Renal disease in small-vessel vasculitis
ABSTRACTGlomerulonephritis (GN) is a common manifestation of the antineutrophil cytoplasmic antibody–associated systemic vasculitides (AASV), which include granulomatosis with polyangiitis and microscopic polyangiitis. The level of renal involvement at presentation is highly predictive of survival and should be assessed early so that kidney function can be preserved. AASV patients with urinary sediment but normal function have a twofold greater risk of death than those with no renal involvement. Those with impaired renal function at diagnosis have a fivefold greater risk of death. Renal vasculitis is most prevalent in older patients, who have more severe disease and poorer prognoses. Renal biopsy not only establishes diagnosis but provides information on severity of renal-function impairment and prognosis. Induction of remission with cyclophosphamide is standard treatment. For patients with crescentic, rapidly progressive GN, adjunctive plasma exchange can promote renal recovery. Renal failure occurs in one-fourth of AASV patients after 3 to 4 years; 60% of patients receiving dialysis for acute GN can recover independent renal function. Renal transplant patients with vasculitis fare as well as renal transplant patients without vasculitis. Lastly, renal vasculitis is an independent risk factor for cardiovascular events.
TREATMENT OF AASV
Lower dosage of cyclophosphamide
Standard immunosuppressive treatment for vasculitis is oral cyclophosphamide, 2 mg/kg per day. To reduce toxic effects and amount of the drug used, we tested whether a pulse dose could induce remission. In the EUVAS randomized trial of oral versus pulse cyclophosphamide (the CYCLOPS study),9 149 AASV patients with renal involvement received either pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks, or daily oral cyclophosphamide, 2 mg/kg per day, plus prednisone. The groups did not differ in time to remission (HR, 1.098) or in proportion of patients who had achieved remission at 9 months (88.1% vs 87.7%). The pulse-dose group needed half the amount of drug to achieve remission compared with the oral-dose group. Pulse dosing is currently the preferred method in Europe, where doses are administered in the clinic rather than at home.
In a 4.3-year follow-up, twice as many patients relapsed in the pulse-dose group compared with the oral group (HR, 0.50; P = .029), but there was no difference between groups in renal function (P = .82), end-stage renal disease (ESRD), or death.10 It should be borne in mind that there is a tendency to overtreat. An analysis of four EUVAS trials found a risk of mortality of 11% in the first year; 59% of these were due to treatment-related adverse events.11
Despite being prone to renal failure and infectious complications, elderly patients with ANCA-associated GN who do not have ESRD fare better with immunosuppressive therapy than without in terms of progression and survival. Cyclophosphamide dosage should be reduced in these patients.
Plasma exchange
In crescentic disease and rapidly progressing renal failure, plasma exchange (PE) with albumin reduces circulating antibodies by up to 60% and promotes renal recovery. The MEPEX trial compared the addition of either PE or intravenous methylprednisolone (MEP) to oral cyclophosphamide and prednisolone in 137 newly diagnosed AASV patients with severe crescentic GN (serum creatinine > 500 μmol/L).12 Two-thirds of the group were oliguric. After 3 months, 69% of PE-treated compared with 49% of MEP-treated patients were alive and had achieved independent renal function (P = .02). There was also a reduction in risk for ESRD of 24% at 12 months in the PE versus MEP group. Mortality was similarly high in both groups, however; roughly one-third had died by 12 months, reflecting the higher rates of complications in this older-aged group (median, 66 years).
For patients undergoing PE who have a sudden drop in hemoglobin, gastrointestinal bleeding is only one possible underlying condition. The patient may have bleeding into the pulmonary parenchyma, and computed tomography of the lung should be performed. This is more likely to occur when plasma is exchanged with albumin rather than fresh frozen plasma.
Renal replacement therapy
End-stage renal disease occurs in approximately 25% of patients 3 to 4 years after they present with AASV. Renal-limited disease occurs most often in those with MPA. When there is active rather than sclerotic disease but irreversible renal failure is suspected, immunosuppression can be tried for 3 months. If there is no response, improvement in renal function is unlikely and immunosuppressive treatment is continued only for extrarenal disease. Patients with ESRD can be treated with hemodialysis, peritoneal dialysis at home, or kidney transplant.
Lionaki et al13 described the rate of relapse in AASV patients before and after kidney dialysis compared with that in AASV patients with preserved renal function. Over a median of 40 months, 136 of 523 patients progressed to ESRD. Rate of relapse of vasculitis was significantly lower for the patients on chronic dialysis (0.08 episodes per person-year) than for the same patients before dialysis (0.2 episodes) and for the patients with preserved renal function (0.15 episodes). Infections, an important cause of death, were twice as frequent for patients on dialysis and maintenance immunosuppression.
Weidanz et al14 reported on a retrospective case series that examined whether immunosuppressive therapy with its risk of infection is beneficial for vasculitis patients on dialysis. They retrospectively examined 46 cases of AASV over 30 years and found that the patients with ESRD received less immunosuppression, but their rate of infection was twice that of pre-ESRD patients, and mortality quadrupled while on dialysis. The mode of dialysis did not affect survival, however. These results may support early discontinuation of immunosuppressive treatment in patients with ESRD and suggest that it be used only in those with active disease.
Renal transplant
At the time of transplantation, patients receive a massive immunosupressive induction regimen consisting of anti-CD25 antibody and triple conventional immunosuppressive drugs, usually a calcineurin inhibitor, antimetabolite, and prednisolone. Survival in transplant patients with vasculitis is not significantly different from that of other kidney transplant patients.15
Patients should not receive transplants until at least 12 months after induction of remission; patients who underwent transplant less than 12 months after remission had a mortality HR of 2.3 (P < .05).16 Vasculopathy occurs more frequently in ANCA-positive patients, which leads to graft loss.
Graft loss due to recurrent vasculitis is also possible. Nachman et al17 found double the rate of infection for transplant compared with nontransplant AASV patients, but the rate of relapse was lower than the rate before transplant or for patients on dialysis. There was no significant difference in rates of relapse between patients with or without circulating ANCA at the time of transplant or between those having GPA, MPA, or renal-limited disease.18
Cardiovascular risk
Renal involvement in vasculitis increases cardiovascular morbidity. Vasculitis patients with renal involvement (n =113) were matched with patients with chronic kidney disease and other contributing cardiovascular risk factors.18 After approximately 4 years of follow-up, the vasculitis patients had an HR of 2.23 (P = .017) for cardiovascular events. AASV patients with the highest excess risk had histories of cardiovascular events (HR, 4), dialysis dependency (HR, 4.3), poor renal function at admission (HR, 0.977), and history of smoking (HR, 3.9).
CONCLUSION
Level of renal function at diagnosis is an important predictor of survival. Poor renal function correlates with mortality, especially in the elderly. Pathologic classification of renal vasculitis based on histopathology obtained from the kidney biopsy correlates closely with prognosis. About 60% of initially dialysis-dependent patients with active GN can regain independent renal function. Those on dialysis have a lower rate of relapse of active vasculitis than do those with independent renal function; patients with kidney transplants have the lowest rate of relapse. There is a doubling of infection rate in patients who have ESRD and who receive any form of renal replacement therapy. Lastly, renal involvement in AASV is an independent and serious contributor to risk for cardiovascular disease.
