Renal Disease in Systemic Sclerosis (Scleroderma), Including Scleroderma Renal Crisis

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Renal disease in systemic sclerosis (scleroderma), including scleroderma renal crisis
Authors: John Varga, MD, Andrew Z Fenves, MD

Section Editors: Richard J Glassock, MD, MACP, Gary C Curhan, MD, ScD
Deputy Editor: Alice M Sheridan, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2017. | This topic last updated: Jun 16, 2016.
INTRODUCTION — The pathologic hallmarks of systemic sclerosis (SSc, scleroderma) are uncontrolled
accumulation of collagen and widespread vascular lesions characterized by thickening of the vascular wall
and narrowing of the vascular lumen. (See "Pathogenesis of systemic sclerosis (scleroderma)".)
Scleroderma may affect only the skin and subjacent tissues, or it may be associated with systemic
involvement. The term systemic sclerosis is used when the characteristic skin lesions are associated with
internal organ involvement. (See "Overview of the clinical manifestations of systemic sclerosis (scleroderma)
in adults".)
Renal involvement is common in patients with SSc, with the most serious manifestation being scleroderma
renal crisis (SRC), which occurs in a minority of patients. (See 'Prevalence and manifestations of renal
disease' below.)
SRC is characterized by three major features (see 'Clinical features' below):
● Abrupt onset of moderate to severe hypertension that is typically associated with an increase in plasma
renin activity
● Acute kidney injury (AKI, acute renal failure [ARF])
● Urinalysis that is normal or reveals only mild proteinuria with few cells or casts
A review of SSc-associated renal disease will be presented here, with the emphasis on SRC. Extrarenal
manifestations of SSc are discussed separately. (See "Overview of the clinical manifestations of systemic
sclerosis (scleroderma) in adults".)
PREVALENCE AND MANIFESTATIONS OF RENAL DISEASE — Autopsy studies reveal histological

evidence of renal involvement in 60 to 80 percent of patients with SSc [1,2]. In addition, as many as 50
percent of patients with SSc have clinical evidence of renal involvement, as manifested by mild proteinuria,
elevated serum creatinine concentration, and/or hypertension [1,3,4]. But, many of these findings can be
attributed to other causes and generally are not progressive.
The most serious renal manifestation, SRC, occurs in 5 to 20 percent of patients with diffuse cutaneous SSc
[1,4-10]. (See 'Scleroderma renal crisis' below.)
The course of renal involvement is benign in most patients who do not have SRC [4]. In some cases, the
renal manifestations are coincidental, not related to SSc. As an example, in a study of 675 patients with SSc,
proteinuria was present in 91 and was considered to be due to penicillamine toxicity in 67 (74 percent), with
proteinuria developing a mean of 1.2 years after drug initiation [4]. Proteinuria usually resolved following
discontinuation of penicillamine. (See "Causes and diagnosis of membranous nephropathy", section on
'Drugs, particularly penicillamine and gold'.)
Impaired renal function in SSc may also reflect prerenal disease associated with heart failure, pulmonary
hypertension, nonsteroidal antiinflammatory drugs (NSAIDs), diuretics, or hypovolemia due to gastrointestinal
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involvement and/or malabsorption [4]. Additional causes of renal dysfunction include direct drug toxicity
(penicillamine, cyclosporine), effects of chronic hypertension, and, rarely, glomerulonephritis. (See 'Diagnosis
and differential diagnosis' below.)
SCLERODERMA RENAL CRISIS — SRC occurs in 5 to 20 percent of patients with diffuse cutaneous SSc
[1,4-10]. It is observed less frequently in limited cutaneous SSc. In a study of 50 patients with SRC, for
example, 86 percent had diffuse cutaneous SSc, and 10 percent had limited cutaneous SSc [9]. Similar
findings were noted in a report of 110 patients with SSc; diffuse cutaneous SSc was present in 78 percent.
Patients with "limited scleroderma" may actually have had very early disease and had not yet developed
diffuse cutaneous disease. SRC in classic anticentromere-positive limited scleroderma is very uncommon.
Clinical features — SRC is an early complication of SSc that almost invariably occurs within the first five
years after the onset of the disease. In the series of 110 cases, SRC occurred at a median duration of 7.5
months from the first non-Raynaud clinical manifestation of the disease [8]. In some cases, SRC is the initial
manifestation of SSc.
As described below, early-stage disease or rapidly advancing skin induration may be associated with an
increased risk of SRC. However, SRC can occur in the absence of warning signs. (See 'Risk factors' below.)
SRC is characterized by the following findings [1,5,7,11]:
● Acute onset of renal failure, usually in the absence of previous evidence of significant kidney disease.
● Abrupt onset of moderate to marked hypertension, often accompanied by manifestations of malignant

hypertension such as hypertensive retinopathy (hemorrhages and exudates) and hypertensive
encephalopathy [11]. In a review of 145 patients, 85 percent had new diastolic hypertension, with a mean
peak blood pressure of 178/102 mmHg [12]. (See "Ocular effects of hypertension".)
In approximately 10 percent of patients, SRC occurs in the absence of hypertension [13]. However,
some of these patients have blood pressures that are higher than their baseline values (eg, 130/85
mmHg in a young, thin woman whose baseline value was 100/70 mmHg). These patients have a worse
renal outcome and higher mortality than patients with SRC who are hypertensive [11,13]. Worse
outcome in normotensive renal crisis has been attributed to several factors, including delayed
recognition of SRC, and hence a delayed intervention, and the possibility that normotensive SRC might
indicate cardiac failure in these patients.
● The urine sediment is usually normal. Proteinuria in the range of 500 mg to 1 gram per day may be
present in those patients who have concomitant hypertension (since essential hypertension is very
common in the general population). However, glomerulonephritis is not a feature of SRC, and,
accordingly, microscopic hematuria or cellular casts are uncommon.
Other findings associated with SRC reflect both the underlying vasculopathy and the marked hypertension.
Microangiopathic hemolytic anemia can be seen (picture 1). (See "Extrinsic nonimmune hemolytic anemia
due to mechanical damage: Fragmentation hemolysis and hypersplenism", section on 'Fragmentation
hemolysis'.)
Additional findings may include heart failure and pulmonary edema, headache, blurred vision with
hypertensive retinopathy, and hypertensive encephalopathy, which is often complicated by generalized
seizures.
Risk factors — A number of risk factors for SRC have been identified. These include diffuse skin
involvement with palpable tendon friction rubs, use of glucocorticoids, the presence or absence of certain
serum autoantibodies, and, perhaps, cyclosporin.
Diffuse skin involvement — The most important risk factor for SRC is diffuse skin involvement,
particularly if it is rapidly progressive [5,7-9,14]. In a series of 110 patients with SSc who developed SRC, 78
percent had the diffuse cutaneous form of SSc [8]. In addition, a retrospective study of 826 patients with SSc
found that rapid progression of skin thickness was an independent predictor of early SRC (odds ratio [OR]
2.05, 95% CI 1.10-3.85) [15]. The presence of palpable tendon friction rubs, common in SSc patients with
diffuse skin involvement, is associated with a greater than twofold increase in the risk for SRC [16]. (See
"Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults", section on
'Musculoskeletal disease'.)
Glucocorticoid use — The use of glucocorticoids, particularly in high doses, has been associated with an
increased risk of SRC [8,9,13,14,17-19]. This was suggested by a retrospective case-control study of 110
patients with SRC [18]. Moderate- to high-dose glucocorticoid therapy (≥15 mg/day of prednisone or
equivalent) in the preceding six months was associated with a markedly increased risk (OR 4.37, 95% CI
2.03-9.43). The use of higher doses of glucocorticoids might result in salt and volume retention, the initiation
or worsening of hypertension, and the triggering of SRC in a subset of these patients. Glucocorticoids may
also increase the expression of the endothelin receptors in the kidney
Other studies have found similar results, with approximately 60 percent of patients with SRC having had prior
recent exposure to glucocorticoids [8,9,11].
Autoantibodies — The presence or absence of certain serum autoantibodies appears to predict the risk
for SRC. Several studies have found an increased risk among patients with SSc who have autoantibodies
directed against RNA polymerase III [8,20,21]. (See "Diagnosis and differential diagnosis of systemic
sclerosis (scleroderma) in adults", section on 'Laboratory testing'.)
The following findings illustrate this association:
● In a retrospective study of patients with SSc, the presence of anti-RNA polymerase III autoantibodies
markedly increased the risk of SRC [8]. Anti-RNA polymerase III autoantibodies were detected in the
serum of 59 percent of 96 patients who developed SRC, compared with only 12 percent of 735 patients
who did not develop SRC.
● In another retrospective analysis of 1029 patients with SSc, anti-RNA polymerase III autoantibody was
detected in 52 percent of those who developed SRC [21].
If testing for anti-RNA polymerase III autoantibodies is not available, a positive test is suggested by a fine
speckled immunofluorescence pattern of antinuclear antibodies (ANAs). In the first study cited above, this
pattern was seen in 60 percent of patients with SRC, compared with only 12 percent in patients without SRC
[8]. In contrast, anticentromere autoantibodies were much less common in patients with SRC (1.8 versus 29
percent in patients without SRC).
Cyclosporine — There is anecdotal evidence that cyclosporine, a renal vasoconstrictor, may accelerate
renal disease in patients with SSc. In one report, acute kidney injury (AKI, acute renal failure [ARF])
developed in three of eight patients treated with cyclosporine [22]. However, a causal relation to the drug,
rather than to SSc itself, could not be determined. (See "Cyclosporine and tacrolimus nephrotoxicity".)
Other risk factors — Additional factors that may identify patients with SSc who are at increased risk for
SRC include contractures at the large joints, new-onset anemia, and new cardiac events such as heart failure
or pericardial effusion [5,14,23]. In contrast, findings that are not predictive of an increased risk of SRC
include preexisting hypertension, elevated serum creatinine, or abnormal urinalysis.
Pathology — The primary histopathologic changes in the kidney are localized in the small arcuate and
interlobular arteries and the glomeruli [5,24]. The characteristic finding is intimal proliferation and thickening
that leads to narrowing and obliteration of the vascular lumen, with concentric "onion-skin" hypertrophy.
These histopathological findings are similar to SSc-associated vascular lesions found in other organs (picture
2A-E).
SRC is a thrombotic microangiopathy similar to malignant nephrosclerosis, thrombotic thrombocytopenic

purpura/hemolytic uremic syndrome (TTP/HUS), radiation nephritis, chronic transplantation rejection, and the
antiphospholipid antibody syndrome. Because of the similar renal histologic findings, renal biopsy does not
definitively establish the diagnosis of SRC.
Despite nonspecific histologic findings, renal biopsy may be helpful in the diagnosis of SRC by ruling out
other diagnoses and by providing useful prognostic information. In a review of renal biopsies from 17 patients
with SRC, both a higher number of thrombosed blood vessels and the presence of severe glomerular
ischemic collapse correlated with persistent renal failure or death [25].
Diagnosis and differential diagnosis — The diagnosis of SRC is based upon the characteristic findings in
high-risk patients with SSc. However, AKI (ARF) is not always due to SRC, and other causes of kidney
disease must be excluded. This is particularly true in patients with few risk factors for SRC. (See "Diagnostic
approach to adult patients with subacute kidney injury in an outpatient setting" and 'Risk factors' above.)
The following criteria for the diagnosis of SRC may be helpful [8,9]: Although there is no generally accepted
or validated definition of SRC, an updated consensus classification has been proposed [26]. This
classification defined blood pressure parameters in SRC and required the presence of at least one
associated feature for the diagnosis of SRC. Hypertension was defined as >140/90 mmHg or a rise in systolic
blood pressure >30 mmHg or in diastolic blood pressure >20 mmHg. Associated manifestations in this
definition included the following: >50 percent increase in serum creatinine over baseline or >120 percent of
upper limit of normal for a local laboratory; proteinuria (>2+ or protein/creatinine ratio above the upper limit of
normal), microscopic hematuria, thrombocytopenia, hemolysis, or hypertensive encephalopathy [26].
● New onset of blood pressure >150/85 mmHg, measured at least twice over the preceding 24 hours.
However, normotensive SRC has been described [13,17]. Thus, the absence of hypertension does not
exclude the diagnosis of SRC. Also, some scleroderma patients may have a low normal baseline value,
so a 20 mmHg increase may be a significant increase, even though it is still "normal," in general.
● Progressive elevation in serum creatinine, which may be associated with oliguria or anuria.
● Additional findings may include one or more of the following:
• Microangiopathic hemolytic anemia and thrombocytopenia
• Acute retinal changes of malignant hypertension, such as retinal hemorrhages and exudates and
papilledema, with or without hypertensive encephalopathy (see "Moderate to severe hypertensive
retinopathy and hypertensive encephalopathy in adults", section on 'Clinical manifestations and
diagnosis' and "Ocular effects of hypertension")
• New-onset proteinuria or hematuria (excluding other causes)
• Flash pulmonary edema
• Characteristic changes on renal biopsy (see 'Pathology' above)
Rarely, AKI associated with severe hypertension occurs in patients who have features of SSc, but lack the
characteristic skin changes, a disease subset called systemic sclerosis sine scleroderma (table 1) [27-29].
(See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Systemic
sclerosis sine scleroderma'.)
In this setting, other signs of SSc should be sought. These include (see "Overview of the clinical
manifestations of systemic sclerosis (scleroderma) in adults"):
● Digital tip pitting and scarring and nailfold microvascular changes, with capillary dilatation and drop-out
[29].
● Evidence of gastrointestinal involvement (such as esophageal or small bowel dysmotility); interstitial lung
disease (interstitial infiltrates in the lower lobes or evidence of restrictive lung disease on pulmonary
function testing); or pulmonary arterial hypertension (detected by echocardiography or an isolated
reduction in diffusion capacity on pulmonary function testing). (See "Clinical manifestations, evaluation,
and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)".)
● The presence of serum autoantibodies against RNA polymerase III or a fine speckled
immunofluorescence pattern on ANA testing. By contrast, the presence of anticentromere antibodies
tends to exclude SRC.
SRC must be distinguished from other forms of thrombotic microangiopathy, particularly TTP and HUS.
Patients with TTP/HUS characteristically present with thrombocytopenia, purpura, and prominent
microangiopathic hemolysis and may have rapidly progressive renal failure. The clinical manifestations may
mimic SRC, but patients with TTP/HUS have no clinical or serologic signs of scleroderma.
Distinguishing TTP/HUS from SRC at presentation may present a considerable and urgent diagnostic
challenge. The diagnosis of TTP/HUS is suggested by the presence of a potential inciting event, such as
diarrhea in children or certain forms of chemotherapy in adults. In addition, TTP is characterized by an
absence or marked reduction in the serum levels of the metalloprotease enzyme ADAMTS13. Renal biopsy
does not distinguish between these disorders. (See "Approach to the patient with suspected TTP, HUS, or
other thrombotic microangiopathy (TMA)" and "Acquired TTP: Clinical manifestations and diagnosis".)
Renal biopsy is generally not required for establishing the diagnosis of SRC, but may be helpful for predicting
the clinical outcome and reversibility of renal failure [25]. (See 'End-stage renal disease' below.)
Rarely, patients with SRC present with ARF (occasionally with normal blood pressure) associated with
antineutrophil cytoplasmic antibody (ANCA)-related crescentic glomerulonephritis [30,31]. In some patients,
the kidney disease is associated with D-penicillamine therapy [31,32]. The diagnosis is confirmed by kidney
biopsy showing a pauci-immune crescentic glomerulonephritis. (See "Clinical spectrum of antineutrophil
cytoplasmic autoantibodies", section on 'Disease associations'.)
Monitoring — SRC is a major complication of SSc and represents a medical emergency. Patients with the
diffuse cutaneous form of SSc and early-stage disease are at greatest risk for SRC, particularly if skin
involvement is advancing. Close monitoring is most important during the first four to five years of SSc since
SRC most frequently occurs during this phase of the disease. (See 'Clinical features' above.)
The primary rationale for monitoring for SRC is that treatment is more likely to be effective when it is initiated
early, before irreversible renal injury has occurred. However, there are no studies that have evaluated the
effectiveness of monitoring patients with SSc for the development of SRC in terms of reducing morbidity and
mortality.
We use the following screening regimen:
● Blood pressure should be measured on a regular basis in all patients with SSc. For high-risk patients
(such as those with early-stage diffuse cutaneous disease, rapidly progressive cutaneous involvement,
or the presence of autoantibodies to RNA polymerase III), we advocate daily home blood pressure
measurements and, for others, biweekly measurements.
In patients with baseline blood pressures of ≤120/70 mmHg, a persistent rise of 20 mmHg in the systolic
blood pressure or a 10 mmHg rise in the diastolic blood pressure raises concern and the need for further
evaluation for other evidence of SRC (including determination of the serum creatinine, urinalysis, and
urine protein quantitation). In patients taking antihypertensive medications, sustained hypertension
>150/90 mmHg, which is not readily corrected with dose adjustment and modest dietary salt restriction,
would trigger further evaluation [8].
● Measurement of serum creatinine with estimation of the glomerular filtration rate (GFR) and dipstick
testing or calculation of the urinary protein-to-creatinine ratio on a random, first morning urine specimen
every three months. An elevation in the serum creatinine (or fall in creatinine clearance, which may need
to be measured directly in patients who have lost muscle mass) or new persistent proteinuria >500
mg/day may be a warning sign of impending SRC. (See "Assessment of kidney function", section on
'Assessment of GFR' and "Assessment of urinary protein excretion and evaluation of isolated non-
nephrotic proteinuria in adults".)
Prevention — There are no prospective studies that demonstrate that the avoidance and/or administration of
any agent lowers the incidence or severity of SRC.
ACE inhibitors and other antihypertensive agents — As described below, angiotensin-converting

enzyme (ACE) inhibitors play a major role in the treatment of SRC (see 'Angiotensin-converting enzyme
inhibitors' below). In contrast, there is no clear evidence of a preventive effect of ACE inhibitors among
patients with SSc. We do not use ACE inhibitors solely for the purpose of preventing the occurrence of SRC.
Retrospective and case-control studies have largely found neither benefit nor harm with ACE inhibitors
related to the development of SRC [8,14,18]. A multicenter randomized, double-blind, placebo-controlled
study of 210 patients evaluated the efficacy of daily quinapril (80 mg/day or the maximum tolerated dose) for
the prevention of vascular damage in SSc [33]. At two to three years, quinapril did not affect the occurrence
of Raynaud phenomenon or ischemic digital ulcers and had no effect on renal function. However, there is
some weak evidence that ACE inhibitors are associated with a higher risk of SRC, but this is not definitive
[8,9]. A prospective observational cohort found a trend of worse outcomes in patients with prior use of ACE
inhibitors [26]. Although further studies are needed to confirm these findings, we do not recommend the use
of ACE inhibitors to reduce the risk of SRC.
A retrospective study found that the risk of SRC was significantly reduced by 90 percent among SSc patients
who were treated with dihydropyridine calcium channel blockers [19]. This observation remains to be
replicated.
Avoidance of glucocorticoids — As previously mentioned, the use of high-dose glucocorticoids is

associated with a marked increase in the risk of SRC (see 'Glucocorticoid use' above). When glucocorticoid
use is unavoidable in patients with SSc (eg, when there is concomitant myositis), we recommend limiting the
dose of prednisone to <15 mg/day and limiting use to the shortest possible period.
Treatment — If left untreated, SRC can progress to end-stage renal disease (ESRD) over a period of one to
two months, with death usually occurring within one year [1]. The mainstay of therapy in SRC is effective and
prompt blood pressure control, which improves or stabilizes renal function in up to 70 percent of patients and
improves survival (80 percent at one year). The success with antihypertensive therapy is dependent upon its
initiation before irreversible renal damage has occurred.
The optimal antihypertensive agent is an ACE inhibitor. The most experience has been with captopril, which
is our preferred ACE inhibitor. Although data are limited with other ACE inhibitors, such as enalapril or
ramipril, these agents may provide comparable benefit. Captopril has the advantage of rapid onset and short
duration of action, which permit rapid dose titration. It is not known whether angiotensin receptor blockers
(ARBs) and direct renin inhibitors are as effective as ACE inhibitors since these agents have not been
adequately evaluated in this setting.
Angiotensin-converting enzyme inhibitors — Compared with other antihypertensive agents, a number

of nonrandomized, uncontrolled, retrospective and prospective studies have shown that the ACE inhibitors
are associated with greater antihypertensive efficacy, better preservation of renal function, and improved
survival in patients with SRC [8,12,34,35]. Captopril was the most commonly used ACE inhibitor. The
following observations illustrate the potential benefit of ACE inhibitor therapy.
A prospective cohort study of 108 patients with SRC seen between 1972 and 1987 found the following
benefits in patients treated continuously with ACE inhibitors (mostly captopril), compared with patients seen
before the availability of ACE inhibitors [34]:
● A significantly higher rate of recovery of renal function. Among patients who survived dialysis for more
than three months, 11 of 20 patients who continued ACE inhibitor therapy were able to discontinue
dialysis after 3 to 15 months, compared with 0 of 15 patients who were not treated with ACE inhibitors
(55 versus 0 percent). A later report from the same investigators found continued improvement in renal
function for up to 18 months in patients treated with ACE inhibitors [12].
● A significantly higher survival rate at one year (76 versus 15 percent).
The efficacy of ACE inhibitors in patients who progress to ESRD is discussed below. (See 'Efficacy of
angiotensin-converting enzyme inhibitors' below.)
Monitoring serum creatinine — SRC is a form of bilateral intrarenal renal artery stenosis. Thus,
patients starting ACE inhibitor therapy may show an initial rise in serum creatinine concentration because of
the ACE inhibitor-induced fall in efferent arteriolar resistance and intraglomerular pressure. (See "Renal
effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'.)
As a result, careful monitoring of serum creatinine is required when therapy is begun. The serum creatinine
concentration is measured daily at the beginning of therapy. Small elevations in serum creatinine are usually
transient and not progressive, and would not be an indication to discontinue the ACE inhibitor.
A complete blood count, fibrin degradation products, serum lactate dehydrogenase, and the blood smear are
also regularly assessed since the degree of microangiopathic hemolysis often reflects the activity of the
disease process and are an indication to intensify therapy.
Unproven efficacy of angiotensin II receptor blockers — Although ARBs might be expected to be

effective in patients with SRC [36], efficacy has not been established. In a case report, recurrent SRC
developed in the transplanted kidney in a patient who was switched from captopril to an ARB because of a
chronic cough [37]. (See 'Renal transplantation' below and "Major side effects of angiotensin-converting
enzyme inhibitors and angiotensin II receptor blockers", section on 'Incidence of cough with ARBs'.)
Non-angiotensin-converting enzyme inhibitor therapy — Some centers have anecdotally reported the
use of other drugs in patients with SRC, but we do not recommend use of any of these agents as initial
therapy:
● In a single-center retrospective chart review of 20 patients with SRC, 10 with associated

microangiopathic hemolytic anemia were treated with plasma exchange therapy in combination with ACE
inhibitors [38]. Patients treated with the combination therapy had a better renal survival rate at one year
(80 percent) compared with those who were treated with ACE inhibitors only (45 percent). A randomized
trial is needed to confirm these observations.
● The nonselective endothelin-1 receptor antagonist, bosentan, was studied in six patients with SRC [39].
When used in combination with ACE inhibitors for six months, bosentan was associated with a trend
toward improved blood pressure control and preserved renal function.
● Intravenous prostacyclin (iloprost or epoprostenol), which is believed to help the microvascular lesion
without precipitating hypotension, has been administered for SRC based upon anecdotal observations of
benefit.
Initial approach — The recommendation for initial therapy with ACE inhibitors for SRC is based upon
small numbers of patients in observational studies. Prospective randomized controlled trials have not been
performed.
Captopril has the advantages of rapid onset (peak effect at 60 to 90 minutes) and short duration of action,
which permit rapid dose titration. Intravenous enalaprilat is not routinely used since it has a long duration of
action (up to 36 hours). However, a single dose may be given in patients who have impaired mental status,
followed by oral captopril therapy through a nasogastric tube.
The therapeutic approach varies with the patient's blood pressure and whether the patient has SRC alone or
in combination with hypertensive encephalopathy or other manifestation of malignant hypertension. In a
review of 145 patients with SRC, 85 percent had new diastolic hypertension, with a mean peak blood
pressure of 178/102 mmHg [12]. However, approximately 10 percent of patients with SRC are normotensive
[13]. All patients are treated with captopril, which is continued even if the serum creatinine initially continues
to rise.
The principal goal of initial captopril therapy is to return the patient to his or her previous baseline blood
pressure within 72 hours. Since the hypertension is usually acute in SRC, rapid blood pressure reduction to
baseline does not usually carry the risks seen with rapid blood pressure lowering in patients with
longstanding hypertension. However, some recommend maximum blood pressure reductions of 20
mmHg/day.
● Among hypertensive patients without evidence of central nervous system involvement (eg,
encephalopathy, papilledema), captopril is begun at a dose of 6.25 to 12.5 mg. There is progressive
dose escalation in 12.5 to 25 mg increments at four- to eight-hour intervals until the goal blood pressure
is reached. The maximum captopril dose is 300 to 450 mg/day.
● Among the infrequent hypertensive patients with evidence of central nervous system involvement (eg,
encephalopathy, papilledema), we administer the same captopril dose escalation regimen and, for acute
blood pressure control, add intravenous nitroprusside, which has a very short duration of action.
Nitroprusside should be discontinued as soon as possible since captopril in increasing doses lowers the
blood pressure. The goal is to return the patient to his or her previous baseline blood pressure within
72 hours. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in
adults", section on 'Goal of therapy' and "Moderate to severe hypertensive retinopathy and hypertensive
encephalopathy in adults", section on 'Choice of antihypertensive drug'.)
● Among the approximately 10 percent of patients who have normotensive SRC, we begin captopril at a
dose of 6.25 mg and, if tolerated, increase the dose to 12.5 mg at the second dose. Further dose
escalation must be done carefully to prevent the induction of hypotension. Some of these patients have
blood pressures that, although within the normal range, are still higher than the patient's baseline (eg,
130/85 mmHg in a young, thin woman whose baseline value is 100/70 mmHg). In such patients, the goal
is lowering the blood pressure to the previous baseline.
Other parameters that can be followed are the platelet count, hemoglobin, haptoglobin, and serum lactate
dehydrogenase, which are markers of the degree of intravascular hemolysis. These parameters usually
improve fairly quickly, even if the serum creatinine continues to rise.
Long-term therapy — A low dose of the ACE inhibitor is continued indefinitely, even if not needed for
blood pressure control. Longer-acting ACE inhibitors, such as enalapril or ramipril, are preferred over
captopril for the maintenance of normal blood pressure, and their use may improve compliance.
The use of potential nephrotoxins, such as nonsteroidal antiinflammatory drugs (NSAIDs) and radiocontrast
agents, should be avoided [7]. Some centers in Europe have used a parenteral infusion of prostacyclin
analogs in combination with ACE inhibitors, but there are no controlled studies supporting this approach.
Addition of other antihypertensive drugs — There are no studies that specifically address the role of other
antihypertensive drugs in patients with SRC who do not achieve sufficient lowering of the blood pressure with
the maximum recommended dose of the ACE inhibitor. We prefer the addition of a dihydropyridine calcium
channel blocker, such as amlodipine.
ARBs have been used in combination with ACE inhibitors in some settings, but only limited data are available
in patients with SRC. Multiple studies of patients with other diseases have suggested that patients treated
with both an ACE inhibitor and ARB are at higher risk for adverse events, compared with those treated with
only one agent. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers", section on 'Increased adverse effects'.)
Data are also limited on the efficacy of ARBs as monotherapy for the treatment of SRC. (See 'Unproven
efficacy of angiotensin II receptor blockers' above.)
Other antihypertensive drugs that can be added, if necessary, include diuretics and alpha blockers. Beta
blockers are usually avoided in patients with SSc because of the theoretical risk of worsening vasospasm
(eg, Raynaud phenomenon).
The addition of endothelin-1 receptor antagonists (such as bosentan) or renin antagonists has been used in
patients with resistant hypertension; however, the long-term safety of these agents has not been
demonstrated [39]. (See "Treatment of resistant hypertension".)
End-stage renal disease — Despite treatment with ACE inhibitors, approximately 20 to 50 percent of
patients with SRC require dialysis [8,12,18]. However, as discussed in the following section, an appreciable
proportion of these patients recover sufficient renal function to discontinue dialysis [8,12].
Efficacy of angiotensin-converting enzyme inhibitors — Data supporting the efficacy of ACE inhibitors
in the treatment of SRC that progresses to ESRD come from observational studies. One such study reported
renal outcomes in 145 patients with SRC who were continuously treated with ACE inhibitors and followed for
5 to 10 years [12]. The following findings were noted:
● Twenty-eight patients (19 percent) died at a mean of three months, 18 of whom required dialysis.
● Fifty-five patients (38 percent) did not require dialysis. These patients had a mean peak serum creatinine
concentration of 3.8 mg/dL (336 micromol/L) that fell to 1.8 mg/dL (159 micromol/L) at 7.1 years. Two of
these patients had slow deterioration of renal function, requiring dialysis at four and six years.
● Thirty-four patients (23 percent overall, 43 percent of patients requiring early dialysis, and 55 percent of
patients requiring early dialysis who did not die) were able to discontinue dialysis after 2 to 18 months
(mean 8 months). The mean serum creatinine was 2.7 mg/dL (239 micromol/L), and, when dialysis was
discontinued, the serum creatinine fell to 2.2 mg/dL (194 micromol/L) at 6.1 years.
In an earlier report from the same group cited above, there was no recovery of renal function in patients who
were not treated with ACE inhibitors [18]. (See 'Angiotensin-converting enzyme inhibitors' above.)
Benefit from ACE inhibitor therapy was also noted in a retrospective single-center study of 110 patients with
SRC (mean blood pressure 193/114 mmHg), all but two of whom were treated with ACE inhibitors [8]. The
ACE inhibitor dose was titrated to initially reduce the systolic blood pressure by 20 mmHg per day.
The following findings were noted:
● Dialysis was required in 72 patients (64 percent), 24 of whom (33 percent) recovered sufficient renal
function to discontinue dialysis.
● Approximately 40 percent of patients required permanent dialysis.
● Patient survival at one and five years was 82 and 59 percent, respectively, with the poorest survival seen
in patients requiring dialysis.
Renal biopsy is generally not required for establishing the diagnosis of SRC (see 'Diagnosis and differential
diagnosis' above), but may be helpful for predicting the clinical outcome and reversibility of renal failure.
Greater numbers of thrombosed vessels, the severity of ischemic glomerular collapse, and peritubular C4
staining may correlate with poor renal outcomes [25].
In summary, despite the improved outcomes associated with long-term ACE inhibitor therapy, the outcome of
SRC remains poor. In addition, SRC recurs in fewer than 5 percent of patients who receive a renal transplant.
The treatment of recurrent SRC is the same as that for the initial episode. (See 'Renal transplantation' below.)
Dialysis — If indicated, either hemodialysis or continuous peritoneal dialysis is an effective therapy for
ESRD due to SRC [12]. However, survival on dialysis in patients with SRC is worse than in other forms of
ESRD, as illustrated in a study from the United States Renal Data System (USRDS) that included 364,000
patients with ESRD on maintenance dialysis, 820 of whom had scleroderma [40]. Two-year survival was
significantly lower in patients with scleroderma (49 percent versus 64 percent in all other patients), even
though the patients with scleroderma were younger. Since vascular access is particularly troublesome in
patients with scleroderma, complications with vascular access may have contributed to the higher mortality.
Given the beneficial effects of ACE inhibitors in SRC, it is important to continue ACE inhibitor therapy, even if
in low doses. The goal remains maintenance of normal blood pressure (eg, <140/90 mmHg), and, in dialysis-
dependent patients, ACE inhibitors may be continued indefinitely as needed for blood pressure control, if
control of extracellular volume is insufficient. In the hemodialysis patient, captopril may only be tolerated on
non-dialysis days.
As noted in the preceding section, considerable recovery of renal function can occur after ACE inhibitor
therapy in patients with SRC, permitting discontinuation of dialysis in many patients (see 'Efficacy of
angiotensin-converting enzyme inhibitors' above). Since the improvement in renal function can continue for
up to 18 months, decisions regarding renal transplantation do not have to be made during or immediately
following an episode of SRC. (See 'Renal transplantation' below.)
Based upon these observations, we do not perform renal transplantation for at least six months after the
initiation of dialysis. Issues related to wait-listing for renal transplantation are discussed separately. (See "The
kidney transplant waiting list in the United States".)
Renal transplantation — There is limited experience with renal transplantation in patients with SRC, in
part because transplantation is sometimes precluded by the severity of the extrarenal manifestations of SSc
[41,42]. The United Network for Organ Sharing (UNOS) database included 260 transplants performed
between 1987 and 2004 for the renal diagnosis of SSc [43].
Renal allograft survival in patients with SRC is reduced, compared with transplant recipients with other
disorders, but outcomes appear to be better than in patients with SRC who are treated with dialysis [23,43-
45]. Reported graft survival rates from the UNOS registry have been 68 to 79 percent at one year, 60 to 70
percent at three years, and 57 percent at five years [23,44].
Despite these relatively low allograft survival rates, patient survival after renal transplantation is superior to
that in dialysis patients with SRC who remain on the waitlist. This was shown in a study of 258 patients with
SRC who were listed for renal transplantation between the years 1985 to 2002 [44]. The one- and three-year
patient survival with transplantation was 90 and 80 percent, respectively, compared with 81 and 55 percent in
those who remained on the waitlist.
As noted above, there is an association between an increased risk of SRC and high-dose glucocorticoids and
cyclosporine [45]. (See 'Glucocorticoid use' above and 'Cyclosporine' above.) To reduce the risk of recurrent
SRC among patients who undergo renal transplantation, we avoid calcineurin inhibitors and high-dose
glucocorticoids (>20 mg prednisone per day). The maintenance immunosuppressive regimen includes low-
dose glucocorticoids (<10 mg prednisone per day), mycophenolate mofetil, and sirolimus.
We continue ACE inhibitors indefinitely. The possible role of ARBs is not clear. In a case report cited above,
recurrent SRC developed in a patient switched from an ACE inhibitor to an ARB [37]. This supports the view
https://www.uptodate.com/contents/renal-disease-in-systemic-sclerosis-scleroderma-including-scleroderma-renal-crisis/print?source=search_re… 10/24
that ACE inhibitors may be superior to ARBs (as well as other antihypertensive drugs) in patients with SSc
[46]. (See 'ACE inhibitors and other antihypertensive agents' above.)
Minimum wait time for transplantation — We generally do not perform renal transplantation for at
least six months after the initiation of dialysis. Recovery of renal function can occur in SRC, permitting
discontinuation of dialysis in many patients (see 'Dialysis' above). Since the improvement in renal function
can continue for up to 18 months, decisions regarding renal transplantation do not have to be made during or
immediately following an episode of SRC.
Recurrent scleroderma renal crisis — The incidence of recurrent SRC in the transplanted kidney is
difficult to ascertain with certainty because the primary renal histopathologic changes associated with SRC
(mucoid intimal thickening of the interlobular arteries and fibrinoid necrosis in the glomeruli) may be difficult to
differentiate from acute or chronic renal allograft rejection. (See "Clinical manifestations and diagnosis of
acute renal allograft rejection" and "Chronic renal allograft nephropathy".)
Recurrence rates in transplanted kidneys are low (2 to 3 percent) [23,44,45]. As an example, in a review from
the UNOS database of 260 transplants for SRC performed between 1987 and 2004, recurrent disease
developed in five (1.9 percent) [23]. Most recurrences occurred within the first one to two years after
transplantation, with many occurring within a few months.
Early loss of native kidney function due to SRC appears to be a risk factor for recurrence in the transplanted
kidney [23]. In addition, recurrent SRC may be preceded by one or more clinical markers that are predictive
of severe SSc, such as progressive skin thickening, new-onset anemia, and cardiac complications such as
pericardial effusion or congestive heart failure [23].
Recurrent SRC in the transplant may follow a similar course as the primary disease. The treatment of
recurrent SRC is the same as that for disease in the native kidney. (See 'Treatment' above.)
Patient survival — SSc is associated with a substantial increase in mortality, compared with the general
population. The main causes are pulmonary and cardiac disease. (See "Overview of the treatment and
prognosis of systemic sclerosis (scleroderma) in adults", section on 'Mortality'.)
SRC is a potentially life-threatening complication. Prior to the widespread use of ACE inhibitors, almost all
patients with significant renal involvement died within one year, compared with a 35 percent cumulative
seven-year survival in all patients with scleroderma [47,48].
Survival in patients with SRC is markedly improved with ACE inhibitor therapy [8,12,34,49]. The following
observations illustrate the range of findings:
● In a review of 110 patients with SSc who developed SRC between 1981 and 1993, one-year mortality
was 24 percent in patients treated with ACE inhibitors, compared with 85 percent in patients treated with
other drugs [34].
● In a later report from the same investigators of 145 patients with SRC, all of whom were treated with
ACE inhibitors, 28 (19 percent) died early, at a mean of three months [12]. These patients were much
more likely to have cardiac disease (43 versus 5 percent in survivors).
Excluding the patients who died early, the mortality risk was related to dialysis status. The 89 patients
who did not require dialysis or required only temporary dialysis had long-term outcomes similar to
patients with diffuse SSc who did not have SRC, with mortality rates of 10 percent at five years and 15 to
20 percent at eight years. In the 28 patients who required permanent dialysis, the respective mortality
rates were approximately 60 percent at five years and 75 percent at eight years.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney
disease in adults".)
SUMMARY AND RECOMMENDATIONS
● As many as 50 percent of systemic sclerosis (SSc) patients have clinical evidence of renal involvement,
such as mild proteinuria, elevated serum creatinine concentration, or hypertension. Renal abnormalities
may reflect prerenal failure, direct drug toxicity, effects of chronic hypertension, and, rarely,
glomerulonephritis. In many cases, the renal abnormalities are unrelated to scleroderma. (See
'Prevalence and manifestations of renal disease' above.)
● Scleroderma renal crisis (SRC) develops in 5 to 20 percent of SSc patients, most commonly within 48
months of diagnosis and in those with diffuse cutaneous SSc. It is characterized by acute kidney injury
(AKI); abrupt onset of moderate to marked hypertension; a normal urinalysis or a urine sediment with
only mild proteinuria and few cells or casts; and/or signs of microangiopathic hemolytic anemia. It is also
important to realize that 10 percent of those with SRC are normotensive. (See 'Prevalence and
manifestations of renal disease' above and 'Clinical features' above.)
● The characteristic histologic finding in the kidney in SRC is intimal proliferation and thickening that leads
to narrowing and obliteration of the vascular lumen, with concentric "onion-skin" hypertrophy. These
changes are indistinguishable from those in malignant hypertension. (See 'Pathology' above.)
● Risk factors for SRC include early-stage disease with diffuse and advancing skin involvement, the
presence of palpable tendon friction rubs, glucocorticoid use, autoantibodies directed against RNA
polymerase, and administration of cyclosporine. (See 'Risk factors' above.)
● The diagnosis of SRC is based upon characteristic findings in high-risk patients with SSc. These include
new onset of blood pressure >150/85 mmHg and progressive decline in renal function, although a few
patients are normotensive. Additional findings may include microangiopathic hemolytic anemia and
thrombocytopenia, acute retinal changes of malignant hypertension, new-onset proteinuria or hematuria
(excluding other causes), and other features. Renal biopsy can be helpful in predicting the persistence of
renal failure. SRC must be distinguished from other forms of thrombotic microangiopathy, particularly
thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). (See 'Diagnosis and
differential diagnosis' above.)
● To permit prompt initiation of treatment of SRC, we recommend close monitoring of all patients with SSc.
We monitor patients as follows (see 'Monitoring' above):
• For high-risk patients (such as those with early-stage diffuse cutaneous disease, rapidly progressive
cutaneous involvement, and palpable tendon friction rubs), we advocate daily home blood pressure
measurements, and for others, biweekly measurements.
• We measure the plasma creatinine concentration and use dipstick testing for protein or calculation
of the urinary protein-to-creatinine ratio on a random first morning urine specimen every three
months.
● There is a paucity of evidence concerning the avoidance and/or administration of any agent that may
lower the incidence of SRC. When glucocorticoid use is unavoidable in patients with SSc, we
recommend limiting the dose of prednisone to <15 mg/day and limiting use to the shortest possible
period (Grade 1B). We do not use angiotensin-converting enzyme (ACE) inhibitors for the purpose of
preventing the occurrence of SRC. (See 'Prevention' above.)
● The therapeutic approach to the patient with SRC varies with the patient's blood pressure and whether
the patient has central nervous system manifestations. We suggest the following general approach
(Grade 2C) (see 'Initial approach' above):
• The principal goal of initial captopril therapy is to return the patient to his or her previous baseline
blood pressure within 72 hours. Since the hypertension is acute in SRC, rapid blood pressure
reduction to baseline does not usually carry the risks seen with rapid blood pressure lowering in
patients with long-standing hypertension. However, some recommend maximum blood pressure
reductions of 20 mmHg per day.
• Among patients with SRC, we recommend the administration of ACE inhibitors rather than other
antihypertensive agents (Grade 1A). We suggest initial use of captopril rather than other ACE
inhibitors because of extensive clinical experience and its short onset and duration of action, which
permit rapid dose escalation (Grade 2B).
• Among hypertensive patients without evidence of central nervous system involvement (eg,
encephalopathy, papilledema), captopril is begun at a dose of 6.25 to 12.5 mg. There is progressive
dose escalation in 12.5 to 25 mg increments at four- to eight-hour intervals until the goal blood
pressure is reached. The maximum captopril dose is 300 to 450 mg/day.
• Among hypertensive patients with evidence of central nervous system involvement, we administer
the same captopril regimen and, for acute blood pressure control, add intravenous nitroprusside.
The nitroprusside should be discontinued as soon as possible since captopril in increasing doses
lowers the blood pressure.
• Among patients who are normotensive, we begin captopril at a dose of 6.25 mg and, if tolerated,
increase the dose to 12.5 mg at the second dose. Further dose escalation must be done carefully to
prevent the induction of hypotension.
● In addition to blood pressure, other parameters that can be followed with treatment are the platelet
count, hemoglobin, haptoglobin, and serum lactate dehydrogenase.
● Despite treatment with ACE inhibitors, approximately 20 to 50 percent of patients with SRC progress to
end-stage renal disease (ESRD). However, among patients with SRC who require dialysis during the
acute episode, an appreciable proportion recovers sufficient renal function to discontinue dialysis over a
period of up to 18 months. (See 'End-stage renal disease' above.)
● Based principally upon survival benefits with kidney transplantation among all patients with ESRD, we
recommend transplantation rather than hemodialysis or peritoneal dialysis among patients with SRC who
require renal replacement therapy (Grade 1B). We do not perform renal transplantation for at least six
months after the initiation of dialysis, given the chance of recovery of renal function. (See 'End-stage
renal disease' above.)
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REFERENCES
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progressive systemic sclerosis. Review of a 25-year experience with 68 cases. Medicine (Baltimore)
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6. Eason RJ, Tan PL, Gow PJ. Progressive systemic sclerosis in Auckland: a ten year review with
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crisis. Rheumatology (Oxford) 2009; 48 Suppl 3:iii32.
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patients and 427 controls. Rheumatology (Oxford) 2012; 51:460.
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133:600.
13. Helfrich DJ, Banner B, Steen VD, Medsger TA Jr. Normotensive renal failure in systemic sclerosis.
Arthritis Rheum 1989; 32:1128.
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15. Domsic RT, Rodriguez-Reyna T, Lucas M, et al. Skin thickness progression rate: a predictor of mortality
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16. Doré A, Lucas M, Ivanco D, et al. Significance of palpable tendon friction rubs in early diffuse cutaneous
systemic sclerosis. Arthritis Care Res (Hoboken) 2013; 65:1385.
17. Kohno K, Katayama T, Majima K, et al. A case of normotensive scleroderma renal crisis after high-dose
methylprednisolone treatment. Clin Nephrol 2000; 53:479.
18. 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.
19. Montanelli G, Beretta L, Santaniello A, Scorza R. Effect of dihydropyridine calcium channel blockers
and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case
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20. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35:35.
21. Nguyen B, Assassi S, Arnett FC, Mayes MD. Association of RNA polymerase III antibodies with
scleroderma renal crisis. J Rheumatol 2010; 37:1068; author reply 1069.
22. 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.
23. Pham PT, Pham PC, Danovitch GM, et al. Predictors and risk factors for recurrent scleroderma renal
crisis in the kidney allograft: case report and review of the literature. Am J Transplant 2005; 5:2565.
24. Donohoe JF. Scleroderma and the kidney. Kidney Int 1992; 41:462.
25. Batal I, Domsic RT, Shafer A, et al. Renal biopsy findings predicting outcome in scleroderma renal
crisis. Hum Pathol 2009; 40:332.
26. Hudson M, Baron M, Tatibouet S, et al. Exposure to ACE inhibitors prior to the onset of scleroderma
renal crisis-results from the International Scleroderma Renal Crisis Survey. Semin Arthritis Rheum
2014; 43:666.
27. Gouge SF, Wilder K, Welch P, et al. Scleroderma renal crisis prior to scleroderma. Am J Kidney Dis
1989; 14:236.
28. Zwettler U, Andrassy K, Waldherr R, Ritz E. Scleroderma renal crisis as a presenting feature in the
absence of skin involvement. Am J Kidney Dis 1993; 22:53.
29. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic,
clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 2000; 43:444.
30. Arnaud L, Huart A, Plaisier E, et al. ANCA-related crescentic glomerulonephritis in systemic sclerosis:
revisiting the "normotensive scleroderma renal crisis". Clin Nephrol 2007; 68:165.
31. 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.
32. Karpinski J, Jothy S, Radoux V, et al. D-penicillamine-induced crescentic glomerulonephritis and
antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature.
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33. Gliddon AE, Doré CJ, Black CM, et al. Prevention of vascular damage in scleroderma and autoimmune
Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the
angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 2007; 56:3837.
34. Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis:
relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;
113:352.
35. Beckett VL, Donadio JV Jr, Brennan LA Jr, et al. Use of captopril as early therapy for renal scleroderma:
a prospective study. Mayo Clin Proc 1985; 60:763.
36. Rajendran PR, Molitor JA. Resolution of hypertensive encephalopathy and scleroderma renal crisis with
an angiotensin receptor blocker. J Clin Rheumatol 2005; 11:205.
37. Cheung WY, Gibson IW, Rush D, et al. Late recurrence of scleroderma renal crisis in a renal transplant
recipient despite angiotensin II blockade. Am J Kidney Dis 2005; 45:930.
38. Cozzi F, Marson P, Cardarelli S, et al. Prognosis of scleroderma renal crisis: a long-term observational
study. Nephrol Dial Transplant 2012; 27:4398.
39. Penn H, Quillinan N, Khan K, et al. Targeting the endothelin axis in scleroderma renal crisis: rationale
and feasibility. QJM 2013; 106:839.
40. Abbott KC, Trespalacios FC, Welch PG, Agodoa LY. Scleroderma at end stage renal disease in the
United States: patient characteristics and survival. J Nephrol 2002; 15:236.
41. Paul M, Bear RA, Sugar L. Renal transplantation in scleroderma. J Rheumatol 1984; 11:406.
42. Merino GE, Sutherland DE, Kjellstrand CM, et al. Renal transplantation for progressive systemic
sclerosis with renal failure: case report and review of previous experience. Am J Surg 1977; 133:745.
43. Bleyer AJ, Donaldson LA, McIntosh M, Adams PL. Relationship between underlying renal disease and
renal transplantation outcome. Am J Kidney Dis 2001; 37:1152.
44. Gibney EM, Parikh CR, Jani A, et al. Kidney transplantation for systemic sclerosis improves survival
and may modulate disease activity. Am J Transplant 2004; 4:2027.
45. Chang YJ, Spiera H. Renal transplantation in scleroderma. Medicine (Baltimore) 1999; 78:382.
46. Steen VD, Medsger TA Jr. Improvement in skin thickening in systemic sclerosis associated with
improved survival. Arthritis Rheum 2001; 44:2828.
47. Medsger TA Jr, Masi AT, Rodnan GP, et al. Survival with systemic sclerosis (scleroderma). A life-table
analysis of clinical and demographic factors in 309 patients. Ann Intern Med 1971; 75:369.
48. Medsger TA Jr, Masi AT. Survival with scleroderma. II. A life-table analysis of clinical and demographic
factors in 358 male U.S. veteran patients. J Chronic Dis 1973; 26:647.
49. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma.
Arthritis Rheum 2000; 43:2437.
Topic 7183 Version 21.0
GRAPHICS
Peripheral smear in microangiopathic hemolytic anemia

showing presence of schistocytes
Peripheral blood smear from a patient with a microangiopathic hemolytic anemia

with marked red cell fragmentation. The smear shows multiple helmet cells
(arrows) and other fragmented red cells (small arrowhead); microspherocytes
are also seen (large arrowheads). The platelet number is reduced; the large
platelet in the center (dashed arrow) suggests that the thrombocytopenia is due
to enhanced destruction.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 70851 Version 8.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several platelets

(arrows) and a normal lymphocyte (arrowhead) can also be seen. The red
cells are of relatively uniform size and shape. The diameter of the normal red
cell should approximate that of the nucleus of the small lymphocyte; central
pallor (dashed arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Light microscopy of glomerulus in scleroderma renal

crisis
Light micrograph showing fibrinoid necrosis in the preglomerular afferent

arteriole (arrow) in scleroderma renal crisis. The normal muscle layer of the
media has been replaced by the fibrinoid material.
Courtesy of Helmut Rennke, MD.
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per

capillary tuft, the capillary lumens are open, the thickness of the glomerular
capillary wall (long arrow) is similar to that of the tubular basement
membranes (short arrow), and the mesangial cells and mesangial matrix are
located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Light microscopy showing thrombotic microangiopathy

with subintimal fibrin deposition in an interlobular artery
Subintimal fibrin deposition without inflammation (arrow) in an interlobular

artery as can be seen acutely in any of the forms of the hemolytic uremic
syndrome, including scleroderma. The marked narrowing of the vascular lumen
will diminish distal perfusion, potentially leading to tissue necrosis if there is
near total or total occlusion.

with mucoid intimal thickening of a muscular renal
artery
Mucoid intimal thickening of muscular renal arteries (arrows) as an early healing

response to previous fibrinoid injury in any of the forms of the hemolytic uremic
syndrome, including scleroderma and malignant hypertension.

with onion-skin thickening of a muscular renal artery
Concentric onion-skin thickening of a muscular renal artery, leading to complete

obliteration of the vascular lumen, during the later healing phase of previous
fibrinoid injury in any of the forms of the hemolytic uremic syndrome, including
scleroderma and acute hypertensive nephrosclerosis (formerly called "malignant
nephrosclerosis").
Courtesy of Carol Black, MD.
Immunofluorescence microscopy showing fibrin

deposition in thrombotic microangiopathy
Immunofluorescence microscopy in the hemolytic uremic syndrome shows fibrin

deposition (bright yellow areas) in branches of a muscular renal artery.
Classification of scleroderma
Pre-scleroderma
Raynaud phenomenon
Nailfold capillary changes and evidence of digital ischemia
Specific circulating autoantibodies - anti-topoisomerase-I (Scl-70), ACA, or anti-RNA polymerase-I, II, or III
Many patients progress to systemic sclerosis within three years
Scleroderma sine scleroderma

Presentation with pulmonary fibrosis or renal, cardiac, or gastrointestinal disease
No skin involvement
Raynaud phenomenon may be present
Antinuclear antibodies may be present - anti-Scl-70, ACA, or anti-RNA polymerase-I, II, or III
Limited cutaneous scleroderma

Raynaud phenomenon for years, occasionally decades
Skin involvement limited to hands, face, feet, and forearms (acral distribution)
Dilated nailfold capillary loops, usually without capillary drop-out
A significant (10 to 15 percent) late incidence of pulmonary hypertension, with or without skin calcification,
gastrointestinal disease, telangiectasiae (CREST syndrome), or interstitial lung disease
Renal disease rarely occurs
ACA in 70 to 80 percent
Anti-Scl-70 in 10 percent
Diffuse cutaneous scleroderma

Raynaud phenomenon followed, within one year, by puffy or hidebound skin changes
Truncal and acral skin involvement; tendon friction rubs; myositis; arthritis
Nailfold capillary dilatation and capillary drop-out
Early and significant incidence of renal, interstitial lung, diffuse gastrointestinal, and myocardial disease
Anti-Scl-70 (30 percent), anti-RNA polymerase-I, II, or III (12 to 25 percent), ACA (<5 percent) antibodies
ACA: anti-centromere.
Contributor Disclosures
John Varga, MD Nothing to disclose Andrew Z Fenves, MD Nothing to disclose Richard J Glassock, MD,
MACP Speaker's Bureau: Genentech [Vasculitis (Rituximab)]. Consultant/Advisory Boards: Bristol-Myers-
Squibb [Lupus nephritis, FSGS (Abatacept)]; ChemoCentryx [Vasculitis, diabetes (Acocapan)]; Retrophin
[FSGS(Sparsentan)]. Equity Ownership/Stock Options: Reata (Bardoxolone). Gary C Curhan, MD,
ScD Grant/Research/Clinical Trial Support: Allena Pharmaceuticals [Oxalate]. Consultant/Advisory Boards:
Allena Pharmaceuticals [Oxalate, nephrolithiasis]; AstraZeneca [Uric acid and gout (Lesinurad)]; Decibel
Therapeutics (Hearing loss. tinnitus). Consultant/Advisory Boards (spouse/partner): Decibel Therapeutics
(Hearing loss, tinnitus)]. Equity Ownership/Stock Options: Allena Pharmaceuticals. Other Financial Interest:
American Society of Nephrology [CJASN Editor-in-Chief]. Alice M Sheridan, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
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04/09/2017 Renal disease in systemic sclerosis (scleroderma), including scleroderma renal crisis - UpToDate

Official reprint from UpToDate®

Authors: John Varga, MD, Andrew Z Fenves, MD

SRC is characterized by three major features (see 'Clinical features' below):

PREVALENCE AND MANIFESTATIONS OF RENAL DISEASE — Autopsy studies reveal histological

SRC is characterized by the following findings [1,5,7,11]:

● Abrupt onset of moderate to marked hypertension, often accompanied by manifestations of malignant

The following findings illustrate this association:

SRC is a thrombotic microangiopathy similar to malignant nephrosclerosis, thrombotic thrombocytopenic

● Additional findings may include one or more of the following:

• Microangiopathic hemolytic anemia and thrombocytopenia

• New-onset proteinuria or hematuria (excluding other causes)

• Flash pulmonary edema

• Characteristic changes on renal biopsy (see 'Pathology' above)

We use the following screening regimen:

ACE inhibitors and other antihypertensive agents — As described below, angiotensin-converting

Avoidance of glucocorticoids — As previously mentioned, the use of high-dose glucocorticoids is

Angiotensin-converting enzyme inhibitors — Compared with other antihypertensive agents, a number

● A significantly higher survival rate at one year (76 versus 15 percent).

Unproven efficacy of angiotensin II receptor blockers — Although ARBs might be expected to be

● In a single-center retrospective chart review of 20 patients with SRC, 10 with associated

The following findings were noted:

● Approximately 40 percent of patients required permanent dialysis.

SUMMARY AND RECOMMENDATIONS

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Topic 7183 Version 21.0

Peripheral smear in microangiopathic hemolytic anemia

Peripheral blood smear from a patient with a microangiopathic hemolytic anemia

Courtesy of Carola von Kapff, SH (ASCP).

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Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets

Courtesy of Carola von Kapff, SH (ASCP).

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Light microscopy of glomerulus in scleroderma renal

Light micrograph showing fibrinoid necrosis in the preglomerular afferent

Courtesy of Helmut Rennke, MD.

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Light micrograph of a normal glomerulus. There are only 1 or 2 cells per

Courtesy of Helmut G Rennke, MD.

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Light microscopy showing thrombotic microangiopathy

Subintimal fibrin deposition without inflammation (arrow) in an interlobular

Courtesy of Helmut Rennke, MD.

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Light microscopy showing thrombotic microangiopathy

Mucoid intimal thickening of muscular renal arteries (arrows) as an early healing

Courtesy of Helmut Rennke, MD.

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Light microscopy showing thrombotic microangiopathy

Concentric onion-skin thickening of a muscular renal artery, leading to complete

Courtesy of Carol Black, MD.

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Immunofluorescence microscopy showing fibrin

Immunofluorescence microscopy in the hemolytic uremic syndrome shows fibrin

Courtesy of Helmut Rennke, MD.

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Nailfold capillary changes and evidence of digital ischemia

Many patients progress to systemic sclerosis within three years

Scleroderma sine scleroderma

Raynaud phenomenon may be present

Limited cutaneous scleroderma