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Renal disease in small-vessel vasculitis
Necrotizing glomerulonephritis (GN) is the classical renal manifestation of the small-vessel vasculitides, which include granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome). MPA is pauci-immune (lacks antibody depositions) and causes focal segmental necrotizing GN. Other small-vessel vasculitides are Henoch-SchÖnlein purpura, which features nephritis from immunoglobulin A–dominant immune deposits, and essential cryoglobulinemic vasculitis, in which cryoglobulin immune deposits lead to membranoproliferative GN.1
Renal involvement occurs in 25% to 75% of patients with antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV), with the higher percentage reflecting patients who first present to a nephrologist rather than a rheumatologist. Roughly 35% are dialysis-dependent, mainly those who are elderly or proteinase-3– or myeloperoxidase-ANCA–positive. In duc tion of remission through immunosuppression allows 50% to 60% of dialysis-dependent patients to recover independent renal function.2,3
PROGNOSTIC SIGNIFICANCE OF RENAL INVOLVEMENT
Patients should be assessed at the earliest opportunity for renal involvement as it is highly predictive of survival. Diagnosis allows immunosuppressive treatment to be started early, when kidney function may still be preserved.
Reinhold-Keller et al3 examined survival by level of renal involvement at diagnosis in 155 patients with GPA who were followed for a median of 7 years. Survival in those with normal renal function, but with nephritic urinary sediment at diagnosis, declined over time compared with patients who had no renal involvement at diagnosis, with a more than twofold greater risk of death (hazard ratio [HR], 2.41; 95% confidence interval [CI] 0.53–11.06). Patients who had impaired renal function at diagnosis had a fivefold greater risk of death (HR, 5.42; 95% CI 1.76–16.68).
Maximum serum creatinine in the first month of treatment is also highly predictive of survival. An outcome analysis followed 80 patients with AASV and renal involvement for a median of 46.7 months.4 Patients were divided equally into groups by maximum serum creatinine levels after the first month of treatment: less than 299 μmol/L, 299 to 582 μmol/L, and greater than 582 μmol/L. All patients were treated for induction of remission with cyclophosphamide and oral corticosteroids. Survival was significantly worse in patients who had the highest maximum serum creatinine in the first month (P = .025).
Pooled prospective data from four European Vasculitis Study Group (EUVAS) trials of 535 patients with AASV and follow-up of 5.2 years found a mortality ratio of 2.6 (95% CI, 2.2–3.1) compared with matched subjects from the general population.5 Stage 5 chronic kidney disease (glomerular filtration rate < 15 mL/min) was a significant negative prognostic determinant of survival in these trials.
A DISEASE OF AGING
Renal vasculitis is most prevalent in people aged 50 years and older and often occurs in those aged 70 years and older.6 Because the very old may not have extrarenal symptoms, it is necessary to maintain a high index of suspicion for AASV and measure urinary sediment and renal function in this age group.
Older patients also present with more severe renal disease and have a poorer prognosis. Harper and Savage compared presentation and outcomes of patients aged 65 years and older with renal AASV with those of patients younger than 65 years.7 Older patients had more severe renal failure than did younger patients (serum creatinine 657 vs 470 μmol/L, respectively; P < .001), and this did not appear to be associated with delayed diagnosis. Survival was worse in those with serum creatinine levels greater than 400 μmol/L irrespective of age; however, when comparing younger and older groups with similar renal insufficiency, older patients were more likely to progress to end-stage renal failure (P = .039), survival was worse (P = .016), and death occurred earlier.7
HISTOPATHOLOGIC CLASSIFICATION
An international working group of renal pathologists8 developed pathologic classifications for rapidly progressive GN caused by AASV: focal (≥ 50% normal glomeruli), crescentic (≥ 50% glomeruli with cellular crescents), mixed (no predominant glomerular feature), and sclerotic (≥ 50% globally sclerotic glomeruli). These correspond to the order of severity of renal-function impairment. A study of 100 biopsies from patients with ANCA-associated GN found that the classifications at presentation closely correlated with outcomes.8
Patients with sclerotic GN had the worst renal function initially, with little improvement at 5 years; hence, immunosuppression is of little value if the kidney is more than 50% sclerotic. Patients with focal disease who had good renal function initially were found to retain good function after 5 years of treatment. Patients in the crescentic class present with rapidly progressive GN and very poor renal function. However, they were found to improve considerably after 5 years and had good recovery (P = .001). Presenting disease manifestations within the kidney are of diagnostic as well as prognostic value.
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.
- Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an International Consensus Conference. Arthritis Rheum 1994; 37:187–192.
- Booth AD, Almond MK, Burns A, et al; for the Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003; 41:776–784.
- Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000; 43:1021–1032.
- Weidner S, Geuss S, Hafezi-Rachti S, Wonka A, Rupprecht HD. ANCA-associated vasculitis with renal involvement: an outcome analysis [published online ahead of print April 6, 2004]. Nephrol Dial Transplant 2004; 19:1403–1411. doi: 10.1093/ndt/gfh161
- Flossmann O, Berden A, de Groot K, et al; for the European Vasculitis Study Group. Long-term patient survival in ANCA-associated vasculitis [published online ahead of print November 24, 2010]. Ann Rheum Dis 2011; 70:488–494. doi: 10.1136/ard.2010.137778
- Hamour SM, Salama AD. ANCA comes of age—but with caveats. Kidney Int 2011; 79:699–701.
- Harper L, Savage CO. ANCA-associated renal vasculitis at the end of the twentieth century—a disease of older patients [published online ahead of print December 21, 2004]. Rheumatology 2005; 44:495–501. doi: 10.1093/rheumatology/keh522
- Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of ANCA-associated glomerulonephritis [published online ahead of print July 8, 2010]. J Am Soc Nephrol 2010; 21:1628–1636. doi: 10.1681/ASN.2010050477
- de Groot K, Harper L, Jayne DRW, et al; for the EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody–associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670–680.
- Harper L, Morgan MD, Walsh M, et al; on behalf of the EUVAS Investigators. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up [published online ahead of print November 29, 2011]. Ann Rheum Dis 2012; 71:955–960. doi: 10.1136/annrheumdis-2011-200477
- Little MA, Nightingale P, Verburgh CA, et al; for the European Vasculitis Study (EUVAS) Group. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis [published online ahead of print July 1, 2009]. Ann Rheum Dis 2010; 69:1036–1043. doi: 10.1136/ard.2009.109389
- Jayne DR, Gaskin G, Rasmussen N, et al; for the European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vascultis [published online ahead of print June 20, 2007]. J Am Soc Nephrol 2007; 18:2180–2188. doi: 10.1681/ASN.2007010090
- Lionaki S, Hogan SL, Jennette CE, et al. The clinical course of ANCA small-vessel vasculitis on chronic dialysis [published online ahead of print June 17, 2009]. Kidney Int 2009; 76:644–651. doi: 10.1038/ki.2009.218
- Weidanz F, Day CJ, Hewins P, Savage CO, Harper L. Recurrences and infections during continuous immunosuppressive therapy after beginning dialysis in ANCA-associated vasculitis. Am J Kidney Dis 2007; 50:36–46.
- Schmitt WH, van der Woude FJ. Organ transplantation in the vasculitides. Curr Opin Rheumatol 2003; 15:22–28.
- Little MA, Hassan B, Jacques S, et al. Renal transplantation in systemic vasculitis: when is it safe [published online ahead of print July 13, 2009]? Nephrol Dial Transplant 2009; 24:3219–3225. doi: 10.1093/ndt/gfp347
- Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: a pooled analysis. Kidney Int 1999; 56:1544–1550.
- Morgan MD, Turnbull J, Selamet U, et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: a matched-pair cohort study. Arthritis Rheum 2009; 60:3493–3500.
Necrotizing glomerulonephritis (GN) is the classical renal manifestation of the small-vessel vasculitides, which include granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome). MPA is pauci-immune (lacks antibody depositions) and causes focal segmental necrotizing GN. Other small-vessel vasculitides are Henoch-SchÖnlein purpura, which features nephritis from immunoglobulin A–dominant immune deposits, and essential cryoglobulinemic vasculitis, in which cryoglobulin immune deposits lead to membranoproliferative GN.1
Renal involvement occurs in 25% to 75% of patients with antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV), with the higher percentage reflecting patients who first present to a nephrologist rather than a rheumatologist. Roughly 35% are dialysis-dependent, mainly those who are elderly or proteinase-3– or myeloperoxidase-ANCA–positive. In duc tion of remission through immunosuppression allows 50% to 60% of dialysis-dependent patients to recover independent renal function.2,3
PROGNOSTIC SIGNIFICANCE OF RENAL INVOLVEMENT
Patients should be assessed at the earliest opportunity for renal involvement as it is highly predictive of survival. Diagnosis allows immunosuppressive treatment to be started early, when kidney function may still be preserved.
Reinhold-Keller et al3 examined survival by level of renal involvement at diagnosis in 155 patients with GPA who were followed for a median of 7 years. Survival in those with normal renal function, but with nephritic urinary sediment at diagnosis, declined over time compared with patients who had no renal involvement at diagnosis, with a more than twofold greater risk of death (hazard ratio [HR], 2.41; 95% confidence interval [CI] 0.53–11.06). Patients who had impaired renal function at diagnosis had a fivefold greater risk of death (HR, 5.42; 95% CI 1.76–16.68).
Maximum serum creatinine in the first month of treatment is also highly predictive of survival. An outcome analysis followed 80 patients with AASV and renal involvement for a median of 46.7 months.4 Patients were divided equally into groups by maximum serum creatinine levels after the first month of treatment: less than 299 μmol/L, 299 to 582 μmol/L, and greater than 582 μmol/L. All patients were treated for induction of remission with cyclophosphamide and oral corticosteroids. Survival was significantly worse in patients who had the highest maximum serum creatinine in the first month (P = .025).
Pooled prospective data from four European Vasculitis Study Group (EUVAS) trials of 535 patients with AASV and follow-up of 5.2 years found a mortality ratio of 2.6 (95% CI, 2.2–3.1) compared with matched subjects from the general population.5 Stage 5 chronic kidney disease (glomerular filtration rate < 15 mL/min) was a significant negative prognostic determinant of survival in these trials.
A DISEASE OF AGING
Renal vasculitis is most prevalent in people aged 50 years and older and often occurs in those aged 70 years and older.6 Because the very old may not have extrarenal symptoms, it is necessary to maintain a high index of suspicion for AASV and measure urinary sediment and renal function in this age group.
Older patients also present with more severe renal disease and have a poorer prognosis. Harper and Savage compared presentation and outcomes of patients aged 65 years and older with renal AASV with those of patients younger than 65 years.7 Older patients had more severe renal failure than did younger patients (serum creatinine 657 vs 470 μmol/L, respectively; P < .001), and this did not appear to be associated with delayed diagnosis. Survival was worse in those with serum creatinine levels greater than 400 μmol/L irrespective of age; however, when comparing younger and older groups with similar renal insufficiency, older patients were more likely to progress to end-stage renal failure (P = .039), survival was worse (P = .016), and death occurred earlier.7
HISTOPATHOLOGIC CLASSIFICATION
An international working group of renal pathologists8 developed pathologic classifications for rapidly progressive GN caused by AASV: focal (≥ 50% normal glomeruli), crescentic (≥ 50% glomeruli with cellular crescents), mixed (no predominant glomerular feature), and sclerotic (≥ 50% globally sclerotic glomeruli). These correspond to the order of severity of renal-function impairment. A study of 100 biopsies from patients with ANCA-associated GN found that the classifications at presentation closely correlated with outcomes.8
Patients with sclerotic GN had the worst renal function initially, with little improvement at 5 years; hence, immunosuppression is of little value if the kidney is more than 50% sclerotic. Patients with focal disease who had good renal function initially were found to retain good function after 5 years of treatment. Patients in the crescentic class present with rapidly progressive GN and very poor renal function. However, they were found to improve considerably after 5 years and had good recovery (P = .001). Presenting disease manifestations within the kidney are of diagnostic as well as prognostic value.
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.
Necrotizing glomerulonephritis (GN) is the classical renal manifestation of the small-vessel vasculitides, which include granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome). MPA is pauci-immune (lacks antibody depositions) and causes focal segmental necrotizing GN. Other small-vessel vasculitides are Henoch-SchÖnlein purpura, which features nephritis from immunoglobulin A–dominant immune deposits, and essential cryoglobulinemic vasculitis, in which cryoglobulin immune deposits lead to membranoproliferative GN.1
Renal involvement occurs in 25% to 75% of patients with antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV), with the higher percentage reflecting patients who first present to a nephrologist rather than a rheumatologist. Roughly 35% are dialysis-dependent, mainly those who are elderly or proteinase-3– or myeloperoxidase-ANCA–positive. In duc tion of remission through immunosuppression allows 50% to 60% of dialysis-dependent patients to recover independent renal function.2,3
PROGNOSTIC SIGNIFICANCE OF RENAL INVOLVEMENT
Patients should be assessed at the earliest opportunity for renal involvement as it is highly predictive of survival. Diagnosis allows immunosuppressive treatment to be started early, when kidney function may still be preserved.
Reinhold-Keller et al3 examined survival by level of renal involvement at diagnosis in 155 patients with GPA who were followed for a median of 7 years. Survival in those with normal renal function, but with nephritic urinary sediment at diagnosis, declined over time compared with patients who had no renal involvement at diagnosis, with a more than twofold greater risk of death (hazard ratio [HR], 2.41; 95% confidence interval [CI] 0.53–11.06). Patients who had impaired renal function at diagnosis had a fivefold greater risk of death (HR, 5.42; 95% CI 1.76–16.68).
Maximum serum creatinine in the first month of treatment is also highly predictive of survival. An outcome analysis followed 80 patients with AASV and renal involvement for a median of 46.7 months.4 Patients were divided equally into groups by maximum serum creatinine levels after the first month of treatment: less than 299 μmol/L, 299 to 582 μmol/L, and greater than 582 μmol/L. All patients were treated for induction of remission with cyclophosphamide and oral corticosteroids. Survival was significantly worse in patients who had the highest maximum serum creatinine in the first month (P = .025).
Pooled prospective data from four European Vasculitis Study Group (EUVAS) trials of 535 patients with AASV and follow-up of 5.2 years found a mortality ratio of 2.6 (95% CI, 2.2–3.1) compared with matched subjects from the general population.5 Stage 5 chronic kidney disease (glomerular filtration rate < 15 mL/min) was a significant negative prognostic determinant of survival in these trials.
A DISEASE OF AGING
Renal vasculitis is most prevalent in people aged 50 years and older and often occurs in those aged 70 years and older.6 Because the very old may not have extrarenal symptoms, it is necessary to maintain a high index of suspicion for AASV and measure urinary sediment and renal function in this age group.
Older patients also present with more severe renal disease and have a poorer prognosis. Harper and Savage compared presentation and outcomes of patients aged 65 years and older with renal AASV with those of patients younger than 65 years.7 Older patients had more severe renal failure than did younger patients (serum creatinine 657 vs 470 μmol/L, respectively; P < .001), and this did not appear to be associated with delayed diagnosis. Survival was worse in those with serum creatinine levels greater than 400 μmol/L irrespective of age; however, when comparing younger and older groups with similar renal insufficiency, older patients were more likely to progress to end-stage renal failure (P = .039), survival was worse (P = .016), and death occurred earlier.7
HISTOPATHOLOGIC CLASSIFICATION
An international working group of renal pathologists8 developed pathologic classifications for rapidly progressive GN caused by AASV: focal (≥ 50% normal glomeruli), crescentic (≥ 50% glomeruli with cellular crescents), mixed (no predominant glomerular feature), and sclerotic (≥ 50% globally sclerotic glomeruli). These correspond to the order of severity of renal-function impairment. A study of 100 biopsies from patients with ANCA-associated GN found that the classifications at presentation closely correlated with outcomes.8
Patients with sclerotic GN had the worst renal function initially, with little improvement at 5 years; hence, immunosuppression is of little value if the kidney is more than 50% sclerotic. Patients with focal disease who had good renal function initially were found to retain good function after 5 years of treatment. Patients in the crescentic class present with rapidly progressive GN and very poor renal function. However, they were found to improve considerably after 5 years and had good recovery (P = .001). Presenting disease manifestations within the kidney are of diagnostic as well as prognostic value.
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.
- Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an International Consensus Conference. Arthritis Rheum 1994; 37:187–192.
- Booth AD, Almond MK, Burns A, et al; for the Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003; 41:776–784.
- Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000; 43:1021–1032.
- Weidner S, Geuss S, Hafezi-Rachti S, Wonka A, Rupprecht HD. ANCA-associated vasculitis with renal involvement: an outcome analysis [published online ahead of print April 6, 2004]. Nephrol Dial Transplant 2004; 19:1403–1411. doi: 10.1093/ndt/gfh161
- Flossmann O, Berden A, de Groot K, et al; for the European Vasculitis Study Group. Long-term patient survival in ANCA-associated vasculitis [published online ahead of print November 24, 2010]. Ann Rheum Dis 2011; 70:488–494. doi: 10.1136/ard.2010.137778
- Hamour SM, Salama AD. ANCA comes of age—but with caveats. Kidney Int 2011; 79:699–701.
- Harper L, Savage CO. ANCA-associated renal vasculitis at the end of the twentieth century—a disease of older patients [published online ahead of print December 21, 2004]. Rheumatology 2005; 44:495–501. doi: 10.1093/rheumatology/keh522
- Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of ANCA-associated glomerulonephritis [published online ahead of print July 8, 2010]. J Am Soc Nephrol 2010; 21:1628–1636. doi: 10.1681/ASN.2010050477
- de Groot K, Harper L, Jayne DRW, et al; for the EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody–associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670–680.
- Harper L, Morgan MD, Walsh M, et al; on behalf of the EUVAS Investigators. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up [published online ahead of print November 29, 2011]. Ann Rheum Dis 2012; 71:955–960. doi: 10.1136/annrheumdis-2011-200477
- Little MA, Nightingale P, Verburgh CA, et al; for the European Vasculitis Study (EUVAS) Group. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis [published online ahead of print July 1, 2009]. Ann Rheum Dis 2010; 69:1036–1043. doi: 10.1136/ard.2009.109389
- Jayne DR, Gaskin G, Rasmussen N, et al; for the European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vascultis [published online ahead of print June 20, 2007]. J Am Soc Nephrol 2007; 18:2180–2188. doi: 10.1681/ASN.2007010090
- Lionaki S, Hogan SL, Jennette CE, et al. The clinical course of ANCA small-vessel vasculitis on chronic dialysis [published online ahead of print June 17, 2009]. Kidney Int 2009; 76:644–651. doi: 10.1038/ki.2009.218
- Weidanz F, Day CJ, Hewins P, Savage CO, Harper L. Recurrences and infections during continuous immunosuppressive therapy after beginning dialysis in ANCA-associated vasculitis. Am J Kidney Dis 2007; 50:36–46.
- Schmitt WH, van der Woude FJ. Organ transplantation in the vasculitides. Curr Opin Rheumatol 2003; 15:22–28.
- Little MA, Hassan B, Jacques S, et al. Renal transplantation in systemic vasculitis: when is it safe [published online ahead of print July 13, 2009]? Nephrol Dial Transplant 2009; 24:3219–3225. doi: 10.1093/ndt/gfp347
- Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: a pooled analysis. Kidney Int 1999; 56:1544–1550.
- Morgan MD, Turnbull J, Selamet U, et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: a matched-pair cohort study. Arthritis Rheum 2009; 60:3493–3500.
- Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an International Consensus Conference. Arthritis Rheum 1994; 37:187–192.
- Booth AD, Almond MK, Burns A, et al; for the Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003; 41:776–784.
- Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000; 43:1021–1032.
- Weidner S, Geuss S, Hafezi-Rachti S, Wonka A, Rupprecht HD. ANCA-associated vasculitis with renal involvement: an outcome analysis [published online ahead of print April 6, 2004]. Nephrol Dial Transplant 2004; 19:1403–1411. doi: 10.1093/ndt/gfh161
- Flossmann O, Berden A, de Groot K, et al; for the European Vasculitis Study Group. Long-term patient survival in ANCA-associated vasculitis [published online ahead of print November 24, 2010]. Ann Rheum Dis 2011; 70:488–494. doi: 10.1136/ard.2010.137778
- Hamour SM, Salama AD. ANCA comes of age—but with caveats. Kidney Int 2011; 79:699–701.
- Harper L, Savage CO. ANCA-associated renal vasculitis at the end of the twentieth century—a disease of older patients [published online ahead of print December 21, 2004]. Rheumatology 2005; 44:495–501. doi: 10.1093/rheumatology/keh522
- Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of ANCA-associated glomerulonephritis [published online ahead of print July 8, 2010]. J Am Soc Nephrol 2010; 21:1628–1636. doi: 10.1681/ASN.2010050477
- de Groot K, Harper L, Jayne DRW, et al; for the EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody–associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670–680.
- Harper L, Morgan MD, Walsh M, et al; on behalf of the EUVAS Investigators. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up [published online ahead of print November 29, 2011]. Ann Rheum Dis 2012; 71:955–960. doi: 10.1136/annrheumdis-2011-200477
- Little MA, Nightingale P, Verburgh CA, et al; for the European Vasculitis Study (EUVAS) Group. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis [published online ahead of print July 1, 2009]. Ann Rheum Dis 2010; 69:1036–1043. doi: 10.1136/ard.2009.109389
- Jayne DR, Gaskin G, Rasmussen N, et al; for the European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vascultis [published online ahead of print June 20, 2007]. J Am Soc Nephrol 2007; 18:2180–2188. doi: 10.1681/ASN.2007010090
- Lionaki S, Hogan SL, Jennette CE, et al. The clinical course of ANCA small-vessel vasculitis on chronic dialysis [published online ahead of print June 17, 2009]. Kidney Int 2009; 76:644–651. doi: 10.1038/ki.2009.218
- Weidanz F, Day CJ, Hewins P, Savage CO, Harper L. Recurrences and infections during continuous immunosuppressive therapy after beginning dialysis in ANCA-associated vasculitis. Am J Kidney Dis 2007; 50:36–46.
- Schmitt WH, van der Woude FJ. Organ transplantation in the vasculitides. Curr Opin Rheumatol 2003; 15:22–28.
- Little MA, Hassan B, Jacques S, et al. Renal transplantation in systemic vasculitis: when is it safe [published online ahead of print July 13, 2009]? Nephrol Dial Transplant 2009; 24:3219–3225. doi: 10.1093/ndt/gfp347
- Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: a pooled analysis. Kidney Int 1999; 56:1544–1550.
- Morgan MD, Turnbull J, Selamet U, et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: a matched-pair cohort study. Arthritis Rheum 2009; 60:3493–3500.