REVIEWS

Scleroderma renal crisis and renal

involvement in systemic sclerosis
Thasia G. Woodworth1, Yossra A. Suliman1,2, Daniel E. Furst1 and Philip Clements1
Abstract | Scleroderma renal crisis (SRC) is a rare, potentially life-threatening complication that
affects 215% of patients with systemic sclerosis (SSc, also known as scleroderma). SRC typically
presents in patients with early, rapidly progressive, diffuse cutaneous SSc within the first 35years
after the onset of a non-Raynaud sign or symptom. SRC is characterized by an acute, usually
symptomatic increase in blood pressure, a rise in serum creatinine levels, oliguria and thrombotic
microangiopathy in about 50% of patients. The prognosis of SRC substantially improved in the
1980s with the introduction of angiotensin-converting-enzyme inhibitors for rapid blood pressure
control, with additional antihypertensive agents as required. However, the survival of patients with
SRC can still be improved. Current patient survival is 7082% at 1year, but decreases to 5060% at
5years despite dialysis support. Patients with SRC who show no signs of renal functional recovery
despite timely blood pressure control are candidates for transplantation. In this Review, we discuss
progress made in the identification and proactive management of patients at risk of SRC and make
recommendations aimed at optimizing management for those who progress to chronic
kidneyfailure.

1
Division of Rheumatology,
David Geffen School of
Medicine, University
of California, 100 Veterans
Avenue, Los Angeles,
California 90025, USA.
2
Rheumatology and
Rehabilitation Department,
Assiut University Hospital,
Assiut, Egypt.
Correspondence to
D.E.F.and P.C.
defurst@mednet.ucla.edu;
pclements@mednet.ucla.edu
doi:10.1038/nrneph.2016.124
Published online 19 Sep 2016
Systemic sclerosis (SSc) is a systemic autoimmune disease
characterized by vasculopathy, inflammation, collagen
deposition and fibrosis in the skin and internal organs.
The type of autoantibody found in patients with SSc
might influence which organs are affected. SSc can be
classified into two forms: limited cutaneous SSc (lcSSc)
with skin thickening at the elbows and knees, and diffuse
cutaneous SSc (dcSSc) with variable skin involvement.
SSc predominantly occurs in women, with a prevalence of
7489 cases per million population and an incidence
of 0.6122cases per million population per year, with
variations between geographical regions13. Morbidity
and mortality in SSc occur as a result of internal organ
involvement that can manifest as pulmonary fibrosis,
pulmonary arterial hypertension (PAH), gastrointestinal
dysfunction, various cancers, and scleroderma renal crisis
(SRC) a rare but life-threatening complication. Renal
vasculopathy is common in patients with SSc, and is
usually asymptomatic, although it can be associated with
isolated proteinuria and/or hypertension4,5. However,
neither of these symptoms predict SRC development6,7.
SRC is clinically characterized by new onset,
often symptomatic hypertension with blood pressure
>140/90mmHg or a >30mmHg rise in blood pressure
from baseline, rising serum creatinine levels and/or oligo
anuria. Microangiopathic haemolytic anaemia (MAHA)
occurs in up to 50% of patients and is characterized by
proteinuria, haematuria, and circulating fragmented red
blood cells810. SRC is more likely to occur in patients with
dcSSc than in those with lcSSc, especially in patients with
rapidly progressive dcSSc within the first 35years of
SSconset8,11.
As discussed further below, predictive factors for SRC
include the presence of anti-RNA polymeraseIII antibod-
ies, tendon friction rubs, and synovitis12. Glucocorticoid
treatment (>7.5mg daily) exerts a dose-dependent effect
on the risk of SRC development8,9,13. Although the finding
is controversial, treatment with angiotensin-converting-
enzyme (ACE) inhibitors before the abrupt onset of ele-
vated blood pressure and rising creatinine levels might be
associated with an increased risk of dialysis or death9,13,14.
In this Review, we describe the progress made over
the past few decades in understanding various aspects
of renal involvement in SSc, with a focus on early detec-
tion, management and prognosis of SRC. We propose
that patients at risk of SRC can be identified, and that
close monitoring and proactive management of these
patients can mitigate the risk of developing overt SRC,
which requires dialysis and potentially, renal transplan-
tation. We outline the evidence supporting this hypoth-
esis and provide recommendations for the optimal man-
agement of patients who present with the earliest signs
of SRC to limit their progression to chronic kidney
disease(CKD).

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Key points Finally, evaluation of 76 patients with SSc and pul-

monary artery hypertension, showed that 45.6% had
Renal dysfunction associated with vasculopathy is a common pathology in systemic renal dysfunction (estimated GFR (eGFR) <60ml/
sclerosis (SSc), and usually exhibits a benign course min/1.73m2) at the time of diagnosis, although only
Scleroderma renal crisis (SRC) is rare it affects 515% of patients, according to 6.5% had experienced a prior episode of SRC18. Impor-
studies published in the past 20years; however, a 2015 case series suggests that the tantly, eGFR was a strong predictor of survival; eGFR
incidence of SRC has decreased to 2.4% <60ml/min/1.73m2 at baseline was associated with a
Predictive factors for SRC include anti-RNA polymerase III antibodies, diffuse threefold increased risk of mortality. These findings
cutaneous disease, tendon friction rubs, and arthritis; glucocorticoid treatment is a might be due to fluid retention and neuroendocrine acti-
risk factor for SRC
vation associated with PAH and right-ventricular heart
SRC should be differentiated from ANCA-positive, rapidly progressive failure. Nevertheless, no apparent association between
glomerulonephritis, as treatment regimens and patient management are different
renal dysfunction and PAH or SRC was observed18.
Control of SRC-associated hypertension with angiotensin-converting-enzyme (ACE) These data from small mechanistic studies are con-
inhibitors in patients with SSc improves outcomes; however, this treatment does not
sistent with the results of a large Canadian longitudinal
prevent SRC, and might increase SRC-associated mortality
study in more than 400 patients with SSc who were fol-
Although prognosis improved with the introduction of ACE inhibitors in the 1990s,
lowed for a median of 2years7. Declines in renal function
SRC remains a major risk factor for mortality in SSc; endothelin receptor antagonists
measured by calculated GFR were generally mild, often
might further improve patient outcomes
associated with comorbidities such as hypertension and
diabetes mellitus, and comparable to declines seen in the
Renal dysfunction in SSc general population. Overall, GFR decline does not seem
Several groups have conducted detailed mechanistic to be progressive in most patients with SSc, and does not
studies in which they evaluated SSc-associated renal dys- predict the onset of SRC.
function with the aim of determining whether monitoring
of renal function can enable prediction of SRC at a stage Renal functional reserve
when intervention could prevent acute kidney injury. No Measurement of renal functional reserve (RFR), a sen-
specific parameter that reflects the effects of vasculopathy
sitive method devised in the 1980s to detect subclinical
on renal function has been shown to p redict SRC thus far.
renal dysfunction, examines the ability of the kidney to
respond to a protein challenge19. RFR is typically calcu-
Glomerular filtration rate lated as the percentage increase in GFR after intravenous
Several researchers have investigated the effects of or oral administration of an amino acid or protein load.
renal vasculopathy on glomerular filtration rate (GFR). A marked reduction in RFR was reported in 21 patients
Kingdon etal. measured GFR in 19 patients with SSc with SSc compared with healthy controls (1.918.6%
and normal creatinine levels using chromium51- versus 34.813.9%, P<0.0002)20. The response to pro-
ethylenediaminetetraacetic acid (51Cr-EDTA) clearance, tein challenge in these patients was inversely dependent
and found a reduced GFR in 18 patients15. Scheja etal. on mean arterial pressure and basal GFR. In a subsequent
also measured GFR using 51Cr-EDTA or iohexol in a study of 28 patients with SSc, 13 of 19 patients with RFR
Swedish cohort of patients with SSc (105 patients with <10% at baseline experienced a decrease in creatinine
dcSSc and 356 with lcSSc) to examine whether renal clearance of 2ml/min/1.73m2 per year during 5years
dysfunction was associated with SSc or comorbidities16. of followup, with a final creatinine clearance of 70ml/
A reduction in GFR to <70% of the age-adjusted value min/1.73m2 in eight patients; 10 patients developed sys-
occurred in 11% of patients with lcSSc and in 8.6% of temic hypertension (grade 1 or 2) and two developed
those with dcSSc during a median follow-up of 7.7years. microalbuminura. No patient with normal basal RFR
Among the patients with decreased GFR, 60% had hyper- (n=9) developed proteinuria or hypertension21. A study
tension, 52% had cardiac involvement, and 19% had that investigated whether RFR (measured after oral pro-
other nephropathies diagnosed by renal biopsy, suggest- tein load) could be used for early detection of clinically
ing comorbid causes for the decrease in GFR. After more relevant renal vasculopathy found comparable results;
than 4 additional years of followup, only four of the 15 24 of 30 patients with SSc, including patients with PAH,
patients with reduced GFR showed further decrease had reduced RFR and in most cases, disease duration was
inGFR16. greater than 4years. Interestingly, reduced basal GFR in
Another study examined 31 patients with SSc who these patients was associated with cumulative dose of
had normal serum creatinine levels and renal ultra- glucocorticoids22. Nevertheless, SRC was not reported in
sound findings, and compared their renal function these studies.
with that of 31 healthy controls. GFR measured using
tectenium99m-diethylenetriaminepentacetate clear- Renal vascular resistance
ance was normal (>89ml/min/1.73m2) in 45.1% of the Renal vascular resistance mirrors the increase in digital
patients with SSc, whereas 22.6% of patients were classi- vascular resistance caused by Raynaud phenomenon
fied with stage III CKD (GFR 3059ml/min/1.73m2); the and is typically observed in patients with SSc, often as
remaining patients had GFRs of 6089ml/min/1.73m2 a premonitory symptom23. Colour-flow Doppler ultra-
(REF.17). Renal dysfunction did not correlate with other sonography, a sensitive and noninvasive technique for
clinical parameters (except for pulmonary disease, evaluating the vasculature24, has been applied to evaluate
P=0.04), antibody profile, or treatments. renal vasculopathy in patients with SSc. Resistance to

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renal artery blood flow measured using this technique
was markedly increased at various renal vascular sites
(including the renal artery and interlobar and cortical
arteries) in patients with SSc and normal creatinine
clearance, compared to healthy controls (P<0.001)25.
Another study examined whether Doppler indices,
measures of intrarenal arterial stiffness, correlated with
GFR and microvascular damage (assessed by digital nail-
fold capillaroscopy) in patients with SSc23. The resistance
index, the pulsatile index (a measure of the variability of
blood velocity within a vessel) and the systolic/diastolic
ratio all negatively correlated with measured GFR, and
decreasing GFR correlated with increasing capillaro-
scopic damage in these patients. Overall, these data sug-
gest that increased vascular resistance as a manifestation
of renal vasculopathy is associated with decreased GFR
in patients with SSc. However, further studies are needed
to determine whether these measures might indicate
progression of renal disease.
The resistance index can also be used to assess the
effects of vasoactive agents. For example, a randomized
study that included 16 patients with SSc showed that
after 6months of treatment, intravenous infusion of ilo-
prost (a stable prostacyclin analogue and vasodilator)
caused a marked reduction in the renal resistance index
compared to oral administration of nifedipine (a calcium
channel blocker), suggesting that iloprost might be use-
ful to treat SSc renal vasospasm26. As frequent infusions
of iloprost are required to obtain persistent vasodilatory
effects, definitive clinical studies using this agent have
not been conducted to date27.
Isolated proteinuria
Urinary albumin excretion is generally recognized as
a marker of renal vascular damage, and an predictor
of cardiovascular morbidity and mortality independ-
ent of other comorbidities, such as diabetes or hyper
tension2831. In a cohort of 675 patients with dcSSc seen
at the University of Pittsburgh, USA, between 1972 and
1993, only 13.6% of patients had proteinuria, which was
associated with dpenicillamine treatment in 74% of
cases4. None of these patients developed CKD during a
median follow-up of 10years; no other renal outcomes
were reported. Another study used detailed urinary pro-
tein analysis (albumin, total protein, and electrophoresis)
to examine the effect of renal vasculopathy at its earliest
stage in a cohort of 80 patients with SSc32. In contrast
to a control group of 18 healthy individuals, none of
whom had proteinuria, 22.5% of patients with SSc had
microalbuminuria, 2.5% had macroalbuminuria, 17.5%
had increased total protein excretion, and 31.3% had
intermediate molecular weight proteinuria, as measured
by urine electrophoresis. The presence of intermediate
molecular weight proteinuria correlated with dcSSc,
gastrointestinal involvement and increased systolic
blood pressure, but not with declining renal function.
Total protein excretion correlated with lung involvement.
Thus, with sensitive methods, clinically relevant albu-
minuria and/or proteinuria can be detected in nearly a
third of patients with SSc, and seems to indicate not only
renal vasculopathy, but also systemic vasculopathy, which
is associated with increased morbidity and mortality.
Further studies are needed to determine whether inter-
vention (for example treatment with an ACE inhibitor)
when proteinuria is detected can improve outcomes.
Isolated hypertension
Patients with SSc can also present with hypertension.
Whether this hypertension is a comorbidity or a mani
festation of renal vasculopathy is unclear. In a study that
included 561 patients with SSc (of whom 60% had lcSSc)
and a mean disease duration of 10.98.8years, 23%
(normal renal function at baseline) and 43% (abnor-
mal renal function at baseline) had hypertension after
>2years of follow-up7. By contrast, only 12% of the
675 patients with dcSSc in the University of Pittsburgh
cohort, who were followed between 1972 and 1993, had
hypertension7. Half of these patients developed hyper-
tension a mean of 6.9years before being diagnosed with
SSc. The remaining patients developed hypertension a
mean of 4.7years after being diagnosed with SSc; 61%
of these patients had received glucocorticoids before
the onset of hypertension, suggesting that this treat
ment could cause hypertension in these cases. Treatment
included ACE inhibitors and/or calcium channel block-
ers. No evidence that essential hypertension alone was
associated with the development of SRC was reported in
either of these studies4,7.
Scleroderma renal crisis
Incidence and prevalence
SRC occurs during the rapid progression of skin thick-
ening in the early stages of dcSSc (<4years after disease
onset)13,14,33,34. Several case series published during the
past 20years and a 2013 systematic literature review
have estimated that SRC develops in ~515% and 15%
of patients with dcSSc, respectively8,13,14,3538. An analy-
sis of data on 637 patients with dcSSc disease duration
<4years from the EUSTAR cohort, however, found that
the prevalence of SRC was only 2.4%39. SRC occurs in
~2% of patients with lcSSc14. Interestingly, the incidence
and prevalence of SRC seem to be decreasing over time,
possibly as a result of early recognition and management
of SRC risk factors and early signs and symptoms in
patients with dcSSc, and of increased attention paid to
mitigating risk factors, such as corticosteroid treatment8,9.
The causes of SRC are unknown. Although the char-
acteristic vascular injury and fibrosis of SSc might be
considered to be risk factors for SRC, evidence from
mechanistic studies (described above) and epidemio
logical studies does not support this hypothesis. A longi-
tudinal observational study assessed key features of renal
function (such as hypertension, GFR, and proteinuria)
in the Pittsburgh cohort of 675 patients with dcSSC who
were evaluated and followed between 1972 and 1993
(REF.4); 145 patients who had developed SRC (19.5%)
were excluded, as they had been reported previously.35
This study found no evidence to support the hypothesis
that pre-existing hypertension or renal function abnor-
malities could predict SRC4. At enrolment, 79 (12%)
patients with dcSSc had isolated hypertension, and 173
(26%) patients had abnormal renal function (azotemia)

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or proteinuria, of whom ~75% had dpenicillamine-
induced proteinuria or other comorbidities. Over
10years of followup, none of the patients with protein-
uria or azotemia developed renal failure that required
dialysis, providing evidence that renal vasculopathy perse
is unlikely to be sufficient to trigger SRC40.
In 2012, the Canadian Scleroderma Research group
reported a longitudinal study of renal function in a large,
multicentre cohort of patients with SSc (n=561) who
were followed from 2004 to 20097. Assessment of renal
function based on estimated creatinine clearance indi-
cated that 112 patients (20%) had abnormal renal func-
tion with no history of SRC at baseline. These patients
had an annual decline in estimated creatinine clearance
that was similar to that of the patients with normal
baseline renal function (0.89% per year, 95%CI 2.02
0.26%), and comparable to the annual decline observed
in the general population41. Only 29 patients (5%) in this
cohort had a history of SRC; these patients also showed
a similar rate of decline in estimated creatinine clear-
ance, but had a lower baseline level of renal function7.
These observations in Canadian patients are comparable
to those made in patients with SRC in the Pittsburgh
cohort who required no dialysis or temporary dialysis35.
These studies, conducted more than 20years apart, pro-
vide evidence that renal vasculopathy in SSc does not, in
and of itself, lead to the development of SRC.
Clinical presentation and definition
Review of the available case series that describe the
key features of SRC (TABLE1) suggests that this disease
should be diagnosed when a patient presents with new
onset, moderate-tosevere hypertension, and/or an acute
increase in serum creatinine33,42. ~50% of patients also
present with MAHA9,27. Controversy persists regarding
a consensus definition of SRC, especially in relation to
acute increases in serum creatinine levels in the absence
of elevated blood pressure, socalled normotensive renal
crisis, which occurs in ~10% of patients27. Renal biopsy is
indicated when the cause of renal failure is unclear and
can be useful to assess prognosis43.
Pathobiology
Vasculopathy with endothelial cell activation and
decreased renal perfusion is thought to contribute to the
development of SRC, but the precise triggers and patho-
genesis of SRC remain to be elucidated (FIG.1). Endothelial
cell injury associated with intimal thickening and fibrotic
onion-skinning of the interlobular and arcuate renal
arteries are dominant histopathological features of SRC42,43
(FIG.2). The juxtaglomerular apparatus can be prominent in
patients with SRC, which might indicate the involvement
of plasma renin levels in the pathogenesis of SRC43. Renin
levels are not always elevated in SRC, however, and are
not associated with SRC severity6; therefore, novel factors
that are associated with SRC have been investigated10,44,45.
For example, endothelin (ET)-1 might have a role in the
development of SRC as affected patients have elevated lev-
els of plasma ET1 and a unique pattern of expression of
endothelin A receptor (ETA) and endothelin B receptor
(ETB) in the renal tissue45,46 (FIG.3).
The consistent observation of MAHA in ~50% of
patients with SRC provides additional evidence for a
role of endothelial cell injury in SRC pathogenesis34.
Furthermore, the absence of inflammatory infiltrates in
renal biopsy specimens and the presence of arteriolar
mucinous intimal thickening, fibrinoid necrosis, and
intimal cell proliferation, suggest that vascular damage
with ischaemia dominates over immune-system activa-
tion43,45. N
evertheless, autoimmunity might be a trigger
for endothelial activation. As discussed in more detail
below, the strong association between anti-RNA poly-
merase (RNAP) III antibodies and SRC highlights a role
for autoimmunity in the complex pathobiology of SRC47.
Further studies to characterize the role of autoantibodies
in SRC pathogenesis are warranted.
Predictive factors
Various factors have been shown to be predictive of SRC
(BOX1). Diffuse skin involvement, especially with rapid
progression, is a primary risk factor for SRC and >80%
of patients who develop SRC have dcSSc14. Data from
the 1980s identified new onset anaemia, cardiac events
(including pericarditis and congestive heart failure), and
rapid skin thickening as the predominant indicators for
the development of SRC in a cohort of 60 patients11.
Although the renal pathology of established SRC does
not include inflammatory infiltrates, systemic inflamma-
tory features, including arthralgias, synovitis, and tendon
friction rubs, have been suggested as additional predictive
factors for SRC34,48. An association between arthralgias
and SRC was reported with an adjusted odds ratio of 4.2
(95%CI 1.2713.85) in a cohort of 91 patients with SRC
and 427 control individuals34. In an inception cohort of
287 patients with dcSSc and tendon friction rubs (median
follow-up of 10.4years) and 287 patients with dcSSc alone
(median follow-up of 7.9years), palpable tendon friction
rubs correlated with a 34-fold increased risk of SRC48. In
addition, in a retrospective analysis of the cohort enrolled
in a dpenicillamine trial in SSc, large joint contractures
were associated with SRC in ~13% of the patients8.
Evaluation of SSc-specific autoantibodies might help
to identify patients at increased risk of SRC. Although
~60% of patients with SRC have anti-topoisomerase anti-
bodies14, the presence of these antibodies is not specific to
SRC. By contrast, SSc-specific anti-RNAP III antibodies
are independently associated with SRC development49,50.
In the International SRC survey, an observational cohort
recruited largely from Canada, the USA and Europe, anti-
RNAP III antibodies were detected in the serum of ~20%
of patients with SRC9. In a large Australian cohort of 461
patients, 151 of whom were recruited within 5years of
diagnosis, 69 patients were positive for anti-RNAP III
antibodies; these autoantibodies were independently
associated with SRC with an odds ratio of 3.8 (95%CI,
2.913.8, P=0.02), a positive predictive value of 25% and
a negative predictive value of 98%49.
A 2014 systematic literature review and meta-analysis,
which was conducted to enable comparison with a French
cohort of 133 patients, highlighted the wide variability of
anti-RNAP III positivity among patients with SRC47. The
prevalence of anti-RNAP III antibodies was 69% in the

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Table 1 | Overview of studies reporting scleroderma renal crisis outcomes, prognosis and risk factors
Study Definition of SRC Number of Number of Number of Number of Number of Risk factors, other
(duration, patients/ patients patients on transplanted deaths (%) outcomes and/or
design) controls treated dialysis/ patients (%) interventions
with ACE off dialysis
inhibitors at study
before SRC/ completion
at diagnosis (%)
Hudson etal.9 Increase in BP, 87/NA 16/ 87 39 (52%)/20 NA Patients with SSc: Death more likely
(20102013, serum creatinine (27%) 27 (36%) at 1year in patients who
international levels above followup received ACE
prospective, baseline and/ inhibitors at SRC
multi-centre or abnormal onset; HR2.42
observational urinalysis, and/or (95%CI 1.025.75)
study) thrombocytopaenia,
and/or haemolysis
Hesselstrand Renal insufficiency, 16 patients Patients Patients Patients Patients with SRC predicted
etal.100 accelerated with SSc and with SSc with SSc with SSc SSc and SRC: 7 by presence of
(19822010, increase in BP SRC/112 and SRC: and SRC: and SRC: 4 (42%) at 5year anti-RNAP III
Swedish matched 1/ 16 13 (81%)/ (25%) followup and 10 antibodies (HR8.90,
single-centre controls with Patients 3(23%) Patients (60%) at 10year 95%CI 2.6829.6)
study) SSc but no SRC with SSc Patients with SSc followup Prior ACE inhibitor
and no SRC: with SSc and no Patients with SSc and glucocorticoid
12/112 and no SRC: SRC: 0 and no SRC: 101 treatment are not
0/0 (90%) at 5year risk factors for SRC
followup and 85
(76%) at 10year
followup
Penn etal.14 New-onset increase 110 patients 20/108 70 (63%)/24 3(3%) Patients: 44 (41%) SRC predicted by a
(19902005, in BP >150/85 with SRC and (23%) at 5year followup positive ANA test and
UK mmHg and 30% 1997patients and 58 (53%) at a speckled pattern in
single-centre decrease in GFR with SSc 10year followup the nucleus (OR 10.9,
retrospective (2%with lcSSc, 95% CI 7.316.5)
case series) 12% with
dcSSc)/ NA
DeMarco Twofold increase in 18 patients with 2/18 NA/NA NA Patients: 9 (50%) Dose-related
etal.8 serum creatinine SRC (13% of the at 41.1 year prednisone, Rodnan
(19911997, levels and/or 134 patients followup skin score 20,
clinical trial malignant increase with dcSSc and large joint
in 17 US in BPMAHA or enrolled in the contractures are
centres) abnormal urinalysis Dpenicillamine predictors of SRC
clinical trial)
Teixeira Rapidly progressive 50 patients with 10/50 28 (56%)/8 NA Patients: 9 (18%) SRC associated
etal.13 oliguric renal failure SRC (86% with (29%) during dialysis with glucocorticoid
(19792003, and/or accelerated dcSSc, 612% period, 11 (22%) at treatment 1month
survey of hypertension; normotensive)/ 1year followup (OR 17.4, 95%CI
retrospective normotensive SRC: NA and16 (31%) at 2.1144.0) and
case series serum creatinine 5year followup 3months prior to
in 63 French 20% above SRC onset (OR 24.1,
centres) baseline levels with 95%CI 3.0193.8)
abnormal urinalysis
and/or MAHA
Guillevin Rapidly progressive 91 patients Patients 49 (53.8%)/ NA Patients: 26 SRC associated
etal.34 renal insufficiency with SRC (22% with SSc 13 (22.4% (29.1%) at 1year with glucocorticoid
(extension without explanation normotensive) and SRC: of those followup, 36 treatment in 64
of Teixeira /427 patients 23/83 dialyzed) (40%) at 5year (70.3%) patients;
etal.13, French with SSc but no Patients followup and no SRC reported
referral SRC with SSc 53 (58.1%) in 156 (36.5%)
centre and no SRC: at 10year control individuals
database, 82 followup who had received
retrospective Controls: glucocorticoids
case series) ~20% at 5year Arthralgias, cardiac
followup involvement and
myopathy predict
SRC
No normotensive
patients with SRC
recovered from
dialysis, eight
patients died

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Table 1 (cont.) | Overview of studies reporting scleroderma renal crisis outcomes, prognosis and risk factors
Study Definition of SRC Number of Number of Number of Number of Number of Risk factors, other
(duration, patients/ patients patients on transplanted deaths (%) outcomes and/or
design) controls treated dialysis/ patients (%) interventions
with ACE off dialysis
inhibitors at study
before SRC/ completion
at diagnosis (%)
Cozzi etal.63 Rapidly progressive 20 (3.3% of the 0/20 11 (55%)/ 7 2 (10%) Patients: 6 10 patients with
(19802006, renal failure without cohort) patients (64% of those (30%) at 1year MAHA who did not
Italian other explanation with SRC/586 dialyzed) followup and 10 respond to ACE
single-centre and/or malignant patients with (50%) at 5year inhibitors received
retrospective hypertension SSc and without followup plasmapheresis,
case series) (systolic SRC Data not seven of these
BP160mmHg reported for patients avoided
or diastolic patients with SSc dialysis
BP110mmHg) without SRC The prognosis of
with or without SRC is improved
MAHA with plasma
exchange in
patients with MAHA
in the short term
Walker etal.37 Hypertension, renal 16 patients with 2/13 16(100%)/ 2 (13%) Patients with Not reported
(19832000, failure SRC (2.8% of 4(25%) SRC: 5 (31%)
South the cohort)/523 due to SRC; 3 for
Australia patients with other reasons
scleroderma SSc without SRC Deaths not
registry, reported for the
retrospective rest of cohort
case series)
Steen etal.35 New onset 145 patients All patients 90 (62%)/ 6 (4%) Patients: 28 39% of the patients
(19791996) hypertension with SRC /662 with SRC 34 (23%) (19% at 1year experienced
(Followup (diastolic BP patients with treated with followup) poor outcomes
initial 110mmHg) with SSc and without ACE inhibitor Controls: NA (permanent dialysis
report36, renal failure, and/or SRC at diagnosis or early death)
single US MAHA Among patients
centre, with good
retrospective outcomes (no
case series) requirement for
dialysis or recovery
of renal function
within 6months),
survival was
comparable to that
of patients with
dcSSc and no SRC
Simeon Hypertension, renal Eight patients ACE inhibitor Not reported NA Seven patients SRC is an
etal.44 failure with SRC treatment (87.5%) at 10year independent
(19761996, not explicitly followup (five of predictor of death in
71 patients with
Spanish reported 22 patients with patients diagnosed
SSc, without
single-centre dcSSc, and two of after the age of 60
SRC
retrospective 57 patients with
study) lcSSc)
ACE, angiotensin-converting-enzyme; ANA, antinuclear antibody; BP, blood pressure; dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic
sclerosis; MAHA, microangiopathic haemolytic anaemia; RNAP, RNA polymerase; SRC, scleroderma renal crisis; SSc, systemic sclerosis. *Data for only 1year followup
in 75 patients, and 5 normotensive patients with no incidence data. Data not available owing to treatment in community medical centres. 13 patients never dialysed.

French cohort and 041% across the 30 studies included
in the meta-analysis, which enrolled a total of 8,437
patients with SSc. Geographic factors, such as the conti-
nent or country of origin of the patients, were markedly
associated with the prevalence of anti-RNAPIII anti
bodies, suggesting that genetic background and environ-
mental factors contribute to the generation of anti-RNAP
III antibodies and, consequently, to the development of
SRC47. Another study reported that patients with SRC
who were positive for anti-RNAP III antibodies were
more likely to carry genetic polymorphisms in the gene
encoding ETA than those who were negative for these
antibodies51. Given previous observations of increased
ET1 receptor expression in renal biopsy tissue obtained
from patients with SRC, these data suggest the possibility
of an ETAanti-RNAP III axis that might contribute to
SRC susceptibility45,46.
Potentially modifiable risk factors
Glucocorticoid therapy is commonly used for a short-
term treatment of the inflammatory features of SSc
(4460% of patients)9,13,14 and is a risk factor for SRC.

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Endothelial cell activation Genetic inuence

Chemokines ER polymorphisms
Vascular damage

Proliferation: Endothelin-1
TGF- External
VEGF Prostacyclin Anti-RNAP III
factors (GCs)
Renal blood ow

Renin-angiotensin

Scleroderma renal crisis Macrophage

PDGF inltration
CTGF (brin)
Immune activation
Fibroblast activation (RNAP III, Th2, Th17,
or myobroblasts IL-6, IL-17a etc.)

Mechanical Mechanical
stress stress
Fibroblast Cytokines Proliferative and
(e.g. TGF-) obliterative vasculopathy
Activated
Proto- lymphocyte
Fibrosis
myobroblast
Myobroblast

Figure 1 | Currently recognized factors that influence the development of scleroderma renal crisis.
Acombination of genetic (endothelin receptor (ER) polymorphisms), autoimmune (anti-RNA polymerase III antibodies
Nature Reviews | Nephrology
(anti-RNAP III), immune cell activation and macrophage infiltration), external (glucocorticoid (GC) therapy) and/or
cellular factors (altered cell proliferation, fibrosis, vascular damage and endothelial cell activation) can trigger
scleroderma renal crisis (SRC), a rare renal complication of systemic sclerosis. Rapid treatment with angiotensin-
converting-enzyme inhibitors can limit the progression of SRC to renal failure, indicating an involvement of the renin
angiotensin system in the pathogenesis of SRC. Elevated levels of circulating endothelin1 and high expression of its
receptors in SRC renal biopsy samples suggest that endothelin1 is a key driver of SRC-associated renal failure.
Despite a dose-dependent increased likelihood of SRC in patients treated with GCs, potentially owing to the effect of
these agents on the inflammatory features of SSc, such as synovitis, arthralgias and tendon friction rubs, their role is
unclear. CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth
factor; TH2, type 2 Thelper cell TH17, type 17 Thelper cell; VEGF, vascular endothelial growth factor.
Microphotography reproduced with permission from Hindawi Publishing Corporation Batal, I. etal. Int. J. Rheumatol.
2010, 543704 (2010).

Ahigh dose of glucocorticoids (>30mg per day) was
first associated with normotensive SRC52. A subse-
quent, retrospective analysis of a cohort of 110 patients
with SSc who developed SRC showed that those who
received a moderate dose of corticosteroids (15mg
per day of prednisone or equivalent) were signifi-
cantly more likely to develop SRC within 6months
after treatment than were patients (matched for age,
gender, race, SSc duration, and tendon friction rubs)
who were newly prescribed low-dose steroids or had
continuously received steroids (regardless of the type
and dose), NSAIDs, calcium channel blockers, or an
ACE inhibitor11,53. A later study conducted in the con-
text of a dpenicillamine clinical trial reported that risk
of SRC increased with prednisone doses >7.5mg per
day8. In another study, 44% of patients diagnosed with
SRC were receiving glucocorticoids, although no clear
association between the treatment and the disease was
reported9. Finally, a review of 44 studies and 93 case
reports found that medium-tohigh doses of glucocor-
ticoids (prednisone 15mg per day, for example) were
associated with an increased risk of SRC54. This risk
was increased when glucocorticoids were used in con-
junction with nephrotoxic drugs, such as calcineurin
inhibitors or anti-thymocyte globulin. Two studies with
different methods reported that prednisone treatment
was associated with respective increases in SCR risk of
1.5% and 4% per mg per day before the onset of SRC9,54.
Differential diagnosis
The diagnosis of acute renal failure as a complication
of SSc is not always obvious. In most reports, 1020% of
patients ultimately diagnosed with SRC were normo-
tensive42. In addition, SRC can be the first manifesta-
tion of SSc10. Thrombotic thrombocytopaenic pur-
pura (TTP)55, anti-neutrophil cytoplasmic antibody
(ANCA)-associated glomerulonephritis and crescentic
rapidly progressive glomerulonephritis (RPGN), which
are uncommon presentations of acute renal failure in
SSc, can initially be confused with SRC. Differentiating
between these different conditions (TABLE2) is crucial to
enable effective management and prognostication5661.

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a b c

Glomerular Thrombotic Hypertensive vascular Initial myoid Advential

ischaemic collapse vacular occlusion damage "onion skinning" accumulation brosis

Figure 2 | Pathology of scleroderma renal crisis. The hallmark of scleroderma renal crisis is a proliferative, obliterative
Nature Reviews | Nephrology
arteriolar vasculopathy with (a) hypertensive vascular damage, thrombotic vascular occlusion, glomerular ischaemic
collapse, and diffuse tubular degeneration (b), onion skinning, and (c)intimal myoid accumulation and adventitial fibrosis.
Parts a and c reproduced with permission from Hindawi Publishing Corporation Batal, I. etal. Int. J. of Rheumatol. 2010,
543704 (2010). Part b reproduced with permission from Hindawi Publishing Corporation Shanmugam, V. K. and
Steen,V.D. Int. J. of Rheumatol., 2010, 538589 (2010).

Thrombotic thrombocytopaenic purpura. SRC can
sometimes be misdiagnosed as TTP owing to the fre-
quent presentation of SRC with MAHA34,42,55,62,63. As
plasmapheresis is indicated for TTP treatment but not
for SRC treatment, distinguishing between these two
conditions is important. Although low ADAMTS 13
levels, due to either autoantibodies or a hereditary defi-
ciency, can support a diagnosis of TTP64, renal biopsy
might be needed to confirm this diagnosis.
ANCA-associated vasculitis with crescentic glomerulo
nephritis. In the past few decades, clinicians have rec-
ognized pauci-immune ANCA-associated vasculitis
(AAV)58,61,65 with RPGN60 as another potential cause
of acute renal failure in SSc. AAV with RPGN is more
likely to be seen late in the disease course in patients
with lcSSc, and in patients with autoimmune overlap
syndromes, or rarely, with mixed cryoglobulinaemia,
than in other patients with SSc59,66. Among the small
number of patients with SSc that have AAV (less than
1%), ~7783% present with acute renal insufficiency,
normal or mildly elevated blood pressure, and active
urine sediment with proteinuria (only ~10% nephrotic
range) without evidence of MAHA56,57,60.
Myeloperoxidase (MPO)-ANCA antibodies together
with renal histopathology showing focal segmental
necrotizing lesions with crescent formation and inflam-
matory infiltrates, scarce deposits of immunoglobulins,
and blood vessels without intimal hyperplasia of fibri-
noid necrosis are diagnostic for AAV with RPGN59,60.
Numerous factors (accumulated from the ~60 cases
reported in the English-language literature) must be
considered for differential diagnosis10,56,57,5961 (TABLE2).
A renal biopsy is required if the diagnosis is unclear.
The presence of ANCA antibodies is not necessarily
indicative of RPGN in asymptomatic patients. In patients
with SSc, the prevalence of ANCA antibodies ranges from
011.7%, according to a 2013 analysis that included nine
reports from tertiary French centres published between
1990 and 2002 and 42 published cases of SSc patients
with AAV61. In these reports, the prevalence of vasculitis
was 14100% among patients with SSC and perinuclear
ANCA and/or anti-MPO antibodies, and <1% in the
French patients with SSc61. Nearly 77% of the patients
with AAV and SSc had renal involvement61.
A 2013 study examined a database of 2,200 patients
with SSc in England to define the clinical, serologic and
immunogenetic features of SSc with AAV. Overlap of SSc
and vasculitis was reported in only 35 patients (1.6%);
only 10 of these patients were ANCA-positive and the
majority (7 patients) had lcSSc with glomerulonephritis
and/or renal arteritis with pulmonary fibrosis59. The find-
ings of an immunogenetic analysis of six patients with SSc
and AAV, among whom only one patient had RPGN, were
consistent with possible shared HLA haplotypes between
SSc and AAV, such as HLADPB1 02:01 or 09:01, which
need to be examined in other similar cohorts59.
Intravenous or oral administration of cyclophospha-
mide and rituximab induce and maintain remission in
most patients with AAV-RPGN6772. In a double-blind,
randomized controlled trial, patients with AAV treated
with a high dose of glucocorticoids for the first 6months
(6080mg per day of prednisone equivalent tapered
over 5.5months as long as remission was maintained)
were administered either rituxamab (once-weekly for
4weeks) or cyclophosphamide (36months) and con-
tinuous azathioprine treatment68. Patients were evalu-
ated for remission at 6months and for sustained remis-
sion. Approximately half of the patients in each group
had major renal disease (defined as biopsy-proven
RPGN and/or a >30% increase in baseline serum creati-
nine levels). 75% of the patients in each group achieved
complete remission with comparable improvements in
renal function68. By contrast, in a separate study, 64% of
21 patients with SSc and AAV-RPGN developed end-
stage renal disease (ESRD) during that follow-up period
despite adhering to aggressive treatment regimens such
as high-dose glucocorticoids and cyclophosphamide;

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36% of the patients died60. The reasons for these differ-
ing outcomes are not obvious, although comorbidities
might have a role.
Treatment of SRC
ACE inhibitors. Since the publication of landmark stud-
ies from Laragh73, Clements74, and Steen36,75, ACE inhibi-
tors have been recognized as effective first-line therapeu-
tics when administered at the onset of SRC. The use of
ACE inhibitors to treat SRC has substantially improved
outcomes from ~85% mortality at 6months without ACE
inhibitors to 2535% with ACE inhibitors36,75. However,
some studies have suggested that using an ACE inhibitor
for any reason before the onset of SRC is associated with a
worse prognosis, especially in normotensive patients13,14;
the reason for this observation is unclear. A2014 inter-
national, multicentre prospective cohort study that
recruited patients with new onset SRC attempted to
resolve this controversy9. 1year data was available for 75
of the 87 patients with SRC, of whom 27 (36%) died, and
19 (25%) required dialysis. In 16 (21%) of the patients,
exposure to an ACE inhibitor before disease onset was
associated with an increased risk of death with a hazard
ratio of 2.42 (95%CI 1.025.75, P<0.05) after adjustment
for glucocorticoid exposure, and a hazard ratio of 2.17
(95%CI 0.885.33, P=0.09) after post hoc adjustment for
pre-existing hypertension9. The mortality of patients with
and without prior ACE inhibitor exposure was 50% (8 of
16) and 32% (19 of 59), respectively.
A French casecontrolled study that included 91
patients with SSc and SRC and 427 patients with SSc
only, reported a 25% incidence of death in patients who
received ACE inhibitor treatment before SRC onset,
and a 19% incidence of death in patients who did not
receive this therapy before SRC onset34. Alternative anti-
hypertensive treatment options, such as calcium channel
blockers, seem to be preferable to ACE inhibitors to treat
essential hypertension in patients with SSc, especially in
those with early-stage dcSSc76.
We consider impending SRC to be a medical emer-
gency, and patients at high risk of SRC (BOX2) should
be taught to monitor their blood pressure regularly and
to report elevations >140/90 mmHg. Our approach
is to normalize blood pressure within 72h with captopril
treatment (an ACE inhibitor with a short half-life, which
facilitates rapid titration) even if creatinine clearance
temporarily decreases, which is a common phenomenon.
We then aim to stabilize the patient on enalopril a
longer half-life ACE inhibitor to avoid the adverse
effects that can occur with captopril use, such as rashes
and cytopenias. The use of ACE inhibitors in patients
with SRC was first described in two patients treated with
captopril in 1979 (REF.73), and in four patients in 1981
(REF.74). ACE inhibitors are the first-line therapy for nor-
malizing blood pressure; if maximum doses (including
doses higher than label guidance) are not sufficient, we
add a dihydropyridine calcium channel blocker, such as
amlodipine, and/or a diuretic, depending on the patients
fluid status77.
Given the rarity of SRC, only observational stud-
ies on the use of ACE inhibitors have been reported
(TABLE1). The first study, conducted in 1990, showed
markedly improved survival in patients with SRC as a
result of rapid reduction of blood pressure with capto-
pril, combined with other antihypertensive agents such
as calcium channel blockers and angiotensin receptor
blockers (ARBs) that are required to ensure normali-
zation of blood pressure36,77. Of note, a study of 25,620

a Control b Control c SRC d SRC

ET-1

e Control f Control g SRC h SRC

ET-A

i Control j Control k SRC l SRC

ET-B

Figure 3 | Renal expression of endothelin ligand and receptors in scleroderma renal crisis. Immunostainings
Nature show
Reviews | Nephrology
higher levels of endothelin1 (ET1) and their receptors endothelin receptor A (ETA) and endothelin receptor B (ETB) in
glomeruli (c,g) and tubular structures (k,g) of patients with scleroderma renal crisis (SRC) than in equivalent structures in
healthy individuals (j, glomeruli (a,f) and tubular structures (b,e,i)). ET-1, ET-A and ET-B are also expressed in SRC
proliferative lesions (d,g,h,l). Figure reproduced with permission from Oxford University Press Penn, H. etal. Q.J.Med.,
106, 839848 (2013).

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Box 1 | Mitigating the risks of scleroderma renal crisis
Monitor blood pressure and serum creatinine levels and periodically perform urinalysis
in patients with the following features:
Early, diffuse cutaneous disease11,14,37,39
Rapid progression of skin thickening; modified Rodnan skin score >208
Serum anti-RNA polymerase III antibodies14,34,49,100
Tendon friction rubs48
Large joint contractures8
Arthralgias/synovitis12,13,34
Glucocorticoid use8,13,34,53,54
Use lowest dose of glucocorticoids for the minimum duration to treat patients with
inflammatory symptoms8,54,76
Treat patients with essential hypertension with non-angiotensin-converting-enzyme
inhibitor regimens that include a calcium channel blocker whenever possible76
Use calcium channel blockers for patients with peripheral vasculopathy76
patients with atherosclerotic vascular disease or diabe-
tes mellitus conducted from 2001 to 2007 showed that
combining an ACE inhibitor with an ARB leads to fur-
ther loss of renal function, hyperkalaemia, and sympto-
matic hypotension78. The eGFR declined on average by
2.82ml/min/1.73m2 in patients who received ramipril
(ACE inhibitor), by 4.12ml/min/1.73m2 in those who
received telmisartan (ARB), and by 6.11ml/min/1.73m2
in those on combination therapy78. Some clinicians
have extrapolated these results to the treatment of SRC,
and discourage the use of ARBs in combination with
ACEinhibitors.
Third-line agents to treat SCR can include diuretics for
fluid overload, and/or centrally acting agents such as clo-
nidine. Although blockers can increase the likelihood
of hypotension when used in combination with an ACE
inhibitor, experts recently surveyed by the Canadian Scle-
roderma Research Group recommended these agents as
third-line treatments77,79. blockers should be avoided
as these might exacerbate Raynaud phenomenon80.
Endothelin1 receptor antagonists. ET1 receptor antag-
onists (ERAs) are used to treat patients with SSc, PAH
and digital ulcers. Although ERAs are less efficacious in
SSc-associated PAH than in other forms of PAH81, the
clinical success of blocking ET1 receptors to limit
the impact of pulmonary vasculopathy and enable heal-
ing of digital ulcers in patients with SSc suggests that
ERAs might also be beneficial in SRC45,46.
In 2011, a French study reported overexpression of
ET1 in microangiopathic lesions in the glomeruli, arte-
rioles, and interlobular arteries in renal biopsy samples
obtained from 14 patients with SRC compared to biopsy
specimens from control individuals (healthy individ-
uals and patients with diabetic nephropathy, haemo-
lytic uraemic syndrome or other diseases)45. 12 of those
patients received glucocorticoids before the diagnosis
of SRC; therefore, the researchers hypothesized that
glucocorticoids might regulate the expression of the
human ET1 gene45. This speculation seems worthy of
furtherinvestigation.
A 2013 report described marked elevations of serum
ET1 levels in patients with SRC. Median serum levels
were 1.48pg/ml in 27 patients with SRC, compared to
0.5pg/ml in 20 healthy individuals, and 0.54pg/ml in
27 patients with SSc without SRC46. Immunostaining of
renal biopsy specimens showed increased expression
of ET1, ETA and ETB receptors in the glomeruli,
interstitium, and vascular lesions of patients with SRC
compared to control samples46 (FIG.3).
A case series of six patients with SRC treated con-
comitantly with an ACE inhibitor and the dual ERA
bosetan (62.5mg twice per day for the first month fol-
lowed by 25mg twice per day for 5months) demon-
strated acceptable safety of this treatment regimen46.
Three patients developed hypertension when bosetan
was withdrawn, but no notable differences in mortality
were reported among the six patients included in the
study in comparison to historical data from the centre.
A single case report found long-term improvement
in kidney function in a patient with SRC after admin-
istration of bosetan and ramipril. Specifically, blood
pressure was maintained, proteinuria disappeared after
3months of treatment, and eGFR improved from 10ml/
min/1.73m2 to 33ml/min/1.73m2 during 5years of
followup82. No safety issues that would preclude further
studies were reported. A single arm interventional study
to investigate the effects of bosentan on renal function in
patients with SRC is now underway83.
Additional research is needed to develop treatments
that go beyond the control of hypertension with ACE
inhibitors or ARBs to prevent or slow CKD. The addition
of an ERA to the ACE inhibitor and/or ARB treatment
is being evaluated in phaseIII studies, as ERAs might
improve renal injury and inflammation as well as control
of hypertension84. Preclinical and clinical studies show
that ET1 is a major contributor to progression to ESRD,
largely through activation of ETA, despite the use of an
ACE inhibitors and ARBs84. Renal cell injury, inflamma-
tion and fibrosis continue in patients with hypertension
and diabetes treated with ACE inhibitors or ARBs, as
manifested by persistent proteinuria as well as decline
in renal function (albeit at a slower rate than without
such treatment)85,86.
In animal models of chronic renal failure, ERAs have
been shown to ameliorate, or even reverse renal injury
and/or fibrosis84. Thus far, reductions in proteinuria
have been consistently seen with the use of ERAs in 11
phaseII and III studies completed (nine) or ongoing
(two) in patients with diabetic or non-diabetic CKD84;
longer-term studies are underway to determine whether
ERA treatment might also delay progression to ESRD84,87.
ET-A-specific ERAs are generally better tolerated than
nonspecific ERAs84. Given the need for improved out-
comes in SRC, and the apparent safety of using ACE
inhibitors with bosentan, further investigation is war-
ranted to determine whether such combination therapy
can improve patient outcomes46.
Prognosis and outcomes
Dialysis. Treatment of SRC with ACE inhibitors greatly
improves prognosis in the majority of patients88. A 1990
study reported mortality rates of 15% after 1year of treat-
ment with an ACE inhibitor in patients with SRC com-
pared to 76% without ACE inhibitor treatment36. Among

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Table 2 | Differential diagnosis of acute renal failure in scleroderma

Characteristics SRC AAVRPGN
Demographics
Onset More likely in rapidly progressive dcSSc during first More likely in lcSSc after 5years of disease
5years
Gender and age Predominately occurs in women in their fifth and Predominately occurs in women, especially
group sixth decades of life in fifth and sixth decades of life
Clinical features
Hypertension Malignant; <10% of the patients are normotensive Absent to mildly elevated
Urinary sediment Urinary protein <1g Red blood cell casts, proteinuria (~10% of
patients are nephritic)
Autoantibodies Anti-RNA polymerase III antibodies Myeloperoxidase anti-neutrophil
cytoplasmic antibodies
Renal biopsy Proliferative obliterative vasculopathy with Focal segmental necrotizing lesions,
crescentic onion skin narrowing of arterioles with crescent formation, inflammatory infiltrate,
glomerular ischaemia scarce deposits of immunoglobulins
Management
Treatment Aggressive blood pressure control with ACE Cyclophosphamide, corticosteroids
inhibitor and other medications as needed; dialysis (consider rituximab)
as required; renal transplantation if no return of
renal function in first year
AAVRPGN, anti-neutrophil cytoplasmic antibody-associated vasculitis with rapidly progressive glomerulonephritis; ACE,
angiotensin converting enzyme; dcSSC, diffuse cutaneous systemic sclerosis; lcSSC, limited cutaneous systemic sclerosis;
SRC, scleroderma renal crisis.

outcomes compiled from 10 cohort studies in the past
15years (TABLE1), a study that included 145 patients with
SRC treated with an ACE inhibitor found that 89 patients
(61%) experienced good outcomes, with 55 (38%) not
requiring dialysis and 34 (23%) requiring temporary dial-
ysis; 56 (38%) patients experienced poor outcomes, with
28 (19%) surviving on dialysis and 28 (19%) dying within
the first 6months35.
Levels of Nterminal pro-btype natriuretic peptide
(NTproBNP) might be a useful predictor of dialysis in
patients with SRC, and could be a non-invasive way of
assessing prognosis. Patients with SRC who require per-
manent, temporary, or no dialysis exhibited NTproBNP
concentrations of 3373pg/ml, 1729pg/ml, and 119pg/ml,
respectively89. The importance of renal clearance of this bio-
marker was not reported and well-controlled p rospective
studies are needed to c orroborate these findings.
The mortality rate in SRC is greatly influenced by
dialysis status. Patients who require permanent dialysis
often experience worse outcomes than those on tempo-
rary dialysis14. In the prospective cohort of the Interna-
tional Scleroderma Renal Crisis survey, which included
75 patients with SRC, 36% died in the first year whereas
25% remained on dialysis a year after SRC onset9. Sur-
vival was inversely associated with age and disease dura-
tion, and decreased from 7082% at 1year to 5059%
after 5years9,14.
Renal transplantation. In patients with SRC-related
ESRD, renal replacement therapy (including haemo
dialysis or peritoneal dialysis) and kidney transplantation
are potential therapeutic options. Similar to patients with
other causes of ESRD, kidney transplantation in patients
with SRC-associated ESRD confers a survival advantage
over dialysis90. Proceeding with renal transplantation
should not be undertaken without critically evaluating the
renal and clinical status of the patient, in terms of consist-
ent blood pressure control, signs of renal function recov-
ery, and comorbidities. A renal biopsy might be useful to
determine whether recovery of renal function is possible14.
In addition, assessment of renin and ET1 levels might
be useful to assess whether SRC disease processes remain
active; whether this is the case remains to be determined.
Two large case series, each consisting of >100 patients
with SRC requiring dialysis, found that recovery of renal
function occurred in 4050% of patients at a mean of
8months in one study (range 318months), and a median
of 11months in the second study (range 134months)14,35.
Conversely, the Australian and NewZealand dialysis
and transplant registry study reported that only 10% of
patients (13 of 127) recovered sufficient renal function
to discontinue dialysis, and recovery occurred in the
first 1218months (mean 14.1months) following dialy
sis initiation. This seemingly low recovery rate might be
due to the exclusion of patients with early renal func-
tional recovery (<3months after dialysis initiation) from
theanalysis91.
Delaying transplantation until 1824months after
dialysis initiation might be prudent if sufficient evidence
suggests an improvement in renal function; this deci-
sion will vary on a casebycase basis. Patients without
any evidence of an improvement in renal function
over a 12month period might be considered for renal
transplantation to improve their quality of life90.
Recurrence. Registry studies have reported a much lower
rate of SRC recurrence (1.92.1%) than that documented
in case reports (2050%)9092. Data obtained from 260

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Box 2 | Diagnosis and pre-emptive treatment of scleroderma renal crisis
Diagnosis
Acute increase in blood pressure during self monitoring
Acute increase in serum creatinine levels7,14
New anaemia11,53
New cardiac events: pericarditis, or pericardial effusion in congestive heart failure11,34
Treatment
Administration of angiotensin-converting-enzyme inhibitors as rapidly as possible to
control blood pressure to <130/90 mmHg
Timely addition of calcium channel blockers and other medications (except
blockers) as needed
Monitoring of blood pressure several times per day
Monitoring of serum creatinine levels daily
Admission to intensive care if inadequate blood pressure, and/or increasing
symptoms such as headache, oliguria, increasing serum creatinine, chest pain,
dyspnoea, or central nervous system symptoms
transplantation procedures performed between 1987
and 2004 in patients with SRC documented in the United
Network for Organ Sharing database showed that only
1.9% of patients (5 of 260) experienced graft loss due
to SRC recurrence, with graft loss occurring between
70 and 805days after SRC recurrence90. The Australian
and NewZealand registry study reported data on 24
renal allografts transplanted in patients with SRC; all six
living-donor kidney grafts (four allografts followed for at
least 10years) and 28% of the deceased donor grafts were
still functioning at last follow up91.
Predictors and risk factors for recurrent SRC in the
kidney allograft have not been well studied, and might
be influenced by selection bias9092. Among the five well-
described transplant recipients with SRC reported in the
literature, signs of SSc disease activity preceded allograft
SRC, including skin tightening in four patients, anaemia
in two patients, and pleuropericarditis with pericardial
effusion in two patients92. The time from SRC to ESRD
in native kidneys was 2weeks in all five patients with
recurrent SRC in the allograft, despite antirejection
therapy. Nonetheless, rapid onset of ESRD does not
necessarily result in disease recurrence.
Given the sparsity of data regarding SRC recurrence,
making evidence-based recommendations on specific
antirejection drugs that might predispose to SRC recur-
rence is difficult. The low recurrence rates of SRC among
patients transplanted between 1985 and 2002 (2.1%)90
enable us to speculate that moderate doses of gluco
corticoids (1520mg per day) are not independent risk
factors for recurrent SRC.
Post-transplantation management. Experience with
regards to preventing allograft rejection and maximiz-
ing renal function after transplantation in patients with
SRC-associated ESRD is largely anecdotal, but is well
rationalized based on the mechanism of action of various
antirejection strategies. In vitro studies and experimen-
tal animal models have demonstrated that inhibition of
mTOR decreases collagen production from dermal fibro-
blasts, suggesting a potential beneficial role of mTOR
inhibitors in the treatment of fibrotic skin disorders93. In a
48week, single-blind, randomized phaseI/II pilot study
that evaluated sirolimus versus methotrexate in early
dcSSc, improvements in the modified Rodnan skin score
and disease activity scores were comparable between the
two treatment groups94. However, hypertension, oedema
and increased levels of creatinine were more common
with sirolimus. A single-arm, open-label, safety trial of
ciclosporin in ten patients with SSc versus historical pla-
cebo controls also showed improved skin scores; UCLA
skin score decreased by 35% at 48weeks in six of 10
patients treated with ciclosporin but remained stable in
control individuals. As expected, renal function declined
transiently in most patients (by as much as 21%), but
was manageable with dose reduction95. Thus, while evi-
dence-based recommendations are lacking, sirolimus or
mTOR-inhibitor-based immunosuppression might be a
preferred treatment option over calcineurin inhibition in
patients with SRC who undergo renal transplantation96.
Renal transplant recipients often receive an ACE inhib-
itor due to their well-recognized renoprotective effect97.
Recurrent SRC has been described in a renal transplant
recipient who was switched from captopril (an ACE inhib-
itor) to losartan (an ARB)98, but the evidence to recom-
mend or refute the use of ARBs to treat or prevent SRC
is insufficient. Non-dihydropyrimide calcium channel
blockers are also routinely prescribed to renal transplant
recipients to permit calcineurin inhibitor dose reduction97.
In summary, although experience with kidney trans-
plantation in patients with SRC-associated ESRD is lim-
ited, the available data suggest that over time, quality of
life is improved by successful transplantation in compar-
ison to the challenges associated with chronic dialysis.
Recurrence of SRC in the allograft is uncommon97. Risk
of recurrent SRC is unclear if corticosteroid-based anti-
rejection regimens combined with ACE inhibitor admin-
istration to control hypertension are followed. With cur-
rently available information, it seems sensible to manage
renal transplant recipients taking into account risk factors
associated with primary SRC, and to use glucocorticoids
as conservatively as possible.
Conclusions
No evidence exists that renal vasculopathy perse is a risk
factor for SRC. The incidence of SRC seems to be decreas-
ing, in part as a result of increasing attention to preventive
measures. Proactive management by close monitoring of
blood pressure in patients with early dcSSc and rapidly
progressing skin disease, especially in those with anti-
RNAP III antibodies, is a good example of such preven-
tive measures. In addition, the presence of active inflam-
mation characterized by tendon friction rubs and/or
arthritis should alert the patient and physician to an
increased risk of SRC. Taking into account this increased
risk should result in limiting glucocorticoid use to the
lowest dose and the shortest duration possible, despite
painful inflammatory symptoms, given strong evidence
of an association between near term use of glucocorti-
coids and the development of SRC. Numerous studies
have highlighted the need to improve 5year survival,
which has remained in the range of 5070% in most case
series (TABLE1). Currently, SRC treatment relies on early

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detection and aggressive blood pressure control with an
ACE inhibitor, combined with other antihypertensive
drugs and/or dialysis as indicated.
As noted above, early detection of SRC seems achieva-
ble by asking patients with risk factors to take blood pres-
sure readings at home at least three times a week. If blood
pressure increases above 140150/90mmHg, readings
should be repeated after 1h and if still elevated, a doctor
should be contacted. Serum creatinine levels should then
be measured and the patient started on an ACE inhibitor
if indicated, and/or hospitalized as appropriate (BOX2).
Reasonably good evidence supports an association
between treatment of hypertension with ACE inhibitors
before the onset of SRC and an increased risk of death
in patients with dcSSc during the first 45years of dis-
ease9,13,14; administration of an ACE inhibitor is not gen-
erally recommended during this period. SRC is relatively
rare in patients with early lcSSc and the data are so sparse
that whether an ACE inhibitor should be avoided is not
clear. Data from a retrospective observational study of
410 Italian patients with SSc (disease duration <5years),
suggested that dihydropyridine calcium channel block-
ers might decrease the risk of SRC (HR0.094, 95%CI
0.0380.236, P<0.001)76.
Renal biopsy is not necessary if a patient with dcSSc
presents with classical features of new onset, symp-
tomatic hypertension and rising serum creatinine,
especially if urine sediment is unremarkable14. If a
patient with SSc presents with rising serum creatinine
and is normotensive, with or without an active urine
sediment, a renal biopsy might help to define diagnosis
and guide treatment, especially in the rare occurrence
of ANCA-positive RPGN, or to exclude comorbid dis-
eases that can present as renal failure, such as diabetes
or hypertension43. Renal biopsy might also assist prog-
nosis assessment and timing of renal transplantation in
patients with SRC who become dialysis dependent14.
Most reports recommend delaying renal transplanta-
tion in patients with SRC for up to 1824months after
initiation of dialysis unless no sign of any renal recov-
ery exists after ~12months. We recommend screening
potential kidney donors, as timely transplantation is
likely to improve quality of life and limit morbidity and
mortality associated with poor vascular access and other
dialysis complications.
The 5year survival of patients with SSc-associated
SRC has not increased beyond the improvements
achieved with timely ACE inhibitor treatment9,10,42, and
consequently, additional strategies to improve outcomes
in SRC are urgently needed. Results of pilot studies using
ERAs provide sufficient evidence of safety and poten-
tial efficacy to conduct a randomized, controlled trial
to determine whether timely addition of an ERA to
the treatment regimen can limit the need for dialysis
and improve outcomes in patients SSc-associated SRC.
Although challenging, such a trial could be accom-
plished using an ethics committee-approved protocol
including web-based recruitment and regular survey
follow-up across multiple investigative sites methods
that have been applied in previous studies99.

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Acknowledgements
Y.A.S. is funded by an Egyptian government scholarship pro
gramme of joint supervision in collaboration with D.E.F and
the Division of Rheumatology, David Geffen School of Medi
cine, UCLA, Los Angeles, California, USA. We thank Gabriel
Valdivia (University of California, Los Angeles, USA) for
administrative assistance.
Author contributions
D.E.F. and T.G.W. wrote the article and provided substantial
contribution to discussion of content. D.E.F., T.G.W. and P.C.
reviewed and/or edited the manuscript before submission. All
authors researched data for the article.
D.E.F. received research funding and consultation fees, and is
on the advisory boards for Actelion, Gilead Sciences Inc.,
United Biosource Corporation (UCB), Pfizer, and Novartis.
Y.A.S., T.G.W. and P.C. declare no competing interests.
DATABASES
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NATURE REVIEWS | NEPHROLOGY VOLUME 12 | NOVEMBER 2016 | 691

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