Scleroderma Renal Crisis: Not so easy to diagnose and manage…

Author: Tim Montrief (@EMinMiami, EM Resident Physician, Jackson Memorial Health System) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case: A 56-year-old man diagnosed with diffuse scleroderma 6 months earlier presents to the emergency department with 1 hour of progressive chest pain and dyspnea. His blood pressure (BP) is 216/126 mm Hg, pulse rate 130 beats/min, respiratory rate 40 breaths/min, and temperature 36°C (97°F). He is fully oriented but in severe respiratory distress. Auscultation demonstrates extensive pulmonary rales. He has classic cutaneous findings of scleroderma including taut skin, sclerodactyly, and Raynaud’s phenomenon. Laboratory values are notable for renal insufficiency (blood urea nitrogen 30 mg/dL, creatinine 2.0 mg/dL), the ECG shows left ventricular strain, and the chest radiograph shows severe pulmonary edema. What are your next steps?

Background

Scleroderma, also called systemic sclerosis (SSc), is a rare, life-threatening, autoimmune mediated, widespread inflammatory connective tissue condition causing fibrotic changes in the skin and vasculature, ultimately affecting the major organ systems.^1,2  The pathologic hallmark of SSc is uncontrolled accumulation of collagen and widespread vasculopathy characterized by thickening of the vascular wall and narrowing of the vascular lumen. While the exact pathogenesis of SSc remains elusive, autoantibody production, lymphocyte and fibroblast activation, vascular proliferation, obliterative microvascular disease, and connective tissue fibrosis all likely play a role.³  SSc affects women 4 times as often as men, with an average age of onset between 30 and 60 years of age.^2,4,5

SSc is determined by the extent of cutaneous manifestations and classified as either limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc).^1-4,6  The magnitude of skin and organ involvement directly correlates to the patient’s clinical course, morbidity, and mortality, with the most dismal prognosis associated with diffuse disease.^1,2  LcSSc predominantly affects the peripheral aspects of the body distal to the elbows and knees and is characterized by sclerodactyly and acrosclerosis.^1,7  However, lcSScmay present with Raynaud disease, dysphagia, calcinosis cutis, telangiectasia, pulmonary hypertension, or biliary cirrhosis.^2,7

Conversely, dcSSc involves the more proximal aspects of the extremities and the trunk, including the cardiac, pulmonary, gastrointestinal, and renal systems.^1,5-8  Scleroderma renal crisis (SRC) is a life-threatening complication commonly associated with dcSSc, predominantly occurring within the first 5 years after disease onset.⁴  The pathophysiology of SRC centers around an abrupt onset of moderate to severe hypertension that is typically associated with an increase in plasma renin activity and acute kidney injury (AKI).^1,2,9  SRC occurs roughly in 4–6%^10,11 of SSc patients, predominantly affecting those with diffuse SSc.¹²  Historically, SRC has been reported to occur in up to 25% of SSc patients, whereas recent literature suggests a decrease to less than 5% of these patients and less than 2% of those with lcSSc.¹⁰  In approximately 10% of patients, SRC occurs in the absence of hypertension, leading to the definition of normotensive SRC.^4,13

There are a number of risk factors that predict the occurrence of SRC, including SSc duration < 4 years, diffuse and rapidly progressive skin thickening, palpable tendon friction rubs, and new anemia or cardiac events (e.g., pericardial effusion or congestive heart failure).^14-18  Another important risk factor for SRC is the use of glucocorticoids, particularly in high doses (e.g.prednisone >15 mg per day), which exhibits a dose-dependent effect on the risk of SRC development.^{19-2  1}Glucocorticoids result in salt and volume retention, the initiation or worsening of hypertension, and greater chance of SRC in a subset of patients.

Clinical features of scleroderma renal crisis

Although there is no generally accepted or validated definition of SRC, an updated consensus classification has been proposed(Table 1),^9,22  focusing on an abrupt onset of moderate to severe hypertension and a decline in renal function.^1,2  Supportive features include evidence of microangiopathic hemolytic anemia (MAHA), findings of accelerated hypertension on retinal exam, oliguria/anuria, flash pulmonary edema, and stereotypical features of SRC on renal biopsy.²²

Differential Diagnosis of SRC

Discovering the underlying etiology of acute renal failure as a complication of SSc is not always obvious, and the diagnosis of SRC is challenging. In case of acute renal failure with SSc, a number of differential diagnoses should be considered.²³  Renal arterial stenosis can present with malignant HTN.^24,25  Hypovolemia can mimic SRC. Thrombotic thrombocytopenic purpura (TTP), anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, crescentic rapidly progressive glomerulonephritis (RPGN), and atypical hemolytic uremic syndrome (aHUS), which remain uncommon presentations of acute renal failure in SSc, can present similarly to SRC.^26-30  Differentiating these conditions is crucial to enable effective management and prognostication for these patients.

Even in a patient with cutaneous signs of SSc, the presence of MAHA and accelerated hypertension or the findings of thrombotic microangiopathy raise the possibility of a primary hematological diagnosis, including thrombotic TTP and aHUS.²⁶ A low ADAMTS13 activity is a key feature of TTP, which helps distinguish it from SRC-related thrombotic microangiopathy, although a renal biopsy might be needed to confirm this diagnosis.^22,31-32  In most institutions, results of the ADAMTS13 assay will not be available early enough to affect the immediate clinical management. Furthermore, there have been reports of patients presenting with both SRC and TTP.^33-35  The distinction has significant clinical importance as plasmapheresis, the primary treatment for TTP or aHUS in the acute phase, has not a demonstrated treatment for patients with SRC. Fever and hemorrhagic manifestations are the principal clinical findings that differentiate cases of TTP and aHUS from SRC.²²

Pauci-immune ANCA-associated vasculitis (AAV) with glomerulonephritis is another potential cause of acute renal failure in SSc patients.^36-41  Likewise, less than 1% of patients with SSc develop AV, although up to 12% of these patients have ANCA antibodies.^42,43  It is important to note that malignant HTN and thrombotic microangiopathy are often absent in cases of AAV with glomerulonephritis.^43-45  Distinguishing between AAV with glomerulonephritis and SRC is important, as treatment and prognosis differs greatly between the two. For instance, intravenous or oral administration of cyclophosphamide and rituximab induce and maintain remission in most patients with AAV and glomerulonephritis, however, this is not a proven therapy for SRC.⁴⁶

History and physical pearls

The diagnosis of SRC is based upon the characteristic findings in high-risk patients with SSc, and primarily centers on a presentation of rapidly progressive hypertension and renal failure. The presentation of patients with SRC, as with many diseases, may include variable history, physical examination, and diagnostic findings. Typically, patients who go on to have renal crisis do not have hypertension prior to the acute onset, and the rise in blood pressure is rapid. In cases where blood pressure is checked regularly, normal blood pressures have been seen as recently as 24 hours prior to the diagnosis of SRC.⁴⁷  As in other causes of accelerated hypertension, patients may complain of severe headache with visual disturbances or other encephalopathic symptoms. Hypertensive encephalopathy in SRC is characterized by an acute or subacute onset of lethargy, fatigue, and confusion.^13,48  If untreated, this hypertensive encephalopathy may lead to cerebral hemorrhage, particularly in the presence of thrombotic microangiopathy, resulting in coma and death.⁴⁹  Seizures, either focal or generalized, may be the first manifestation of SRC.^50,51  Patients may present with signs and symptoms of elevated renin levels and accelerated hypertension, including signs of congestive cardiac failure, pericardial effusion, or arrhythmias.⁵²  Fundoscopy may demonstrate hypertensive retinopathy.⁵³

The presenting BP of the patient with SRC varies, but a large majority has significant hypertension, with up to 90% having BP levels greater than 150/90 mmHg, and 30 % having diastolic recordings greater than 120 mmHg.²²  A BP in the normal range is observed in approximately 10% of SRC cases, although these patients usually have a significantly raised BP compared to their baseline measurements.⁴⁷

As in other forms of AKI, patients may present with oliguria or with uremic symptoms. In severe cases of SRC, vascular occlusion and tissue ischemia may lead to renal infarcts and subcapsular hemorrhages visible on autopsy.⁵⁴  Given the rapidly progressive nature of SRC, patients may present with flash pulmonary edema due to congestive heart failure related to HTN and/or diastolic left ventricular dysfunction in the context of oliguric renal failure.^22,55  Progressive dyspnea may present with evidence of pulmonary hemorrhage as well.¹³  Approximately half of patients with SRC will present with evidence of MAHA.^5,56  Physical exam signs include jaundiced or pale skin, dark urine, and splenomegaly.

Thus, in any patient presenting with malignant hypertension or AKI, SSc should be considered. Clinical features that help identify patients with SSc in this context are recent-onset Raynaud’s phenomenon, acute onset of fatigue, weight loss, polyarthritis, swollen extremities, carpal tunnel syndrome, and tendon friction rubs.^57-59  The skin thickening that progresses to a diffuse form of SSc usually presents after a few months from the first symptoms.⁴⁸  However, it is important to note that SRC can occur in patients without evidence of skin thickening or other manifestations of SSc.^60,61  The main clinical features of SRC in published data for cohorts are provided in Figure 1.

Laboratory and Imaging considerations

When evaluating a patient for SRC, laboratory and imaging is guided by clinical presentation and differential diagnosis. It is reasonable to obtain a complete blood count and serum chemistries evaluating for anemia, thrombocytopenia, electrolyte abnormalities, and kidney function. A urinalysis with microscopy and peripheral blood smear may help further characterize AKI and thrombocytopenia. Laboratory findings consistent with SRC include a markedly elevated serum creatinine (increased ≥10% from baseline). Urinalysis frequently shows mild proteinuria (0.5 to 2.5 g/l), and microscopic hematuria which corresponds to hemoglobinuria in most cases.^20,48  Proteinuria in the nephrotic range may be due to toxicity of NSAIDs, and any intentional or unintentional ingestions should be considered.^19,62  A number of substances may precipitate SRC, including cocaine and cyclosporine.^63,64  Additionally, thrombotic microangiopathy, characterized by hemolytic anemia and thrombocytopenia, occurs in up to 50% of cases.^20,48  Additional investigations may include coagulation studies, including fibrinogen, and cardiac enzymes. Rheumatologic testing, while not required, may help the emergency physician differentiate SRC from other rheumatological disorders. Anti-nuclear antibodies (abs) are common in patients with SRC, including anti-topoisomerase abs, anti-RNA polymerase III abs, and anti-centromere abs.⁶⁵  When distinguishing SRC from TTP, ADAMTS13 activity may be helpful, although it is rarely available in the ED.

Imaging is not necessary to diagnose SRC, although it can provide valuable information. Renal ultrasound is typically unremarkable in SRC but may be useful in some patients to rule out urinary tract obstruction or nephrolithiasis as a cause of AKI. Additionally, the renal vascular resistive index, a measure of intrarenal vascular elasticity and compliance assessed using Doppler ultrasound, can be helpful. The resistive index is sensitive to renal vascular disease and correlates with GFR and digital microvascular damage in scleroderma.⁶⁶  In the patient presenting with acute pulmonary edema, point-of-care echocardiography may show pericardial effusions and left ventricular systolic dysfunction, which are common findings secondary to the increased afterload on the heart in SRC. Signs of pulmonary hypertension are occasionally seen on echo, but in patients with SRC, this is primarily a transient secondary phenomenon due to accelerated hypertension rather than chronic pulmonary arterial hypertension.^21,22  A chest x-ray may help rule out other causes of acute dyspnea, including pneumonia and pneumothorax, and a computed tomography scan of the brain may help evaluate for intracranial catastrophes in the encephalopathic patient.

Management of scleroderma renal crisis

General Considerations

If left untreated, SRC can progress to end-stage renal disease (ESRD) over a period of 1-2 months, with death usually occurring within 1 year.⁴⁷  While the early diagnosis and initiation of treatment in SRC remains difficult, prompt recognition of SRC is imperative. The mainstay of therapy in SRC is effective and prompt blood pressure control, which has been shown to improve or stabilize renal function in approximately 70% of patients and improving survival in nearly 80% at 1 year.⁶⁷  However, the success with antihypertensive therapy is dependent upon its initiation before irreversible renal damage has occurred.⁶⁸  General supportive care and symptomatic management are necessary components of SRC treatment. In addition to close hemodynamic monitoring and renal replacement therapy (RRT) when required, a higher-level care of the patient with SRC may include ventilatory support in the patient with severe pulmonary edema and sedation or anti-seizure medications for those with hypertensive encephalopathy. Early consultation with both nephrology and intensive care teams, when appropriate, should be sought. Given the remaining diagnostic uncertainty in this field, if a diagnosis of TTP or HUS is suspected in a scleroderma patient, plasmapheresis should be considered in close consultation with a hematologist.²⁶

ACE Inhibitors (ACEi)

The optimal antihypertensive agent for SRC is an ACEi. Immediately upon diagnosis of SRC, an ACEi should be introduced or the dose increased if the patient is already taking one at home.^69,70  A short-acting ACEi (e.g., captopril) may theoretically be preferable in the hemodynamically unstable patient, but there is little evidence that it is preferable in general to a once-daily medication (e.g., enalapril or ramipril).⁶⁸  A short-acting ACEi has the advantage of rapid onset with peak effect at 60-90 min and short duration of action, permitting rapid dose titration compared with enalapril, which is not routinely used in the ED due to its longer duration of action (up to 36 h).^22,71  In consultation with a nephrologist, a long-acting ACEi may be added at a moderate dose (e.g. ramipril 5 mg).

Among hypertensive patients without evidence of central nervous system involvement (eg, encephalopathy, papilledema), captopril is begun at a dose of 6.25-12.5 mg with a progressive dose escalation in 12.5-25 mg increments at 4-8-hour intervals until the goal blood pressure is reached (Figure 2).⁵  The maximum captopril dose is 300-450 mg/day. For hypertensive patients with evidence of CNS involvement, you may administer the same captopril dose escalation regimen and for further acute blood pressure control, add intravenous agents. In normotensive SRC patients, initiate captopril at a dose of 6.25 mg and, if tolerated, increase the dose to 12.5 mg at the second dose.⁵  Further dose escalation must be done carefully to prevent hypotension and is commonly titrated in the inpatient setting. For those patients who have blood pressures within the normal range, yet still higher than the patient’s baseline, the goal is lowering the blood pressure to the previous baseline. Any rise in serum creatinine after initiating an ACEi should not trigger dose reduction or ACEi cessation, as the rise in serum creatinine is likely secondary to the underlying SRC than the ACEi.²²

Throughout treatment, it is recommended that a methodical reduction in BP be pursued, as a precipitous decrease leads to reduced renal perfusion and increases the risk of acute tubular necrosis. The eventual goal is to reach the patient’s pre-SRC BP with 72 hours.⁷⁰  In the absence of a diagnosis of hypertensive emergency, a steady reduction in the systolic blood pressure (SBP) of 20 mm Hg and diastolic blood pressure (DBP) of 10 mm Hg per day is preferable.²²  Although SRC-related hypertension is acute, rapid BP reduction to baseline has not been shown to bear the same risks as seen with rapid BP reduction in patients with chronic hypertension; nevertheless, conventional practice standards are not to exceed a maximum reduction in the systolic blood pressure (SBP) of 20 mm Hg and diastolic blood pressure (DBP) of 10 mm Hg per day. However, in the case of hypertensive emergency, aim to reduce the mean arterial pressure by 10-20% within one hour, targeting a DBP of 100-110 mm Hg within 24 hours.⁷²  (Figure 2)

Other BP Lowering Agents

While theoretically angiotensin receptor blockers (ARBs) should prove effective in SRC, these agents have not been adequately evaluated in this setting, and efficacy has not been established.^73,74  However, due to the limited evidence, consensus opinion recommends these agents as possible second line agents if hypertension is unresponsive to an ACEi.^22,75  There is no evidence regarding the role of direct renin inhibitors.²²  Dihydropyridine calcium channel blockers (CCBs), most commonly nifedipine, are appropriate for the treatment of vasospastic conditions, including Raynaud disease, which occurs in more than 90% of dcSSc patients. CCBs, particularly short-acting, are commonly recommended agents for SCR resistant to ACEi and/or ARBs.^70,75  Other antihypertensive drugs that can be added to ACEi monotherapy, if necessary, include diuretics for fluid overload, and/or centrally acting α-blockers such as clonidine.^70,75  Although α-blockers may increase the likelihood of hypotension when used in combination with an ACEi, expert consensus recommends these agents as adjunctive treatments.^70,76  Beta blockers are usually avoided in patients with SSc due to the theoretical risk of worsening vasospasm, including Raynaud phenomenon.⁷⁷  The addition of endothelin-1 receptor antagonists (e.g.bosentan) has been used in patients with resistant hypertension. However, the long-term safety of these agents has not been demonstrated, and they are not routinely suggested as pharmacotherapy for SRC.^78,79

In those patients presenting with signs and symptoms of hypertensive emergency, more aggressive management may be pursued.⁷⁰  The parenteral antihypertensive agents most often used in the initial treatment of these patients with SRC include sodium nitroprusside, nitroglycerin, and enalaprilat.^69,72  These infusions should be discontinued as soon as possible with the addition of  short-acting ACEi’s in increasing doses which may lead to significant hypotension.

Dialysis and Renal Transplantation

Despite appropriate ACEi therapy, dialysis is needed in approximately 60% of patients with SRC.^12,48  If indicated, either hemodialysis or continuous peritoneal dialysis is an effective therapy for ESRD due to SRC.^5,67,80-82  There is limited experience in regards to renal transplantation in patients with SRC, in part because transplantation is sometimes precluded by the severity of the extrarenal manifestations of SSc. Early consultation with a nephrologist is encouraged for all cases of SRC.

Alternative therapies

Historically, treatment with the copper chelating agent d-penicillamine was once believed to be clinically beneficial, but has fallen out of favor in contemporary literature.^83-85  Recent literature has shown d-penicillamine to be associated with significant adverse effects with no reduction in morbidity or mortality.^70,86  Therefore, its use is strongly discouraged in patients with SRC.^67,70

Therapies for SSc

Treatment regimens for SSc without evidence of SRC are aimed at improving peripheral circulation, preventing the synthesis and release of harmful cytokines, and inhibiting fibrosis.⁸⁷  This is commonly done using immunosuppressive agents, including vitamin D analogues, UV-A phototherapy, corticosteroids, cyclosporine, azathioprine, and methotrexate.^86,88  However, the aforementioned agents have no therapeutic role in the acute management of SRC.⁷⁰

Prognosis and disposition

Before the 1970s and the widespread use of ACEi’s, SRC almost always resulted in renal failure and death, usually within months of diagnosis.⁶⁷  The use of an ACEi greatly improved the prognosis of SRC, and patients who survive SRC without the need for dialysis or only temporary dialysis have excellent outcomes with a 5-year survival of 90%.^70,79,89  Many of these patients will require close hemodynamic monitoring only available in the intensive care setting.

Conclusion

SRC remains a rare diagnosis, affecting up to 6% of patients with SSc, but continues to have a large burden of morbidity and mortality. Due to the fact that the presentation of SRC is variable, with some patients being hypertensive and others being normotensive, and some with evidence of renal insufficiency, clinicians should be aware of potential presentations and clinical histories associated with SRC. Prompt recognition and initiation of aggressive antihypertensive therapy with an ACEi in the ED offers the best opportunity for a good outcome. Early consultation with the critical care and nephrology teams is important, as roughly 60% of SRC patients will require dialysis.

 Pearls and Pitfalls

• Scleroderma renal crisis (SRC) develops in 5-20% of SSc patients, most commonly within 48 months of diagnosis and in those with dcSSc.
• The diagnosis of SRC is based upon characteristic findings in high-risk patients with SSc, including new onset of blood pressure >150/85mmHg 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 significant hypertension, new-onset proteinuria or hematuria, and other less common features.
• SRC treatment focuses on early nephrology consultation and aggressive BP control
  • Among hypertensive patients without evidence of central nervous system involvement (eg, encephalopathy, papilledema), captopril can be started at 6.25-12.5 mg with a progressive dose escalation in 12.5-25 mg increments at 4-8-hour intervals until the goal blood pressure is reached.
  • For those hypertensive patients with evidence of hypertensive emergency, you may administer the same captopril dose escalation regimen as above and, for further acute blood pressure control, add intravenous agents.

Case Resolution

You intubate the patient, and the serum renin plasma activity returned at 24.5 ng/mL per hour (normal range=0.77 to 4.6 ng/mL per hour). You promptly initiate blood pressure control with intravenous nitroglycerin, furosemide, and nitroprusside. This is followed by high-dose intravenous enalaprilat and admission to the ICU. The patient responds well to therapy and is discharged a week later.

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