Rheumatology 2008 47(Supplement 5):v54-v56; doi:10.1093/rheumatology/ken307
© 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
Renal manifestations of systemic sclerosis—clinical features and outcome assessment
C. P. Denton1
1Centre for Rheumatology, Royal Free Hospital, London, UK.
Correspondence to: C. P. Denton, Centre for Rheumatology, Royal Free Hospital, London NW3 2QG, UK. E-mail: c.denton{at}medsch.ucl.ac.uk
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Abstract
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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 SRC—such as frequency and duration
of dialysis, or recovery of renal function.
KEY WORDS: Scleroderma, Renal crisis, Incidence, Biopsy, Treatment, Endothelin-1
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Introduction
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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.
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Overview of renal involvement in SSc
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Scleroderma renal crisis
SRC occurs in 10–15% of the patients with dcSSc and only
vary rarely (1–2%) 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].
Management of renal crisis 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 10–20
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 pro-inflammatory 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.
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Other forms of renal involvement in SSc
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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 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].
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Renal function assessment in SSc
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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.
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Measurement and significance of proteinuria
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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.
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Levels of cytokines, growth factors and oxidant stress as markers of scleroderma renal disease
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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-β
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].
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Renal biopsy analysis
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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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Renal blood flow assessment
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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.
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Methodologies for clinical studies that evaluate renal involvement in SSc
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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 case–control 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 anti-RNA 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.
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Outlook
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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].
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Acknowledgements
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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.
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References
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- Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. Q J Med (2007) 100:485–94.[Web of Science]
- 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) 67:110–6.[Abstract/Free Full Text]
- Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis (2007) 66:940–4.[Abstract/Free Full Text]
- 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) 33:90–2.[Abstract/Free Full Text]
- 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) 46:2983–9.[CrossRef][Web of Science][Medline]
- 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) 41:1613–9.[CrossRef][Web of Science][Medline]
- 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) 15:135–41.[Web of Science][Medline]
- 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) 24:1944–8.[Web of Science][Medline]
- 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) 4:2027–31.[CrossRef][Web of Science][Medline]
- Kamen DL, Wigley FM, Brown AN. Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis in scleroderma—a different kind of renal crisis. J Rheumatol (2006) 33:1886–8.[Abstract/Free Full Text]
- 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) 42:26–33.[Abstract/Free Full Text]
- Denton CP, Bickerstaff MC, Shiwen X, et al. Serial circulating adhesion molecule levels reflect disease severity in systemic sclerosis. Br J Rheumatol (1995) 34:1048–54.[Abstract/Free Full Text]
- 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) 91:561–6.
- Vancheeswaran R, Magoulas T, Efrat G, et al. Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J Rheumatol (1994) 21:1838–44.[Web of Science][Medline]
- 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) 18:425–7.[CrossRef][Web of Science][Medline]
- 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) 117:395–402.[CrossRef][Web of Science][Medline]
- Fonseca C, Renzoni E, Sestini P, et al. Endothelin axis polymorphisms in patients with scleroderma. Arthritis Rheum (2006) 54:3034–42.[CrossRef][Web of Science][Medline]
- Wollheim FA. ACE inhibitors could prevent long-term damage in systemic sclerosis patients experiencing scleroderma renal crisis. Clin Exp Rheumatol (2002) 20:613–4.[Medline]
Submitted 1 May 2008;
Accepted 3 July 2008
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Introduction