Rheumatology 2008;47:v54v56

doi:10.1093/rheumatology/ken307

Renal manifestations of systemic sclerosisclinical features and

outcome assessment
C. P. Denton1
Renal manifestations occur frequently in scleroderma (SSc). Commonest is a reduction in renal function due to chronic disease but most
clinically important is the scleroderma renal crisis (SRC). This life-threatening complication occurs in up to 15% of the cases of dcSSc.
Mortality is reduced by use of angiotensin converting enzyme (ACE) inhibitors. Renal outcome can be assessed by quantifying renal function,
measuring proteinuria, exploring the frequency of renal crisis episodes and through assessment of renal outcome following SRCsuch as
frequency and duration of dialysis, or recovery of renal function.
KEY

WORDS:

Scleroderma, Renal crisis, Incidence, Biopsy, Treatment, Endothelin-1.

Management of renal crisis in SSc

Renal complications are common in scleroderma (SSc) although

they are not always clinically significant. Compared with other
disease manifestations it is a major advantage in renal assessment
in SSc that renal function can be quantitative as there are a large
number of easily measurable variables. These are listed in Table 1.
However, interpretation of the significance of individual measurements is less clear. In assessing scleroderma renal disease the most
important end-point is reasonably considered to be scleroderma
renal crisis (SRC); however, this is confounded by the absence of
an adequately clear definition. In addition, renal involvement due
to more than one pathology is often present and it has been shown
that asymptomatic chronic kidney disease is often present in SSc.

In all cases, hospital admission and prompt initiation of ACE

inhibitor (e.g. captopril or once-daily agents as oral therapy) as
cornerstone of therapy is recommended. Dose should be increased
daily to achieve a systolic blood pressure reduction of 1020
mmHg/24 h, even if there is continued deterioration in renal
function, which can be followed by daily creatinine clearance or
calculated glomerular filtration rate (GFR). Patients are routinely
given continuous low-dose prostacyclin that may help control
blood pressure and has potentially beneficial effects on renal blood
flow [7], endothelial cell function and production of proinflammatory or profibrotic factors [8]. This is currently without
formal confirmation of benefit. Additional antihypertensive
agents may be useful including combinations of ARB and ACE
inhibitors or calcium channel blockers, nitrates (especially if
pulmonary oedema) or other vasodilator agents such as doxazosin.
Care must be taken to monitor cardiac function closely. Vasodilatation may be associated with relative hypovolaemia. SVR
monitoring using an oesophageal Doppler probe can be used and
offers an alternative to more invasive monitoring such as
pulmonary arterial balloon catheter.
Although improved by treatment, outcome of SRC remains
inadequate. Early mortality approaches 10% and up to half of the
patients need dialysis. This may be temporary, with up to half of
the cases needing renal replacement therapy eventually coming off
dialysis although this may be between 6 and 24 months after the
initial SRC. For this reason, even though allografts appear no less
successful in SSc than in SLE, final decisions should not be made
until at least 2 yrs after the renal crisis. There is firm evidence that
renal transplant offers superior survival in SSc compared with
long-term dialysis [9]. Almost all cases of suspected SRC managed
in our unit have renal biopsy, which may provide prognostic
information and also confirms the diagnosis. A number of cases
of SSc with inflammatory glomerular pathology have been
identified and these require potentially very different treatment
to classical SRC.

Overview of renal involvement in SSc

Scleroderma renal crisis
SRC occurs in 1015% of the patients with dcSSc and only vary
rarely (12%) in lcSSc [1, 2]. Most cases occur within the first 12
months of the disease and in up to a quarter of patients with SRC,
the diagnosis of SSc is made at the time of the renal presentation.
Typically, patients present with accelerated hypertension and
progressive renal impairment. End-organ damage can result in
encephalopathy with generalized seizures or flash pulmonary
oedema. Microangiopathic anaemia is common, and disseminated
intravascular coagulation may develop (Table 2). Approximately
two-thirds of the cases of SRC require renal replacement therapy
[1]. Of these, half eventually recover sufficiently to discontinue
dialysis. This can occur for up to 24 months, and so decisions
about renal transplantation should be postponed until that time.
The possibility for delayed renal recovery distinguishes SRC from
other causes of end-stage renal failure. Historically, SRC was the
commonest form of scleroderma-associated death [3]. Dramatically improved outcomes in the short-term are achieved with the
use of angiotensin converting enzyme (ACE) inhibitors as routine
therapy for established SRC. It remains unclear whether these or
related drugs, such as angiotensin receptor blockers (ARBs),
are effective in preventing or abrogating SRC. Corticosteroids,
along with cyclosporin [4], have been implicated as precipitants of
SRC [5, 6].

Other forms of renal involvement in SSc

Several patterns of renal pathology are recognized in patients with
SSc: almost all involve vascular abnormalities. Apart from SRC
described above, many patients demonstrate less severe renal
complications, probably associated with reduced renal blood flow
and the consequent reduction in GFR. The mechanism of this
slowly progressive form of chronic renal disease is unclear.
Other acute renal complications may occur, especially in
overlap syndromes with lupus nephritis. There may be serological
clues that a patient is evolving within the CTD spectrum that
anticipate clinical changes, such as the development or a rise in

Centre for Rheumatology, Royal Free Hospital, London, UK.

Submitted 1 May 2008; accepted 3 July 2008.

Correspondence to: C. P. Denton, Centre for Rheumatology, Royal Free

Hospital, London NW3 2QG, UK. E-mail: c.denton@medsch.ucl.ac.uk

v54
The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Introduction

Renal manifestations of SSc

v55

TABLE 1. Potential outcome measures for renal disease in scleroderma

TABLE 2. Key features of scleroderma renal crisis

Outcome

SRC is a clinical syndrome of acute renal failure and accelerated hypertension in

the presence of SSc.
Risk factors
 Recent-onset diffuse scleroderma
 Active, progressive skin disease
 Tendon friction rubs
 Anaemia
 New cardiac events
 Steroid use (15 mg prednisolone/day)
 Presence of anti-RNA polymerase III

Comments

Renal function assessment

Isotope GFR
Gold standard assessment is isotope
GFR that is independent of urinary collection.
Venous access may be difficult.
Creatinine clearance
Low cost but full collection may
be difficult for SSc cases.
eGFR
Good correlation with other measures.
More sensitive to change than serum creatinine.
Serum creatinine
Low sensitivity for change and confounded by
muscle mass, which is often reduced in SSc.
Urinary protein excretion

Renal blood flow

assessment
Vascular markers

Renal biopsy
Dialysis requirement

Low frequency and in 20% of the cases

presenting feature of SSc limit utility as
an outcome measure.
Criteria for renal crisis still not universally agreed.
Useful to differentiate other pathology and
predict long-term outcome but not always
required for management.
Frequency and duration of dialysis important
outcome measure for contemporary
management of renal crisis.

titre of an associated anti-dsDNA antibody. It has been suggested

that ANCA reactivity may predict unusual renal complications of
SSc, such as glomerulonephritis and renal vasculitis [10]. Some of
these changes occur in SSc patients treated with D-penicillamine.
Indolent chronic renal involvement, characterized by a slow
reduction in GFR accompanied by proteinuria, has been
described in SSc [11].

Renal function assessment in SSc

Measurement of GFR is central to the determination of renal
blood flow and intrinsic renal damage. Although isotope GFR is
considered the gold standard it is also possible to assess renal
function by creatinine clearance or estimated GRF. The latter
takes account of size and surface area and several different
formulae are available. It has been demonstrated in SSc that the
modification of diet in renal disease (MDRD) formula correlates
well with other estimates and with GFR measured by creatinine
clearance, and thus is probably the test of choice for non-invasive
monitoring of renal function.

Measurement and significance of proteinuria

Simple measures of renal function are helpful in assessing the
presence of clinically significant renal disease and have an
important place in clinical practice. However, the significance of
borderline abnormalities and value for predicting future clinically
important events is much less clear. Protein:creatinine ratio is a
more convenient measure of proteinuria than 24 h excretion as it
can be performed on a single urine sample. The significance of
change in response to therapy is uncertain.
Markers of tubular proteinuria have been examined in one
small study. There was a high frequency of proteinuria but this did
not correlate with renal function as assessed by the MDRD
formula to estimate GFR. Likewise, there were a significant
number of cases demonstrating glomerular proteinuria and
microalbuminuria. This may be of clinical significance but
prospective studies are necessary.

Levels of cytokines, growth factors and oxidant stress as

markers of scleroderma renal disease
In the research arena, there are many potential measures of renal
pathophysiology that can be assessing serum, plasma and urine.
These include mediators of fibrosis such as TGF-
and connective
tissue growth factor (CTGF), vascular markers such as soluble
vascular cell adhesion molecule-1 (sVCAM-1) [12, 13], markers of
prostacyclin synthesis such as isoprostanes, and peptides such as
ET-1 that may have broader roles in pathogenesis. At present,
soluble markers are of interest in research protocols rather
than for routine management. Similarly, there is evidence of
up-regulation of a number of key vascular and fibrotic markers in
renal biopsy specimens. The association of SRC with increased
plasma concentration of ET-1 [14] as well as up-regulation of
ET-1 and endothelin receptors in renal biopsy samples [15]
suggests that endothelin receptor antagonists (ETRAs) may be of
value in SRC, perhaps as an adjunct to conventional therapy.
This is being explored in clinical trials, although the potential role
of endothelin in renal homeostasis may be relevant. It is
noteworthy that renal dysfunction is not regarded as a significant
side-effect of licensed ETRAs such as bosentan or sitaxentan that
are in current use for pulmonary arterial hypertension. The
sporadic nature of SRC may be explained by association with
anti-RNA polymerase antibodies [16], which in turn have genetic
association with genetic polymorphisms in endothelin receptor
subtypes [17].

Renal biopsy analysis

Although renal biopsy is often performed in SSc cases it is not
likely to be useful as an end-point for clinical studies. In SRC, it is
of value to perform a biopsy to confirm diagnosis and assess the
extent of acute markers of vascular injury that associate with
outcome. In addition, biopsies provide valuable opportunities to
explore expression and activity of key potential mediators or
markers of renal damage (see above). In cases where there is
diagnostic uncertainty such as those with co-existent clinical or
serological features of SLE or vasculitis, it is essential that cases of
significant renal impairment are biopsied to determine the
presence of inflammatory glomerular disease that may require
additional or different management to that of hypertensive renal
crisis. Likewise, any cases of renal impairment or significant
proteinuria in the absence of hypertension require consideration
for renal biopsy. One possibility in this case is a normotensive
SRC, a subset of SRC with especially poor outcome. Interestingly,
in a recent series examining biopsy changes in SRC, chronic renal
scarring did not seem important but the presence of acute vascular
injury predicted poor outcome [1].

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Clinical outcome
Renal crisis frequency

Significant proteinuria suggests renal crisis

(although usually <1 g/24 h).
Tubular and glomerular proteinuria at lower levels
frequent but significance uncertain.
Doppler assessment feasible as a research
tool but operator dependent.
ET-1, VCAM-1 and other markers of vascular
injury often elevated in scleroderma and
especially at the time of renal crisis.

Key clinical features

Patients with SRC will typically have an acute or sub-acute presentation with fluid
overload and/or symptoms of end-organ complications of hypertension.
 New onset hypertension (>90%)
 Acute renal failure
 Hypertensive retinopathy (>60%)
 Pulmonary oedema (>50%)
 Encephalopathy (20%)
 Seizures (10%)

C. P. Denton

v56

Renal blood flow assessment

Acknowledgements

There have been several studies exploring the use of Doppler

angiology to assess renal blood flow. These have included some
interventional studies that have shown, for example, improved
renal blood flow after prostacyclin infusion. For this reason such
non-invasive tests may have a useful place in the evaluation of
specific renal cases. Such approaches are far from applicable to
routine assessment at present.

Supplement: This paper forms part of the supplement entitled

Update in systemic sclerosis. This supplement was supported by
an unrestricted grant from Encysive.
Disclosure statement: C.P.D. has been a consultant for and has
received honoraria and research grants from Actelion
Pharmaceuticals and Encysive Pharmaceuticals.

Methodologies for clinical studies that evaluate renal

involvement in SSc

Outlook
Even today, the long-term mortality after SRC remains poor, especially if chronic dialysis is needed. This may reflect co-morbidity in a
subgroup of patients with active or extensive SSc but emphasizes
that this is an important complication. In the future, the main points
that need to be addressed in research are whether additional
vasoactive mediators may be targeted in a way that further improves
outcome, what the significance of renal impairment in SSc is and
whether treatments may prevent the development of SRC and so be
used prophylactically in high-risk cases [18].

Rheumatology key messages

 SRC, interstitial fibrosis and glomerulonephritis all occur in
scleroderma.
 SRC requires prompt diagnosis and treatment with ACE inhibitors.
 Renal biopsy confirms diagnosis and provides critical insight into
pathogenesis.
 Endothelin is a logical potential target for therapy in renal
scleroderma.

References
1 Penn H, Howie AJ, Kingdon EJ et al. Scleroderma renal crisis: patient characteristics
and long-term outcomes. Q J Med 2007;100:48594.
2 Teixeira L, Mouthon L, Mahr A et al. Mortality and risk factors of scleroderma
renal crisis: a French retrospective study of 50 patients. Ann Rheum Dis
2008;67:1106.
3 Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis,
19722002. Ann Rheum Dis 2007;66:9404.
4 Denton CP, Sweny P, Abdulla A, Black CM. Acute renal failure occurring in
scleroderma treated with cyclosporin A: a report of three cases. Br J Rheumatol
1994;33:902.
5 DeMarco PJ, Weisman MH, Seibold JR et al. Predictors and outcomes of
scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early
diffuse systemic sclerosis trial. Arthritis Rheum 2002;46:29839.
6 Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that
either precipitate or protect from the development of scleroderma renal crisis.
Arthritis Rheum 1998;41:16139.
7 Della Bella S, Molteni M, Mascagni B, Zulian C, Compasso S, Scorza R. Cytokine
production in scleroderma patients: effects of therapy with either iloprost or
nifedipine. Clin Exp Rheumatol 1997;15:13541.
8 Scorza R, Rivolta R, Mascagni B et al. Effect of iloprost infusion on the resistance
index of renal vessels of patients with systemic sclerosis. J Rheumatol
1997;24:19448.
9 Gibney EM, Parikh CR, Jani A, Fischer MJ, Collier D, Wiseman AC. Kidney
transplantation for systemic sclerosis improves survival and may modulate disease
activity. Am J Transplant 2004;4:202731.
10 Kamen DL, Wigley FM, Brown AN. Antineutrophil cytoplasmic antibody-positive
crescentic glomerulonephritis in sclerodermaa different kind of renal crisis.
J Rheumatol 2006;33:18868.
11 Kingdon EJ, Knight CJ, Dustan K et al. Calculated glomerular filtration rate is a useful
screening tool to identify scleroderma patients with renal impairment. Rheumatology
2003;42:2633.
12 Denton CP, Bickerstaff MC, Shiwen X et al. Serial circulating adhesion molecule
levels reflect disease severity in systemic sclerosis. Br J Rheumatol
1995;34:104854.
13 Stratton RJ, Coghlan JG, Pearson JD et al. Different patterns of endothelial cell
activation in renal and pulmonary vascular disease in scleroderma. Q J Med
1998;91:5616.
14 Vancheeswaran R, Magoulas T, Efrat G et al. Circulating endothelin-1 levels in
systemic sclerosis subsetsa marker of fibrosis or vascular dysfunction?
J Rheumatol 1994;21:183844.
15 Kobayashi H, Nishimaki T, Kaise S et al. Immunohistological study endothelin-1 and
endothelin-A and B receptors in two patients with scleroderma renal crisis. Clin
Rheumatol 1999;18:4257.
16 Harvey GR, Butts S, Rands AL, Patel Y, McHugh NJ. Clinical and serological
associations with anti-RNA polymerase antibodies in systemic sclerosis. Clin Exp
Immunol 1999;117:395402.
17 Fonseca C, Renzoni E, Sestini P et al. Endothelin axis polymorphisms in patients
with scleroderma. Arthritis Rheum 2006;54:303442.
18 Wollheim FA. ACE inhibitors could prevent long-term damage in systemic
sclerosis patients experiencing scleroderma renal crisis. Clin Exp Rheumatol
2002;20:6134.

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Design of studies to evaluate treatments that could affect renal

disease in SSc is complicated by the fact that much renal
involvement is not of immediate clinical significance and the
relative rarity of SRC, which makes it a challenge to evaluate, in a
prospective cohort of patients. To overcome this other study
designs have been used. The first studies that explored the efficacy
of ACE inhibitors in treatment of SRC used casecontrol design
and suggested a dramatic benefit, making subsequent conventional placebo-controlled studies unethical. Other information has
come from cohorts of patients examined in other clinical trials
such as the D-penicillamine study or from retrospective data
collection in well-characterized groups of patients [5]. However,
such approaches have significant limitations. In the future, it may
be possible to perform prospective randomized studies that look
into preventative strategies. This has been suggested although it is
unclear whether case enrichment would be needed to ensure an
adequate event frequency. For example, restricting cases to early
dcSSc may be appropriate or focusing on cases that carry the antiRNA polymerase III autoantibody, which is strongly associated
with SRC. Perhaps the most robust end-point for SRC study is the
frequency of such events according to consensus criteria.