Robert Fox, MD

Disclosures

July 12, 2005

Question

What is scleroderma renal crisis and how is it managed?

Gadintshware Gaoatswe, MD

Response From the Expert

   Robert I. Fox, MD, PhD 
Member, Rheumatology and Medicine Department, Scripps Memorial Hospital, La Jolla, California

Severe and life-threatening renal disease develops in approximately 10% to 15% of patients.[1] This form of renal involvement is termed scleroderma renal crisis and is characterized by:

  • The acute onset of renal failure

  • The abrupt onset of moderate to marked hypertension (although some patients remain normotensive)[2]

  • A urine sediment that is usually normal or reveals only mild proteinuria with few cells or casts

Blood pressure control with angiotensin-converting enzyme (ACE) inhibitors with gradual reduction of malignant hypertension is the cornerstone of treatment. Other agents such as calcium channel blocking agents may be added. Renal dialysis may even be required. It is important that the blood pressure be lowered gradually (ie, avoid use of intravenous nitroprusside or labetalol) and do not let the patient develop hypovolemia. An excellent review summarizes pathogenesis and treatment.[1]

Comment

Scleroderma renal crisis constitutes one of the medical emergencies in rheumatology.[3] Blood pressure control is the mainstay of therapy in scleroderma renal crisis. Aggressive treatment of hypertension can stabilize or even improve renal function in up to 55% to 70% of cases, if begun before marked irreversible vascular injury has occurred.[4] An ACE inhibitor is the agent of choice, leading to an improvement in blood pressure in up to 90% of patients by reversing the angiotensin II-induced vasoconstriction. This hypotensive response has, in some patients, also led to regression of the sclerodermatous skin changes and improvement in the Raynaud phenomenon.[5] How this might occur is not known, although a reduction in microvascular pressures or an increase in local flow may be involved. Nevertheless, the mortality is high and a poor outcome is common.[6]

The overall benefit of blood pressure control is best achieved by a gradual reduction in pressure (10-15 mmHg per day) until the diastolic pressure reaches 85-90 mmHg. An excessive reduction in pressure and hypovolemia should be avoided because both can further diminish renal perfusion and superimpose acute tubular necrosis upon the lesions of scleroderma. Thus, parenteral antihypertensive agents (such as intravenous nitroprusside or labetalol) should be avoided, if possible, as should other nephrotoxins such as nonsteroidal anti-inflammatory drugs and radiocontrast agents. A central venous pressure line or Swan-Ganz catheter can be useful in monitoring hemodynamics when parenteral drugs must be used.

When compared with other antihypertensive agents, the ACE inhibitors have increased antihypertensive efficacy, appear to be associated with improved survival, and lead to better preservation of renal function. As an example, one prospective (although not controlled) study of patients with scleroderma renal crisis noted the following advantages in patients treated with an ACE inhibitor when compared against those treated with other drugs[1]:

  • A calcium channel blocker, usually nifedipine, can be added if there is an inadequate response to the ACE inhibitor. In addition, other therapies have also been used in scleroderma renal crisis.
     

  • Intravenous prostacyclin (epoprostenol), which is believed to help the microvascular lesion without precipitating hypotension, is often administered at the onset of hypertensive renal crisis in the United Kingdom. This is based upon anecdotal observations of benefit.
     

  • Fish oil is sometimes prescribed in view of its theoretically beneficial hemodynamic and antiplatelet properties. However, its efficacy is unproven.
     

  • Short-term hemodialysis can be started if necessary, and continuous peritoneal dialysis often works well if long-term renal replacement is needed. As noted above, there is frequently considerable recovery of renal function after an acute scleroderma crisis, which may permit the discontinuation of dialysis in those with advanced renal failure.[4] The improvement in renal function can continue for up to 2 years. As a result, any decisions regarding renal transplantation should not be made during or shortly after the acute episode.

There is little experience with renal transplantation in scleroderma, as transplantation is often limited by the severity of the extrarenal manifestations.[7] Allograft survival is lower compared with that of transplant recipients without scleroderma. Among the reported patients, graft survival rates at years 1-5 post transplantation were 62%, 60%, 57%, 50%, and 47%, respectively.[8,9] The use of cyclosporine does not appear to be associated with either improved or decreased allograft survival.

The recurrence rate has been estimated to be approximately 20%.[10] However, the exact frequency of recurrent disease is difficult to ascertain, since the primary histologic changes induced by scleroderma (mucoid intimal thickening of the interlobular arteries and fibrinoid necrosis in the glomeruli) may be difficult to differentiate from acute or chronic vascular rejection.

Renal allograft recipients with recurrent disease tend to follow a malignant course, similar to that in primary scleroderma renal crisis.[11]

Scleroderma Without Overt Clinical Renal Disease

Even scleroderma patients without overt clinical renal disease have physiologic evidence of compromised renal function.[1] Assessment of renal function in such patients may show decreased renal plasma flow, higher renal vascular resistance, and a blunted response to an amino acid challenge (a challenge that substantially increases the glomerular filtration rate in healthy subjects).[1]

Prevention

Therapy is most likely to be effective in scleroderma renal disease if initiated early, before marked and often irreversible injury has occurred. As noted above, patients with diffuse skin disease are at greatest risk. Monitoring is most important during the first 5 years of scleroderma, since most cases of renal disease occur by this time.

  • Blood pressure measurement on a monthly basis. For patients who show any signs of a rising blood pressure without evidence of renal disease, we switch to home blood pressure measurement several times per week.
     

  • Measurement of the plasma creatinine concentration and dipstick testing for protein or calculation of the protein-to-creatinine ratio on a random urine specimen every 3-6 months.
     

  • An elevation in the plasma creatinine concentration (or fall in creatinine clearance, which may need to be measured in patients who have lost muscle mass) or new persistent proteinuria > 500 mg/day are important warning signs of impending renal crisis.

There has been suggestion that the use of corticosteroids may play a role in the onset of scleroderma renal crisis.[7,12]

Differential Diagnosis

Renal biopsy does not definitively establish the diagnosis of scleroderma renal disease because indistinguishable changes can occur in any of the other forms of thrombotic microangiopathy, including malignant nephrosclerosis (due to accelerated hypertension), the hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, radiation nephritis, chronic transplantation rejection, and the antiphospholipid antibody syndrome. The hemolytic-uremic syndrome or the related disorder thrombotic thrombocytopenic purpura, however, usually presents with prominent thrombocytopenia and a microangiopathic hemolytic anemia (which may also be induced to a less marked degree by the vascular injury in scleroderma). The diagnosis of one of these disorders is typically suggested from the acute onset of severe hematologic manifestations and a possible inciting cause, such as diarrhea in children or certain forms of chemotherapy in adults.

Pathogenesis

The primary histologic changes in the kidney are in the arcuate and interlobular arteries and the glomeruli.[5] Fibrin thrombi and areas of fibrinoid necrosis are seen acutely. Key factors involved in progression of renal disease include accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments, epithelial to mesenchymal transformation, and vascular changes.[13] The relevant factors mediating these events include the renin-angiotensin system, the profibrotic growth factors, transforming growth factor-beta and connective tissue growth factor, and reactive oxygen species.

Healing leads sequentially to mucoid intimal thickening and then to concentric "onion-skin" hypertrophy of the interlobular arteries, similar to the vascular lesions in other organs. Despite the similarity to the renal changes induced by malignant hypertension, vascular disease is the primary event in scleroderma, as evidenced in part by the occasional occurrence of scleroderma renal crisis in the absence of hypertension.[8] Nevertheless, it is likely that severe hypertension, when present, potentiates the underlying vascular injury. Hyperreactivity of blood vessels to the cold and to catecholamines also may play a contributory role.[14]

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