Introduction
Scleroderma renal failure is a highly fatal complication of scleroderma which causes overall inflammation and tightening of connective tissues with serious implications on kidney functioning. Scleroderma is a muti-systemic autoimmune disorder that primarily affects the skin. Renal failure is seen in about 10 % of all scleroderma patients.
Who Is Susceptible to Scleroderma Renal Crisis?
Historically, the renal crisis has been observed in 20 percent of patients suffering from scleroderma. The complication has shown a declining candle with time. Currently, about five to 10 percent of scleroderma patients progress to the renal crisis. The condition, previously, showed a predilection to the African-American and the male population, but current studies have nullified any associated preference. A seasonal variation is evident, with a greater number of cases during fall and winter.
What Causes Scleroderma Renal Crisis?
Out of all scleroderma renal crisis patients, 10 to 25 percent are pertinent in diffuse scleroderma and one to two percent with limited scleroderma variant. The renal crisis usually develops early in the course of scleroderma with up to three-fourths of the crisis presenting within the first four years of diagnosis, with a median time adjusted at eight months. In a few cases, a scleroderma renal crisis may occur without any initial presentation of scleroderma which is known as scleroderma renal crisis sans scleroderma.
Predictive factors of scleroderma renal crisis include:
- Diffuse cutaneous involvement.
- Rapid progression of scleroderma.
- Anti-RNA polymerase III antibodies in serum.
- Greater than 15 mg/day of corticosteroid therapy.
- Tendon friction rubs.
- Anemia.
- Pericarditis.
- Congestive cardiac failure.
What Is the Pathophysiology of Scleroderma Renal Crisis?
The pathophysiology of the scleroderma renal crisis remains partly understood. A hypothesis states that injury to the endothelial cell results in structural damage to the blood vessels with intimal thickening, proliferation, and fibrin deposition. Another hypothesis suggests that vascular hyperactivity leads to Raynaud’s phenomenon that leads to decreased renal perfusion and increased scleroderma renal crisis frequency in winter. Cortical blood flow is significantly decreased in patients with renal crisis and progressive renal failure. Activation of the R-A-A-S system (renin-angiotensin-aldosterone system) has been studied as physiopathologic to the scleroderma renal crisis.
Factors responsible for reduced vascular flow which then may trigger scleroderma renal crisis:
- Sepsis.
- Dehydration.
- Cardiac arrhythmia.
- Congestive heart failure.
- Use of nephrotoxic drugs.
- Use of controlled substances like cocaine.
- Medications like Cyclosporine and corticosteroids.
- Medium to high doses of corticosteroids (greater than 15 mg/day).
- Increased circulating levels of endothelial-1 (ET-1).
- Prostacyclin.
- Blood pressure.
- Fluid shifts.
What Is the Histopathology of Scleroderma Renal Crisis?
Histopathological changes are seen in small interlobular and arcuate arteries with pathologic changes which are similar to those seen in malignant hypertension and thrombotic microangiopathies.
Histologic slides produced from renal samples present with:
- Myxoid intimal proliferation.
- Luminal narrowing.
- Smooth muscle cell infiltration.
- Deposition of collagen occurs in the intima.
- Concentric fibrosis or onion skin appearance.
- Superimposed fibrin thrombi.
- Fibrinoid necrosis of the media of the vessels.
- Ischemic collapse or fibrinoid necrosis of the glomeruli.
- Ischemic injury.
- Tubular degeneration.
- Acute necrosis.
- Tubular atrophy.
- Interstitial fibrosis.
- Vascular injury.
What Are the Signs and Symptoms of Scleroderma Renal Crisis?
The symptoms of scleroderma renal crisis present with a combination of sudden severe hypertension with oligo-anuric renal failure in patients with prior diffuse scleroderma.
The symptoms of scleroderma renal crisis are:
- Non-nephrotic proteinuria (150 mg to 3.5 g of protein excretion in urine per day).
- Hematuria (blood in urine).
- Benign urine sediment (microscopic gritty particles or mucus in the urine).
- Hypertensive retinopathy.
- Encephalopathy.
- Headache.
- Confusion.
- Seizures.
- Changes in mental status.
- Altered vision.
- Congestive heart failure.
- Rapidly progressive dyspnea.
- Pulmonary hemorrhage.
- Diastolic left ventricular dysfunction.
- Pericardial effusion.
- Thrombocytopenia.
- Lethargy.
- Microangiopathic hemolytic anemia.
- Weight loss.
- Polyarthritis.
- Swollen hands and lower legs.
- Carpal tunnel syndrome.
- Tendon friction rubs.
How to Diagnose Scleroderma Renal Crisis?
The presence of renal involvement in scleroderma patients may be suspected and regular monitoring may be conducted to aid in early diagnosis. The diagnosis is usually with the help of serological studies. The physical or clinical presentation is that of diffuse or limited scleroderma. The renal crisis presents with systemic manifestation, detectable via blood and urine markers in laboratory studies.
- Urine Analysis:
- Mild proteinuria (0.5 to 2.5 g/L of urine).
- Hematuria.
- Serological Analysis:
- Hemolytic anemia.
- Increased serum creatinine levels.
- Schistocytes (indicating hemolysis).
- Moderate thrombocytopenia (more than 50,000/ mm3)
- Anti-topoisomerase antibodies.
- Anti-RNA polymerase III antibodies.
- Anti-centromere antibodies.
How to Treat Scleroderma Renal Crisis?
Early treatment planning against scleroderma renal crisis is questionable as the occurrence of renal events post-scleroderma is variable. ACE inhibitors like Captopril are currently used against the condition which has, historically, shown therapeutic results. The ACE inhibitors must be continued even with progressive deterioration of kidney function. Angiotensin II inhibitors are also indicated but with comparatively less efficacy. If maximum dosages of ACE inhibitors are found to be insufficient, then a dihydropyridine calcium channel blocker can be added to the regimen. Diuretics must be avoided as they stimulate the R-A-A-S (pathophysiologic to the condition).
A continuous low-dose Prostacyclin (vasodilator) regimen can be added to the standard pharmacotherapy. In events of thrombotic microangiopathy, plasma exchange has been suggested but has shown limited success with low success. Plasma exchange has been fruitful in a handful of patients presenting with microangiopathy associated with autoantibodies against the ADAMTS13 antigen.
ACE inhibitors may result in further decline in kidney function and the patient must be considered for dialysis. Since ET-1 has been found etiologic, endothelin receptor antagonists may be included in the management protocol. On extreme ends, if there is no significant improvement even after two years of therapy, a kidney transplant may be performed. Kidney transplant followed by long-term dialysis has shown significant survival benefits.
What Is the Prognosis of Scleroderma Renal Crisis?
Before the introduction of ACE inhibitors, the survivability of patients was not considered beyond 12 months in 90 % of the patients, whereas now, 85 % survivability can be anticipated after one year and 65 % after five years of initiation of treatment. 33 % of the patients require transplantation, out of which more than half would eventually recover to continue with long-term dialysis. The mortality rate is higher in patients needing dialysis. Recurrence, post-transplantation, is rare and seen in less than 5 % of transplants. The recurrence is mostly seen if the initial progression of the disease was very aggressive.
What Is the Differential Diagnosis of Scleroderma Renal Crisis?
- Thrombotic microangiopathy.
- Malignant hypertension.
- Rapidly progressive glomerulonephritis
- Autoimmune thrombotic thrombocytopenic purpura.
- Renal toxicity of D-penicillamine.
- Renal arterial stenosis.
- Pauci-immune ANCA-associated vasculitis (AAV).
What Are the Complications of Scleroderma Renal Crisis?
- Kidney failure.
- Chronic allotrophic graft rejection.
- Recurrent scleroderma renal crisis.
- Death.
- Multisystem organ failure.
Conclusion
Scleroderma renal crisis was considered a definitively fatal condition before the discovery of ACE inhibitors. Currently, early diagnosis and therapy have shown great leaps in prognosis and have dipped the fatality rate considerably. Scleroderma patients must be monitored regularly and interdisciplinarily to detect early signs and prevent progressive damage to the kidneys. With adequate care, the patient can hope for uneventful life standards.
