant, Clinical Research

Sorry, this entry is only available in Italian.

La mia vita di nefrologo con la passione per la clinica e la ricerca

La passione per la medicina interna e la nefrologia

La mia passione per la Medicina Interna è iniziata nel 1962 quando fui conquistato dall’approccio didattico del Prof. Virgilio Chini, che svolgeva le lezioni di Clinica Medica al quinto e sesto anno del Corso di Laurea in Medicina e Chirurgia nell’Università di Bari, presentando e commentando casi clinici complessi. Il Prof. Chini era un allievo del Prof. Frugoni, Clinico Medico, prima nell’Università di Padova e poi in quella di Roma.

In qualità di studente interno venivo da un’attività svolta prima in Anatomia Umana con il Prof. Rodolfo Amprino per 2 anni e dopo in Patologia Speciale Medica con il Prof. Claudio Malaguzzi-Valeri per altri 2 anni.  L’attrazione per la Medicina Interna si concretizzò con un internato di 2 anni in Clinica Medica dove trascorsi molto tempo in corsia. Durante quel periodo preparai una tesi di laurea sulla proteinuria dal titolo “Studio elettroforetico e cromatografico delle proteine urinarie”. In quell’occasione conobbi il mio maestro Prof. Lorenzo Bonomo, allora Aiuto del Prof Chini, che mi introdusse allo studio della immunologia e protidologia. Nel luglio del 1964 conseguii la laurea con il massimo dei voti e la lode e ricevetti il premio di laurea Lepetit per l’ottima tesi sperimentale. Dopo due anni, con l’aiuto del mio maestro, i risultati della tesi furono oggetto della mia prima pubblicazione su una rivista internazionale.

Dopo la laurea frequentai la Scuola di Sanità Militare per Allievi Ufficiali a Firenze, e dopo il Corso fui inviato, in qualità di Ufficiale Medico, prima al Battaglione Sila di Cosenza e dopo all’Ospedale Militare di Bari. Durante la frequenza della Scuola di Specialità in Medicina Interna ero allocato nel piano riservato ai medici della Clinica Medica. Pertanto la mia vita di specializzando fu un lungo periodo vissuto in corsia per l’attività clinica ed in laboratorio per l’attività scientifica. Fu in quel periodo che, praticando anche molta attività interventistica, come svuotamento di toraci con versamento pleurico, addomi con versamento ascitico, biopsie epatiche, e continuando ad occuparmi di proteinuria, fui inviato dal mio Maestro a Roma a frequentare per un trimestre l’Istituto di Patologia Speciale Medica del Policlinico Umberto I di Roma, diretto dal Prof. Cataldo Cassano, dove sotto la guida del suo Aiuto, Prof. Giuseppe Andres, imparai ad eseguire la biopsia renale previa insufflazione di ossigeno creando, in tal modo, un retropneumoperitoneo per visualizzare meglio il rene che doveva essere biopsiato. In quell’occasione imparai anche ad applicare la tecnica dell’immunofluorescenza sul tessuto renale. Al rientro a Bari iniziai ad effettuare le biopsie renali.

Dopo 4 anni di specialità di Medicina interna, prima di conseguire il diploma, fui invitato a partecipare ad un bando nazionale per una borsa di studio per soggiorno di due anni in una università europea. Fu così che nel 1968 iniziò la mia attività clinica e di ricerca presso l’Università Cattolica di Louvain (Belgio), dove sotto la guida di due eminenti figure della Nefrologia (Prof. C. Van Ypersele) e della Trapiantologia (Prof. G. Alexandre) mi fu affidato il compito di seguire i pazienti con trapianto di rene e di studiare la proteinuria in collaborazione con i Proff. E.C. Laterre e J.F. Heremans (illustre protidologo europeo). Il focus dello studio era la beta2 microglobulina urinaria, espressione di danno tubulare, nel trapianto di rene.

La passione per la ricerca clinica in nefrologia

Dopo due anni di attività a Louvain rientrai a Bari e nel 1971, a seguito della apertura della prima Scuola di Specialità in Nefrologia in Italia, mi avviai a conseguire quella specialità che sancì definitivamente la mia vita di nefrologo clinico e ricercatore, studiando oltre alle proteinurie, gli aspetti immunologici delle glomerulonefriti nell’Istituto di Clinica Medica, diretta dal mio Maestro, Prof. Lorenzo Bonomo. In quella sede ho trascorso 20 anni della mia carriera accademica, prima in qualità di libero docente in Patologia Speciale Medica, poi di ricercatore universitario, professore associato ed infine di professore ordinario in Medicina Interna (Terapia Medica Sistematica), per poi passare alla Nefrologia. Un percorso analogo a quello di tanti altri nefrologi che venivano dagli Istituti di Semeiotica Medica, Patologia Speciale Medica e Clinica Medica. La mia presenza in Clinica si alternò con altri periodi di soggiorno all’estero. Pertanto, trascorsi, prima, un anno a Londra presso il Guy’s Hospital dove, sotto la guida dell’amico Stewart Cameron, illustre nefrologo internazionale, studiai alcuni aspetti terapeutici delle glomerulonefriti e, successivamente, andai per alcuni mesi a Cleveland, Ohio (U.S.A.), presso l’Istituto di Anatomia Patologica della Case Western Reserve University, dove con l’amico Steven Emancipator approfondimmo alcuni aspetti immunologici della glomerulonefrite a depositi mesangiali di IgA. Quest’attività di ricerca fu proseguita da alcuni miei allievi che frequentarono per anni quell’istituto. Durante la mia permanenza a Cleveland maturai l’idea che era arrivato il momento di pensare al futuro, ovvero formare un gruppo misto di giovani medici e biologi perché l’esperienza maturata all’estero mi fece capire che per la ricerca era necessaria una stretta collaborazione tra ricercatori medici e biologi.

 

Sviluppo e realizzazione della Scuola Nefrologica Barese

Dopo il mio rientro dall’Università Cattolica di Louvain, invitai alcuni miei collaboratori a trascorrere brevi periodi di soggiorno in Europa. Ma dopo aver conseguito il titolo di professore ordinario e con l’esperienza maturata all’estero, arrivai alla conclusione che un giovane ricercatore per realizzare un progetto, doveva trascorrere un soggiorno di almeno due anni, per imparare nuove tecniche ed ottenere risultati per almeno una pubblicazione scientifica relativa al progetto. L’ideale era inviare giovani che avessero già acquisito una certa esperienza clinica e scientifica. Pertanto un giovane specializzando con tre anni di attività clinica e di ricerca scientifica in laboratorio era la persona ideale per poter realizzare in altra sede un progetto biennale o di maggior durata [1].

Nel 1985, in occasione del 18° Congresso dell’American Society of Nephrology a New Orleans, cominciarono i primi contatti. Nel corso di tre decenni, molti allievi frequentarono università americane ed europee (Tabella 1) ed il Congresso annuale dell’American Society of Nephrology divenne il punto di riferimento dove gli allievi mi relazionavano sulla loro attività scientifica. Ma la mia presenza fisica non si fece mancare in tutte quelle sedi dove, invitato a tenere delle conferenze, trascorrevo alcuni giorni nella sede con l’allievo per programmare le attività future dopo il rientro a Bari. Inoltre, ogni anno, il mio gruppo di lavoro presentava uno o più abstract al Congresso dell’American Society of Nephrology. Sono state queste le occasioni in cui gli allievi hanno presentato i dati dei loro progetti e si sono posti all’attenzione della comunità scientifica internazionale.

ALLIEVO MENTORE ISTITUZIONE
Pastore A. Spath P.J. Central Laboratory, Swiss Red Cross, Bern, Switzerland
Germinario C. Lambert P.H. Centre of Vaccinology, University of Geneve, Switzerland
Russo R. Kazatchkine M.D. Service de Néphrologie and INSERM U28, Hospital Brousias, Paris, France
Grasso C. Lubec G. Dept of Pediatrics, University of Vienna, Austria
Gesualdo L. Emancipator S.N. Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
Grandaliano G. Abboud H.E. Dept of Medicine, University of Texas Health Science Center, San Antonio, USA
Scivittaro V. Emancipator S.N. Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
Ranieri E. Storkus W.J. Dept of Surgery, University of Pittsburg School of Medicine, Pennsylvania, USA
Montinaro V. Rifai A. Dept of Pathology, Rhode Island Hospital, Providence, USA
Castellano G. Daha M.R. Dept of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands
Zaza G. Evans W.E. St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Rossini M. Fogo A.B. Dept of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Strippoli G.F.M. Graig J.C. NHMRC Centre of Clinical Research Excellence in Renal Medicine, University of Sydney, Australia
Pesce F. Falchi M. Dept of Genomics of Common Diseases, Imperial College London, London, UK
Simone S. Abboudh H.E. Dept of Medicine, University of Texas Health Science Center, San Antonio, USA
Fiorentino M. Kellum S. A. Centre of Critical Care Nephrology, University of Pittsburg, Pittsburg, USA
Tabella 1: Elenco degli allievi che hanno frequentato Istituzioni cliniche e di ricerca all’estero.

Durante il periodo di permanenza degli allievi all’estero, il primo elemento da tenere sotto controllo era lo stato di accoglienza ed il lavoro svolto dall’allievo in modo che l’istituto ospite potesse finanziare il secondo anno di permanenza. Secondo punto, era necessario trovare una collocazione al rientro in sede per non perdere l’allievo con l’esperienza acquisita che doveva servire a far crescere il gruppo. Terzo punto, trovare fondi per attrezzare la clinica di nuove strumentazioni che gli allievi avevano già utilizzato in altre sedi. Quarto punto, dare una continuità alla ricerca preparando progetti che potessero essere finanziati in Italia o all’estero con il coinvolgimento dei colleghi che avevano ospitato i miei allievi.

Questo programma, meditato e modificato dal punto di vista organizzativo nel corso degli anni, ha permesso di realizzare una Scuola dove sono stati studiati e approfonditi i diversi campi della ricerca in Nefrologia, Dialisi e Trapianto (Tabella 2). Ovviamente nell’attuare un programma, che si è svolto durante tutta la mia carriera accademica e continua oggi con la ricerca effettuata nella Fondazione Schena, da me costituita nel 2012, ho incontrato anche molte difficoltà che ho dovuto superare.

Glomerulonefriti primitive e secondarie
Immunocomplessi circolanti
Sistema del complemento e angioedema ereditario
Sistema della coagulazione
Pielonefrite
Biopsia renale (istologia ed immunofluorescenza)
Proteinurie
Calcolosi renale
Pre-eclampsia
Cellule staminali renali
Biocompatibilità delle membrane dialitiche
Trapianto renale
Studi clinici randomizzati ed osservazionali
Intelligenza Artificiale in Nefrologia
Revisioni sistematiche e meta-analisi
Tabella 2: Aree di ricerca della Scuola Barese in Nefrologia, Dialisi e Trapianti.

I principi meritocratici della Scuola sono sempre stati: serietà professionale basata su un’ottima conoscenza clinica, e serietà scientifica supportata da un’ottima produzione scientifica con traiettoria costante e consistenza di contenuto. La Scuola ha organizzato Congressi Scientifici Nazionali ed Internazionali in Puglia e ha ospitato, per ben due volte, il Congresso Nazionale della Società Italiana di Nefrologia, festeggiando nel 2007, il 50° anniversario della Costituzione della Società [2].

La Scuola Nefrologica Barese nel corso degli anni ha vinto molti progetti con finanziamenti forniti da istituzioni pubbliche e private in Italia e all’estero (Tabella 3), ed anche dopo ho continuato questo cammino con la Fondazione Schena. L’attività di ricerca è stata svolta sempre nel Policlinico di Bari e per 10 anni anche nel Consorzio C.A.R.S.O. di Valenzano, da me diretto, dove la Scuola e la Fondazione hanno vinto progetti di ricerca per un valore totale di 20 milioni di euro (Figura 1). Successivamente, in qualità di Emerito, sono rientrato nel Policlinico di Bari dove continuo a svolgere attività di ricerca con i miei collaboratori.

CNR
Ministero Pubblica Istruzione
Regione Puglia
Università di Bari
Ministero dell’Università e della Ricerca
Ministero della Sanità e dopo della Salute
Istituto Superiore di Sanità
Extramural Grant Baxter
National Institutes of Health
European Commission
Industrie per studi clinici randomizzati
Tabella 3: Lista delle Istituzioni che hanno finanziato la Scuola Nefrologica Barese e la Fondazione Schena.
Il gruppo di ricerca della Scuola Nefrologica Barese che lavorava nel Consorzio
Figura 1: Il gruppo di ricerca della Scuola Nefrologica Barese che lavorava nel Consorzio C.A.R.S.O. Da sinistra verso destra: I ricercatori PhD De Palma G, Serino G, Cox SN, il sottoscritto, Sallustio F, Curci C. e Pesce F.

 

Origini storiche della Scuola Nefrologica Barese

La Figura 2 mostra l’albero genealogico della Scuola Nefrologica Barese che, come tutte le specialità, proviene da una delle Scuole di Medicina Interna. Nel nostro caso il fondatore è stato Francesco Orsi (1828-1909), Clinico Medico dell’Università di Pavia, che portò in cattedra due allievi, Pietro Grocco (1856-1916) a Firenze e Carlo Forlanini (1847-1918) a Pavia. Pietro Grocco fu il maestro di tre noti Clinici Medici come Raffaello Silvestrini (1868-1959) a Perugia, Pio Bastai (1888-1975), prima a Padova e dopo a Torino, e Cesare Frugoni (1881-1978) che dall’Università di Padova fu chiamato all’Università di Roma. I primi allievi e futuri cattedratici, furono Guido Melli (1900-1985) a Milano, Flaviano Magrassi (1908-1975) a Napoli e Virgilio Chini (1901-1983) a Bari. Tra gli allievi del Prof Chini, vanno ricordati Claudio Malaguzzi Valeri (1910-1995) prima patologo medico e dopo clinico, Oronzio Schiraldi (1924-2022) infettivologo e Lorenzo Bonomo (1924-2020) clinico medico prima nell’Università di Bari e dopo nell’Università La Sapienza di Roma.

Figura 2: Albero genealogico della Scuola Nefrologica Barese.
Figura 2: Albero genealogico della Scuola Nefrologica Barese.

La Scuola Nefrologica Barese iniziò i primi passi con il Prof. Albero Amerio (1916-2006), nefrologo ed aiuto del Prof Malaguzzi-Valeri. Fu il primo ad istituire in Italia la Scuola di Specialità in Nefrologia, ed il sottoscritto, allievo del Prof. Bonomo, in Clinica Medica, fu uno dei primi a frequentare la Scuola di Specialità negli anni ’70. Oggi, a seguito di quel progetto descritto e realizzato nel corso di 30 anni, la nefrologia pugliese è rappresentata da 5 professori ordinari di cui in questo momento l’ultimo è Giovanni Strippoli, già professore ordinario aggiunto di Epidemiologia Clinica nell’Università di Sydney e oggi ordinario di Nefrologia nell’Università di Bari. Comunque ai Professori Ordinari, Loreto Gesualdo nell’Università di Bari, Giuseppe Grandaliano nell’Università Cattolica di Roma, Giovanni Stallone nell’Università di Foggia e Giuseppe Castellano nell’Università Statale di Milano, si devono aggiungere i professori associati Carlo Manno, Giovanni Battista Pertosa, Gianluigi Zaza ed i prossimi professori associati Francesco Pesce a Roma e Marco Fiorentino a Bari. Tutti questi allievi hanno svolto un ruolo importante dal punto di vista scientifico e clinico nello sviluppo della Scuola Nefrologia Pugliese, come vincitori di progetti di ricerca finanziati e nuove attività cliniche avviate nella Scuola e partecipando a numerosi Congressi Nazionali ed Internazionali (Figura 3).

Partecipazione della Scuola Nefrologica Barese al Congresso della Società Italiana di Nefrologia (SIN)
Figura 3: Partecipazione della Scuola Nefrologica Barese al Congresso della Società Italiana di Nefrologia (SIN), Rimini, ottobre 2022. Da sinistra verso destra: il sottoscritto, Pontrelli P, Ranieri E, Simone S, Grandaliano G, Pertosa G, Pesce F e Porri MG.

Comunque desidero sottolineare che non si può dimenticare l’importante ruolo svolto dai biologi nella Scuola. È stata molto fertile la collaborazione tra nefrologi e biologi ai fini della ricerca scientifica nel corso degli anni. Pertanto oggi sono presenti nella Scuola biologi che hanno dato lustro dal punto di vista scientifico e che sono progrediti nella carriera accademica, come Elena Ranieri, Professore Ordinario di Patologia Clinica nell’Università di Foggia, Paola Pontrelli Professoressa Associata di Patologia Clinica e Fabio Sallustio, Professore Associato di Scienze Biologiche nell’Università di Bari. Il numero di biologi e biologhe che ha frequentato la Scuola, nel corso degli anni, è stato elevato per l’enorme attività scientifica che è stata e viene tuttora svolta. Questo fertile connubio tra Nefrologi e Biologi ha radici profonde. Su mia proposta negli anni ’90, nella Facoltà di Medicina di Bari, fu istituita la Scuola Diretta a Fini Speciali di Tecnico di Laboratorio Biomedico, trasformata negli anni successivi in Laurea di primo livello e dopo in Laurea magistrale.

Negli anni successivi furono costituiti il Consorzio Europeo per gli studi della IgA nefropatia, supportato da un finanziamento dell’Unione Europea, la Rete regionale di omiche applicate agli esseri viventi, supportato da un finanziamento del Ministero dell’Università, e la rete nazionale di omiche applicate ai Trapianti Renali, supportato da un finanziamento del Ministro della Salute.

Un’altra importante iniziativa, che ha permesso a medici e biologi di collaborare nella ricerca, fu la richiesta, da parte mia, di istituire il Dottorato di ricerca in Scienze Trapiantologiche. Questa richiesta fu da me avanzata dopo aver costituito il Dipartimento di Emergenza e Trapianti di Organi e Tessuti, che diressi per il primo triennio. Inoltre per più di 25 anni sono stato il coordinatore delle attività trapiantologiche in Puglia. Dopo 24 trapianti di rene da donatore vivente, effettuati dal 1973 al 1983, iniziò negli anni ’90 un’intesa attività prima con il trapianto di rene, dopo quello di fegato ed infine quello di cuore. Recentemente, in occasione del Congresso Nazionale della Società Italiana Trapianti di Organi e Tessuti, che si è tenuto a Trieste nel mese di ottobre 2022, mi è stata assegnata una Targa per aver dedicato una vita all’attività dei trapianti di organi (Figura 4). In quell’occasione si è trascorsa una bella serata con i colleghi nefrologi partecipanti al programma nazionale trapianti di reni (Figura 5).

Figura 4: Premio “Una vita al servizio dei Trapianti di Organi”.
Figura 4: Premio “Una vita al servizio dei Trapianti di Organi”. Trieste, ottobre 2022. Da sinistra verso destra: Stallone G, Gesualdo L, il sottoscritto, Grandaliano G, Castellano G e Zaza G.
Una serata a Trieste con alcuni nefrologi coinvolti nel programma trapianti di rene a livello nazionale.
Figura 5: Una serata a Trieste con alcuni nefrologi coinvolti nel programma trapianti di rene a livello nazionale. Da sinistra verso destra: Biancone L (Torino), La Manna G (Bologna), Maggiore U (Parma), Garosi G (Siena), Zaza G (Foggia), Castellano G (Milano), Gesualdo L (Bari), il sottoscritto, Minetti E (Milano), Stallone G (Foggia), Grandaliano G. (Roma).

 

La mia famiglia e l’attività extra-lavorativa

Devo confessare che non sono stato un padre esemplare per la mia scarsa presenza in famiglia; però sono stato fortunato perché questo compito è stato completamente svolto da mia moglie che, in qualità di docente nella scuola, ha saputo seguire con affetto i nostri due figli sino al conseguimento della laurea.  Mio figlio Stefano, oggi, è Professore Associato di Cardiochirurgia nel Medical College of Wisconsin, Milwaukee, USA. Mia figlia Valentina, dopo un lungo periodo trascorso nel mondo della moda, ha deciso da qualche anno di intraprendere una nuova attività costituendo la Puglia Concierge per turisti stranieri.

La mia passione per lo sport

Questa passione è vissuta da molti decenni praticando sport non agonistico, quale una corsa di 8-10 km un paio di volte a settimana prima ed ora una volta a settimana, preferibilmente la domenica. Nel mese di marzo ho partecipato alla Run Like a Deejay di 10 km in pianura a Bari con buon successo (Figura 6). Quindi nel mio libro “Manuale della Dieta Mediterranea” dove consiglio ai pazienti di praticare attività fisica moderata, a seconda dell’età, metto in pratica questo consiglio anche per me stesso ogni settimana. Ho constatato di persona come con l’avanzare dell’età, dopo la corsa, c’è una maggiore velocità di pensiero e ideazione, grazie all’ossigenazione delle cellule cerebrali durante l’attività fisica.

Sono un appassionato di calcio, tifoso della Juventus e del Bari. Vado spesso allo stadio, specialmente quando ci sono squadre che possono esprimere il bel gioco. basato sulla velocità, prestanza fisica ed intelligenza nel saper smarcarsi. I recenti campionati del mondo sono stati una prova testimoniale di questo tipo, intelligente e divertente, di gioco del calcio.

Figura 6: Arrivo al traguardo dopo aver percorso la Run Like a Deejay di 10 km in pianura a Bari nel marzo 2023.
Figura 6: Arrivo al traguardo dopo aver percorso la Run Like a Deejay di 10 km in pianura a Bari nel marzo 2023.

La mia passione per il cinema ed il teatro

Il buio della sala cinematografica mi affascina perché è il luogo ideale per apprezzare e criticare un buon film; d’altronde i film in concorso nei Festival si proiettano solo in sale cinematografiche. Si tratta di un luogo completamente differente da quello di casa dove spesso, alla televisione, si vedono anche buoni film ma non si apprezzano perché, stando in casa, ti ricordi sempre quello che c’è da fare. Pertanto la prova di questa passione è testimoniata dalla frequentazione delle sale cinematografiche quando sono proiettati film interessanti. In conclusione, il film la domenica è quasi d’obbligo.

Frequento meno il teatro, ma sono presente quando ci sono delle buone rappresentazioni teatrali realizzate da artisti di alto livello professionale.

 

Conclusioni

Lo scopo di questo articolo è stato, principalmente, quello di narrare come è nata la Scuola Nefrologica Barese, basata principalmente sul mio impegno e su quello dei miei allievi. La mia più viva speranza è che i miei allievi si ricordino sempre di perseguire obiettivi di eccellenza scientifica e, quando dovranno scegliere una persona da formare, quale potenziale futuro giovane ricercatore, osservino sempre i due principi fondanti della Scuola: serietà professionale, basata su un’ottima conoscenza clinica, e serietà scientifica, supportata da un’ottima produzione scientifica.

 

Bibliografia

  1. Timio M. Professor F.P. Schena: an all-round protagonist of nephrology. G Ital Nefrol. 2010 Nov-Dec;27(6):681-4.
  2. Schena F.P., Fogazzi G.B. Interviste con la Storia della Nefrologia Italiana. pag 165- 174, 2016 Wichtig Editore, Milano.

Italian Pioneers in Cardionephrology: how some fundamental Italian cardiorenal researches have passed into oblivion

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Attilio Losito

Attilio Losito

Former director of the Struttura Complessa di Nefrologia e Dialisi Santa Maria Della Misericordia Hospital, Perugia, Italy

Corresponding author:
Dr Attilio Losito
via P Pellini 4 06123, Perugia
email: alosito3@gmail.com

 

Abstract

A historical research was made on papers published by Italian scientists on cardiorenal diseases. The investigated period is between the beginning of the 20th century and the entry of Italy into the Second World War, 1940. 34 papers dealing with the relationship between the kidney and the cardiovascular system were retrieved. All but two articles were published in Italian medical periodicals. The topics covered are varied and range from cardiotoxicity of substances in uremia to the role of renal disease in vascular damage. Some articles are forerunners of later pathophysiological concepts and research technologies. These concern early atherosclerotic vascular damage and the presence of dialyzable cardiotoxic substances in renal insufficiency. Unfortunately, these highly innovative researches have had little diffusion and have fallen into oblivion in Italy and abroad. In conclusion, our research shows that in the first half of the 20th century in Italy there was a lively interest in cardio-renal diseases and that some researchers had produced precursor results of what was confirmed many years later.

Keywords: cardionephrology, cardiorenal studies, Italian scholars, history of nephrology

Introduction

Thanks to the Mario Timio’s series of congresses in Assisi, dedicated to Cardionephrology, this branch of Nephrology has experienced growing success in Italy and in the world since 1987 [1]. Although the term Cardionephrology apparently was coined in 1991, studies on the relationship between kidney disease and the heart have a much longer history [2–4]. An attempt to define cardiorenal disease was made in 1914 in Philadelphia by the renowned clinician Alfred Stengel (1868-1939). According to this eminent clinician “the term comprises cases of combined cardiovascular and renal disease without such manifest predominance of either as to justify a prompt determination of the one element as primary and important and the other as secondary and unimportant” [5]. This term was also used in death certificates in USA [4]. Among the early studies on cardiorenal syndromes, the best known are those performed in UK, France and USA [3, 4].

In Italy in the first half of the 20th century such definition was not diffused, although the relationship between heart and kidney was the object of several studies. The heart involvement in uremia, in acute and chronic glomerulonephritis and the early atherosclerotic changes associated with chronic renal failure were the topics most frequently dealt with. To our knowledge, these studies remained almost as unknown abroad as at home. Only belatedly through the references of the paper on “The pathogenesis of renal cardiopathy” from the Pisa group published in 1957 some early Italian work on cardiorenal disease has come to light [6].

To what extent the lack of acknowledgment and of citations of early Italian studies in the cardiorenal field can be justified can only be established from a retrospective survey of the early research carried out in this field. We have therefore undertaken this study with the aim of retrieving Italian papers dealing with cardiorenal disease, published in the first half of the 20th century. We subsequently analyzed the retrieved studies and compared them with contemporary international researches.

 

Material and Methods

We searched the medical bibliographic databases for articles that dealt with kidney pathophysiology and disease written by Italian authors, published between the year 1900 and 1940, entry of Italy into the Second World War. Then many Italian doctors were drafted into the army and stopped their normal activities. Moreover, the war was a turning point for medical research worldwide since because of it changed completely [7]. Therefore, we chose 1940 as the end limit for our research. Among the papers we have therefore selected those that dealt with the relationship between the kidney and the cardiovascular system. The articles in this selection were analyzed for the purposes of this research.

 

Results

We retrieved 638 papers of Italian authors published in the period 1900-1940. Among these, 34 (5.4%) dealt with the relationship between the kidney and the cardiovascular system. All but two papers were published in Italian journals. The main topics dealt with are shown in chronological order in Table1.

Year Subject Bibl Ref #
1911 Urea concentrations and heart function 8
1914 Heart Hypertrophy in unilateral kidney disease 9
1924 Lipid metabolism in GN and uremia 10
1924 CV changes in different kidney diseases 11
1930 Heart failure and the kidney 12
1935 Heart involvement in acute GN 13
1936 Vascular lesions in chronic GN 14
1939 Electrocardiographic changes in Uremia 15
1940  Atherosclerosis, myocardium changes and heart failure in chronic GN 15
Table 1: Cardiorenal topics in Italian researches (1900-1940). GN: Glomerulonephritis. CV: Cardiovascular.

Representative papers are listed in the references [8-16]. In Figure1 is shown the cover of the oldest cardiorenal Italian paper we were able to retrieve, published in a French journal. Almost all authors were from internal medicine institutes. Only one was a surgeon [17].

Cover of one of the oldest cardiorenal Italian papers published in a French journal.
Figure 1: Cover of one of the oldest cardiorenal Italian papers published in a French journal. The subject is the effect of urea on the heart, one of the hottest topics of the period.

 

Characteristics of researches

Most were clinical studies. Others were clinico-pathological [9, 14, 16]. Only two were based on experiments made in lab with animals [15, 17]. Blood pressure measurement, electrocardiogram, x-ray and blood chemistry were the clinical investigation tools employed. Since early researches much emphasis was placed on the role played by urea or other toxic substances produced by kidney disease on the heart [8, 18]. Later papers generally dealt with single nephropathies in their relationship with heart diseases. An attempt was also made to list individual types of renal diseases with their association with cardiovascular complications [19].
Several papers aimed at discriminating the effects of hypertension on the cardiovascular system from those produced directly by kidney disease [9,13]. The cardiovascular complications investigated were heart hypertrophy and failure, arrhythmias and electrocardiographic changes, macrovascular and microvascular changes. In none of the retrieved papers pericarditis was a subject of research. Generally, the authors published only one paper on cardiorenal disease. Only one researcher published several papers on this subject, in the period from 1935 to 1940, Fernando Marcolongo (1905-1969) from Turin [13, 16, 20-22].

 

Discussion

We found that from the beginning of the 20th century to the war, Italian researchers published a fair amount of papers dealing with cardiorenal diseases [18]. The results of some of these studies have maintained their value over time and have proved to be the forerunners of research lines that are still current today. Table 2 summarizes the results of two papers that we believe are the most relevant in this respect.

Year Research Bibl Ref#
1939 Study of the effect of serum from uremic patients on guinea pig heart. Dialysis of serum removed its toxic effect on myocardium. First demonstration of dialyzable heart toxic substances in uremia. 14
1940 Demonstration that early coronary atherosclerosis in chronic glomerulonephritis is independent of hypertension and other general risk factors. Clinical and pathological study. 15
Table 2: Outstanding cardiorenal Italian researches (1900-1940).

Generally, the different themes dealt with in the articles we retrieved do not differ from those of contemporary international medical literature, except for pericarditis. This uremic complication, although dealt with in the Italian textbooks of the time, is not present in the articles we have found. Uremic pericarditis, on one hand, was the object of several researches carried out in the US during the same period [23, 24]. On the other hand, it should be emphasized the particular interest shown by some Italian authors towards vascular lesions, which today we would define as atherosclerotic, associated with chronic nephropathies. In some of the papers, the hypothesis that atherosclerotic lesions are a direct consequence of nephropathy is put forward [14].

The most significant and original research on the relationship between vascular lesions and chronic nephropathies is the one carried out by Marcolongo [16]. This study was based on pathological observations, during a period of several years, and the respective clinical characteristics of 44 cases of chronic glomerulonephritis. The conclusions of the study are original and differ from what was generally believed not only in Italy but also in the US at the time and years later [25, 26]. In fact, against common thought, this research suggests a direct role played by nephropathy in the pathogenesis of coronary atherosclerotic lesions. In particular, this research, carried out on young subjects, indicates a particular role of nephropathy in the interrelation between coronary artery disease, hypertension and heart failure. In the sample population studied the other well-known risk factors for atherosclerosis were absent. The short duration of arterial hypertension, resulting from the young age and the short time of the disease, ruled out its role in the pathogenesis of the coronary lesions. Therefore, nephropathy was indicated as the key element in favoring the early development of coronary damage.

This, to our knowledge, is the first study identifying a specific role of the kidney in the development of vascular damage. Unfortunately, the well-known studies made in the US, dealing with the same matter, published many years later do not mention this innovative research published in Italy at the time of the start of the Second World War [27, 28]. The only recognition of this innovative research came many years later in the seminal article on renal heart disease from the Pisa group [6]. We attribute the Italian language of the medical periodical and the date of publication, coinciding with Italy’s entry into World War II, among the causes of the scarce recognition obtained by this innovative research.

Another research that deserves a particular mention is an animal testing carried out in Genoa [15]. The experiment consisted in studying the effects of the serum of uremic patients, its dialysate or its ultrafiltrate on the heart of guinea pigs. The authors found that the injection of dialyzed sera from the uremic patients did not induce any cardiac changes in the guinea pig. Conversely, the dialysate and the ultrafiltrate of the uremic serum induced a myocardial toxicity which manifested itself with various alterations of the electrocardiogram. To rule out a possible interference of hypertensive substances the experiment was repeated with the serum of a hypertensive subject without uremia. In this case the injection of the ultrafiltrate did not induce any myocardial change. The authors conclude that they demonstrated for the first time that uremic serum contains myocardiotoxic substances. Most interestingly their experiment shows that these substances are removable with ultrafiltration or dialysis. This research introduces for the first time in the scientific world the possible removal of cardiotoxic uremic substances with dialysis. Surprisingly, this discovery was ignored in subsequent years even in well-documented texts such as Cameron’s on the history of dialysis or in other more recent historical reviews on cardionephrology [29, 4]. We ascribe to the use of the Italian language and to the time of publication, simultaneous to the war declaration, the cause of this outstanding research going unnoticed.
As far as the author is concerned, it is worth underlining that most of the authors of these early researches have subsequently played an important role in Italian internal medicine before and after the Second World War. Some of them such as Nicola Pende (1880-1970) and Luigi Condorelli (1899-1985) obtained chairs at the most prestigious Italian universities and founded illustrious schools of internal medicine and cardiology. The same observation was previously made for early scholars of nephrology [30, 31]. Marcolongo became professor of internal medicine and was among the founders of the Italian Society of Nephrology [32].

Our investigation of early cardiorenal studies in Italy allows us some brief considerations. The first is that the problem of the complex pathological relationships between kidney and heart was well present in the scholars of the time. Therefore, many researches were conducted on the subject. Some of these, even in the light of subsequent scientific advances, appear to be forerunners of new knowledge. Unfortunately, for a whole series of circumstances related to the troubled period and the use of Italian in the publication, these results were not sufficiently widespread in the scientific community. Consequently, the value of these researches did not obtain the deserved recognition and went soon into oblivion. Other similar forgetfulnesses have been reported recently in the nephrology field [33]. We, therefore, hope with our research that we have drawn historical attention to these forgotten studies.

 

Acknowledgments

We are grateful to Mrs. Susanna Mattioli of the Biomedical Library of the University of Perugia for her invaluable help in retrieving the historical papers.

 

Bibliography

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Pius X (1835-1914): the last gouty pope

Posted on Scarica PDF

Corresponding author:
Natale Gaspare De Santo
Salita Scudillo 20,
80131, Napoli
E-mail: NataleGaspare.Desanto@unicampania.it

 

Abstract

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults. It is due to the deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia. Gout is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2460 BC. It is known as “the rich man’s disease”, “the patrician malady”, “a disease of plenty”, “disease of kings”, “disease of Western Society”, and also “a life-style disease”. Few studies have addressed the problem of gout among popes, affluent people who usually live longer than their contemporaries and are among the most scrutinized persons. Pius X (1835-1914) was the last pope with gout.

Gout seems to have affected 26 out of 265 popes (9.81%) from Saint Peter to Benedict XVI (34-2013 AD). The first was Gregory I Magnus, who was pope in the years 590-604, the last was Pius X, who reigned from 1903 to 1914 at age 79. Their age at death was 71.7 ±9.2 years (Mean ± SD). All popes were elderly men, some had voracious appetites and/or were wine drinkers. Several were sedentary and obese, while others were sober eaters, who took long walks or went riding. Chiragra (arthritic pain in the hands), podagra (arthritic pain in the big toe) and renal stone disease were among the most frequent disturbances.

The causes of death, due to CKD, strokes and infections are discussed along with the fact that gout disappeared from the Vatican Palace on August 22, 1914. However, in accordance with the Theory of Epidemiological Transition, gout seems likely to become a problem for the general population, increasingly adopting unhealthy lifestyle choices, in the absence of a correct education.

Keywords: gout, popes, Pius X, renal death, death due to infection, death due to stroke

Introduction

Gout is a chronic, painful, non-infectious, non-lethal disease associated with crystal deposition of uric acid, when uric acid concentration exceeds 6.8 mg/dl plasma. The kidneys may cause hyperuricemia – the prevalence of which increases in the old and very old, – but are also the target of hyperuricemia (renal stones, renal disease and its progression). Hyperuricemias are due to either renal overload, renal underexcretion or a combination of both; renal overload may be due to overproduction by dietary purines, endogenous purine synthesis, purine breakdown and purine salvage [1–6]. Gout, known also as the “patrician malady” and the “disease of distinction” [7,8] is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2640 BC [9].

Popes by definition belong to the most affluent class and their lifespan is longer than their contemporaries. In fact, a total of 51 pontiffs reigning in the years 1493 to 2005 lived to a mean age of 63.9 years and died an average of 10.0 years after being enthroned [10]. We have studied the narratives around popes, from Saint Peter to Benedict XVI [11–15], and demonstrated a high prevalence of gout. In a recent review [16] we identified a total of 25 gouty popes: 14 out of 25 (58%) had risk factors; 5 out of 25 (25%) had comorbidities; 21 out of 25 (84%) were unable to perform their duties; 8 out of 25 (32%) died of stroke; 12 of them (68%) had renal disease; 12 out of 17 (70.6%) underwent a renal death. Renal disease did not affect age at death [16].

This paper focuses on the last gouty pope, Pope Pius X. His death has been traditionally but wrongly attributed, even by us, to acute pneumonia. The present study now points out that his death was most likely linked to uremia, due to lasting gout, the final straw being acute pulmonary infection.

 

Historical case report – Pius X (1835-1914), Pope (8/4, 1903-8/22,1914)

Pius X (Figure 1), born Giuseppe Melchiorre Sarto on June 2, 1835 at Reise (Province of Treviso), was ordained priest in 1858 and, in the same year, became parish priest. Later he was nominated bishop of Mantua (1884), cardinal and patriarch of Venice (June 1893) and elected Pope on August 4, 1903; he reigned until August 22, 1914. A renowned orator, he is remembered for his expertise in sacred music and for hiring Lorenzo Perosi for the Choir of the Sistine Chapel, for his antimodernism and the refusal of science, for the letters sent to European powers to avoid the First World War, and for the wide pastoral care and the love for the poor. In his last will and testament wrote “born poor, lived poor, want to die poor”. Roger Aubert, the Belgian historian Roger Aubert (1914-2009) has defined Pius X as the greatest reformer of the internal life of the Church after the Council of Trent [17].

His health has been described as good until the end of his days and his death ascribed to “acute tracheitis, bronchitis, infection-inflammation of the lower left lung lobe”, a disease of acute onset followed by rapid worsening. He was under the care of Andrea Amici (1870-1920), archiater and chief of medical services in the Vatican, and of Ettore Marchiafava (1847-1935), professor of pathology at the University La Sapienza in Rome. His disease lasted from Saturday August 15 (he celebrated the last mass) to the night of August 20, 1920. The course was characterized by a worsening fever that, in his last hours, peaked at 40°C and was associated with dyspnea [18-20].

Figure 1: Picture of Pope Pius X (1835-1914), October 1903, from Herder Verlag, Freiburg im Breisgau: Die katholischen Missionen (digitally colored). Image in the public domain, https://commons.wikimedia.org/wiki/File:Pius_X,_by_Francesco_De_Federicis,_1903_(retouched,_colorized).tif

However, we now know that Giuseppe Sarto, since his early years of priesthood, had suffered from gout, which flared painfully from time to time and was tolerated by him. As a pope, for obvious state reasons, he was forced to frequent health checks and restrictive dietary impositions [21]. The disease flared up in August 1920 and was associated with chest pain, fever, nephritis (uncurable at that time). The disease extended to the bronchial tree and caused the pneumonia that killed him [22]. So, the diagnosis was pneumonia, heart failure, pericarditis and uremia due to gout.

He was beatified in 1951 by Pius XII. As far as we know, he was the last gouty pope and after him the disease was never again associated with the papacy.

 

Discussion

Recent studies have defined gout as a “papal disease” [16]. Pope Pius X is the last in the list of 26 gouty popes of the Catholic Church between the years 590-1914 (Table 1). Gout affected 9.77% of all popes and he was the 18th out of 26 (69.3%) gouty popes to die of a renal cause. The disease left him, like 22 out of 26 (84.6%) other popes, unable to perform his duties.

No. Popes Family name Start of pontificate End of pontificate Inhability to perform Renal/non renal death** Age of death
1 St Gregory I Anici 9/3, 590 3/12, 604 yes Non-renal 64
2 Sisinnius NK 1/15, 708 2/4, 708 yes Non-renal 58
3 Sergius II Sergio 1/2 844 1/17 847 yes Non-renal 57*
4 Boniface VI NK 4/5, 896 4/20 896 Non-renal NK
5 Honorius IV Giacomo Savelli 4/2, 1285 4/3, 1297 yes Non-renal 77*
6 Boniface VIII Benedetto Caetani 12/24, 1294 10/11, 1303 yes Non-renal 73
7 Clement VI Pierre Roger 5/7, 1342 12/6, 1352 Non-renal 62
8 Nicholas V Tommaso Parentucelli 3/6, 1447 3/24, 1455 yes Renal 58
9 Callistus III Alonso de Borja 4/8, 1455 8/6, 1458 yes Renal 80
10 Pius II Enea Silvio Piccolomini 8/19, 1458 8/15, 1464 yes Renal 66
11 Sixtus IV Francesco della Rovere 8/9, 1471 8/12, 1484 yes Renal 70*
12 Pius III Francesco Todeschini Piccolomini 9/22, 1503 10/18, 1503 yes Renal 64
13 Julius II Giuliano della Rovere 11/1, 1503 2/21, 1513 Non-renal 70
14 Julius III Giovanni Maria del Monte 2/7, 1550 3/23, 1555 yes Non-renal 68
15 Marcellus II Marcello Cervini degli Spannoni 4/1, 1555 4/30, 1555 yes Renal 54*
16 Pius IV Giovanni Angelo Medici di Marignano 12/25, 1559 12/9, 1565 yes Renal 66
17 Clement VIII Ippolito Aldobrandini 1/30, 1592 3/3, 1605 Renal 70*
18 Gregory XV Alessandro Ludovisi 2/9, 1621 7/8, 1623 yes Renal 69
19 Innocent X Camillo Pamphilj 10/4, 1644 1/7, 1655 yes Non-renal 80
20 Clement X Lorenzo Altieri 4/29, 1670 7/22, 1676 yes Non-renal 86
21 Innocent XI Benedetto Odescalchi 9/21, 1676 8/12, 1689 yes Renal 78
22 Innocent XII Antonio Pignatelli 7/12, 1691 9/28, 1700 yes Non-renal 85*
23 Clement XII Lorenzo Corsini 7/12, 1730 2/6, 1740 yes Renal 88*
24 Benedict XIV Prospero Lorenzo Lambertini 8/17, 1740 5/3, 1758 yes Renal 83*
25 Pius VIII Francesco Saverio Castiglioni 3/31, 1829 11/30, 1830 yes Non-renal 69
26 Pius X Giuseppe Melchiorre Sarto 8/4, 1903 8/20, 1914 yes Renal 79
All popes 84.6% 50% Renal 71.9 ±9.2#
Table I: Gouty popes (no. 26). Data for popes nos. 1-25 in reference no.16. (* affected by stroke; ** presumed Renal/Non Renal death; # Mean ±SD; NK = not known).

The mean age at death of the 26 popes listed in Table I was 71.7 ±9.7 years and no difference was found between the age at death of popes who died of a renal cause and those who died of a non-renal cause. Pius X died from an acute infectious disease, which is always a risk for a gouty person. In fact, compared to the general population, gout patients have an increased association with all-cause disease mortality, especially attributed to cardiovascular diseases, cancer, and infectious diseases [23].

In a study by Vargas-Santos et al. [24] enrolling 19,497 people with a new diagnosis of gout and 194,947 controls, a strong association was found between gout and risk of death due to renal disease. Furthermore, a study by Spaetgen et at. [25] investigated the risk of various types of infections (pneumonia and urinary tract infection), and infection-related mortality in patients with gout using data from the UK Clinical Practice Research Datalink. Their study was the first evaluating the risk of community-acquired infections in patients with gout versus matched controls. Gout was associated with a 34% increased risk of pneumonia. Also, in a national study across the United States [26], the most common infection was pneumonia (52%) in 1998-2000 and sepsis (52%) in 2015-2016. Older age was associated with a greater risk.

There is a strong suspicion, still to prove, of an association between lung infection and the lung dysfunction described in uremia for the first time in 1932 by Ehrich and McIntosh in 3 patients with Bright’s disease [27]. They believed that some toxic or metabolic factor resulted in edema and congestion with “formation of an exudate which failed to resorb and then went on to organization” [27], a dysfunction that has been extensively studied in recent years. A restrictive dysfunction, associated with gravity of CKD, was disclosed by Mukai et al. [28], whereas Zoccali et al. [29] have shown, by systematically applying chest ultrasound in ESRD patients, that hidden or clinically manifest lung congestion is exceedingly frequent in this population an may be detected at a preclinical stage.

Gout, probably the first known non-communicable disease, might not represent in principle the best candidate to be discussed in terms of “Theory of Epidemiologic Transition”. This theory was advanced in a landmark paper by Abdel R. Omran [30] after infectious diseases were conquered [31] after World War II and degenerative and “man-made diseases” started emerging. Using demographical tools, Omran analyzed the changing patterns of population age distribution in relation to changes in mortality, fertility, life expectancy, causes of death. He identified 3 ages in humankind: the age of famine and pestilence (life expectancy <30 years), the age of “receding pandemics” (life expectancy 30-50 years), and the “age of degenerative diseases and man-made disease” (life expectancy >50 year). The theory has been updated frequently, and finally poverty (initially neglected) has been taken into consideration along with incomes and education [30–36].

This is relevant and makes the theory suitable to explain the high prevalence of gout in popes and the low, but slightly increasing, prevalence in the general population. The data shall be discussed in terms of lifestyles, income and education. It has been shown that affluent and educated people also adopt immoderate lifestyles causing non-communicable diseases associated with morbidity and mortality [30–36]. However, these people, when made aware of the risks, often agree to modify their lifestyles choices, whereas poorer, uneducated people do not. Thus, the latter group tends to experience the morbidity and mortality of the disease (third transition phase) at the time when rich well-educated individuals achieve protection [36].

By applying the above concepts to gout (Figure 2), we can say that popes before 1915 had a high prevalence of gout due to lifestyles choices causing it. These were later corrected through education and gout disappeared. Thus, in 2021, gout has no room in the apostolic palaces. At the same time, poor people, because of undernutrition, working conditions, and frequent movements back and forth from the workplace, were “protected” from gout, and therefore, before 1915, the prevalence of gout was zero. After World War II the general population has become sedentary, while the availability of proteins and the abuse of spirits, wines and other alcoholic beverages, as well as beverages rich in glucose, has sharply increased. Therefore, in the USA, Italy and France, the blood concentration of uric acid has been slightly but steadily increasing; the prevalence of gout is still minimal, but increasing, and will continue to do as long as education fails to encourage healthier lifestyles.

Lifestyles causing and preventing gout
Figure 2: Lifestyles causing and preventing gout, and trends in the prevalence of gout in popes and general population before 1915 and in 2021

Acknowledgements

We thank for the English revision Joseph Sepe MD, Professor of Biological Sciences, University of Maryland Global Campus, USA and Adjunct Professor – Department of Mathematics and Physics University of Campania, Luigi Vanvitelli, Naples, Italy.

 

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Nephrology and nephrologists in Italy between the two World Wars

Posted on Scarica PDF

Attilio Losito

Attilio Losito

Già direttore della Struttura complessa di Nefrologia Dialisi e Trapianto dell'Ospedale Santa Maria della Misericordia di Perugia.

Corrispondenza a:
Attilio Losito
Via Pellini 4, 06123 Perugia Italia
email: alosito3@gmail.com

 

Abstract

The First World War was a turning point for medicine worldwide and the following 20 years brought many important innovations. Kidney studies in Italy were part of this general trend. In this contribution, all the papers relating to kidney physiology, pathology and therapeutics produced by Italian scientists in the years between the two World Wars are retrieved and examined. The authors who produced strictly nephrological articles are also singled out and their activity described. This research retrieved 638 articles dealing with kidneys and published by Italian scientists over the period described. The topics covered were up-to-date, and the level was consistent with that of foreign contemporaries. Among the authors, a group of young scientists particularly dedicated to the study of the kidney emerges. Most of them would subsequently be among the founders of the Italian Society of Nephrology and leaders of Italian nephrology.

Keywords: history, nephrology, Italy, scientists, World Wars

Introduction

World War I was a turning point for medicine. Giorgio Cosmacini, doctor and historian of medicine, in his book “War and Medicine” defines war as a “paradoxical” source of progress from a medical point of view [1]. The need to treat a huge number of soldiers wounded and/or suffering from serious and new pathologies forced doctors to seek new, previously unknown, answers to deal with new emergency situations. The results of this research had a tremendous impact on world medicine in the years following the conflict.

The Italian doctors, especially the younger ones, who found themselves serving in war zones also benefited from those experiences and from contacts with colleagues in the allied armies. The clinical and research approach changed, both in terms of timing and methods. Kidney diseases occupied a prominent position among war-related morbidities. For example, since the first months of the conflict, there had been reports of an apparently new type of “nephritis”: the “trench nephritis” or war nephritis.
This new form of nephropathy attracted the attention of the greatest clinicians of the time including William Osler (1849-1919) [2]. Italian doctors promptly turned their attention to this new form and such was the interest that the first post-war congress of the Italian Society of Internal Medicine dedicated a session to it. Significantly, this meeting was held in Trieste that, at the time, had just become Italian (Fig. 1) [3]. Due to the techniques used and the progress achieved, we may consider this as the start of a new cycle of nephrology studies compared to the previous two decades [4].

Figure 1: Session of the 1919 Internal Medicine Congress held in Trieste, dedicated to war nephritis
Figure 1: Session of the 1919 Internal Medicine Congress held in Trieste, dedicated to war nephritis

We, too, chose to start from this date for an excursus on Italian nephrology between the two wars.

 

Materials and methods

We have searched all the scientific articles concerning kidney studies (anatomy, physiology, clinic) published by Italian authors between the two World Wars. The specific nephrological items searched in the literature between 1918 and 1939 are listed in Table I.

Subject N. of Papers %
Nephropaty (general) 118 18.4
Glomerulonephritis 82 12.8
Renal function 73 11.4
Hematuria 63 9.8
Kidney stones 45 7.0
Polycystic kidney 38 5.9
Diuretics 38 5.9
Albuminuria 36 5.6
Azotemia 37 5.7
Renal diabetes 26 4.0
Hypertension & Kidney 21 3.2
Creatinine 17 2.6
Nephrosis 15 2.3
Nephrosclerosis 12 1.8
Uremia 10 1.5
Pielonephritis 7 1.0
Total 638 100
Table I: Kidney studies published by Italian authors between World War One and World War Two

Within these subject areas, we have also singled out specific issues, emerged during the observed period, that were not dealt with in previous years and that that are still of scientific interest today. We also examined the respective chapters of two major Italian medical treatises, published in 1931 and 1939.

Of each author we have encountered, we have reported the age and the subsequent professional development, searching for those who, in the second post-war period, would have a role in modern Italian nephrology and in the foundation of the Italian Society of Nephrology (SIN) in 1957 [5].

 

Results

We retrieved 638 published papers dealing with kidney studies published by 343 Italian authors (Table I). The mean number of papers per author was 1.6.

Subject of the papers

The largest group has been labeled “general nephropathies” and includes different types of conditions, investigations, and therapies.

The second group concerns glomerulonephritis. This includes 10 papers on “trench nephritis”. These are of particular interest since they show that their authors were up to date on research carried out in other countries and that their pathogenetic hypotheses were sufficiently well founded [6]. It was believed that the conditions of the soldiers in the war environment had created a general and/or renal vulnerability and that this favored infectious processes, causing glomerulonephritis. Histologically it was identified as a diffuse proliferative form. The long-term prognosis was considered poor. Most concepts, especially those concerning the infective etiology, were in good keeping with the conclusions drawn on the matter by the top medical figures of the time [7].

The investigation of renal function is the subject of 11.8% of the papers. The analysis shows that in Italy in the mid ’30 this was a much-debated topic. In a 1931 medical treatise, the concentration-dilution test was deemed the most reliable assessment of renal function [8]. No clearance tests were taken into account. In the following years new concepts and new tests came into play. The urea clearance as a measure of the efficiency with which the kidneys remove urea from the blood stream was introduced after the WW1 and spread rapidly [9]. Its precision in assessing glomerular filtration was however invalidated by the rate of urea reabsorption by the tubules.

Rehberg had tried to overcome this drawback by devising a clearance method aimed at measuring the glomerular filtration based on an administration of a substance only filtered by the glomeruli [10]. Unfortunately, the load of creatinine administered was so large that the high blood concentration attained caused a tubular excretion of the substance together with glomerular filtration, altering the results [11]. Therefore, in Italy, the assessment of glomerular filtration through the recently proposed formula caused enthusiasm and controversy at the same time. Some studies did not fully support the results obtained by applying Rehberg’s method to the measurement of glomerular filtration in renal diseases [12]. On the other hand, other scientists found that this method could be improved to provide reliable results. In this way, by introducing the concentration of naturally occurring plasma creatinine in the formula of Rehberg, the Italian doctor Ferro-Luzzi was the first in the world to describe the clearance of endogenous creatinine and to obtain reliable results (Fig. 2) [13,14,15]. These studies were among the few to be published on foreign journals. The same applies to a basic science study on glomerular filtration published on an American journal and that deserves particular attention as it was written by a young Italian scientist destined for a very brilliant academic career Fig. 3 [16].

Figure 2: One of the papers on the use of the creatinine clearance by Ferro-Luzzi published in a German journal
Figure 2: One of the papers on the use of the creatinine clearance by Ferro-Luzzi published in a German journal
Figure 3: The first nephrological paper published by an Italian scientist in an American Journal
Figure 3: The first nephrological paper published by an Italian scientist in an American Journal

Azotemia (BUN) and creatinine are the subject of 8.3% of published research and are closely related to the studies of semeiology and renal physiology.

Among the other studies, those dealing with the relationship between kidney and hypertension should be highlighted. These 21 papers represent 12.5% of all hypertension articles and provide interesting insights into the research trends of the time. Renal denervation was attempted as a treatment for arterial hypertension [17]. The possibility of irradiating the carotid sinus to reduce blood pressure was also explored [18]. Finally, attempts at surgical therapy for arterial hypertension proposed by important clinicians of the time also deserve to be reported [19].

Other subject listed in table I are of lesser relevance or are tainted by concepts that have completely disappeared in the evolution of nephrology. An example is represented by the “nephrosis” group: this word, at the time, indicated conditions completely different from what we mean today.

The progress made in Italy, with the aforementioned studies, and abroad during the decade 1930-40 is well evidenced and discussed in the ponderous section (397 pages) on the kidney of the “Ceconi and Micheli” internal medicine treatise of 1940 [20]. From those pages, and the relative bibliographic references, we could also identify the Italian authors considered as “opinion leaders” in kidney studies at the time.

Authors

In order to single out the authors with a greater nephrological interest, we have arbitrarily selected those with a number of publications on the topic equal to or greater than five. In Table II these authors are listed along with their age and research location. All of them came from the most prestigious Italian universities, where studies on the kidney had already developed in previous years [4].

Author N°papers Birth and death City of work
Ferro-Luzzi Giovanni 28 1903-2000 Roma-Messina
Marcolongo Fernando 23 1905-1969 Torino
Condorelli Luigi 17 1899-1985 Napoli-Catania
Cesa-Bianchi Domenico 6 1879-1956 Milano
Gavazzeni Mauro 6 1904-1935 Pavia
Bufano Michele 5 1901-1993 Parma
Fieschi Aminta 5 1904-1991 Pavia
Table II: Authors with 5 or more nephrological papers

Interestingly, all but one were quite young at the time of the nephrological research we have retrieved. Three of them stand out for the number of published articles and their quality: Ferro-Luzzi, Marcolongo and Condorelli.

Ferro-Luzzi produced a series of studies on the kidney published in important international German-language journals between 1931 and 1939. The most interesting were those on plasma creatinine and its pioneering use in the calculation of clearance [13, 22]. Ferro-Luzzi is also the most cited Italian author in the chapter on renal function of the aforementioned treatise by Ceconi and Micheli [20]. For historical purposes, it should be noted that Filippo Romeo (1908-1981), who was a little younger than Ferro-Luzzi, conducted some nephrological research in association with him and, many years later, was one of the founders of the SIN [22]. This collaboration was interrupted when Ferro-Luzzi went to direct the Italian hospital in Asmara in 1939, where he founded the local medical school and remained until 1955.

Marcolongo belonged to the Turin academic school of Ferdinando Micheli (1872-1937). Since his degree in medicine in 1927, he devoted much of his research activity to the study of the kidney under all its physio-pathological, clinical and therapeutic aspects. In recognition of his experience in the nephrology field, he was entrusted with writing the chapter on kidney diseases of various medical treatises, first of all the Ceconi-Micheli of 1939 [20]. He obtained the academic position of professor of medicine in Siena and, years later, he appears among the members of the first board of the newly formed SIN.

Condorelli appears in this list not only for the number of kidney studies published, but also because he is the first Italian to publish a nephrological article in an American journal (Fig. 3, above) [16]. After this early interest in nephrology, Condorelli extended his research to other organs, especially the heart, where he obtained even more brilliant results. At the height of his career, he became a renowned professor of medicine at the University of Rome.

The presence of Bufano and Fieschi in our list of authors is of particular interest, since both of these researchers played an important role in post-war nephrology. Bufano created one of the most important Italian nephrological schools in Parma and was one of the founders of SIN. From an academic point of view, he achieved the position of professor of medicine in Rome. Fieschi, later a member of the first board of the SIN, was a pioneer of renal dialysis. In fact, in 1947, before becoming professor of medicine in Genoa, he conceived and built his original model of artificial kidney [23].

A sad fate awaited the last of these authors. Gavazzeni, who had carried out some brilliant research in the department of Adolfo Ferrata (1880-1946) in Pavia, died as a hero in the war of 1935 [24]. The city of Bergamo named a street after him.

Finally, after having considered some of the most prolific authors in the nephrological field, we cannot forget those who were taking their first steps back then. Among them, especially noteworthy are Domenico Campanacci (1898-1986) and Cataldo Cassano (1902-1998) who, in the early ’30s, had proposed their theories on the nature of lipoid nephrosis [25]. Years later, both authors founded important nephrological schools.

 

Conclusions

From the results of this investigation on kidney studies in Italy between the two World Wars we can draw a few conclusions. Italian scholars were very active in this area of medicine and their knowledge was up to date and on the same level of their colleagues abroad. The most productive researchers were young, which may indicate that the complex issues inherent to kidney function required a fresh and prepared mind. Therefore, only few selected researchers chose to approach this field. All of them carried out their research in the context of the most advanced medical schools in Italy. Here, a fruitful synthesis took place between these researchers’ new ideas and the structures most suitable for supporting their work. The quality of these young researchers is also confirmed by their success in their subsequent academic career. It is astonishing that all of them obtained positions of great importance in Italian medicine and inspired internal clinical schools or, more specifically, nephrological institutions. Finally, the names of many of these scholars appear in the formal act of foundation of the SIN, which ratified the existence of a substantial number of clinicians and researchers dedicated to the study of the kidney in Italy. This confirms the very close connection existing between “modern” Italian nephrology and what was achieved in this field between the two World Wars.

 

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