CURRENT THERAPY FOR IGA NEPHROPATHY

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CURRENT THERAPY FOR IGA NEPHROPATHY
BRIEF REVIEW          www.jasn.org

Current Therapy for IgA Nephropathy
Jürgen Floege and Frank Eitner
Division of Nephrology and Immunology, RWTH University of Aachen, Aachen, Germany

ABSTRACT
IgA nephropathy (IgAN) is a very common glomerulonephritis worldwide. In this                are detected in 5 to 20% of all cases. Full-
review, we discuss therapeutic options in four clinical scenarios encountered in             blown IgAN with glomerular IgA plus C3
patients with IgAN: first is the patient with minor urinary abnormalities where the          deposits as well as mesangioproliferative
mainstay of treatment is long-term, regular follow-up to detect renal progression            changes were noted in 1.6% of Japanese
and hypertension. Second is the typical patient presenting with microhematuria,              graft kidneys before implantation.2 Thus,
significant but non-nephrotic proteinuria, hypertension, and variable degrees of             the majority of patients with IgAN must
renal failure. Here the mainstay of treatment is optimized supportive care. If this          run a clinically inconspicuous course
does not lower proteinuria below 1 g/d, corticosteroid monotherapy may be                    and spontaneous remissions of the dis-
effective, as long as the GFR is above 50 ml/min. There is insufficient data to              ease must exist. Indeed, in Chinese IgAN
advocate the use of other immunosuppressive drugs or even combination therapy                patients with isolated microhematuria
in such patients. Third is the atypical patient with overt nephrotic syndrome, or            followed for up to 12 years, microhema-
acute or rapidly progressive kidney injury where a possible vasculitic form of IgAN          turia disappeared in 14%, and in less
should be sought and, if present, treated with immunosuppression. In other                   than one third, proteinuria increased
atypical patients with secondary IgAN, treatment should target the underlying                above 1 g/d or GFR fell.3 Repeat biopsy
primary disease. And fourth is the transplanted patient with recurrent IgAN where            studies confirm that glomerular changes,
the mainstay of treatment is optimized supportive care.                                      including IgA deposits, can completely
                                                                                             disappear spontaneously or after treat-
J Am Soc Nephrol 22: 1785–1794, 2011. doi: 10.1681/ASN.2011030221
                                                                                             ment in both native4 – 6 and transplanted
                                                                                             kidneys.7,8 These studies have two im-
                                                                                             portant clinical implications: IgAN—at
Although IgA nephropathy (IgAN) is the           who requires close follow-up and treat-     least in early stages— can be spontane-
most common noninfectious glomeru-               ment; atypical manifestations including     ously reversible and patients with iso-
lonephritis worldwide, there are remark-         overt nephrotic syndrome, acute or rap-     lated urinary abnormalities, particular
ably few randomized controlled trials            idly progressive kidney injury, or sec-     those in whom IgAN has been con-
and very rarely do patient numbers ex-           ondary forms of IgAN; and finally recur-    firmed, need to be followed long-term, as
ceed 200. Consequently, most guidelines          rent IgAN after renal transplantation. A    there may be progressive disease in ap-
relating to IgAN in the KDIGO Clinical           synopsis of our suggested approach is       proximately 30%. Although such long-
Practice Guideline for Glomerulonephritis        given in Figure 1. Supportive care          term follow-up is often recommended,
(to be published in late 2011) will be           throughout the manuscript refers to         especially in young patients, at least in our
based on a low to very low level of evi-         measures listed in Table 1, which are not   experience it is rarely maintained through-
dence and, in many cases, suggestions            specific for IgAN and which have been       out the necessary 10 or more years. Auto-
cannot even be offered. Thus, the major-         shown to retard progression of chronic
ity of patients will continue to be treated      glomerular diseases.
based largely on opinion. This review will                                                   Published online ahead of print. Publication date
attempt to incorporate evidence-based                                                        available at www.jasn.org.
recommendations, but it will also cover          THE SILENT MAJORITY                         Correspondence: Dr. Jürgen Floege, Department
areas founded exclusively on opinion.                                                        of Nephrology and Clinical Immunology, RWTH Uni-
We have based the review on four classi-         Most IgAN Likely Goes Unnoticed,            versity Hospital Aachen, Pauwelsstr. 30, 52074
                                                                                             Aachen, Germany. Phone: ⫹49 241 80 89530; Fax:
cal clinical scenarios encountered in            Is Very Benign, and Does Not Need           ⫹49 241 80 82446; E-mail: juergen.floege@rwth-
IgAN patients: that is, the coincidental         Treatment                                   aachen.de
discovery of minor urinary abnormali-            In autopsy series1 and zero-hour allo-      Copyright © 2011 by the American Society of
ties (the majority); the typical patient         graft biopsies,2 glomerular IgA deposits    Nephrology

J Am Soc Nephrol 22: 1785–1794, 2011                                                               ISSN : 1046-6673/2210-1785           1785
CURRENT THERAPY FOR IGA NEPHROPATHY
BRIEF REVIEW      www.jasn.org

                                                BIOPSY-PROVEN, PRIMARY IgAN

                       LOW RISK                     MODERATE TO HIGH RISK              ACUTE OR RAPID
                (minor urinary abnormalities,       (proteinuria > 0.5–1 g/d and/or
               GFR normal, no hypertension)        GFR reduced and/or hypertension)
                                                                                         GFR LOSS

                                                                                                                  AKI due to macro-
                       Monitor annually               Optimize supportive therapy                                 hematuria or other
                     for at least 10 years                                                                         common cause

                  Proteinuria >0.5–1 g/day
                                                                                       Nephrotic syndrome            Supportive
                  GFR normal or slowly ,                 GFR < 30–50 ml/min
                                                                                           or RPGN                    therapy
                    but > 30–50 ml/min

                                                      Continue supportive therapy
                Continue supportive therapy
                                                        No immunosuppression          Add immunosuppression
                  for at least 3–6 months
                                                           (except if RPGN)

                     Continue supportive                   Add corticosteroid,
                        therapy alone,                 if proteinuria > 1g/day or
                 if proteinuria < 1g/day and             progressive GFR-loss
                GFR-decline < 30%/6 months           despite blood pressure control

         Figure 1. Synopsis of suggested therapeutic approaches to patients with IgAN depending on the clinical setting.

mated reminder systems might provide               year or at year 1.12 Uncontrolled hyper-        are ongoing. Whether it is beneficial to
some help here.                                    tension has an additive effect with protein-    base clinical decisions on this classifica-
                                                   uria in driving progression of disease.9,11     tion system, in particular, the novel pa-
                                                   The third consistent indicator of risk is a     rameters of mesangial and endocapillary
THE TYPICAL PATIENT WITH IgAN                      decrease in GFR at presentation.10 This is      hypercellularity, has not yet been tested.
                                                   expected since loss of renal function likely    Finally, how the presence of cellular cres-
Proteinuria, Hypertension, and GFR                 identifies the subgroup of IgAN patients        cents in a patient who does not exhibit a
Are Key Determinants of the Type                   who are already progressive. Finally, renal     rapidly progressive (vasculitic) course of
of Treatment                                       prognosis is worse in obese IgAN pa-            IgAN should ultimately affect treatment
The degree of proteinuria is one of the            tients,13,14 possibly related to superim-       modality is unresolved. There is relative
strongest predictors of outcome in                 posed obesity-related renal changes.15          consensus, however, that crescents in
IgAN.9 –11 The risk for renal failure in-          Nonsurgical weight loss can indeed lead to      ⬍50% of the glomeruli in an otherwise
creases with higher proteinuria. Vice              a reduction of proteinuria.16                   stable patient should not automatically
versa, lowering proteinuria markedly de-               In terms of histologic parameters           prompt immunosuppression since insti-
creases risk regardless of whether the ini-        (Figure 2), the IgAN Oxford classifica-         tution of adequate supportive therapy
tial proteinuria is mild or in the ne-             tion17,18 may offer important advances          may indeed lead to resolution of cres-
phrotic range.9,11 Whereas most studies            by providing evidence that not only             cents.
use a proteinuria cutoff of 1 g/d, above           chronic fibrotic changes, particularly
which increased risk for renal failure de-         glomerulosclerosis and tubulointersti-          One Size Fits All: Optimized
velops,9 –11 others contend that an in-            tial fibrosis, but also mesangial and en-       Supportive Therapy Is the
creased risk starts above 0.5 g/d.12 Fur-          docapillary hypercellularity predict            Cornerstone for All Patients at Risk
thermore, it unresolved, which is the best         prognosis. Various validation studies,          of Progression
predictor, proteinuria at initial presenta-        such as the VALIGA study of the Euro-           There is no doubt that an optimized sup-
tion or the level maintained over the first        pean Renal Association (ERA-EDTA),              portive regimen constitutes the corner-

1786        Journal of the American Society of Nephrology                                                     J Am Soc Nephrol 22: 1785–1794, 2011
CURRENT THERAPY FOR IGA NEPHROPATHY
www.jasn.org    BRIEF REVIEW

Table 1. Supportive therapy of IgAN                                                                        warfarin [INR 1.3 to 1.5]) compared
Level 1 recommendations                                                                                    with no treatment, but angiotensin-
  ● Control blood pressure (sitting systolic BP in the 120s)                                               converting enzyme (ACE) inhibitors
  ● ACE inhibitor or ARB therapy with uptitration of dosage or combination ACE inhibitor                   were avoided in these patients.27 Most
    and ARB therapy                                                                                        other studies on this topic suffer from
  ● Avoid dihydropyridine calcium-channel blockers unless needed for BP control                            the fact that antiplatelet therapy was
  ● Control protein intake                                                                                 not standardized (aspirin, warfarin, or
Level 2 recommendations
                                                                                                           dipyridamole were used), often com-
  ● Restrict NaCl intake/institute diuretic therapy
                                                                                                           bined with immunosuppression, and
  ● Control fluid intake
  ● Non–dihydropyridine calcium-channel blocker therapy
                                                                                                           were retrospective and nonrandom-
  ● Control each component of the metabolic syndrome                                                       ized. At present, no recommendation
  ● Aldosterone antagonist therapy                                                                         on the use of such drugs is possible in
  ● Beta-blocker therapy                                                                                   IgAN patients.
  ● Smoking cessation                                                                                          Tonsillectomy, combined with im-
  ● Allopurinol therapy                                                                                    munosuppression, in patients at risk
  ● Empiric NaHCO3 therapy, independent of whether metabolic acidosis is present or not                    for progressive IgAN, is mostly recom-
Other measures to retard IgAN progression                                                                  mended in Japan, based largely on ret-
  ● Avoid NSAIDs altogether, or no more than once or twice weekly at most                                  rospective data.28,29 A recent small Jap-
  ● Avoid prolonged severe hypokalemia
                                                                                                           anese study in transplanted patients
  ● Avoid phosphate cathartics
                                                                                                           with recurrent IgAN30 reports that ton-
  ● Ergocalciferol therapy to correct vitamin D deficiency
  ● Control hyperphosphatemia and hyperparathyroidism; in animal models and in human
                                                                                                           sillectomy reduces proteinuria from
    studies, controlling hyperphosphatemia slows CKD progression                                           880 to 280 mg/d, whereas little change
Recommended supportive therapy options in patients with, or at risk of, progressive IgAN (modified after   was noted in a non– operated control
reference 20). The goal is to implement all level 1 recommendations and as many level 2                    group. Another recent Japanese study
recommendations as feasible. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker;        in primary IgAN also reports that ton-
CKD, chronic kidney disease; NSAID, non-steroidal anti-inflammatory drug.
                                                                                                           sillectomy combined with immuno-
                                                                                                           suppression is more effective in induc-
                                                                                                           ing remission of proteinuria and/or
stone of any therapeutic approach to                 there was a 75% probability of at least a             hematuria than immunosuppression
IgAN patients at risk for progression. In            minor effect.23 Long-term follow-up of                alone.31 Limitations of both studies in-
fact, this will be the only area where there         the largest randomized trial so far 24                clude their small size, nonrandomized
will be KDIGO recommendations (as op-                noted a better preservation of renal                  nature, and nonsystematic renin-ang-
posed to suggestions with lower degree               function in the fish oil group. In a                  iotensin blockade. Given that other
evidence). These measures are summa-                 smaller Italian randomized trial in pro-              studies have been unable to document
rized in Table 1. In view of space limita-           teinuric IgAN patients with preserved                 a benefit in IgAN patients who are
tions, we will not discuss this issue in de-         renal function, proteinuria decreased                 Caucasian, 32,32a we feel that an ade-
tail. The reader is referred to excellent            by 75% in the fish oil group but re-                  quately powered randomized con-
reviews on this topic.19 –21 Of note, most           mained stable in controls;25 however, a               trolled trial will be required before
randomized trials in IgAN suffer from                tendency of the control group toward                  tonsillectomy can be routinely re-
lack of optimized and comprehensive                  worse prognostic features at baseline                 commended in the care of IgAN pa-
supportive care. We therefore initiated              (numerically lower mean GFR, higher                   tients. An exception may be when there
the STOP-IgAN trial,22 which will test in            proteinuria, and more men) was nota-                  is a clear temporal relationship be-
high-risk IgAN patients whether immu-                ble. Essentially no side effects were                 tween tonsillitis episodes and bouts of
nosuppression exerts an added benefit                noted. In contrast, another more re-                  macrohematuria.
after the supportive therapy has been op-            cent randomized trial failed to detect a                  A recent Finnish study investigated
timized over 6 months. We recently fin-              benefit from fish oil;26 whether this was             the relationship between alcohol con-
ished recruitment and data are expected              related to a slightly higher baseline                 sumption and progression of IgAN.33
by 2014.                                             proteinuria in the fish oil group re-                 Better kidney function was associated
                                                     mains unresolved. At present, fish oil                with light-to-moderate alcohol con-
Nonestablished and Controversial                     in IgAN is literally a matter of taste.               sumption after correction for hyper-
Nonimmunosuppressive Treatment                          Antiplatelet and anticoagulant                     tension and 24-hour protein excretion.
Approaches                                           drugs are mostly used in Asia for the                 Light consumption (one drink per day)
In a meta-analysis of fish oil therapy in            treatment of IgAN. A small random-                    in women and moderate consumption
patients with IgAN, no statistically sig-            ized trial suggested benefit from dipy-               (1 to 3 drinks per day) in men appears
nificant benefit was noted, although                 ridamole (75 mg three times daily and                 optimal. Although this certainly does

J Am Soc Nephrol 22: 1785–1794, 2011                                                                                      IgA Nephropathy      1787
CURRENT THERAPY FOR IGA NEPHROPATHY
BRIEF REVIEW      www.jasn.org

                                                                                               Similarly, a low-dose corticosteroid reg-
  A                                               B
                                                                                               imen (20 mg/d, tapered over 2 years)
                                                                                               from Japan was ineffective in a random-
                                                                                               ized trial.38
                                                                                                   Corticosteroid-related side effects, even
                                                                                               with the more aggressive Pozzi regimen,
                                                                                               were reported to be minor. This is in con-
                                                                                               trast to the orthopedic literature in which
                                                                                               9 g of methylprednisolone markedly ex-
                                                                                               ceeded the threshold of 2 g of methylpred-
                                                                                               nisolone administered within 3 months,
  C                                               D                                            above which the incidence of aseptic osteo-
                                                                                               necrosis starts to rise.39,40
                                                                                                   Supportive therapy in the IgAN pa-
                                                                                               tients was not optimal by current stan-
                                                                                               dards in the study of Pozzi et al.36; a sim-
                                                                                               ilar benefit was noted after instituting an
                                                                                               ACE inhibitor alone.41,42 This is consis-
                                                                                               tent with a retrospective analysis in 702
                                                                                               IgAN patients where corticosteroid pulse
                                                                                               therapy as well as ACE-inhibitor therapy
  E                                               F                                            independently reduced progression of
                                                                                               disease.43 Both the trial of Manno et al.
                                                                                               and Lv et al. 35,34 (Table 2) suffer from
                                                                                               their study design, as patients were re-
                                                                                               quired to discontinue prior ACE inhibi-
                                                                                               tor or angiotensin receptor blocker
                                                                                               (ARB) therapy. Then, in the combina-
                                                                                               tion groups, they started receiving simul-
                                                                                               taneously an ACE inhibitor and cortico-
                                                                                               steroids. Consequently, a high number
Figure 2. The range of histologic findings in IgA nephropathy with an evaluation based         of patients who would have ended up in a
on the Oxford classification.17,18 All sections are PAS stains. (A) Glomerulus without         low-risk category with ACE inhibitor
mesangial proliferation and matrix increase (M0 with the majority of glomeruli showing         treatment alone were assigned additional
this phenotype). (B) Glomerulus with segmental mesangial hypercellularity (arrow) (M1          immunosuppression.44 In our own on-
with the majority of glomeruli showing such a phenotype). (C) Endocapillary hypercellu-
                                                                                               going STOP-IgAN study,22 we noted
larity (E1). (D) Glomerulus with segmental necrosis and extracapillary proliferation. (E)
Overview of a case with sclerotic and atrophic changes. Right-sided glomerulus with
                                                                                               that, during the 6-month run-in phase,
segmental glomerulosclerosis and a focal adhesion (arrow) surrounded by increased              which is meant to uptitrate renin-angio-
interstitial matrix and tubules with segmental dedifferentiation (tubular atrophy) (S1 for     tensin blockers to their maximum anti-
glomerular sclerosis and T1 for tubular atrophy and interstitial fibrosis). (F) Higher mag-    proteinuric effect, proteinuria decreased
nification of the glomerulus illustrated in Figure 2E with segmental glomerulosclerosis        to ⬍0.75 g/d in most patients with IgAN
and an adhesion (arrow) (S1).                                                                  (unpublished data).
                                                                                                   A pragmatic approach suggests first
not establish a causal or even therapeu-         preserved renal function, and a GFR           optimizing supportive therapy in IgAN
tic relationship, patients should be             above 50 ml/min, can reduce proteinuria       patients at risk for progression (see
made aware of these findings.                    and decrease the risk of subsequent renal     above). If this is not sufficient to lower
                                                 failure.34 –37 Whereas corticosteroid ther-   proteinuria below about 1 g/d, patients
Proteinuric Patients, Despite                    apy in the first trial consisted of com-      should be offered a 6-month trial of cor-
Optimized Supportive Care, Should                bined pulse and oral steroids, a purely       ticosteroids as long as their GFR is higher
Be Given a 6-Month Course of                     oral regimen was used in the subsequent       than 50 ml/min (Figure 1). Table 2 sug-
Corticosteroids If GFR Is Above                  trials and appeared effective as well (Ta-    gests that strictly alternating or low-dose
50 ml/min                                        ble 2). In contrast, in a smaller United      corticosteroid therapy is ineffective. It is
Three randomized controlled trials have          States trial,26 using a much longer but       unresolved which of the three high-dose
shown that a 6-month course of cortico-          strictly alternating steroid regimen, no      daily regimens is more beneficial. The
steroids in IgAN patients with relatively        benefit was noted at 2 years (Table 2).       longest follow-up data are available for

1788        Journal of the American Society of Nephrology                                               J Am Soc Nephrol 22: 1785–1794, 2011
Table 2. Corticosteroid monotherapy
                                                   Trial                        Pozzi et al., Italy37,36            Katafuchi et al., Japan38      Hogg et al., United States26              Manno et al., Italy35              Lv et al., China34
                                         Corticosteroid regimen        Intravenous methylprednisolone 1 g/d         Oral prednisolone 20           Oral prednisone every other       Oral prednisone for 6 months            Oral prednisone for 6–8
                                                                          for 3 consecutive days at the               mg/d tapered to 5              day 60 mg/m2 for 3                (1 mg/kg/day for 2 months,               months (0.8–1 mg/kg/
                                                                          beginning of months 1, 3, and 5,            mg/d at 18 months              months, then 40 mg/m2             then reduced by 0.2 mg/                  day for 2 months,
                                                                          plus oral prednisone 0.5 mg/kg                                             for 9 months, and then 30         kg/day per month)                        then reduced by 5–10
                                                                          every other day for 6 months                                               mg/m2 for 12 months                                                        mg every 2 wk)
                                         Control regimen               Supportive only                              Dipyridamole                   Placebo                           Supportive only                         Supportive only
                                         RAS blockade                  14% at baseline, allowed during              2% at baseline; allowed        Enalapril if hypertensive         Ramipril in all patients                Cilazapril in all patients
                                                                          follow-up                                   during follow-up
                                         Key outcome in steroid        Ten-year renal survival (⫽absent             Significant reduction in       No benefit in the steroid         Mean annual loss of GFR 6.2             Significantly fewer
                                           group versus control           doubling of serum creatinine), 53%          proteinuria but not           group versus placebo at 2         ml/min in controls versus 0.6            patients with a 50%

  J Am Soc Nephrol 22: 1785–1794, 2011
                                                                          in controls versus 97% in the               ESRD frequency                years                             ml/min in the steroid group              increase in serum
                                                                          steroid group                                                                                                                                        creatinine in the
                                                                                                                                                                                                                               steroid group
                                         Therapeutic regimens and outcomes in randomized controlled trials in IgAN patients. RAS, renin-angiotensin system; ESRD, end-stage renal disease.

                                         Table 3. Mycophenolate mofetil monotherapy
                                                       Trial                                  Maes et al., Belgium48                                 Tang et al., China46,47                                     Frisch et al., United States49
                                         MMF regimen                                          2 g/d for 3 years                            1.5 to 2.0 g/d depending on body weight                            Titrated up to 2 g/d for 1 year
                                                                                                                                             for 6 months
                                         Control regimen                                      Placebo                                      Supportive only                                                    Placebo
                                         RAS blockade                                         All patients                                 All patients                                                       All patients
                                         Key outcome in MMF group                             No effect on GFR or                          Reduction in proteinuria, stabilization of                         No effect on GFR or proteinuria
                                           versus control                                      proteinuria                                   GFR
                                         Therapeutic regimens and outcomes in controlled trials in IgAN patients. MMF, mycophenolate mofetil; RAS, renin-angiotensin system.

                                         Table 4. Immunosuppressive combination therapy
                                                      Trial                    Ballardie et al., United Kingdom66                Yoshikawa et al., Japan64                  Yoshikawa et al., Japan65                     Pozzi et al., Italy45
                                         Combination regimen                 Oral prednisolone 40 mg/d reduced to          Oral prednisolone (2 mg/kg per day,        Oral prednisolone (2 mg/kg per day,            Same as shown in Table 2 36 ⫹
                                                                               10 mg (end of year 2) ⫹ oral                  maximum, 80 mg/d for 4 weeks               maximum, 80 mg/d for 4 weeks                   oral azathioprine 1.5 mg/kg
                                                                               cyclophosphamide 1.5 mg/kg per                tapered to alternate steroid at 1          tapered to alternate steroid at 1              per day for 6 months
                                                                               day for 3 months, and then oral               mg/kg until end of year 2) ⫹ oral          mg/kg until end of year 2) ⫹ oral
                                                                               azathioprine 1.5 mg/kg per day for            azathioprine (2 mg/kg per day for 2        azathioprine (2 mg/kg per day for 2
                                                                               minimum 2 years and up to 6 years             years) ⫹ anticoagulants (heparin           years) ⫹ warfarin ⫹ dipyridamole
                                                                                                                             followed by warfarin and
                                                                                                                                                                                                                                                          www.jasn.org

                                                                                                                             dipyridamole)
                                         Control regimen                     Supportive therapy only                       Supportive therapy ⫹ anticoagulants        Above regimen without azathioprine             Same as shown in Table 2 36
                                                                                                                             (see above)

IgA Nephropathy
                                         RAS blockade                        Inconsistent                                  Not reported                               Prohibited                                     45% at baseline
                                         Key outcome in combination          Marked improvement of renal survival          Higher reduction in proteinuria and        More complete remissions of                    No difference between groups
                                           group versus control                 at 5 years                                   percentage of sclerosed glomeruli          proteinuria
                                         Comment                                                                           Study included pediatric patients only     Study included pediatric patients only
                                                                                                                                                                                                                                                          BRIEF REVIEW

                                         Therapeutic regimens and outcomes in controlled trials in IgAN patients. RAS, renin-angiotensin system.

1789
BRIEF REVIEW       www.jasn.org

the Pozzi regimen.37 Patient preferences,         sufficient at present to suggest their use     serum creatinine below 2 mg/dl and a
anticipated risk of side effects in a given       in IgAN patients. Of note, as discussed        proteinuria above 1 g/d, despite RAS
patient, and also local conditions should         below, neither cyclosporine A, tacroli-        blockade, were assigned to receive corti-
currently dictate the choice of regimen.          mus, or sirolimus prevent recurrence of        costeroids or additional oral azathio-
Successful re-treatments in patients who          IgAN in a renal graft.                         prine. Outcome after a median of 4.9
experienced a relapse of proteinuria after                                                       years was not different between the two
steroid therapy have been reported.45             Immunosuppressive Combination                  groups.45
                                                  Therapy Is Not Recommended                        In general, side effects in the combi-
Data on Mycophenolate Mofetil                     A number of retrospective studies or case      nation therapy groups are more frequent
(MMF) Monotheray in IgAN Are                      series, mostly from Asia, have reported        and severe than those in monotherapy
Inconclusive                                      beneficial outcomes in high-risk IgAN pa-      groups and include, among others, glau-
Three randomized controlled trials, one           tients treated with combinations of corti-     coma, cataracts, and aseptic necrosis of
each from China,46,47 Belgium, and the            costeroids plus cyclophosphamide or aza-       the femoral head in children,65,64 my-
United States48,49 have assessed the value        thioprine versus controls.57– 61 Selection     elodepression,66 secondary diabetes,66
of MMF in high-risk patients with IgAN            and observation bias as well as nonopti-       pulmonary tuberculosis,66 and pneumo-
(Table 3); a fourth trial50 is ongoing. One       mized supportive measures render an in-        cystis pneumonia.45 In our ongoing STOP-
additional study, published in Chinese,           terpretation of these studies difficult. In    IgAN trial, one patient receiving immuno-
reports better proteinuria reduction with         contrast, one trial from Singapore62 and       suppressive combination therapy based
1 to 1.5 g/d MMF, reduced to 0.5 to 0.75          one from Australia63 found no evidence for     on the Ballardie protocol66 died from
g/d within 12 months, as compared with            a benefit of cyclophosphamide, dipyrid-        pneumogenic sepsis (unpublished ob-
high-dose oral prednisone.51 Supportive           amole, plus warfarin on renal function as      servation). Clearly, this is a major con-
care and BP control were unclear, ren-            compared with controls.                        cern in a slowly progressive disease such
dering an interpretation of this study dif-           More recent prospective randomized         as IgAN, which needs to be weighed
ficult. In the other Chinese trial, 2 g/d of      controlled trials on immunosuppressive         against the risk of losing renal function.
MMF, on top of an ACE inhibitor, led to           combinations in IgAN have also yielded in-        At present, we feel that immunosup-
better reduction of proteinuria and sta-          consistent outcomes (Table 4). In two Jap-     pressive combination therapy is not war-
bilization of renal function in 20 IgAN           anese trials, both from the same group,64,65   ranted in IgAN patients unless there are
patients than ACE inhibitor alone.46,47 In        children with IgAN and severe histologic       features of rapidly progressive glomeru-
contrast, the Belgian and United States           changes and/or significant proteinuria, yet    lonephritis and/or a vasculitic course
trials in mostly Caucasian patients found         normal GFR, received azathioprine plus         (see below).
no effect on proteinuria48,49 despite a de-       corticosteroids plus anticoagulants versus
sign similar to that in the latter Chinese        anticoagulants alone.64 In the other trial,    The Patient with GFR below 30 to
trial.46,47 Whether ethnic factors, the           azathioprine plus corticosteroids plus anti-   50 ml/min: Comprehensive
higher dose of MMF per body weight in             coagulants were tested against steroids        Supportive Therapy Only
the Chinese trials, or other unidentified         alone.65 In both cases, the combination        Almost all randomized controlled trials
factors account for these striking differ-        therapy led to higher rates of complete re-    exclude IgAN patients with a GFR below
ences is unresolved.52                            mission of proteinuria.                        30 ml/min and contain very few patients
    At present, it appears prudent to largely         In 2002, Ballardie et al.66 published a    with a GFR between 30 and 50 ml/min. A
restrict the use of MMF to patients of Asian      small randomized trial comparing cyclo-        case series in patients with a median GFR
origin who fail to respond to supportive          phosphamide plus corticosteroids fol-          of 22 ml/min reported benefits from se-
therapy and/or corticosteroids or in whom         lowed by azathioprine plus corticoste-         quential cyclophosphamide or steroid-
the use of steroids is problematic because        roids versus controls. Renal survival at 5     bolus therapy followed by MMF,67 but a
of comorbidities or side effects. If MMF is       years was 72% in the immunosuppressed          randomized controlled trial using MMF
used in IgAN patients with a reduced GFR,         group versus 6% in controls.66 RAS             alone in advanced IgAN failed to induce
pneumocystis carinii prophylaxis is impor-        blockade was infrequent and BP control         any benefit.49 At present there is not
tant, given several deaths in Chinese IgAN        not ideal by today’s standards. In addi-       enough evidence to advocate immuno-
patients on MMF.53                                tion, the patient group was highly select      suppressive therapy in advanced IgAN
                                                  in that patients exhibited impaired renal      once the patient has a serum creatinine
Other Immunosuppressive                           function at baseline with reciprocal se-       above 2.5 to 3 mg/dl, that is, the thresh-
Monotherapy Approaches Are Not                    rum creatinine plots suggesting end-           old that sometimes is referred to as the
Established                                       stage renal failure within 5 years, pro-       “point of no return.”68,69 Comprehen-
Some data have been published on alter-           nounced proteinuria, and no advanced           sive supportive therapy, however, must
native immunosuppressants in IgAN pa-             tissue scarring. Finally in 2010, Pozzi et     be continued in such patients as it can
tients, including mizoribine54 and cyclo-         al.45 published a randomized controlled        stabilize renal function for years at even
sporine A.55,56 None of the evidence is           trial in which 207 IgAN patients with a        very low levels.70 –72

1790         Journal of the American Society of Nephrology                                               J Am Soc Nephrol 22: 1785–1794, 2011
www.jasn.org      BRIEF REVIEW

THE ATYPICAL PATIENT                           proteinuria; however, there was no effect          images illustrating the Oxford classification
                                               on GFR after about 3 years.79                      of IgAN.
The Patient with Acute Kidney
Injury (AKI) or Rapidly Progressive            The Patient with Secondary IgAN
Loss of Renal Function                         Secondary IgAN is most commonly seen               DISCLOSURES
AKI resulting primarily from non– dis-         in patients with chronic liver and inflam-           None.
ease-specific causes is a common presen-       matory bowel diseases; however, associ-
tation in the rare elderly patient with        ations have been reported for numerous
IgAN.73 The cause is usually apparent          other immunologic and infectious dis-              REFERENCES
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