Immunotherapy in Renal Diseases

Immunotherapy in Renal Diseases Ajay Kher,

MBBS

a,

*, Vijay Kher,

MD, DM

b

KEYWORDS  Glomerulonephritis  Nephrotic syndrome  Immunosuppression  Crescentic glomerulonephritis

Key Points  Immunotherapy for renal disease over the last 50 years has resulted in significant improvement in outcomes.  Corticosteroids are the mainstay of treatment of minimal change disease.  Evaluation of the risk of progression to end-stage renal disease is required before treating membranous and immunoglobulin-A nephropathy.  Corticosteroids with cyclosporin are used to treat focal segmental glomerulosclerosis, many novel therapies are under investigation.  Lupus nephritis is a classic immune-mediated disease, treated with corticosteroids, cyclophosphamide or mycophenolate mofetil.  Crescentic glomerulonephritis (antineutrophil cytoplasmic antibody vasculitis or anti– glomerular basement membrane) is usually treated with combination therapy of cyclophosphamide, corticosteroids, and plasmapheresis.  The role of novel targeted therapies such as rituximab, belimumab, and ecluzimab is being established.

Among renal diseases immunotherapy is used for treatment of glomerulonephritis, kidney transplantation, renal cell carcinoma, and occasionally acute interstitial nephritis. Immunotherapy in renal disease has evolved with the development and availability of various drugs during different eras. Such therapy consisted initially of corticosteroids in the 1950s, and progressively came to include cyclophosphamide, nitrogen mustard, and azathioprine (AZA) in the 1960s and 1970s. Cyclosporine and later tacrolimus, mycophenolate mofetil (MMF), immunoglobulins with or without

a

The Transplant Institute, Beth Israel Deaconess Medical Center, 110 Francis Street, 7th Floor, Boston, MA 02215, USA b Division of Nephrology and Renal Transplant Medicine, Kidney and Urology Institute, Medanta-The Medicity, Gurgaon, India * Corresponding author. E-mail address: [email protected] Med Clin N Am 96 (2012) 545–564 doi:10.1016/j.mcna.2012.04.007 medical.theclinics.com 0025-7125/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.

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plasmapheresis, anti–B-cell mediated therapies such as rituximab or belimumab, and other novel targeted therapies have now become available. This review focuses on the use of these agents for the treatment of various forms of glomerulonephritis. The reader is referred to recent reviews for more information on immunotherapy for renal transplantation,1,2 renal cell cancer,3 and acute interstitial nephritis.4 Glomerular diseases are immunologically mediated disorders, which manifest as: 1. 2. 3. 4. 5.

Acute nephritis syndrome Nephrotic syndrome Rapidly progressive glomerulonephritis Chronic glomerulonephritis Asymptomatic urinary manifestations.

The diagnosis of different glomerular diseases is based on clinical features and syndromes, laboratory characteristics, and renal histology, usually including immunofluorescence, light microscopy, and electron microscopy. The differential diagnosis of nephritic syndrome, nephrotic syndrome, and rapidly progressive glomerulonephritis is presented in Box 1. Box 1 Differential diagnosis of nephrotic or nephritic syndrome Nephrotic syndrome Minimal change disease Membranous nephropathy Focal segmental glomerulosclerosis Amyloidosis Light chain deposition disease Diabetes mellitus Preeclampsia Nephritic syndrome Postinfectious glomerulonephritis Membranoproliferative glomerulonephritis Lupus nephritis Immunoglobulin-A (IgA) nephropathy Fibrillary glomerulonephritis Cryoglobulinemia Hereditary nephritis Pauci-immune glomerulonephritis (granulomatosis with polyangiitis, microscopic polyarteritis nodosa) Anti–glomerular basement membrane (GBM) disease (Goodpasture syndrome) Rapidly progressive glomerulonephritis Pauci-immune glomerulonephritis (granulomatosis with polyangiitis, microscopic polyarteritis nodosa) Anti-GBM disease (Goodpasture syndrome) Immune complex glomerulonephritis (Lupus, IgA, postinfectious, and so forth)

Immunotherapy in Renal Diseases

NONIMMUNOSUPPRESSIVE TREATMENTS

The rate of progression of kidney disease varies with the activity of the original disease and the efficacy of the treatment. After a substantial loss of nephrons has occurred, even if the original disease is not active, the adaptive hyperfiltration leads to a common pathway to progression of chronic kidney disease (CKD). Treatment of hypertension and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for reduction of proteinuria should be used to slow the progression of CKD. These interventions and other treatments for the management of associated conditions of anemia, bone and mineral disorders, and cardiovascular disease are not discussed here, and the reader is referred to other reviews on this issue.5 MINIMAL CHANGE DISEASE

Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children. Historical studies before the advent of antibiotics and steroids show that 40% of children with nephrotic syndrome died of infections, renal failure, or thromboembolism.6 Initial Treatment

Corticosteroids are the treatment of choice for MCD (Box 2), and this is based on large trials in children and smaller ones in adults that show benefit.7–11 The early study of corticosteroids in the 1970s found that prednisone led to a rapid decrease in proteinuria compared with controls. However, it also noted that a significant proportion (>50%) of the control group also had resolution of the proteinuria, although it took more than 2 years.8 Since then many studies have shown that in comparison with the quick response to steroids in children (within 8 weeks), adults need to be treated for longer, although the response rates are similar.11 Studies have used different doses of steroids; most recommend using prednisone 1 mg/kg of body weight daily for at least 8 weeks. For those who have attained complete remission by 8 weeks, the prednisone dose can be tapered. Slow tapering is recommended to sustain the remission. For those who have not attained remission, prednisone is continued at full dose until 1 to 2 weeks after remission is attained. Most of those who will respond Box 2 Treatment of minimal change disease Initial treatment Prednisone 1 mg/kg daily for at least 8 weeks Relapse Prednisone 1 mg/kg daily Frequently relapsing and steroid dependent Cyclosporine (4–6 mg/kg/d in divided doses) OR Cyclophosphamide (oral 2 mg/kg daily for 8–12 weeks) Steroid-resistant disease Cyclosporine (4–6 mg/kg/d in divided doses) OR Cyclophosphamide (oral 2 mg/kg daily for 8–12 weeks)

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usually do so by 16 weeks and those who do not are labeled as steroid resistant. There is a small number with spontaneous early remission (5%–10%), with up to 70% in remission by 3 years.8,11,12 Hence, steroids help in inducing early remissions and to maintain it. Patients may have some decrease in renal function at the time of nephrotic syndrome but they return to normal once nephrosis resolves.11–15 The outcome of treated MCD is good, and an important prognostic factor is the initial response to steroid therapy.16 Most patients attain complete remission. Developing end-stage renal disease (ESRD) from MCD is rare and is seen only in steroid-resistant cases. On repeat biopsy all such cases have focal segmental glomerulosclerosis (FSGS), usually thought to be the result of mislabeling of FSGS as MCD on the original biopsy sample, although it could also be due to progression from MCD to FSGS.11,17 Treatment of Relapse

Relapse will occur in 50% to 75% of patients after stopping steroids, and 10% to 25% will have frequent relapses.11,12,15 There are no trials to guide therapy for relapses, but a repeat course of steroids usually resolves the flare.13,14 If the patient is having significant steroid toxicity or has frequent flares, it is reasonable to consider steroid-sparing strategies and use other immunosuppressive agents. Steroid-Dependent Disease or Frequently Relapsing MCD

Continuous low-dose steroids,13 cyclophosphamide,13,15 or cyclosporine18–21 may be used for patients who have either steroid-dependent or frequently relapsing disease. Treatment with these agents is begun after a remission has been induced by steroids. Steroid-Resistant MCD

Five percent to 10% of adults with MCD will be steroid resistant. Some of them may have FSGS after being mislabeled because of sampling issues, as already mentioned. Cyclosporine is preferred for the treatment of steroid-resistant MCD because it is also effective for steroid-resistant FSGS.19,20,22,23 Those who are unable to tolerate cyclosporine or are resistant to it may be treated with cyclophosphamide.22,24 MEMBRANOUS NEPHROPATHY

To understand the role of immunosuppressive therapy in membranous nephropathy, it is important to appreciate the natural history of the disease and the prognostic risk factors. Spontaneous complete remission occurs in up to 30% of patients at 5 years and partial remission occurs in 25% to 40%; progression to ESRD is approximately 14% at 5 years, 35% at 10 years, and 41% at 15 years.25,26 Similarly, it has been noted that in those with penicillamine-associated or gold-associated membranous nephropathy it may take many months for the proteinuria to resolve, even after removal of the offending agent.27,28 A significant proportion of patients will have spontaneous remission, and the overall outcomes are benign. Hence, immunosuppressive therapy should only be used for those with substantial risk for progression to ESRD. Many studies have shown that older age at presentation, male gender, nephrotic-range proteinuria, and higher serum creatinine at presentation are associated with risk of progression to ESRD. Persistence of high levels of proteinuria has been shown to be predictive of progression to ESRD,29 and has been validated in 2 separate cohorts.30 Based on follow-up of 6 months, patients can be classified as low risk, moderate risk, or high risk for progression to ESRD. Immunosuppressive therapy would be recommended only for moderate and high risk of progression.

Immunotherapy in Renal Diseases

First-line therapy is cyclophosphamide with prednisone or cyclosporine with prednisone; those who fail on one regimen are treated with the other, and those who fail on both are treated with rituximab (Box 3). Trials have shown that cytotoxic therapy (cyclophosphamide or chlorambucil) with steroids are effective in preventing progression to ESRD and in inducing remission.31,32 As cyclophosphamide is equally as effective as chlorambucil and is associated with fewer side effects, most clinicians prefer cyclophosphamide for cytotoxic treatment of membranous nephropathy.33 Treatment is given for 6 months with alternating months of steroids and cyclophosphamide. Cyclosporine with low-dose prednisone has also been shown to be effective in inducing remission and preventing progression to ESRD.34–36 Tacrolimus has also been effective, although most clinicians use cyclosporine, having had more experience with this drug in treating the condition. The duration of cyclosporine treatment is based on the response to initial therapy. Once complete remission is achieved therapy can be tapered and stopped, whereas for those in partial remission the therapy is continued for 1 to 2 years. High relapse rates have been noted after stopping treatment with either cyclophosphamide or cyclosporine. The treatment of the relapse depends on the initial regimen and the response, and can be another course of cyclophosphamide or cyclosporine or a switch to the other regimen. Those who do not respond to the first-choice therapy with a reduction in proteinuria in 6 months are considered to be resistant to it, and should be treated with the other regimen. Rituximab may be used for treatment of resistant patients, based on observational studies.37,38 Phospholipase A2 receptor (PLA2R), a transmembrane receptor, is expressed on glomerular podocytes and has been shown to be a major antigen for idiopathic membranous nephropathy.39 Anti-PLA2R antibodies were found in 70% of those with idiopathic membranous nephropathy, and a decline in it was noted to precede resolution of proteinuria in those treated with rituximab while a relapse was preceded by an increase in these antibodies.40,41 In the future, these may provide additional monitoring parameters and may guide therapy based on their presence and levels.

PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

FSGS is a histologic pattern of injury, which may present in response to previous glomerular injury or hypertrophy (secondary) or without an identifiable cause (primary), or can be due to genetic mutations of podocyte proteins (mutations in nephrin, podocin, and a-actinin-4). The clinical presentation may aid in this distinction, as primary FSGS usually presents acutely with overt nephrotic syndrome (edema, hypoalbuminemia)

Box 3 Treatment of membranous nephropathy Steroids (intravenous methylprednisolone 1 g/d for 3 days followed by prednisone 0.5 mg/kg/d during months 1, 3, and 5) AND cyclophosphamide (oral 2–2.5 mg/kg/d during months 2, 4, and 6) OR Cyclosporine (125–225 ng/mL) AND low-dose prednisone (0.15 mg/kg/d, maximum 15 mg/d) Resistant disease Use the other agent (cyclophosphamide AND steroids OR cyclosporine AND prednisone) OR Rituximab (2 doses of 1 g given 2 weeks apart or 4 weekly doses of 375 mg/m2)

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whereas secondary FSGS presents with proteinuria but without edema or hypoalbuminemia. It is important to differentiate between these conditions because the treatment is different for each. Immunosuppressive therapy is the mainstay in the treatment of primary FSGS but is not of benefit for genetic or secondary FSGS. Nonimmunosuppressive therapy, as already mentioned, should be used in all types of FSGS. The following discussion concerns patients with primary FSGS. Prognostic Factors and Risk Factors for Progression

The natural history of FSGS in untreated patients is a progressive course toward ESRD. Factors that influence prognosis are the degree of proteinuria, renal function at presentation, pathologic findings, and response to treatment. Those with nephrotic syndrome have 5- and 10-year renal survival rates of 60% to 90% and 30% to 55%, respectively.42–45 Those with massive proteinuria (>10 g/d) have a worse prognosis, with progression to ESRD within 5 years. In comparison, those with non-nephrotic proteinuria and normal renal function have a good prognosis, with >85% renal survival at 10 years. Worse renal function at presentation is associated with worse outcomes.45,46 The presence of fibrosis on the biopsy is a poor prognostic sign.44 Among the various histologic variants of FSGS, collapsing FSGS has the worst prognosis.47 The response to treatment is a strong predictor of outcomes. Those who achieve partial or complete remission with treatment have much better outcomes than those who do not achieve remission.42,43,46,47 Treatment

The initial treatment is with prednisone (Box 4), although as there are no randomized studies the recommendation is based on observational experience. Prednisone has provided rates of 40% to 80% complete or partial response.42,48,49 Prednisone is usually continued for 12 to 16 weeks. Dosing regimen for prednisone is 1 mg/kg daily or 2 mg/kg on alternate days. Those who respond will have some effect within 8 to 12 weeks. Duration for 6 to 8 months is required, and shorter courses lead to fewer remissions.47,50 The management of the steroid course is based on the response. For those with complete remission, steroids may be tapered over another 3 months. For those with partial remission, steroids are tapered more slowly. Patients who do not respond within 3 to 4 months are considered steroid resistant and are treated with cyclosporine. Cyclosporine is also used for treatment of those who are steroid dependent. Treatment of relapses is based on previous response and the toxicity, and may comprise a repeat course of steroids or cyclosporine. Randomized trials and uncontrolled studies have shown that cyclosporine with low-dose prednisone is effective in reducing proteinuria; however, its impact on progression to ESRD is not known.23,51,52 Box 4 Treatment of primary FSGS Initial treatment Prednisone (1 mg/kg daily or 2 mg/kg on alternate days) for 12–16 weeks Steroid-resistant or -dependent disease Cyclosporine (100 mg twice a day or 2–4 mg/kg/d) with low-dose steroids (prednisone 15 mg/d or 0.15 mg/kg/d) OR MMF

Immunotherapy in Renal Diseases

Cyclosporine is used at a dose of 2 to 4 mg/kg/d in divided doses or 100 mg twice a day with target levels between 100 and 175 ng/mL, with low-dose prednisone 15 mg/d (0.15 mg/kg/d). Randomized and observational studies have suggested some benefit of MMF with or without steroids in FSGS.53,54 LUPUS NEPHRITIS

Renal involvement is common in lupus and can present with different pathologic lesions. Immunosuppressive therapy is warranted for patients with diffuse and focal proliferative lupus nephritis, which is discussed here. Immunosuppressive therapy for proliferative lupus, similar to antineutrophil cytoplasmic antibody (ANCA) disease and anti–glomerular basement membrane (anti-GBM) disease consists of 2 phases, first an induction phase and then a maintenance phase (Box 5). The induction phase consists of use of potent immunosuppression to induce remission, then once it is achieved a maintenance phase begins with use of less aggressive therapy. The duration of each of these phases is variable and has to be individualized based on the response of the disease, the risk for progression, and the side effects of the medications. Induction

Landmark studies from the National Institutes of Health55–58 demonstrated the benefit of cyclophosphamide (0.5–1.0 g/m2, given monthly for 6 months and then quarterly for 2 years) with steroids over steroids alone, and also showed that prolonged administration at quarterly intervals decreased the relapses. Good overall outcomes were achieved with the combination of cyclophosphamide with steroids, but were Box 5 Treatment of lupus nephritis Induction phase Steroids (methylprednisolone intravenous pulse 500–1000 mg/d for 3 days followed by prednisone 1 mg/kg/d) AND Cyclophosphamide (intravenous 6 doses of 500 mg every 2 weeks OR intravenous 0.5–1 g/m2 monthly for 4–7 months) OR MMF (1 g/d for 1 week, 2 g/d for 1 week, then 3 g/d until remission achieved) Maintenance phase MMF (2 g/d) for 18 to 24 months OR Azathioprine (2 mg/kg/d) Resistant disease Treat with other induction agent (cyclophosphamide or MMF with steroids) OR Rituximab (2 doses of 0.5–1 g 2 weeks apart or 4 weekly doses of 375 mg/m2) Lupus diffuse proliferative with membranous nephritis MMF AND tacrolimus AND steroids

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associated with significant side effects. Hence, studies were conducted to assess less intense immunosuppressive regimens. The Euro-lupus trial showed that a shorter and lower-dose cyclophosphamide regimen (6 fixed doses of 500 mg given every fortnight, total 3 g) with prednisone followed by AZA provided similar short-term and long-term outcomes, with fewer adverse events. The trial also showed that early response to therapy was predictive of good outcomes long term59–61; however, this study had no African Americans. Another option for low-dose cyclophosphamide therapy is use of 4 to 7 doses of monthly intravenous cyclophosphamide with transition to AZA or MMF once remission is induced, allowing for lower doses for those who achieve remission earlier.62 The majority of these patients were African Americans or Hispanics, who have worse outcomes, and hence the results may not be applicable to other populations. Another option is induction with MMF as used in the ALMS trial.63 The target dose here was 3 g daily, which was reached by a progressive increase in dose weekly from 1 g daily for the first week. There were no differences in the primary or secondary outcomes when compared with cyclophosphamide. In a subset analysis MMF was found to work better for African Americans,64 this result being similar to those of other trials that have shown worse outcomes with cyclophosphamide in African Americans.65 Long-term follow-up of a Chinese study comparing MMF with cyclophosphamide showed similar remission rates with lower rates of infections.66,67 A meta-analysis also showed decreased remission rates and increased adverse events with cyclophosphamide.68 It is noteworthy that the MMF trials have only a short-term follow-up and also that these studies were not powered to show safety benefits. Maintenance

Following reduction or cessation of immunosuppression, up to 50% of patients may relapse.66,69–72 Hence, after attainment of remission, immunosuppression is continued to maintain remission and reduce relapses. The ideal maintenance regimen is not defined. Most studies have used either AZA or MMF for 12 to 24 months. AZA and MMF have better efficacy and safety profiles than continued intravenous cyclophosphamide.62 The MAINTAIN trial compared AZA (2 mg/kg/d) with MMF (2 g/d), and after 3 years no significant difference in the rate of renal relapse (25% vs 19%) was noted. Occurrence of adverse events was similar except for anemia and leukopenia, which were more common in the AZA arm.73 The ALMS trial was a multinational trial that compared induction with MMF with cyclophosphamide, and those who achieved remission were then randomized to maintenance therapy with either MMF or AZA.74 The investigators showed that renal outcomes were significantly better with MMF maintenance, independent of the induction agent used. This finding, combined with the trend toward benefit in the MAINTAIN trial, leads to a recommendation for the use of MMF rather than AZA. AZA may be preferred for those who do not tolerate MMF or for women who wish to become pregnant. The usual dose of MMF is 2 g/d, tapered over time in stable patients. Resistant Lupus Nephritis

Patients who do not respond to the initial therapy (cyclophosphamide or MMF) and are considered resistant to the initial therapy are usually treated with the other agent. Patients who fail or cannot tolerate both regimens may be considered for treatment with rituximab. However, this protocol is based on small observational studies, and no long-term safety or efficacy data are available. Different regimens of rituximab have been used, and include 2 doses of 0.5 to 1 g on days 1 and 15,75 or 4 weekly doses of 375 mg/m2.76

Immunotherapy in Renal Diseases

Diffuse Proliferative Lupus with Membranous Nephritis

Patients with combined diffuse proliferative and membranous lupus have a worse prognosis than those with diffuse proliferative nephritis alone.77 Moreover, those with combined lesions had a lower rate of achieving remission (27% vs 60%) and poorer renal survival at 10 years (50% vs 75%). Patients with combined lesions respond better to induction therapy with MMF (0.75–1 g/d) and tacrolimus (3–4 mg/d with trough 5–7 ng/mL) compared with intravenous cyclophosphamide, with higher complete remissions at 9 months (65% vs 15%) and similar partial response rates (30% vs 40%).78 All patients also received steroids. IMMUNOGLOBULIN-A NEPHROPATHY

Immunoglobulin A (IgA) nephropathy is the most common form of glomerulonephritis.79 IgA nephropathy has a spectrum of disease ranging from persistent asymptomatic microscopic hematuria without proteinuria with normal renal function to severe nephritic presentation. The classic presentation is with gross hematuria in the setting of a recent upper respiratory infection. Patients with IgA nephropathy are generally thought to have good prognosis; however, long-term follow-up has shown that some of them will progress to ESRD. Those with no or little proteinuria have good outcomes, but a substantial proportion may develop proteinuria and renal insufficiency over the long term. Progression to ESRD is 15% to 25% in 10 years and 20% to 30% in 20 years.80–83 Clinical predictors of progression to ESRD are elevated serum creatinine, hypertension, and persistent proteinuria greater than 1 g/d.84–86 Histologic features predictive of progression include markers of inflammatory disease (crescent formation, immune deposits in the capillary loops) and markers of chronic fibrotic disease (interstitial fibrosis, tubular atrophy, glomerulosclerosis). A consensus on pathologic classification of IgA nephropathy has been developed. The Oxford classification has been validated in multiple different cohorts.87–89 A prognostic scoring system has also been developed.86 The treatment of IgA nephropathy is uncertain and is difficult to assess because of its slow progression.90,91 Nonimmunosuppressive therapies should be used in all patients, and immunosuppression limited to selected patients. Hence, immunosuppressive therapy is limited to those who are thought to be at high risk of progression to ESRD. Patients with isolated hematuria with no proteinuria and normal function usually are not biopsied and not treated, but should be monitored for signs of progression. Patients with more severe disease (nephrotic-range proteinuria, rising creatinine level, and severe histologic findings) may benefit from immunosuppressive therapy in addition to nonimmunosuppressive therapy. The benefits of steroids have been studied in uncontrolled and small randomized studies.92–95 Steroids are associated with a reduction in proteinuria and may be associated with improved renal survival. A prospective study among patients with moderate proteinuria (1–3.5 g/d) who were randomly assigned to supportive care or steroids (1 g intravenous methylprednisolone for 3 days on months 1, 3, and 5 with alternate-day prednisone at 0.5 mg/kg for 6 months) showed that steroids were associated with reduced incidence of doubling of serum creatinine at 5 years (2% vs 21%) and 10 years (2% vs 30%).93,94 Combined treatment with steroids and angiotensin inhibitors provides additional benefit in comparison with angiotensin inhibitors alone.96,97 Crescentic IgA Nephropathy

There are no randomized trials evaluating treatments for crescentic IgA nephropathy. Observational data suggest benefit through the use of aggressive treatment as used

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for other forms of rapidly progressive glomerulonephritis (crescentic glomerulonephritis). This therapy includes pulse methylprednisolone followed by oral prednisone with cyclophosphamide, with or without plasmapheresis.98–101

GRANULOMATOSIS WITH POLYANGIITIS (WEGENER SYNDROME) AND MICROSCOPIC POLYANGIITIS

Renal presentation in these conditions is with nephritic syndrome or rapidly progressive glomerulonephritis, which are associated with ANCA. Kidney biopsies show segmental necrotizing glomerulonephritis with few or no immune deposits (pauci-immune), and crescents are commonly present. Induction

Initial treatment is usually with cyclophosphamide and prednisone (Box 6). Recent studies have shown that short-term results are equally good with rituximab, hence it may be used for those unable to tolerate or who refuse treatment with cyclophosphamide. Aggressive treatment is warranted, because if left untreated there is high mortality from this disease.102 Steroids should not be used alone, as the remission rate is substantially lower than that of cyclophosphamide (56% vs 85%) and the relapse rates are higher.103 Cyclophosphamide can be dosed as daily oral dose or monthly intravenous pulses. Trials have shown that both of these regimens induce remission at similar rates. Higher cumulative cyclophosphamide dose, lower rates of relapse, and more leukopenia and infection are associated with oral dosing of cyclophosphamide.104–107 For steroids a 3-day course of methylprednisolone pulse (7–15 mg/kg, 500–1000 mg) is followed by prednisone (1 mg/kg, 60–80 mg/d). These regimens attain remission rates of 85% to 90%, with 75% attaining complete remission. Most patients achieve a remission within 2 to 6 months.105,108,109

Box 6 Treatment of granulomatosis with polyangiitis (Wegener syndrome) and microscopic polyangiitis Induction phase Steroids (methylprednisolone intravenous 500–1000 mg daily for 3 days followed by prednisone 1 mg/kg) AND Plasmapheresis for those with pulmonary hemorrhage, severe renal disease, or combined ANCA and anti-GBM disease AND Cyclophosphamide (by mouth or intravenous) OR Rituximab Maintenance phase Azathioprine (12–18 months) OR Methotrexate (12–18 months)

Immunotherapy in Renal Diseases

Two randomized trials have shown the efficacy of rituximab in the initial treatment of ANCA vasculitis.110,111 However, both only had short-term follow-up; hence, rituximab remains a treatment option for those who do not tolerate or refuse cyclophosphamide therapy or for those who fail treatment with cyclophosphamide. The RAVE trial randomly assigned rituximab or cyclophosphamide to 197 patients with granulomatosis with polyangiitis (75%) or microscopic polyangiitis (24%), of whom 49 were newly diagnosed while the rest had relapsing disease.111 All patients received steroids. Rituximab was not inferior in inducing remission but was superior in doing so in those with relapsing disease. The other trial had 44 new patients assigned in 3:1 ratio to 4 doses of rituximab with 2 doses of cyclophosphamide versus cyclophosphamide for 3 to 6 months followed by AZA. No differences in sustained remission were noted.110 Plasmapheresis is recommended for selected patients with ANCA disease, combined ANCA and anti-GBM disease, pulmonary hemorrhage, or severe renal disease. An initial trial suggested that plasmapheresis was of benefit in those with severe renal failure requiring dialysis on presentation.112 The MEPEX trial randomized 137 patients with pauci-immune glomerulonephritis and serum creatinine greater than 5.7 mg/dL to plasmapheresis or a methylprednisolone pulse. All patients received oral prednisone and cyclophosphamide (for 3 months) followed by maintenance with AZA. Plasmapheresis was noted to be associated with higher likelihood of being dialysis independent at 3 months and 1 year.113 There have been no randomized trials of plasmapheresis in pulmonary hemorrhage in ANCA disease; however, its use is based on the benefit seen in antiGBM disease and the possible benefit from rapid removal of ANCA, and the benefit seen in those treated with it in comparison with historical controls.114 Maintenance

After remission is attained, all patients are switched from cyclophosphamide to less toxic immunotherapy (AZA or methotrexate). Dialysis-dependent patients with no renal recovery after 2 to 3 months should not receive continued immunosuppression, unless required for extrarenal manifestations. Methotrexate in weekly oral doses has been shown to be effective in maintaining remission115; however, patients with serum creatinine levels persistently above 2.5 mg/dL were excluded. AZA has also been shown to be effective in maintaining remission after cyclophosphamide induction.109 Methotrexate and AZA provide similar efficacy and are associated with similar relapse rates.116 Azathioprine has also been compared with MMF.117 Relapses were more frequent in the MMF group while the rates of adverse events were similar. Hence, either AZA or methotrexate may be used for maintenance, whereas MMF should not be used. AZA may be preferred for women desiring pregnancy or for those with a significantly reduced glomerular filtration rate. Cyclophosphamide is continued for 1 to 2 months after remission is induced. The transition to AZA or methotrexate is initiated based on the last dose of cyclophosphamide and the white blood cell count. There are no studies to guide the duration of therapy, which is usually continued for 12 to 18 months after stable remission. Treatment of Relapses

Relapses are common in ANCA disease, and may occur during maintenance therapy or after cessation of therapy. The rates of relapse vary widely from 11% to 57%.108,109,117 Those with mild or non–organ-threatening relapses may be treated by increasing the dose of steroids and maintenance medications if already using such agents, or reinstitution of maintenance medications and a short course of steroids.

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ANTI-GBM (GOODPASTURE) DISEASE

Anti-GBM disease presents clinically as rapidly progressive glomerulonephritis, and pathologically presents with crescentic glomerulonephritis; immunofluorescence shows linear deposits of immunoglobulin G. Anti-GBM can present as a renal limited disease or as a pulmonary-renal syndrome. Untreated it has extremely poor outcomes, with almost universal mortality from renal failure or pulmonary hemorrhage.118 Early diagnosis and treatment is key.119,120 A retrospective study120 showed that patients with serum creatinine less than 5.7 mg/dL at presentation had 1-year patient and renal survival of 100% and 95%, respectively, whereas those who required immediate dialysis had a 1-year patient and renal survival of 65% and 8%. The first-line treatment is prednisone, cyclophosphamide, and plasmapheresis (Box 7).120–123 The only randomized study of plasmapheresis showed that 2 of 8 patients who received pheresis versus 6 of 9 who received only immunosuppression became dialysis dependent.124 However, these differences were not statistically significant. Most clinicians still recommend using pheresis, based on the improved outcomes seen in the pheresis era in comparison with historical controls and the biological plausibility of benefit from quicker removal of pathogenic anti-GBM antibodies by pheresis. Pulse methylprednisone (15–20 mg/kg for a maximum of 1000 mg) is given daily for 3 days, followed by prednisone (1 mg/kg daily for maximum of 60–80 mg/d) accompanied by cyclophosphamide (2 mg/kg daily orally). There is a low risk of recurrence of this disease and anti-GBM antibody formation can spontaneously cease, although it may take many months. Hence the duration of therapy is unknown. Plasmapheresis is performed for 2 to 3 weeks, cyclophosphamide can be stopped after 2 to 3 months, and prednisone can be stopped after 6 months.119,123 However, therapy can be individualized based on monitoring of anti-GBM antibody levels, and may be tapered earlier if they have been persistently negative or need to be extended or intensified if antibody levels are persistent or reappear. There is a subset of patients who have combined ANCA and anti-GBM disease. In these cases the initial management is the same as that for anti-GBM disease, and long-term management is the same as for ANCA disease, as these patients have a substantial risk for relapse. NOVEL IMMUNOTHERAPIES FOR GLOMERULONEPHRITIS

As newer mechanisms of pathogenic pathways of glomerulonephritis are unraveled, many novel designer drugs targeted to specific pathogenic molecules are being used.  Rituximab (a chimeric monoclonal anti-CD20 antibody) has been used in resistant or steroid-dependent MCD and focal segmental glomerulosclerosis.125–128 Box 7 Treatment of anti-GBM disease Steroids (intravenous methylprednisolone 15–20 mg/kg for 3 days followed by prednisone 1 mg/kg daily) AND Cyclophosphamide (by mouth 2 mg/kg daily) AND Plasmapheresis

Immunotherapy in Renal Diseases

 





It has also been used in membranous nephritis and in resistant or relapsing ANCA vasculitis, as already described. Belimumab (a humanized monoclonal anti–B-lymphocyte stimulator antibody) has been recently approved by the Food and Drug Administration for systemic lupus erythematosus.129 Adalimumab is a humanized monoclonal anti–tumor necrosis factor (TNF)-a antibody. TNF-a is an inflammatory cytokine released by macrophages and renal tubular cells in glomerulonephritis, and has been incriminated for progressive sclerosis and for proteinuria in angiotensin II–induced renal injury. Phase I and II trials of adalimumab for the treatment of FSGS are currently ongoing as the FONT trials I and II.130 Fresolimumab is a humanized monoclonal anti–transforming growth factor (TGF)-b antibody. TGF-b is a cytokine implicated as a modulator of extracellular matrix production and is associated with interstitial fibrosis. TGF-b is also a regulator of podocyte structure and function, and activates the Smad cascade. Fresolimumab is an engineered humanized G4 subclass monoclonal antibody to TGF-b (antagonizing all 3 isoforms of TGF-b) and is being tried in phase I and II trials on FSGS.131 Eculizumab (a monoclonal antibody against complement protein C5) is approved for treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Trials are also under way for its use in dense deposit disease.

SUMMARY

Therapy for renal diseases has come a long way during the last 50 years as regards the use of immunosuppressive drugs. Clinicians are surely and steadily moving toward targeted therapies as the understanding of pathogenic mechanisms is improving. It is hoped that in the future more specific drugs are developed for the treatment of renal diseases. REFERENCES

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