Nephrol Dial Transplant (2014) 29: 1628–1632
doi: 10.1093/ndt/gft344
Advance Access publication 11 September 2013
NDT Perspectives
Providing guidance in the dark: rare renal diseases and the
challenge to improve the quality of evidence
Davide Bolignano1,*, Evi V. Nagler2,*, Wim Van Biesen2,* and Carmine Zoccali1
1
CNR-IBIM, Istituto di Biomedicina, Epidemiologia Clinica e Fisiopatologia, delle Malattie Renali e dell’Ipertensione Arteriosa, Reggio Calabria,
Italy and 2Renal Division, Ghent University Hospital, Ghent, Belgium
Correspondence and offprint requests to: Davide Bolignano; E-mail: [email protected]
*
ERBP Methods Support Team.
disease, where we have detailed pathophysiologic knowledge
and also specific treatments. However these diseases are typically included among orphan diseases. The definition of
orphan diseases has the broad scope of raising the attention of
public and the scientific community on a growing series of
rare diseases where knowledge on the pathophysiology and
natural history is limited with little awareness among doctors
and with no or very costly treatment. Approximately 80% of
these conditions are genetic in nature. Progresses in genetics,
from basic to clinical science, have opened unprecedented opportunities for the identification of faulty gene(s) responsible
for these diseases thereby allowing the development of genetic
tests and well-targeted treatments. Importantly, knowledge
derived from the study of these disorders may also lead to a
better understanding of normal biological processes as well as
of other polygenic and acquired diseases. In this article, we
discuss why the scientific evidence to support clinical practice
is limited, what the consequences are for evidence-based medicine and how the quality of evidence and the guidance in these
diseases can be improved.
A B S T R AC T
Among renal diseases, over 100 conditions meet the epidemiological criteria to be defined as rare, including disorders in development, transport and metabolism. Clinical management
of rare diseases is likely to be less investigated than that of
common disorders and for this reason the scientific evidence
to support clinical practice is limited. Furthermore, no specific
and validated methods for designing, carrying out or analyzing
clinical trials in small populations exist with important consequences for evidence-based medicine. In this paper we aim at
discussing the inherent difficulty in finding evidence in rare
renal diseases, providing some suggestions on how the quality
of evidence and the guidance in these diseases can be improved.
Keywords: evidence, guideline, orphan disease, rare disease
INTRODUCTION
In the USA, the National Institute of Health Office of Rare
Diseases Research [1] defines as ‘rare’ a disease that affects
<200 000 people. In Europe, a disease is considered rare when
the prevalence is lower than 5 per 10 000 persons. It has been
estimated that, so far, between 5 000 and 8 000 rare diseases
have been characterized, which collectively affect 6–8% of the
European population [2]. Clinical management of rare diseases is inherently bound to be less investigated than that of
common disorders and for this reason these diseases are often
without specific treatment (orphan diseases). Rare diseases
exist, such as nephrogenic diabetes insipidus and Fabry’s
© The Author 2013. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
RARE RENAL DISEASES
Among renal diseases, over 100 conditions meet the epidemiological criteria to be defined rare, including disorders in development, transport and metabolism [3]. The list comprises the
wide spectrum of polycystic kidney disorders, Fabry and
Alport disease but also less known and more rare conditions
(see Table 1). Some of these diseases selectively affect the
kidney, while others may extend to other organs, either before
or after renal involvement. In nephrology, rare diseases are
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Table 1. Main rare renal diseases
Glomerular, tubular and metabolic disorders
Disorders of kidney development/morphology
(i)
Adenine-phosphoribosyl-transferase deficiency
(i)
(ii)
Alport syndrome (XL, AR, AD)
(ii) Bardet–Biedl syndrome types 1–12
(iii)
Alport syndrome with leiomyomatosis
(iii)
(iv) Bartter syndrome types 1–4
(v)
Cystinosis
(vi) Cystinuria—dent disease—lysinuric proteinintolerance
Alström syndrome
Branchio-oto-renal syndrome
(iv) Fraser syndrome
(v)
Ellis–van Creveld syndrome
(vi) Hypoparathyroidism, deafness, renal syndrome
(vii)
Denys–Drash syndrome
(vii)
Ivemark syndrome
(viii)
Diabetes insipidus, nephrogenic
(viii)
Jeune syndrome
(ix)
Distal renal tubular acidosis
(ix)
Joubert syndrome-related disorders
(x)
Fabry disease
(x)
Kallman syndrome
(xi)
Frasier syndrome
(xi)
Meckel–Gruber syndrome
(xii) Gitelman syndrome
(xii) Medullary cystic kidney disease
(xiii) Gordon syndrome
(xiii) Multicystic renal dysplasia
(xiv) Hypophosphatemic rickets
(xiv) Nephronophthisis types 1–11
(xv)
Liddle syndrome
(xvi) Lowe syndrome
(xv)
Oral-facial-digital syndrome 1
(xvi) Polycystic Kidney Diseases (autosomal dominant, types 1 and 2,
autosomal recessive)
(xvii)
Nail–Patella syndrome
(xviii)
Nephrotic syndrome (Congenital-Finnish type)
(xvii)
(xix)
Nephrotic syndrome (due to mitochondrial or lysosomal disorders)
(xviii) Renal coloboma syndrome
(xx)
Nephrotic syndrome (steroid resistant) types 2, 3 and 4
(xxi)
Pierson syndrome
(xxiii) Proximal renal tubular acidosis
(xix)
Renal cysts and diabetes syndrome
(xx)
Renal hypoplasia/dysplasia syndrome
(xxi)
Sensenbrenner syndrome
(xxiv) Pseudohypoaldosteronism types 1 and 2
(xxii) Townes–Brocks syndrome
(xxv)
(xxiii) Vesicoureteral reflux
Renal amyloidosis (familiar)
NDT PERSPECTIVES
(xxii) Primary hyperoxaluria type 1, 2 and 3
Renal agenesis
(xxvi) Renal glicosuria
(xxvii)
Schimke immuno-osseous dystrophy
(xxviii)
‘SeSAME’ syndrome
(xxix)
Xanthinuria—distal renal tubular acidosis
mostly genetic so that the terms ‘inherited’ or ‘congenital’ are
often used interchangeably with ‘rare’. Diseases caused by
monogenic alterations are less common, often first expressed
in childhood and associated with typical phenotypes and weak
or no environmental influence. Polygenic disorders are more
common, manifest later in life and are strongly influenced by a
complex interaction between genetic and environmental
factors. Although a single rare disorder of the kidney can
hardly be considered to be a public health challenge, however,
taken all together, rare renal diseases affect a significant
number of individuals with important economic impacts on
health services. Collectively, rare renal disorders rank worldwide as the fifth cause of end-stage kidney disease (ESKD) requiring renal replacement therapy after diabetes,
hypertension, glomerulonephritides and pyelonephritis with
an estimated total contribution of 10% to the annual incidence
of ESKD [4]. However, so far, only for few rare renal diseases
have disease-specific international registries been established
and publically available information on these disorders is
often sparse and scarce. Providing evidence-based, balanced
recommendations on diagnosis and management of these
Rare diseases in nephrology
diseases is therefore a challenging, but necessary task for the
renal community.
THE CONUNDRUM OF WEAK EVIDENCE IN
RARE RENAL DISEASES
Observational studies represent a valid source of knowledge
for addressing simple research questions in common as well as
in rare diseases. Observational studies can provide key information on the epidemiology (e.g. incidence) and natural
course of a given disease and suggest potential risk factors associated with different phenotypic manifestations of rare diseases. Because of sample size problems, cohort studies in rare
diseases are tantalizing. Case–control studies in rare diseases
are the only solution for diseases with a long latency period.
However, this study design is weaker for assessing causal relationships than cohort studies and is more prone to bias.
The randomized controlled trial (RCT) is the golden standard for generating unbiased information on the benefits of an
intervention. However, performing RCTs in most rare renal
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Table 2. Main registries, networks and medical information resources for rare diseases
Name
Description
Web address
ORDR
National Institute of Health Office of Rare Diseases
Research
European portal of rare diseases
European organisation for rare diseases
National organization for rare diseases
Consortium for podocytopathies
European consortium for primary hyperoxaluria
International registry for cystinosis
UK registry for rare kidney diseases
Consortium of European partners in the field of kidney
research focusing on orphan nephropathies
Nephrotic Syndrome Study Network
Rare Kidney Stone Consortium
ERA-EDTA Working Group on Inherited Kidney
Disorders
Registry including patients on RRT, including those for
ESKD due to rare diseases
Registry including paeditraic patients on RRT, including
those for ESKD due to rare diseases
http://rarediseases.info.nih.gov
Orphanet
Eurordis
NORD
PodoNet
OxalEurope
Cure Cystinosis
Renal RADAR
EUNEFRON
NEPTUNE
RDCRN
WGIKD
NDT PERSPECTIVES
ERA-EDTA
registry
ESPN registry
diseases is a most challenging undertaking. These conditions
affect a few thousand or, sometimes, even fewer than one
hundred patients on a world scale and therefore trials are often
unrealistic. A RCT of sufficient power would need to recruit
patients from very large areas over long periods, so that financial constraints are prohibitory for setting up this sort of trials.
National or international registries, medical information platforms and regularly updated portals (see Table 2) may be
useful to increase awareness and improve knowledge of rare
conditions and to maximize recruitment of patients from multiple centres/countries thereby avoiding fragmentation of data
collection. Furthermore, some rare renal diseases have also
early manifestations in childhood. Although the need for
RCTs in children is increasingly recognized in paediatric research and legislative measures have been taken by local governments to encourage RCTs in children, the enrollment of a
large number of paediatric patients remains problematic.
Finally, some rare kidney diseases are characterized by a very
long course with variable phenotypic manifestation, making the
follow-up and the correct definition of outcomes challenging.
HOW CAN THE QUALITY OF EVIDENCE BE
ENHANCED IN RARE RENAL DISEASES?
From a statistical point of view, the number of subjects recruited in a trial should be sufficient to reject the null hypothesis (no difference in effect between the interventions) in
favour of the alternative hypothesis (a difference in effect
exists between the interventions) for a given level of significance. The probability of reaching a true positive conclusion is
known as the study power, which can be maximized by increasing the number of participants [5]. Since enrollment of a
large number of patients in rare diseases is challenging, alternative strategies to show a particular effect, if in reality there is
one, have been proposed [6]. Some of these techniques can be
considered ‘neutral’, such as (i) use of a crossover design (ii)
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http://www.orpha.net
http://ww.eurordis.org
http://www.rarediseases.org
http://www.podonet.org/opencms/opencms/podonet/podonet_en/home
http://www.oxaleurope.org
https://cystinosis.patientcrossroads.org
https://www.renalradar.org
http://www.eunefron.org
https://rarediseasesnetwork.epi.usf.edu/NEPTUNE/
http://www.rarekidneystones.org
http://www.era-edta.org/wgikd/ERAEDTA_working_group_on_Inherited_kidney_disorders.htm
http://era-edta-reg.org/
http://espn-reg.org/
performing repeated measurements and (iii) analysis of covariance instead of single comparison of outcome between
groups. Others are more dubious, and do not always lead to
more or better evidence, such as use of composite or surrogate
outcomes and interim analyses. Other ‘tailored’ designs have
also been proposed to reduce the sample needed to reach statistical significance. In ‘sequential’ designs, for instance repeated statistical analyses are performed on accumulating data,
and the study is stopped as soon as the information is sufficient to reach conclusions [7]. Study designs exist that do not
contemplate a pre-study calculation of sample size. In this
‘adaptive’ design approach, modifications after interim analyses are permitted. For example, on the basis of observed
results at a certain time point, the required sample size for
further recruitment can be re-assessed [8]. Such an adaptive
design was adopted in the PRIMO (Paricalcitol capsules benefits in Renal failure-Induced cardiac MOrbidity) study [9]. In
this study, because of limited prior data to estimate sample
size, an interim efficacy analysis at a pre-specified time point
and conditioned on the status of enrollment was planned for
eventual sample size re-estimation. The decision to increase
sample size was based on the observed treatment effect of paricalcitol on left ventricular hypertrophy. However, all these
‘methodological tips and tricks’ are always a slippery slope,
and one should always be very critical in their interpretation.
In ‘open-ended’ RCTs patients can be continuously enrolled until a reliable positive or negative conclusion about the
treatments is made. The single-patient (n-of-1) clinical trial is
another interesting opportunity in at least some diseases. This
trial design is a multiple crossover study conducted in single
individuals where a single enrolled patient is exposed repeatedly to different treatments in a randomized order. Unlike
traditional trials, the unit of randomization is the intervention
rather than the patient, and the outcome is the conclusion
about the best treatment for a particular patient [10]. Hackett
et al. conducted a study with this design on a patient affected
by ornithine transcarbamylase (OTC) carrier deficiency, a rare
D. Bolignano et al.
F I G U R E 1 : Intervention on the precision of effect estimation when
calculating the power of the study as a way to optimize the sample
size in small populations. Here, we consider a hypothetical RCT on a
given rare renal disease with a prevalence of 1:50 000, in which a treatment is supposed to produce a reduction of 20% of risk to develop
end-stage renal disease. The study power is fixed to be 80%. Setting
the confidence interval at 99% (maximum precision), we would need
600 patients to observe the above cited effect. However, the number
of subjects to be enrolled can be significantly reduced (at cost of lower
precision) if less narrow CIs are considered, becoming 400 at 95%,
300 at 90%, 260 at 85% and even 220 at 80% level of precision.
(viii)
Expert opinion.
In rare renal diseases, the basis of evidence for treatments is
generally weak and, in very rare diseases, the combined evaluation of single-case studies is often the only evidence that can
be obtained. Can principles of clinical guidance applied to
common diseases be appropriate also for rare diseases? A systematic search by the German Institute for Quality and Efficiency in Health Care (IQWiG) revealed no different
methodological approaches for the development of clinical
practice recommendations in rare diseases when compared
with guidelines for common disorders [12]. This document
underlined that the issue of ‘scarce evidence’ is a limitation
pertaining also guidelines on common diseases. Therefore, in
C A N W E P R O V I D E AC C E P TA B L E G U I D A N C E I N principle, there is no reason to adopt a different approach or
RARE RENAL DISEASES?
pose different requirements for rare diseases. A position document by the European Medicines Agency (EMEA) [13] supClinical practice guidelines are built up on the basis of eviports the concept that rules for the production of guidelines
dence-based medicine but available scientific knowledge and
on common diseases are also applicable to rare diseases.
available good quality studies are ranked according to an acEMEA emphasizes that all forms of evidence, even anecdotal
cepted ‘evidence ladder’ for studies related to intended effects
case-reports, may provide relevant information and should
of therapy:
then be taken into consideration.
(i)
Systematic reviews of reliable RCTs including metaanalyses with low-heterogeneity between the results.
(ii)
(iii)
Other meta-analyses of RCTs.
Single RCT(s).
(iv)
(vi)
Meta-analyses of observational studies (cohorts and
case–control).
Single observational studies (cohorts and case–
control).
Published case series/case-reports.
(vii)
Anecdotal case-reports.
(v)
Rare diseases in nephrology
T H E I M P O R TA N C E O F I N T E R N AT I O N A L
REGISTRIES
In this scenario establishing large, international registries is of
paramount importance. These registries may indeed help in
the assessment of effectiveness and safety of treatments and
even represent an important source for historical controls. The
International registry of Hemolytic Uremic Syndrome (HUS)
and Thrombotic Thrombocytopenic Purpura (TTP) is a successful example [14, 15]. The registry has been established
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NDT PERSPECTIVES
X-linked disorder of the urea cycle with variable clinical manifestations in females, including end-stage renal disease. The
treating physician and patient were blinded to treatment (L-arginine, an obligate OTC carrier). Either placebo capsules or Larginine capsules were given for weekly periods. Plasma arginine and glutamine levels and changes in quality of life were
considered as weekly efficacy indicators. After the end of the
study a clear benefit of L-arginine compared with placebo was
demonstrated for that particular patient. Other acceptable statistical approaches to trials in small populations include the
adoption of less conservative statistical cut-off levels, such as
P-values >5% and the use of one-side instead of two-sides tests
of significance [11]. Although one-sided tests are commonly
considered not trustworthy, these types of tests can be used to
maximize the power of effect detection if one knows exactly
which is the direction of the effect that has to be expected. For
example, let us imagine we want to test a new drug able to
prevent renal stones formation in patients affected by cystinosis. The drug is cheaper than the other available drugs and previous evidence shows that it was efficacious to prevent lithiasis
in all cases. Under these circumstances, given that we exactly
know the direction of the effect (only improvement and no
worsening), it would be appropriate to use a one-sided test, i.e.
a test requiring a smaller sample size when compared with a
two-sided traditional test. Less conservative approaches can be
applied also to the assessment of the study power, starting
from the assumption that confidence intervals (CIs) of treatment effect estimation, although closely linked to the statistical
significance, are much more informative than P-values. Generally, for a given treatment effect, the confidence interval (CI) is
reduced as the sample size is increased. However, when the recruitment of a high number of patients is difficult, such as in
rare diseases, the sample size could be reduced at the cost of a
reasonable reduction in the precision of effect estimation (see
Figure 1).
with the aim to study the genetic and biochemical abnormalities of HUS/TTP, collect clinical and genetic data of patients
and their families, find the best therapeutic approach for patients and provide up-to-date information to physicians and
families. The registry has been established in 1996 and until
now 730 cases of HUS/TTP have been referred to the registry
from about 180 European and extra-European centres. The
International Registry for Hereditary Kidney Stone Diseases is
an ongoing initiative started in July 2003 [16] which collects
medical information worldwide from over 1100 patients affected by Primary Hyperoxaluria (PH), Dent disease, Cystinuria and Adenine phosphoribosyltransferase (APRT)
deficiency with the aim to increase knowledge about these rare
disorders, provide evidence to establish patient care guidelines
and create the basis for future clinical trials. Clinical and laboratory data from 203 subjects have been recorded so far.
Other international registers on rare renal diseases are the UK
Registry for Rare Kidney Diseases (RADAR) [17] and the
Cure Cystinosis International Registry (CCIR) [18].
NDT PERSPECTIVES
PLANNING INTERVENTIONAL STUDIES IN
RARE DISEASES
When designing a drug trial in a rare disease, a detailed background on the pharmacology of a drug being tested is desirable
and pharmacology studies can also help to identify sources of
heterogeneity in patients affected by the disease. For rare diseases with very long course, the use of surrogate end points
may be acceptable but the relationship between these surrogates and clinical efficacy should be preliminarily established
to properly evaluate the balance of risks and benefits.
An example of validated surrogate end point is cyst volume
in patients with ADPKD. Kidney enlargement resulting from
the expansion of cysts is a quantifiable parameter and higher
rates of kidney enlargement reflect a more rapid decrease in
renal function [19].
SUMMARY
No specific and validated methods for designing, carrying out
or analysing clinical trials in small populations exist. Although
high-quality data adhering to good clinical practice standards
are desirable, a more pragmatic attitude can be justified in
certain situations. However, a careful balance between potential benefit and harm, not only for the individual patient but
also for the society at large, should be maintained, to avoid
either that effective treatments are withheld, or useless treatments provided. At least, the guidance should be made transparent, by providing a crisp description of how the literature
was searched, how retrieved evidence was interpreted, and
what considerations were taken into account when formulating the recommendation. The use of ‘expert groups’ supported
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by a team of methodologists, where consensus between experts
in the field of the disease is obtained during balanced face-to
face discussions, might be a possible way to balance personal
experience and available (as few as it might be) evidence.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
None declared.
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Received for publication: 5.2.2013; Accepted in revised form: 8.7.2013
D. Bolignano et al.