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Renal diseases in haemophilic patients:

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 European Journal of Haematology 91 (287294)

REVIEW ARTICLE

Renal diseases in haemophilic patients: pathogenesis and

clinical management
Pasquale Esposito1, Teresa Rampino1, Marilena Gregorini1, Gianluca Fasoli1, Gabriella Gamba2,
Antonio Dal Canton1
1
Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico S.Matteo and University of Pavia, Pavia; 2Department of Internal
Medicine, Haemophilia and Thrombosis Centre, Fondazione IRCCS Policlinico S.Matteo and University of Pavia, Pavia, Italy

Abstract
Haemophilia A and B are genetic X-linked bleeding disorders, caused by mutations in genes encoding
factors VIII and IX, respectively. Clinical manifestations of haemophilia are spontaneous haemorrhage or
acute bleeding caused by minor trauma, resulting in severe functional consequences that can culminate in
a debilitating arthropathy. Life expectancy and quality of life of patients with haemophilia have dramatically
improved over the last years, mainly for new therapeutic options and the awareness to the risk of HCV
and HIV infections. Different clinical problems arise from this important change in history of patients with
haemophilia. In particular, ageing-related diseases, such as diabetes, hypertension and cancer, and chronic
viral infections are emerging as new challenges in this patient population. Among the different types of
chronic illnesses, renal diseases are of special interest as they involve some difficult management issues.
In fact, decisions regarding adequate preventive strategies and viral infection treatment, the choice of the
dialytic modality, placement of vascular access and prescription of dialytic treatments are particularly
complicated, because only few data are available. In this review, we discuss the pathogenesis of renal
damage in patients with haemophilia, especially in those with blood-transmitted viral infections, and the
major issues about the management of renal diseases, including problems related to dialytic treatment and
kidney transplantation, providing practical algorithms to guide the clinical decision-making process.

Key words haemophilia A; renal diseases; vascular access device; haemodialysis; peritoneal dialysis; bleeding; viral infections

Correspondence Pasquale Esposito, MD, Unit of Nephrology, Dialysis and Transplantation, Fondazione Policlinico San Matteo,
Piazzale Golgi 19, 27100 Pavia, Italy. Tel/Fax: +390382503883; e-mail: pasqualeesposito@hotmail.com

Accepted for publication 3 May 2013 doi:10.1111/ejh.12134

Haemophilia A and B are X-linked bleeding disorders, with
a prevalence of 1 in 5000 and 1 in 30 000 male live births,
respectively.
Mutations are present in genes encoding for the factor VIII
(FVIII) haemophilia A and factor IX (FIX) haemophilia
B determining alterations in the intrinsic pathway of blood
coagulation (1). Haemophilia A and B are classied as mild,
moderate or severe depending on factor plasma levels: <1%,
15% and >5 to 40%, respectively (2).
Clinical manifestations of haemophilia are frequent acute
bleeding episodes caused by minor trauma, and haemophilic
patients with severe disease are at high risk of spontaneous
haemorrhage in joints and muscles that can culminate in a
debilitating arthropathy (3).
Life expectancy and quality of life of these patients have
dramatically improved over the last years, and it is now
approaching that of the general male population, at least in
countries that can afford regular coagulation replacement
therapy (4). A recent investigation on Italian patients with
haemophilia reported that the mortality rate ratio, standard-
ized to the male Italian population, decreased during the
periods 19901999 and 20002007 (1.98 vs. 1.08, respec-
tively), while life expectancy increased (71.2 yr in 2000
2007 vs. 64.0 in 19901999). These values were fairly
normal and similar to those reported for the general popula-
tion (5). Various clinical problems arise from this important
change in history of patients with haemophilia. In particular,
ageing-related diseases, such as diabetes, hypertension and

2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 287
Renal diseases in haemophilia
cancer, and chronic infections are emerging as new chal-
lenges in this patient population (6, 7). Among the different
types of chronic illnesses, renal diseases are of particular
interest, as they involve some issues difcult to manage. In
fact, decisions regarding appropriate preventive strategies,
the choice of dialytic modality, placement of vascular access
and prescription of dialytic treatments are particularly com-
plicated, because few data are available. In this review, we
discuss the major issues about the pathogenesis and manage-
ment of renal diseases in patients with haemophilia, includ-
ing problems related to dialytic treatment and kidney
transplantation.
Renal involvement in haemophilia: focus on the role
of blood-transmitted viral infections
Early reports showed that renal failure was a rare complica-
tion of hereditary clotting disorders.
Small et al. (8) in a prospective study, performed over
11 yr, demonstrated that the majority of patients with hae-
mophilia did not develop renal disease and none of them
required dialysis. This tendency has changed in the course
of time, and more recent investigations highlighted that the
potential number of haemophilic patients with kidney
diseases is increased (9). The reasons for this change could
be found in the prolonged life expectancy, with the conse-
quent ageing, of haemophilic patient population, as well as
in the progressive inclusion of high-risk patients in dialysis
and kidney transplantation programmes (10, 11). Kulkarni
et al. (12) evaluated the incidence of both acute and
chronic renal failure in a population of over 3000 males
with haemophilia followed up for a 6-yr period. During the
surveillance period, the 2.9% of these patients presented
alterations in renal function requiring hospitalization. The
average rate of acute renal disease was 3.4 per 1000
patients per year (vs. estimated rate of 1.9 in the general
male population), while chronic renal disease was diag-
nosed in a rate of 4.7 per 1000, vs. the estimated rate of
2.9 per 1000 for US males, indicating that renal diseases in
patients with haemophilia are more common than previ-
ously thought.
Several factors might be implicated in the initiation and
progression of kidney damage in the course of haemophilia,
including hypertension, older age, diabetes and viral infec-
tions (12; Table 1). The relationship between renal disease,
hypertension and diabetes is not surprising, as these condi-
tions represent the main causes of end-stage renal disease
(ESRD) also in the general population (13).
On the contrary, the prominent role of viral infections in
renal diseases appears more remarkable. It should be consid-
ered that almost all the patients with haemophilia treated
with large-pool coagulation factor concentrates before the
mid-1980s have been infected with HCV and, to a lesser
extent, with HIV transmitted through clotting factor
288
Esposito et al.
concentrates (14). These infections, which may coexist, in
some cases have led to chronic disease involving the liver,
immune system and kidneys.
Renal complications are common in HIV-infected patients
(up to 30%) sometimes causing the progression to chronic
kidney disease (CKD; 15). HIV is associated with a number
of renal syndromes, including acute kidney failure,
HIV-associated nephropathy (HIVAN), immune complex
glomerulonephritis, thrombotic microangiopathy and vasculi-
tis (15). In addition, it is well known that some antiretroviral
drugs may exert nephrotoxic effects, thus contributing to the
development and progression of CKD (16). HIVAN, the
most frequent renal manifestation of HIV, is caused by
a direct infection of kidney epithelial cells by the virus,
and it is characterized by the presence of proteinuria in
the nephrotic range and a progressive renal failure, corre-
lated to the histological picture of a collapsing segmental
glomerulosclerosis (17).
The most effective treatment for HIV-related kidney dis-
eases is the strict control of the viral replication (HIV RNA)
with highly active antiretroviral therapy (HAART), which
seems effective also in slowing CKD progression to ESRD
(18). It is important to remark that clinical studies analysing
the outcome of HIV-infected patients with HIVAN showed
that, despite antiretroviral therapy, HIVAN led to ESRD in
more than a half of cases, underlining that an early diagnosis
and treatment of this condition is crucial (19). The principles
of HAART in patients with renal diseases follow the recom-
mendations given for the general population, bearing in
mind that an appropriate dose reduction is needed for anti-
retrovirals eliminated mainly via the kidney (20).
Also HCV infection is correlated to renal disorders. Both
glomerular and tubulointerstitial diseases associated with
HCV have been described, including membranoproliferative
glomerulonephritis, which may be associated with cryoglob-
ulinaemia, and it is usually manifested by proteinuria (some-
times with a nephrotic syndrome), microhaematuria and
progressive renal insufciency (21). In addition to symptom-
atic therapy with diuretics and renal-protective agents, such
as angiotensin-converting enzyme inhibitors and angiotensin
receptor blockers, the cornerstone of treatment for
HCV-related kidney disease is the antiviral therapy, aimed at
eradication of and reduction in HCV replication (22). In
patients with haemophilia, the pharmacological treatment of
HCV is not different from the one established for other
infected subjects. Combination therapy with pegylated inter-
feron and ribavirin is the current standard treatment for
HCV infection, while triple therapy with interferon, ribavirin
and protease inhibitors has been recently approved for less
responsive subjects (mainly those with HCV genotype 1;
23). In addition, HCV-infected patients with severe active
renal disease are also candidates for receiving more aggres-
sive treatments with corticosteroids, cytotoxic agents, plas-
mapheresis or rituximab (24).
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Esposito et al.
Table 1 Causal and risk factors for renal diseases in patients with
haemophilia
Risk factors
Hypertension
Diabetes
Older age
HIV infection (different clinical presentations) (15)
HCV infection (different clinical presentations) (22)
Drug nephrotoxicity (antivirals, antibiotics, etc.)
Kidney bleeding1
Notice that different factors may coexist in the same patients.
1
Acute kidney injury was described only in patients taking antifibrino-
lytic agents (25, 26).
Repeated kidney bleedings could constitute another patho-
genetic factor of renal damage in patients with haemophilia.
In fact, cases of acute kidney injury secondary to tubular
obstruction or cortical necrosis following renal bleeding trea-
ted with antibrinolytic agents have been reported (25, 26),
and previous studies reported a reduction in kidney function
in patients with haematuria (27). However, more recent data
do not conrm these early ndings, and now the role of
kidney bleeding in renal disease pathogenesis remains to be
claried (28).
Finally, it has to be mentioned that, at least theoretically,
the increased protein load, due to the frequent clotting factor
concentrate administration, could also impact on kidney
function, mainly inuencing the progression of the renal
damage. This issue, not adequately evaluated in previous
studies, should be taken into account in the management of
patients with haemophilia suffering from CKD.
Overall, these considerations point out that patients with
haemophilia present many risk factors for the development
of renal diseases. The adoption of adequate supportive and
specic treatments, such as the control of hypertension, dia-
betes and viral infections, is essential to prevent and treat
renal diseases, also considering that once chronic renal dam-
age is established, often it progresses to the advanced stages,
nally requiring renal replacement therapy (RRT).
Choice of RRT modality
When renal failure progresses to ESRD, RRT is necessary
to supply the loss of kidney function.
Different options exist for patients requiring RRT, includ-
ing peritoneal dialysis (PD) and extracorporeal haemodialy-
sis (HD). Each technique presents advantages and
disadvantages, and the choice of the dialytic modality should
be tailored to the individual patient needs. In the particular
setting of patients with haemophilia, some cases successfully
treated with both PD and HD have been reported.
Bajo et al. (29) reported the experience of three patients
with hereditary coagulopathy (two affected by haemophilia
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Renal diseases in haemophilia
A and one by Von Willebrand disease) who were treated
with PD. Two of them were initially addressed to HD, but
for the important complications of this technique (i.e. severe
bleeding from catheter insertion site and a peri-arteriovenous
stula haematoma), they were later switched to PD. There-
fore, because of the reduced risk of bleeding and not
requirement of clotting factor infusions after treatment, the
authors concluded that PD should be considered the treat-
ment of choice in patients affected by coagulopathy. Even if
similar cases of successful PD treatment in patients with
haemophilia have also been reported (30, 31), PD seems not
to be suitable for any patient with haemophilia, because of
the difcult management of decompensated HCV patients
with ascites and the potential risk of haemoperitoneum,
peritonitis and peritoneal catheter infection, especially in
HIV-positive subjects.
Haemodialysis, the most diffused dialytic modality in the
general population, constitutes the alternative to PD even if,
also in this case, the clinical experience in patients with hae-
mophilia (affected by both haemophilia A and B) is limited
(3234). With respect to PD, HD offers the advantage to be
performed in a hospital setting, where expert nurses and
physicians can supervise the procedure. Moreover, the use
of arteriovenous stula (AVF) as vascular access may signif-
icantly reduce the risk of infections. However, HD exposes
these patients to an increased risk of bleeding, in which pre-
vention requires the regular administration of coagulation
factor in concomitance of each HD session.
Therefore, it appears evident that the choice of the dialytic
modality is often difcult, bearing in mind that not only
clinical aspects, but also other factors, such as patient mobil-
ity, job, home activities and familial setting should be evalu-
ated (see Table 2; 35).
Dialysis access placement
After the choice of treatment modality, the placement of a
dialysis access is mandatory.
To perform PD is required a peritoneal catheter, while HD
needs a vascular access providing an adequate blood ow.
The placement and management of venous accesses is one
of the most important issues in patients suffering from hae-
mophilia. In fact, these patients usually require frequent
intravenous injections of clotting factor concentrate to treat
haemorrhages or prevent bleeding. When repeated venepunc-
tures are not possible, the use of central venous access
devices (CVADs) or, alternatively, the creation of an AVF is
recognized as valuable infusion tool (36).
Central venous access devices s include tunnelled fully
implantable subcutaneous devices (ports) and tunnelled or
non-tunnelled external catheters (central venous catheters
CVCs). Among patients with haemophilia, ports are pre-
ferred, because of long-lasting, inferior rate of infection and
easier management (37). On the opposite, external catheters
289
Renal diseases in haemophilia Esposito et al.

Table 2 Criteria for the choice of dialytic modality in patients with haemophilia requiring RRT

PD
PROS CONS
General considerations Easier for working people and for travelling Major abdominal surgery
Residual renal function preservation Weight gain and body image issues
Requires an adequate patient mobility,
social and familial setting
Protein loss leading to malnutrition
Haemophilic-specific No use of needles Increased risk of peritonitis
considerations No requirements of clotting factor infusion in Difficult management in cirrhotic patients
relation to the treatment Risk of haemoperitoneum
HD
PROS CONS
General considerations Performed in a hospital setting under the More restricted diet
monitoring of expert personal A more rigid treatment schedule that
Allows off days without treatment may conflict with work
Haemophilic-specific Reduction in infection rate (AVF) AVF:
considerations Allows a strict control of coagulative parameters Use of needles
Administration of clotting factor after each
dialysis treatment
CVC:
High infection and thrombosis rate

RRT, renal replacement therapy; PD, peritoneal dialysis; HD, haemodialysis; AVF, arteriovenous fistula; CVC, central venous catheter.

are of choice in patients requiring HD as they allow an easy
and safe connection to the dialysis circuit. CVAD placement
requires a prophylactic clotting factor administration, aiming
to prevent a procedure-related bleeding. Different periopera-
tive protocols have been described, but it can be generalized
that preoperative factor level (FVIII or FIX) should be of
100% and replacement therapy should be continued daily for
at least 3 d after the procedure, maintaining level at
50100% and then at 3075% for other 15 d. (38).
Once placed, complications associated with CVAD and
in particular with CVCs in patients undergoing HD
include catheter-related infections, local haemorrhages,
mechanical failure and thrombosis (39). Infections are the
most frequent complication; in a meta-analysis including a
large number of patients with haemophilia, Valentino et al.
(40) found that 44% of 2704 patients with CVADs presented
a local or systemic infectious episode, requiring in some
cases the catheter removal. Thrombotic complications, in
particular deep venous thrombosis (DVT), are also possible
in haemophilic patients with CVADs, leading to device
occlusion or infection. In the past, it was thought that throm-
bosis was rare in these patients, but more recent data have
documented different results. Journeycake et al. (41) found
that 8 of 15 (53%) boys with haemophilia and CVCs pre-
sented radiological evidence of DVT, even if only 3 of them
(20%) had clinical signs suggestive for thrombosis. These
ndings have been conrmed by following studies, and
now, it is well accepted that thrombosis prevention and
monitoring is a part of the CVAD management in patients
with haemophilia (42). Due to the high rate of complications
associated with CVAD use, AVF has been considered a
valuable alternative for patients with haemophilia, especially
in those at major risk of infection, such as patients present-
ing circulation clotting factor inhibitors (43). The creation of
an AVF requires an accurate presurgical examination, aimed
to evaluate vein calibre and vessel state and identifying a
suitable vascular site. Usually, AVF is created in the upper
forearm or in the wrist of non-dominant arm by an anasto-
mosis between the brachial or radial artery and a nearby
vein, using end-to-side or side-to side techniques. Periopera-
tive haemostatic treatment is similar to that described for the
CVAD placement, requiring preoperative administration of
clotting factors and daily infusions for further 56 d. After
the creation of an AVF, it is necessary to wait for its matu-
ration before the use. This process may take some weeks,
and AVF has to be carefully monitored by clinical and
instrumental (Doppler ultrasonography) evaluations (44).
AVF complications can be distinguished into early
including haematomas, distal steal syndrome and an inade-
quate maturation and late including limb hypertrophy,
aneurysms and overow (45). Previous experiences in AVF
creation and management in patients with haemophilia
(mainly children) showed that this approach was safe and
effective also in the long term. Surgical procedures did not
present important complications, and a good rate of AVF
maturation was obtained with satisfactory access patency,
while both early and late complications were fully manage-
able (4547). Such good results led some haemophilic centre
to the adoption of AVF as the rst-choice venous access
(44).
Regarding the specic setting of patients with haemophilia
requiring HD, successful treatments have been reported

290 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Esposito et al.
using both CVCs and AVF (3234, 48). However, being
burdened by a high risk of infections and thrombosis, CVCs
should be considered only as a temporary access, mainly in
patients requiring HD for acute kidney injury, whereas for
other patients with ESRD, AVF is thought to be the optimal
permanent access (49).
RRT prescription
The general principle for RRT prescription is to treat
patients with haemophilia like their age peers without hae-
mophilia. Replacement therapy must be adapted to the base-
line plasma factor deciency and the risk of bleeding carried
out by therapeutic procedures and eventually antithrombotic
drugs (50).
Actually, PD does not require specic prescriptions, as
it does not need clotting factor replacement in relation
with dialysis procedures. Both continuous ambulatory peri-
toneal dialysis (CAPD) and automatic peritoneal dialysis
(APD) appear suitable options for these patients and can
be performed according to the usual scheduling, giving
attention to the possible occurrence of peritonitis and
haemoperitoneum.
On the opposite, HD prescription is more challenging,
being the major concerns the heparinization during dialysis
and the modality of recombinant factor VIII administration.
In the course of HD treatment, heparinization is required
to prevent clot formation in the extracorporeal circuits, but
this exposes patients with haemophilia to an increased bleed-
ing risk. Different approaches have been developed to over-
come this problem. Regional heparinization was used in the
rst reported cases of patients with haemophilia undergoing
HD. This strategy implies that heparin administrated in the
arterial line is neutralized by protamine infused into the
venous line before blood is returned to the patient. Previous
experience in patients with haemophilia reported well-
tolerated HD treatment using 5000 IU of heparin and 80 mg
of protamine sulphate (51).
However, this theoretically useful approach appears dif-
cult to manage in the daily practice, mainly because of the
individual variability in response to protamine administration
(52).
More recently, citrate has been described as an alternative
effective regional anticoagulant strategy (53). It has been
demonstrated that citrate, which acts by binding ionized cal-
cium, signicantly decreases the risk of bleeding in patients
undergoing RRT in intensive care units (54).
So, although no data have been reported, the use of citrate
appears to be a promising approach also in patients with
haemophilia.
Besides regional anticoagulation strategies, it has to be
remarked that some authors reported successful cases of
patients with haemophilia treated with HD without any anti-
coagulation (50).
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Renal diseases in haemophilia
Figure 1 Decision-making process in patients with haemophilia requir-
ing RRT. Circles indicate the main steps in the decision process.
Abbreviations are as follows: RRT = renal replacement therapy,
PD = peritoneal dialysis, HD = haemodialysis, CVC = central venous
catheter, AVF = arteriovenous fistula. AVF is considered the first-
choice vascular access for chronic HD. 1 = consider the possibility of
avoiding anticoagulation (mainly in patients with severe forms of hae-
mophilia). 2 = not required in patients with CVC.
Decisions about dose and schedule of factor infusion are
other crucial steps to minimize the potential bleeding
associated with HD. Currently, in patients with haemophilia
A, the most commonly suggested protocol for the prophy-
laxis is the infusion of 2540 IU/kg of clotting factor con-
centrates three times a week, but dose and frequency of
infusions should be adjusted, according to clinical and
laboratory monitoring (55).
Regarding the schedule of factor administration, it should
be considered that HD treatment does not affect factor VIII
levels, as, because of its high molecular weight (light chain
80 000 Da and heavy chain 90 000200 000 Da), it does
not pass through dialysis membranes.
Therefore, at least theoretically, clotting factor could be
infused both during and after HD session, even if the con-
cerns about coagulation of the dialysis circuit suggest admin-
istrating the replacement factor at the end of each treatment
through the arterial line of dialysis machine.
Bearing in mind all these considerations, according to
our previous experiences, at our institution, we have estab-
lished to begin HD treatments in patients with haemophilia
avoiding intradialytic anticoagulation and administrating
about 30 IU/kg of clotting factor at the end of each
HD session, strictly monitoring clinical and biochemical
parameters.
However, it has also to be underlined that this approach
could be soon modied by the introduction in the clinical
practice of new long-acting FVIII and FIX molecules, cur-
rently under investigation, which impact on RRT manage-
ment, and prescription is completely unknown (56).
291
Renal diseases in haemophilia
Finally, no particular concerns should exist on the poten-
tial protein overload consequent to the clotting factor
administration in patients undergoing RRT. In fact, these
patients are at risk of protein-energy malnutrition, and inter-
national guidelines on nutritional management of patients
with ESRD recommend a normalhigh protein intake to
guarantee an optimal metabolic balance (57).
Renal transplantation
Some cases of successful kidney transplantation in paediatric
and young adult patients with haemophilia have been
reported (5860). Renal function recovered early after trans-
plantation, while the main clinical problems regarded the
management of bleeding risk, in particular post-transplant
massive intravesical haemorrhage.
However, as long-term results are good, kidney transplan-
tation may be a suitable option for patients with haemo-
philia, considering the need (such as for other major surgical
interventions) of replacement therapy with the clotting
factors in peri- and postoperative periods.
In particular, according to current guidelines, preoperative
factor levels should be 80100%, while in the postoperative
period, minimal factor levels should be maintained above
50% in the rst postoperative week and above 30% in the
late postoperative period (61, 62).
Conclusions
Management of haemophilia and its complications, including
the whole spectrum of the renal diseases till RRT, is com-
plex and requires a full expertise, including haemophilia cen-
tres, internists, infectivologists, surgeons and nephrologists.
Previous experiences demonstrate that, although challeng-
ing, a good management of renal diseases and RRT in
patients with haemophilia is possible and feasible also in the
daily clinical practice.
Considering all the aspects discussed above, we elabo-
rated a step-by-step algorithm to guide the decision-making
process for patients with haemophilia requiring RRT
(Fig. 1).
Finally, even if the experience in the kidney transplanta-
tion is very limited, we think that this possibility has not to
be denied to patients suffering from haemophilia.
Acknowledgments
We thank all our colleagues who were involved in the dis-
cussion and revision of the manuscript:
Chiara Rocca, MD, Francesca Bosio, MD, Valeria Corrad-
etti MD, Teresa Valsania MD, Eleonora Francesca Pattoni-
eri, MD, Noemi Maggi, MD, Gianluca Marchi, MD,
Giuseppe Sileno, MD, Francesca Montagna, MD and Stefa-
nia Bianzina, MD.
292
Esposito et al.
Conflict of interest
All authors state no conict of interest. The authors did not
receive any nancial support for this study. The manuscript
has not been published previously and is not being consid-
ered concurrently by another journal.
References
1. Hemophilia. The Merck Manuals: The Merck Manual for
Healthcare Professionals. http://www.merckmanuals.com/pro-
fessional/sec11/ch136/ch136c.html#sec11-ch136-ch136d-524.
(Accessed 15 February 2013)
2. White GC 2nd, Rosendaal F, Aledort LM, Lusher JM, Roths-
child C, Ingerslev J. FactorVIII and Factor IX Subcommittee.
Denitions in hemophilia. Recommendation of the scientic
subcommittee on factor VIII and factor IX of the scientic
and standardization committee of the International Society on
Thrombosis and Haemostasis. Thromb Haemost 2001;85:560.
3. Buchanan GR. Hemophilia. Pediatr Clin North Am
1980;27:30926.
4. Saba HI, Tran DQ Jr. Challenges and successes in the
treatment of hemophilia: the story of a patient with severe
hemophilia A and high-titer inhibitors. J Blood Med
2012;3:1723.
5. Tagliaferri A, Rivolta GF, Iorio A, et al. ; Italian Association
of Hemophilia Centers. Mortality and causes of death in Ital-
ian persons with haemophilia, 1990-2007. Haemophilia
2010;16:43746.
6. Franchini M, Mannucci PM. Past, present and future of hemo-
philia: a narrative review. Orphanet J Rare Dis 2012;7:24.
7. Mannucci PM, Mauser-Bunschoten EP. Cardiovascular disease
in haemophilia patients: a contemporary issue. Haemophilia
2010;16(Suppl 3):5866.
8. Small S, Rose PE, McMillan N, Belch JJ, Rolfe EB, Forbes
CD, Stuart J. Haemophilia and the kidney: assessment after
11-year follow-up. Br Med J (Clin Res Ed) 1982;285:
160911.
9. Konkle BA, Kessler C, Aledort L, Andersen J, Fogarty P,
Kouides P, Quon D, Ragni M, Zakarija A, Ewenstein B.
Emerging clinical concerns in the ageing haemophilia patient.
Haemophilia 2009;15:1197209.
10. Fransen van de Putte DE, Fischer K, Makris M, Tait RC,
Collins PW, Meijer K, Roosendaal G, Chowdary P, Schutgens
RE, Mauser-Bunschoten EP. Increased prevalence of hyper-
tension in haemophilia patients. Thromb Haemost
2012;108:7505.
11. Konkle BA. The aging patient with hemophilia. Am J Hema-
tol 2012;87:S2732.
12. Kulkarni R, Soucie J, Evatt B. Renal disease among males
with hemophilia. Haemophilia 2003;9:70310.
13. White SL, Cass A, Atkins RC, Chadban SJ. Chronic kidney
disease in the general population. Adv Chronic Kidney Dis.
2005;12:513.
14. Alter HJ, Klein HG. The hazards of blood transfusion in
historical perspective. Blood 2008;112:261726.
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Esposito et al.
15. Miro JM, Cofan F, Trullas JC, et al. Renal dysfunction in the
setting of HIV/AIDS. Curr HIV/AIDS Rep 2012;9:18799.
16. Bagnis CI, Deray G. Renal consequences of HIV and HIV
therapy. Curr Opin HIV AIDS 2007;2:3147.
17. Medapalli RK, He JC, Klotman PE. HIV-associated nephropa-
thy: pathogenesis. Curr Opin Nephrol Hypertens
2011;20:30611.
18. Novak JE, Szczech LA. Management of HIV-infected patients
with ESRD. Adv Chronic Kidney Dis 2010;17:10210.
19. Bige N, Lanternier F, Viard JP, et al. Presentation of HIV-
associated nephropathy and outcome in HAART-treated
patients. Nephrol Dial Transplant 2012;27:111421.
20. Thompson MA, Aberg JA, Cahn P, et al. ; International
AIDS Society-USA. Antiretroviral treatment of adult HIV
infection: 2010 recommendations of the International AIDS
Society-USA panel. JAMA 2010; 304: 32133.
21. Kamar N, Izopet J, Alric L, Guilbeaud-Frugier C, Rostaing L.
Hepatitis C virus-related kidney disease: an overview. Clin
Nephrol 2008;69:14960.
22. Latt N, Alachkar N, Gurakar A. Hepatitis C virus and its renal
manifestations: a review and update. Gastroenterol Hepatol
(N Y) 2012 Jul;8:43445.
23. Zoulim F, Bailly F. New approaches to the management of
hepatitis C in haemophilia in 2012. Haemophilia 2012;18
(Suppl 4):2833.
24. Iannuzzella F, Vaglio A, Garini G. Management of hepatitis
C virus-related mixed cryoglobulinemia. Am J Med
2010;123:4008.
25. Odabas AR, Cetinkaya R, Selcuk Y, Kaya H, Coskun U.
Tranexamic-acid-induced acute renal cortical necrosis in a
patient with haemophilia A. Nephrol Dial Transplant
2000;16:18990.
26. Pitts TO, Spero JA, Bontempo FA, Greenberg A. Acute renal
failure due to high-grade obstruction following therapy with
epsilon-aminocaproic acid. Am J Kidney Dis 1986;8:4414.
27. Forbes CD, Prentice CR. Renal disorders in haemophilia A
and B. Scand J Haematol Suppl 1977;30:4350.
28. Benedik-Dolnicar M, Benedik M. Haematuria in patients with
haemophilia and its inuence on renal function and protein-
uria. Haemophilia 2007;13:48992.
29. Bajo MA, del Peso G, Jimenez V, Aguilera A, Villar A,
Jimenez C, Selgas R. Peritoneal dialysis is the therapy of
choice for end-stage renal disease patients with hereditary
clotting disorders. Adv Perit Dial 2000;16:1703.
30. Kothapalli SR. Peritoneal dialysis in a patient with haemo-
philia and chronic renal failure. Postgrad Med J
1989;64:506.
31. Solak Y, Turkmen K, Atalay H, Turk S. Successful peritoneal
dialysis in a hemophilia A patient with factor VIII inhibitor.
Perit Dial Int 2010;30:1146.
32. Kato N, Chin-Kanasaki M, Tanaka Y, Yasuda M, Yokomaku
Y, Sakaguchi M, Isshiki K, Araki S, Ohta S, Uzu T. Success-
ful renal replacement therapy for a patient with severe
hemophilia after surgical treatment of intracranial hemorrhage
and hydrocephalus. Case Reports in Nephrology 2011;
824709.
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Renal diseases in haemophilia
33. Kusztal M, Kuzniar J, Weyde W, Klinger M. Haemodialysis
in a patient with haemophilia B. Nephrol Dial Transplant
2008;23:4245.
34. Roy-Chaudhury P, Propper DJ, Catto GRD. Renal replace-
ment therapy for hemophiliacs. J Nephrol 1993;6:934.
35. Wuerth DB, Finkelstein SH, Schwetz O, Carey H, Kliger AS,
Finkelstein FO. Patients descriptions of specic factors lead-
ing to modality selection of chronic peritoneal dialysis or
hemodialysis. Perit Dial Int 2002;22:18490.
36. Valentino LA, Kawji M, Grygotis M. Venous access in the
management of hemophilia. Blood Rev 2011;25:115.
37. Komvilaisak P, Connolly B, Naqvi A, Blanchette V. Over-
view of the use of implantable venous access devices in the
management of children with inherited bleeding disorders.
Haemophilia 2006;12:8793.
38. Ewenstein BM, Valentino LA, Journeycake JM, et al.
Consensus recommendations for use of central venous access
devices in haemophilia. Haemophilia 2004;10:62948.
39. Izzi G, Franchini M, Bonetti L, Tagliaferri A. The use of
central venous catheters in haemophilia patients. Haemophilia
2010;16(Suppl 1):2931.
40. Valentino LA, Ewenstein B, Navickis RJ, Wilkes MM.
Central venous access devices in haemophilia. Haemophilia
2004;10:13446.
41. Journeycake JM, Quinn CT, Miller KL, Zajac JL, Buchanan
GR. Catheter-related deep venous thrombosis in children with
hemophilia. Blood 2001;98:172731.
42. Price VE, Carcao M, Connolly B, Chait P, Daneman A,
Temple M, Stain AM, Sung L, Al-Tralbosi H, Blanchette VS.
A prospective, longitudinal study of central venous catheter-
related deep venous thrombosis in boys with hemophilia.
J Thromb Haemost 2004;2:73742.
43. Morado M, Jimenez-Yuste V, Villar A, et al. Complications
of central venous catheters in patients with haemophilia and
inhibitors. Haemophilia 2001;7:5516.
44. Mancuso ME, Berardinelli L. Arteriovenous stula as stable
venous access in children with severe haemophilia. Haemo-
philia 2010;16(Suppl 1):258.
45. Mancuso ME, Berardinelli L, Beretta C, Raiteri M, Pozzoli E,
Santagostino E. Improved treatment feasibility in chil-
dren with hemophilia using arteriovenous stula: the results
after seven years of follow-up. Haematologica 2009;94:
68792.
46. Santagostino E, Gringeri A, Berardinelli L, Beretta C, Muc
a-Perja M, Mannucci PM. Long-term safety and feasibility of
artriovenous stulae as vascular accesses in children with
hemophilia: a prospective study. Br J Haematol
2003;123:5026.
47. McCarthy WJ, Valentino LA, Bonilla AS, Goncharova I,
Taylor A, Pooley TA, Jacobs CE. Arteriovenous stula for
long-term venous access for boys with hemophilia. J Vasc
Surg 2007;45:98690.
48. Barbosa Silva PA, Soares SM, Fraguas G, de Oliveira Vaz
FM, Jose da Silva M, Gabriel da Silva J. Management of a
hemophilia patient in renal replacement therapy. Dial Trans-
plant 2011;40: 2623.
293
 Renal diseases in haemophilia
49. Vascular Access 2006 Work Group. Clinical practice guide-
lines for vascular access. Am J Kidney Dis 2006;48 (Suppl 1):
S176247.
50. Lambing A, Kuriakose P, Lanzon J, Kachalsky E. Dialysis in
the haemophilia patient: a practical approach to care. Haemo-
philia 2009;15:3342.
51. Endo Y, Mamuya S, Nakamoto Y, Muira A, Watanuki T.
Chronic renal failure in an aged hemophilia A patient treated
with hemodialysis. ACTA Hematol 1984;47:1737.
52. van Veen JJ, Maclean RM, Hampton KK, Laidlaw S, Kitchen
S, Toth P, Makris M. Protamine reversal of low molecular
weight heparin: clinically effective? Blood Coagul Fibrinolysis
2011;22:56570.
53. Davenport A. Alternatives to standard unfractionated heparin
for pediatric hemodialysis treatments. Pediatr Nephrol
2012;27:186979.
54. Wu MY, Hsu YH, Bai CH, Lin YF, Wu CH, Tam KW.
Regional citrate versus heparin anticoagulation for continuous
renal replacement therapy: a meta-analysis of randomized con-
trolled trials. Am J Kidney Dis 2012;59:8108.
55. Richards M, Williams M, Chalmers E, Liesner R, Collins P,
Vidler V, Hanley J; Paediatric Working Party of the United
Kingdom Haemophilia Doctors Organisation. A United King-
dom Haemophilia Centre Doctors Organization guideline
approved by the British Committee for Standards in Haema-
tology: guideline on the use of prophylactic factor VIII
294
View publication stats
Esposito et al.
concentrate in children and adults with severe haemophilia A.
Br J Haematol 2010;149:498507.
56. Pipe SW. The hope and reality of long-acting hemophilia
products. Am J Hematol 2012;87(Suppl 1):S339.
57. Fouque D, Vennegoor M, ter Wee P, et al. EBPG guideline
on nutrition. Nephrol Dial Transplant 2007;22(Suppl 2):
ii4587.
58. El Bakkouri J, Mamdouh A, Faez S, Medkouri G, Ramdani
B, Benchemsi N. Kidney transplantation in a patient with
haemophilia A. Transfus Clin Biol 2009;16:4713.
59. Gomperts ED, Malekzadeh MH, Fine RN. Dialysis and renal
transplant in a hemophiliac. Thromb Haemost 1981;46:6268.
60. Koene RA, Gerlag PG, Jansen JL, Moulijn AC, Skotnicki SH,
Debruyne FJ, Kunst VA, Geerdink P, Wijdeveld PG. Successful
hemodialysis and renal transplantation in a patient with hemo-
philia A. Proc Eur Dial Transplant Assoc 1977;14:4016.
61. Hermans C, Altisent C, Batorova A, Chambost H, De Moer-
loose P, Karafoulidou A, Klamroth R, Richards M, White B,
Dolan G European Haemophilia Therapy Standardisation
Board. Replacement therapy for invasive procedures in
patients with haemophilia: literature review, European survey
and recommendations. Haemophilia 2009;15:63958.
62. Goldmann G, Holoborodska Y, Oldenburg J, Schaefer N,
Hoeller T, Standop J, Kalff JC, Hirner A, Overhaus M. Peri-
operative management and outcome of general and abdominal
surgery in hemophiliacs. Am J Surg 2010;199:7027.
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd