Treating anaemia in patients with chronic kidney disease: what evidence for using ESAs, after a 30-year journey?

Abstract

Erythropoiesis Stimulating Agents (ESAs) are well-tolerated and effective drugs for the treatment of anaemia in patients with chronic kidney disease.

In the past, scientific research and clinical practice around ESAs have mainly focused on the haemoglobin target to reach, and to moving towards the normality range; more cautious approach has been taken more recently. However, little attention has been paid to possible differences among ESA molecules. Although they present a common mechanism of action on the erythropoietin receptor, their peculiar pharmacodynamic characteristics could give different signals of activation of the receptor, with possible clinical differences.

Some studies and metanalyses did not show significant differences among ESAs. More recently, an observational study of the Japanese Registry of dialysis showed a 20% higher risk of mortality from any cause in the patients treated with long-acting ESAs in comparison to those treated with short-acting ESAs; the difference increased in those treated with higher doses. These results were not confirmed by a recent, post-registration, randomised, clinical trial, which did not show any significant difference in the risk of death from any cause or cardiovascular events between short-acting ESAs and darbepoetin alfa or methoxy polyethylene glycol-epoetin beta. Finally, data from an Italian observational study, which was carried out in non-dialysis CKD patients, showed an association between the use of high doses of ESA and an increased risk of terminal CKD, limited only to the use of short-acting ESAs.

In conclusion, one randomised clinical trial supports a similar safety profile for long- versus short-acting ESAs. Observational studies should always be considered with some caution: they are hypothesis generating, but they may suffer from bias by indication.

Keywords: anaemia, erythropoiesis stimulating agents, ESAs, mortality, chronic kidney disease, long acting, short acting

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Introduzione

Dalla pubblicazione dello storico lavoro di Eschbach più di 30 anni fa [1], il trattamento dell’anemia con i farmaci stimolanti l’eritropoiesi (Erythropoiesis Stimulating Agents, ESAs) ha rivoluzionato la qualità della vita dei pazienti con malattia renale cronica (Chronic Kidney Disease, CKD). In quegli anni i pazienti erano gravemente anemici e spesso sopravvivevano con livelli di emoglobina anche inferiori a 5 g/dL, ricorrendo a periodiche trasfusioni, con alto rischio di trasmissione di un’epatite allora sconosciuta, definita “non A-non B” (oggi chiamata C) e con conseguente accumulo di grandi quantità di ferro. Nei casi più gravi i nefrologi erano costretti ad intervenire con un trattamento chelante a base di desferriossamina, a sua volta gravato da serie complicanze come la mucoviscidosi. Improvvisamente, grazie all’utilizzo dell’eritropoietina, i pazienti ricominciarono a vivere. Tale era l’entusiasmo dei nefrologi nel poter finalmente correggere efficacemente la grave anemia dei loro pazienti cronici, che si fecero trascinare fino a una correzione troppo rapida dei valori di emoglobina, portando a complicanze come un aumento dei valori pressori sino a severe crisi ipertensive e, a volte, convulsioni. 

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SGLT2 inhibitors, beyond glucose-lowering effect: impact on nephrology clinical practice

Abstract

Epidemiological data show an increasing diffusion of diabetes mellitus worldwide. In the diabetic subject, the risk of onset of chronic kidney disease (CKD) and its progression to the terminal stage remain high, despite current prevention and treatment measures. Although SGLT2 inhibitors have been approved as blood glucose lowering drugs, they have shown unexpected and surprising cardioprotective and nephroprotective efficacy. The multiple underlying mechanisms of action are independent and go beyond glycemic lowering. Hence, it has been speculated to extend the use of these drugs also to subjects with advanced stages of CKD, who were initially excluded because of the expected limited glucose-lowering effect. Non-diabetic patients could also benefit from the favorable effects of SGLT2 inhibitors: subjects with renal diseases with different etiologies, heart failure, high risk or full-blown cardiovascular disease. In addition, these drugs have a good safety profile, but several post-marketing adverse event have been reported. The ongoing clinical trials will provide clearer information on efficacy, strength and safety of these molecules. The purpose of this review is to analyze the available evidence and future prospects of SGLT2 inhibitors, which could be widely used in nephrology clinical practice.

Keywords: diabetes, oral hypoglycemic agents, SGLT2 inhibitors, chronic kidney disease

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Introduzione

Il diabete mellito (DM) è una delle patologie più diffuse nel mondo: ne soffre circa l’8,5% della popolazione adulta ed il trend nelle ultime decadi mostra un progressivo aumento dell’incidenza e della prevalenza [1].

La malattia renale cronica (MRC) è frequente complicanza del DM, sia di tipo 1 (DM1) che di tipo 2 (DM2). Si calcola che tra il 40 e il 50% dei soggetti affetti da DM2 sviluppa MRC nell’arco della vita e la sua presenza e severità influenzano significativamente la prognosi [2, 3, 4]. Pochi e dibattuti sono i dati relativi alla progressione del danno renale nel diabetico fino alla malattia renale cronica terminale (ESRD). Le cifre sono sottostimate e inficiate dall’elevata mortalità di questi soggetti, molti dei quali muoiono prima di giungere alla necessità di terapia sostitutiva della funzione renale, soprattutto per patologie cardiovascolari (CV) [5, 6, 7]. Negli Stati Uniti nel 2010 la prevalenza di ESRD tra i diabetici adulti è stata di 20/10.000 [8]. Guardando all’eziopatogenesi, il DM è ormai stabilmente la causa principale dell’ESRD. È da ascrivere al DM il 23% e il 16% dei casi incidenti e prevalenti di ESRD, rispettivamente, secondo il più recente report ERA-EDTA (European Renal Association-European Dialysis and Transplant Association) [9]. 

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Economic impact of ferric carboxymaltose in haemodialysis patients

Abstract

Intravenous iron supplementation is essential in hemodialysis (HD) patients to recover blood loss and to meet the requirements for erythropoiesis and, in patients receiving erythropoietin, to avert the development of iron deficiency. In a recent real-world study, Hofman et al. showed that a therapeutic shift from iron sucrose (IS) to ferric carboxymaltose (FCM) in HD patients improves iron parameters while reducing use of iron and erythropoietin. The objective of this economic analysis is to compare the weekly cost of treatment of FCM vs IS in hemodialysis patients in Italy. The consumption of drugs (iron and erythropoietin) was derived from Hofman’s data, while the value was calculated at Italian ex-factory prices. The analysis was carried on the total patient sample and in two subgroups: patients with iron deficiency and patients anemic at baseline. In addition, specific sensitivity analyses considered prices currently applied at the regional level, simulating the use of IS vs iron gluconate (FG) and epoetin beta vs epoetin alfa. In the base-case analysis, the switch to FCM generates savings of -€12.47 per patient/week (-21%) in all patients, and even greater savings in the subgroups with iron deficiency -€17.28 (-27%) and in anemic patients -€23.08 (-32%). Sensitivity analyses were always favorable to FCM and confirmed the robustness of the analysis. FCM may represent a cost-saving option for the NHS, and Italian real-world studies are needed to quantify the real consumption of resources in dialysis patients.

 

Keywords: ferric carboxymaltose, intravenous iron supplementation, chronic kidney disease, hemodialysis, drugs consumption, economic impact

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Introduzione

La prevalenza dei pazienti con malattia renale cronica (MRC) è pari al 10-16% della popolazione adulta mondiale [1] con tassi di incidenza in aumento nel corso degli anni [1,2]. Questo trend rappresenta una sfida per i diversi Sistemi Sanitari e i pagatori in generale, particolarmente quando si consideri il più elevato consumo di risorse nei pazienti più anziani [3,4]. Soprattutto, va evidenziato che la mortalità legata alla MRC è quasi duplicata, tra il 1990 e il 2010, con un aumento, in termini di anni persi per morte prematura, inferiore solo a HIV-AIDS e diabete mellito [5].
 

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Management of hemodialysis patient subject to medical-nuclear investigation

Abstract

In recent years imaging techniques that use radionuclides have become more and more clinically relevant as they can provide functional information for specific anatomical districts. This has also involved nephrology, where radionuclides are used to study patients with different degrees of renal function failure up to terminal uremia. Although chronic kidney disease, and dialysis in particular, may affect the distribution and the elimination of radiopharmaceuticals, to date there are no consistent data on the risks associated with their use in this clinical context. In addition to the lack of data on the safety of radio-exposure in dialysis patients, there is also a shortage of information concerning the risk for healthcare staff involved in conducting the dialysis sessions performed after a nuclear test.

This study, performed on 29 uremic patients who underwent hemodialysis immediately after a scintigraphic examination, assessed the extent of radio-contamination of the staff and of hemodialysis devices such as monitor, kits and dialysate. The data collected has been used to quantify the radiological risk in dialysis after the exposure to the most common radionuclides.

 

Keywords: chronic kidney disease, imaging, radionuclides, hemodialysis, scintigraphy, radiological risk

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Introduzione

Negli ultimi decenni l’evoluzione delle metodiche di imaging ha contribuito significativamente al miglioramento dell’accuratezza diagnostica in medicina. Tra le varie metodiche, quelle utilizzanti radionuclidi, per le caratteristiche in esse presenti, hanno permesso di studiare aspetti particolari della patologia umana. La medicina nucleare usa il principio del tracciante. Le radiazioni, principalmente fotoni gamma, emesse dal radionuclide vengono convertite in immagini planari o tomografiche attraverso la Gamma Camera. Grazie alla versatilità dei radionuclidi, la medicina nucleare trova applicazione in diversi ambiti della clinica [1].

Secondo i dati UNSCEAR 2000 ogni anno vengono effettuati nel mondo circa 32 milioni di esami di medicina nucleare [2]. La crescente diffusione dell’esame scintigrafico e della Tomografia ad Emissione di Positroni (PET), nel corso dell’ultimo decennio, deriva principalmente dalla loro notevole capacità di integrazione e/o sostituzione delle classiche metodiche di imaging pesante (TC, RM, etc.). La scintigrafia è una tecnica di diagnostica funzionale che, previa somministrazione di un tracciante radioattivo (che si distribuisce nel corpo in base alle sue proprietà chimiche e biologiche), ne valuta e/o quantifica la distribuzione negli organi e nei tessuti che si vogliono studiare. La PET è un esame diagnostico che prevede l’acquisizione di immagini fisiologiche basate sul rilevamento di due fotoni gamma che viaggiano in direzioni opposte. Questi fotoni sono generati dall’annientamento di un positrone con un elettrone nativo. La scansione PET, eseguita con fluorodesossiglucosio (FDG), fornisce informazioni metaboliche qualitative e quantitative. L’FDG è un analogo radiomarcato del glucosio che viene assorbito dalle cellule metabolicamente attive come le cellule tumorali. Le scansioni PET sono in grado di dimostrare un’attività metabolica anormale prima che si siano verificati cambiamenti morfologici. L’attività metabolica dell’area di interesse viene valutata sia mediante ispezione visiva delle immagini sia misurando un valore semi-quantitativo dell’assorbimento di FDG chiamato valore di assorbimento standardizzato (SUV). L’applicazione clinica più comune della PET è in oncologia, dove viene impiegata per differenziare le lesioni benigne dalle lesioni maligne, monitorare l’effetto della terapia su neoplasie conosciute, riposizionare e rilevare la recidiva del tumore; viene anche utilizzata in cardiologia, per la valutazione di aree di ischemia, e in neurologia, nella diagnosi differenziale di demenza e sindrome di Parkinson [3,4].

 

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Temporal variation of Chronic Kidney Disease’s epidemiology

Abstract

Chronic Kidney Disease (CKD) is a major risk factor for mortality and morbidity, as well as a growing public health problem. Several studies describe the epidemiology of CKD (i.e. prevalence, incidence) by examining short time intervals. Conversely, the trend of epidemiology over time has not been well investigated, although it may provide useful information on how to improve prevention measures and the allocation of economic resources. Our aim here is to describe the main aspects of the epidemiology of CKD by focusing on its temporal variation. The global incidence of CKD has increased by 89% in the last 27 years, primarily due to the improved socio-demographic index and life-expectancy. Prevalence has similarly increased by 87% over the same period. Mortality rate has however decreased over the last decades, both in the general and CKD populations, due to a reduction in cardiovascular and infectious disease mortality. It is important to emphasize that the upward trend of incidence and prevalence of CKD can be explained by the ageing of the population, as well as by the increase in the prevalence of comorbidities such as hypertension, diabetes and obesity. It seems hard to compare trends between Italy and other countries because of the different methods used to assess epidemiologic measures. The creation of specific CKD Registries in Italy appears therefore necessary to monitor the trend of CKD and its comorbidities over time.

Keywords: chronic kidney disease, CKD, epidemiology, registers, socio-demographic index

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Introduzione

La malattia renale cronica (CKD) è una condizione patologica associata ad un alto rischio di mortalità e di morbidità. È stato infatti dimostrato, in studi di popolazione generale e di pazienti seguiti dalle unità nefrologiche, che la presenza di un valore di filtrato glomerulare stimato (eGFR) <60 ml/min/1,73m2 o di proteinuria si associa ad un alto rischio di sviluppare, nel tempo, eventi cardiovascolari (CV) maggiori (malattia coronarica, scompenso cardiaco, vasculopatia periferica), progressione del danno renale (riduzione del eGFR ed ingresso in dialisi) e mortalità da tutte le cause [15].  

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Protein carbamylation: what it is and why it concerns nephrologists

Abstract

Abstract: Spontaneous urea dissociation in water solution is a prominent source of protein carbamylation in our body. Protein carbamylation is a well-known phenomenon since early seventies. Some years ago, much interest in the diagnostic power of carbamylated protein arouse. Recently the target of the researches focused on its potential cardiovascular pathogenicity. Some authors claimed that this could be a reason for higher cardiovascular mortality in uremic patients. Nutritional therapy, amino acids supplementation and intensive dialysis regimen are some of the therapeutic tools tested to lower the carbamylation burst in this population.

 

Keywords: protein carbamylation, urea, chronic kidney disease

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Biochimica del cianato e della carbamilazione

Il cianato (acido cianico) è una molecola che deriva dalla dissociazione spontanea in soluzione acquosa dell’urea; la reazione completa porta alla produzione di cianato e ammoniaca e in vitro tale reazione è spostata dalla parte della formazione dell’urea per oltre il 99% (1). Il cianato, dunque, è un composto azotato che si produce fisiologicamente nel nostro organismo, ma solo in piccole quantità e si pone spontaneamente in equilibrio col suo isomero più reattivo isocianato.

La concentrazione plasmatica in individui sani di isocianato è di circa 50 nmol/L (1), un valore che, tuttavia, è circa mille volte inferiore rispetto a quanto previsto dai parametri cinetici di decomposizione dell’urea. La stessa osservazione è stata fatta nei pazienti uremici, dove la concentrazione di isocianato rilevata era sì aumentata (140 nmol/l), ma comunque di gran lunga inferiore a quanto atteso (2). La spiegazione di questo fenomeno è che, poiché come detto l’acido isocianico è molto reattivo, parte di questo composto viene consumato come substrato di altre reazioni chimiche. In particolare il cianato è in grado di cedere il gruppo “carbamoile” (-CONH2) ad una molecola organica e questa reazione è generalmente indicata con il nome di carbamilazione. In realtà il termine chimico più appropriato, e raccomandato dalla “International Union of Pure and Applied Chemistry”, sarebbe carbamoilazione (3), ma nella gran parte della letteratura scientifica è utilizzato il primo termine. 

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DPP-4 inhibitors in nephropatics

Abstract

The use of glucose-lowering drugs in advanced stage diabetic nephropathic patients should be done very carefully. Some drugs are contraindicated or not recommended. The same insulin needs a dose reduction to avoid dangerous hypoglycemia. For some years the use of inhibitors of the DDP-4 has been approved in T2DM patients with CKD III and IV stage, proposing the use without limitations even in case of ESRD.

We conducted a prospective observational study of a cohort of 60 patients with T2DM and CKD stage IV, selecting a sample of 15 patients taking an inhibitor of DPP-4 and comparing it with those who took therapy “old” drugs, despite having similar characteristics of CKD.

In both groups, we found: 1) the effectiveness of therapy, through the assessment of glycated hemoglobin and glycemic profile; 2) the possible occurrence of “hypoglycemia”, “side effects”, accelerating the progression of CKD. No patients being treated with inhibitors of DPP-4 have experienced hypoglycemia, or adverse events, or adverse effects on the progression of CKD. The glycated hemoglobin, revealed more stability than the comparison group. Hypoglycaemic episodes were present only in the group receiving intensive insulin. Although kidneys and their dose, in case of high degree of CKD, primarily eliminate inhibitors of DPP-4, with some exceptions, should be reduced, in our experience they have proven beneficial drugs in diabetics with kidney disease, being effective and well tolerated in the case of ESRD, where the only treatment option was represented by insulin.

Keywords: diabetes, chronic kidney disease, drug, tollerability

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Introduzione

La gestione terapeutica del paziente diabetico con Chronic Kidney Disease (CKD) è generalmente complessa. Uno degli aspetti da tenere in grande considerazione è che la terapia farmacologica ipoglicemizzante va rapportata al grado di funzionalità renale residua e va adattata “su misura” al singolo paziente. Alcuni farmaci ipoglicemizzanti orali sono controindicati nelle fasi avanzate della CKD, come la metformina, o vengono sconsigliati, come nel caso delle sulfaniluree, per il potenziale rischio di ipoglicemie da “accumulo”. Anche la stessa terapia insulinica necessita di una riduzione del dosaggio nelle fasi avanzate della insufficienza renale cronica, per evitare pericolose crisi ipoglicemiche [1, 2]. 

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Day of Prevention of Renal Diseases in Amatrice, Italy

Abstract

Chronic kidney disease (CKD) is a very common condition and its prevalence is increasing worldwide. The CARHES study in Italy showed a prevalence of 6.5% in women and 7.5% in men. As a matter of fact, an early diagnosis is essential to slow down the progression and improve the renal and cardiovascular prognosis. For this purpose the A.N.Di.P. association (National Association of Peritoneal Dialysis-Onlus “Enzo Siciliano”) organized the DAY OF PREVENTION OF RENAL DISEASES which was held in AMATRICE the 15th of July 2017 called “WE START A NEW PATH OF LIFE TOGETHER”. The goal of this initiative was to highlight and spread the importance of prevention and early diagnosis of renal disease in Amatrice and its surroundings. During this day, medical history, blood pressure measurements, urinalysis, serum creatinine and serum uric acid were carried out and we suggested to patients how to proceed, if necessary, in a further diagnostic and therapeutic process. We also recommended a correct lifestyle, based on healthy eating and regular physical activity. The choice to dedicate particular attention to the population tragically affected by the earthquake occurred to identify renal diseases, since they are a possible consequence of the earthquake, to draw attention to the importance of renal function and to demonstrate that simple routine checks may lead to an early diagnosis of unrecognized kidney diseases, also reducing cardiovascular risk.

Keywords: Amatrice, chronic kidney disease, crush syndrome

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INTRODUZIONE

La malattia renale cronica (MRC) è una condizione molto diffusa e la sua prevalenza è in aumento in tutto il mondo (13). Lo studio CARHES in Italia ha mostrato una prevalenza del 6,5% nelle donne e del 7,5% negli uomini (45). Si definisce MRC la condizione in cui sia presente almeno da tre mesi una riduzione dell’estimated Glomerular Filtration Rate (eGFR) al di sotto di 60 ml/min/1.73m², oppure la presenza di un marcatore di danno renale quale: proteinuria, alterazioni del sedimento urinario, anomalie elettrolitiche da disordine tubulare, anomalie istologiche, alterazioni dei test di diagnostica per immagini del rene, storia di trapianto renale. La MRC e l’insufficienza renale cronica (IRC) non sono sinonimi poiché negli stadi 1 e 2 della MRC la funzione renale non è particolarmente alterata. La diagnosi e la stadiazione di MRC, secondo le linee guida KDIGO (12), si basano sull’eGFR, sulla presenza o meno di proteinuria, sull’esame delle urine e sull’ecografia renale e prevedono la classificazione della malattia in 5 stadi (Tabella 1). 

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Case of sialadenitis by iodinated contrast medium in a dialysis patient

Abstract

Background
Sialadenitis by iodinated contrast medium (i.c.m) or iodine mumps (IM) is a rare and late benign manifestation that occurs independently of intravenous or endoarterial administration modality. If renal function is normal, i.c.m. does not reach salivary glands concentrations able to induce sialadenitis. However, a critical glomerular filtration reduction may lead to salivary ducts edema and glandular swelling after i.c.m. injection. We report a rare case report of IM in a patient on chronic hemodialysis.
 
Methods
A 72-year-old woman affected by chronic kidney disease on chronic hemodialysis, underwent to endoscopic removal of a rectal cancer. For disease staging, a total body TC with i.c.m. was performed. The following morning, patient showed a soft and aching bilateral paroditidis swelling. Salivary glands ultrasound was diagnostic for sialadenitis. The patient was rapidly treated with betamethasone following by a 240 minutes post-dilution online hemodiafiltration session.
 
Results
Within the next 24h, a complete remission of IM was obtained.
Conclusion
In our patient, a compensatory hyperactivity of the sodium / iodine symporter (NIS) on salivary gland cells may have played a crucial role in IM induction. An high efficiency hemodialysis session within the few following hours after i.c.m injection is a fundamental tool in patients on renal replacement treatment to prevent IM that is an epiphenomenon of i.c.m. accumulation.

 

Keywords: Iodine mumps, chronic kidney disease, hemodialysis, iodine contrast medium, corticosteroids.

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INTRODUZIONE

L’incidenza di complicanze renali ed extrarenali da mezzo di contrasto (m.d.c.) si è ridotta da qualche anno grazie all’impiego sempre più diffuso di mezzi contrastografici a bassa osmolarità (1). Tuttavia, le reazioni anafilattoidi e le reazioni nefrotossiche rappresentano a tuttora le più frequenti complicanze da impiego di m.d.c e sono gravate da elevata comorbidità e mortalità. Nettamente più ridotta è invece oggi l’incidenza di reazioni idiosincrasiche al m.d.c., quali le eruzioni acneiformi, lo iododerma e la scialoadenite o iodine mumps (IM) (2) che, sebbene benigne, sono gravate da segni e sintomi tali da creare disagio e infermità nel paziente. La prevenzione delle complicanze derivanti dall’impiego del m.d.c., pertanto, resta tuttora un obiettivo fondamentale. L’insufficienza renale cronica (IRC) è una patologia in costante crescita, gravata da un notevole impatto socio-economico (35) e caratterizzata da una significativa riduzione della qualità della vita (6). E’ paradossale notare come i pazienti affetti da IRC siano contemporaneamente quelli più a rischio sia di sviluppare complicanze da m.d.c., che particolarmente esposti alla necessità di sottoporsi a procedure contrastografiche, sia a scopo diagnostico che, talora, terapeutico. Tale associazione sfavorevole che grava i pazienti con IRC dipende dalla loro spiccata tendenza a sviluppare complicanze sia cardiovascolari che multi-sistemiche (79). 

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The renal lesions in Bardet-Biedl Syndrome: history before and after the discovery of BBS genes

Abstract

Various renal lesions of the Bardet-Biedl syndrome (BBS) have been described, including macroscopic and microscopic kidney abnormalities, polyuria, polydipsia and chronic renal failure. However, these renal symptoms were completely overlooked for about fifty years after the first description of the syndrome. The observation of a familial origin of the syndrome began in 1753, with Maupertuis and Réaumur describing hereditary forms of polydactyly. In the early 19th century, Martin mentioned an inherited case of blindness. Subsequently, von Graefe (1858) reported on a familial occurrence of both of blindness and deafness. The introduction of the ophthalmoscope by von Helmholtz (1851) allowed for the identification of patients with retinal degeneration. Systematically using this instrument, Laurence and Moon (1866) were the first to describe a familial case of retinal degeneration combined with obesity and cognitive impairment. Due to the influential work of Froehlich, Cushing, and Babinski, attention then shifted to obesity. The syndrome was definitively identified by 1920 through Bardet’s observations familial cases of obesity, blindness, polydactyly, and hypogonadism. Biedl in 1922 observed further cases of the syndrome. In recognition of this history, the disease was named Laurence-Moon-Bardet-Biedl Syndrome. The renal anomalies were not described until fifty years later, in 1977. In 1993, the quest for the genes involved in BBS began with the isolation of 21 different genes. In 2003 two concepts emerged: the existence of a spectrum of ‘ciliopathies’ and the concept of the BBSome. Afterwards, the gene-phenotype relationship was researched using transgenic mice.

Keywords: ciliopathies, hereditary, obesity, retinitis, chronic kidney disease

INTRODUCTION

According to the influential theory of Thomas Kuhn (1922-1996) (1), most scientists work constrained by current influential paradigm and are devoted to solving small problems (‘puzzle-solving’). The dominant paradigm is important for the interpretation of the data, but it may blind scientists to new phenomena not considered part of the paradigm. One example of this theory comes from the field of nephrology, where the pivotal renal anomalies in Bardet-Biedl Syndrome went completely unnoticed for more than 50 years after the discovery of the syndrome. Tus, the BBS syndrome is an example of how an essential clinical element may go unnoticed for a long time and is evaluated only after a shift in the attention of the scientific community (specifically, the introduction of renal biopsy and immunofluorescence).

The Bardet-Biedl Syndrome (BBS) is a rare genetic disorder characterized by retinal degeneration, polydactyly, obesity, learning disabilities, hypogonadism and renal anomalies. Various renal lesions of BBS have been described including (i) fetal lobulation (ii) calyceal clubbing, (iii) focal sclerosing glomerulonephritis, (iv) interstitial nephritis, and (v) changes in the glomerular basement membrane. Polyuria, polydipsia and chronic renal failure have been also reported in many case reports (2). Although the renal anomalies are today one of the primary features of the disease, it took almost 50 years after the description of the syndrome for renal symptomatology to be included.

Here we will review the observations that drew the attention of Bardet and Biedl to the disease and why the renal features were not observed. Afterwards, we will focus on the role that the identification of BBS genes played in changing our perception of the disease and its renal lesions. A timetable of the discoveries is summarized in Table 1.

 

HOW THE SYNDROME WAS DISCOVERED

The identification of BBS required the evolution of the following concepts: 1) the existence of hereditary forms of blindness and polydactyly, which fostered the search for combined hereditary forms of more complex diseases 2) the invention of the ophthalmoscope, which allowed scientists to identify and classify retinal degeneration and 3) a paradigm-shift concerning the nature of obesity, which focused attention on hereditary forms of obesity (such as BBS), but also served as a blinder impeding the identification of other features such as kidney failure.

The observation of a familial origin of the syndrome began in 1753, with Maupertuis and Réaumur (Figure 1, Figure 2) describing hereditary polydactyly. While polydactyly was widely known since ancient times, the hereditary aspect of the malformation gained notice in the late 1700s. Pierre-Louis Moreau de Maupertuis, (born Sept. 28, 1698, Saint-Malo, France—died July 27, 1759, Basel, Switz.), was a mathematician and astronomer who popularized Newton’s theories (3). In Système de la nature ou Essai sur les corps organisés (1751) he studied the transmission of polydactyly in four generations of a Berlin family, providing the first report of the trait as hereditary (4). Renè-Antoine Ferchault de Réaumur (1683-1757), the famous French scientist who gave his name to the temperature scale, is reported by Huxley (1894-1963) (5) to have analyzed data from three families (named Kelleia) from Malta with hereditary polydactyly. Similar to polydactyly, progressive blindness was also known since ancient times; however, the possibility of a hereditary form of blindness was first noted in the early 19th century by Martin. He reported, in the Baltimore Medical and Physical Recorder (1809), on the Lecomptes, a Maryland family of French origin whose members suffered progressive blindness (5). While none of these authors were describing actual cases of BBS, their work did refocus subsequent researchers on hereditary forms of polydactyly and blindness.

Indeed, soon after, Albrecht von Graefe (1828-1870) (6) and thereafter Liebreich first reported a hereditary combination of blindness and deafness in cases of what would be called retinitis pigmentosa, furthering the concept of combined forms of hereditary traits, and these observations are, in fact, cited by Laurence and Moon in their work (see below). Another essential discovery that must be acknowledged for the history of BBS was the invention of the ophthalmoscope in 1851 by Hermann von Helmholtz (1821-1894), which allowed the observation of the retina and hence the definition of retinitis pigmentosa (Figure 3). The use of the new device, the ophthalmoscope, was hence promoted in England by John Zachariah Laurence (1829-1870), a surgeon and ophthalmologist at the ophthalmologic hospital in Southwark (Figure 4). In 1866, together with his colleague Robert Charles Moon (1844-1914) (Figure 5), a house surgeon at the same hospital (who then moved in Philadelphia), they were the first to describe, using the ophthalmoscope, a familial case of combined retinal degeneration, obesity, and cognitive impairment (7).

In the first years of the 20th century, medical attention shifted to hypothalamic forms of obesity-hypogonadism thanks to the work of a neurologist, Joseph Babinski (1857-1932), a pharmacologist, Alfred Fröhlich (1871-1953) (8) and a neurosurgeon, Harvey Cushing (1869-1939) (9). Again, in the history of science, we see how important advances in one field may come through collaborations with other fields, and how this chance partnership was a necessary step in fully defining BBS. Fröhlich’s strong influence is visible when the first report of a BBS case was attributed to a pituitary malfunction.

Around this period a certain number of observations of obesity, polydactyly and retinitis pigmentosa are reported by several authors: in 1887 Ferdinand-Jean Darier (1856-1938) reports the association of retinitis pigmentosa and polydactyly (10). In 1989 Elie von Cyon (also known as de Cyon, 1843-1912) presents the case of a 12-year old boy with obesity, growth and mental retardation, and hereditary polydactyly (11). In 1898 Ed Fournier reports retinitis pigmentosa and syndactyly (12). In 1913 Rozabel Farnes reports adipose-genital syndrome with polydactyly (13). In 1914 an Italian radiologist working in Naples, Mario Bertolotti (1876-1957) presented the case of Marguerite Catt, 39 years old, with polydactyly, mental retardation, obesity, retinitis pigmentosa, and hypogonadism (14). In 1918 J Madigan and Thomas Verner Moore (1877-1969) described a case of mental retardation, obesity, hypogonadism, retinitis pigmentosa, and tapering toes (15).
Finally, in 1920 a French medical student, George Louise Bardet (1885-1966), in his medical degree thesis, collected all these cases and his own observation of a familial case of obesity, hexadactyly, retinitis pigmentosa and hypogonadism and proposed the existence of a triad (13). He discussed this finding using the current paradigm of hypophyseal/hypothalamic obesity: “Two congenital malformations (hexadactyly and retinitis pigmentosa) in a child who became obese from birth. What is the gland which can be incriminated? (…) We believe this case must be attached to a very special clinical variety of hypophysis obesity”. Bardet’s triad (obesity, polydactyly, retinitis pigmentosa) gained success after the father of modern endocrinology, Arthur Biedl (1869-1933), in 1922 observed further cases of the syndrome. Biedl named the syndrome adipose-genital dystrophy and thought it was of cerebral origin, in line with the paradigms of that period (Figure 6). In recognition of this history, the disease was named Laurence-Moon-Bardet-Biedl Syndrome. Later, thanks to the work of Ammann in 1970 and Schachat and Maumenee in 1982, Laurence-Moon and Bardet-Biedl Syndromes came to be considered two different entities and possibly part of the same disease spectrum. In the first half of 1900, BBS was officially defined, but none of these authors noticed abnormalities in kidney function, which is today acknowledged as an important signature of the syndrome.
Why then were the renal features of the syndrome missed for almost 50 years? It is tempting to see this as an example of Kuhn’s hypothesis that scientists work on ‘puzzle-solving’ within an influential paradigm. The paradigm of that period was hypothalamic obesity, whereas kidney failure was not considered. Scientists observing new cases of BBS focused on obesity and dismissed other possible features of the disease.
It is intriguing that, even in 1995, in the excellent editorial by George Bray (born 1931) on the syndrome in Obesity Research, kidney dysfunction is completely ignored by the author (16).

 

THE RENAL LESIONS BEFORE BBS GENES

Awareness of the renal involvement in BBS starts in the late 1960s with the work of McLoughlin and Shanklin (17), Nadjmi (18), Hurley (19) and Falkner (20). McLoughlin and Shanklin (17), Nadjmi et al. (18) first reviewed necropsies of BBS from the literature and found a high incidence of renal/genitourinary malformations; Nadjmi further observed that most of cases reported in the literature since 1940 died for uremia and therefore renal failure was a major cause of early death in BBS patients. According to Nadjmi, the first autopsy reporting a BBS subject passed due to uremia was by Radner in 1940 (Acta Med Scand 105:141); however, genitourinary tract malformations were already observed since 1938 by Griffiths (J Neurol Psychiat 1:1-6), and Riggs (Arch Neurol Psychiat 39:1041). It is possible that the systematic renal involvement in BBS was missed before because the histologic classification of kidney diseases reached its maturity only when kidney biopsy and the kidney immunofluorescence have been available around 1950, thus driving attention to this organ.

The diffusion of the technique of percutaneous kidney biopsy by Nils Alwall (1904-1986) allowed Hurley et al (19) to first report histological data from a series of nine BBS children (Figure 7 A-B). The results were quite variable, from mesangial proliferation to sclerosis, cystic dilatation of the tubules, cortical and medullary cysts, periglomerular and interstitial fibrosis, chronic inflammation.

Falkner et al. (20) found in a 24-month old child with BBS right sided vesical-ureteral reflux, cystocele, urinary tract infections, growth arrest of the right kidney. They also confirm the mesangial hypercellularity by percutaneous biopsy (Figure 7 C).

In 1990 the incidence of renal abnormalities in BBS was finally determined to be very high: up to 90% of the patients, and therefore become a new signature of the syndrome, more than 50 years from its initial definition (2). In the meanwhile, the spectrum of renal abnormalities was stably defined as:

Functional: polyuria, polydipsia, aminoaciduria, reduction of maximum concentrating capacity, chronic renal failure, hypertension

Macroscopic: fetal lobulation, cystic dysplasia and calyceal cysts, small kidneys, calyceal clubbing or blunting

Microscopic: swelling of endothelial cells, tubular and interstitial nephritis with glomerulosclerosis.

In conclusion, we believe that the attention to the nephrological character of the BBS was finally reached only when (i) technical advancements were available (that is the invention of the percutaneous biopsy) and (ii) when a general attention of the medical entourage was driven towards the kidney function: we should remind that in 1943 Willem Johan Kolff (1911 – 2009) first built a dialyzer machine, further developed by Nils Alwall. At the end of 60’ nephrology was a mature science and the greater awareness towards uremia led to a revision of syndromic diseases.

However, the condition remained largely unclear even after the discovery of the renal abnormalities: major advances in a new behind the complex trait was the discovery of the gene defects causing BBS.

 

THE RENAL LESIONS AFTER BBS GENES

The quest for the genes occurred in two phases: from 1993 to 2000 a genetic mapping was pursued, with the identification of several DNA loci involved in the disease. In 2000 the identification of the first BBS gene (now they number 21), MKKS, based on the similarity between the BBS and the McKusick-Kaufman syndrome (MKS), occurred (21). In 2003 Ansley et al demonstrated that mammalian BBS8 gene was restricted to ciliated cells (21). This finding raised the hypothesis that BBS proteins play a role in cilia function. Meanwhile, other genes of the same family were found to cause BBS, with at least 17 different genes implicated up to now.

The field was quite mature at the time because a second, more common condition, was already found to involve cilia: the polycystic kidney disease (PKD). This is also a hereditary condition and followed almost the same path of BBS (anatomical period-genetic period-functional period), which ultimately led to the paradigm of the involvement of cilia dysfunction in the genesis of the disease.

It should be stressed that, again, the major advancement in the paradigm did not come directly from the studies on the disease, but from studies on flagellated protozoa: it was a genetic study on immobile forms of these protozoa which led to the identification of this gene. When the same was found to be involved in PKD and then in other diseases such as BBS, it was almost immediate the formation of a new paradigm of ‘ciliopathies’. All genes involved in these genetic diseases and in the cilium were then functionally grouped in a multiprotein complex called BBSome.

After the period of discovery of BBS genes and the construction of the concept of the BBSome, some new insights in the renal pathology of BBS have been addressed. First, the gene-phenotype relationship has been studied in much detail, with a categorization of mutations leading to various associations of the visual, metabolic and kidney phenotypes (23, 24). Second, a number of transgenic mice are now available for testing of pathogenic hypotheses and new pharmacological approaches. Risk factors for the development of the renal disease have been studied in large cohorts (22 – 24), and the usefulness of renal transplantation has been demonstrated in a separate study (25, 26). A contribution for low protein diet in the preservation of renal function in BBS has also been reported (27). Finally, a study from one of us (28, 29) showed combined impaired water handling in BBS.

These functional changes in BBS kidney might be mediated, at least in part, by mistrafficking of apical membrane proteins, leading to tubular dysfunction (41). In turn, this might be related to the renal hyposthenuria in BBS, that has been recognized as the most common renal dysfunction in the absence of renal insufficiency (42, 43).

 

Acknowledgments

I am indebted with dr. David Widmer, who critically reviewed the manuscript, with useful suggestions and critiques.

 

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