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Home , ACE inhibitor, Glomerulonephritis, IgA nephropathy

BRIEF REVIEW www.jasn.org

Current Therapy for IgA Nephropathy

Ju¨rgen Floege and Frank Eitner

Division of and Immunology, RWTH University of Aachen, Aachen, Germany

ABSTRACT IgA nephropathy (IgAN) is a very common 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 . Second is the typical patient presenting with , graft kidneys before implantation.2 Thus, significant but non-nephrotic , 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, 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 or even combination therapy patients with isolated microhematuria in such patients. Third is the atypical patient with overt , or followed for up to 12 years, microhema- acute or rapidly progressive injury where a possible vasculitic form of IgAN turia disappeared in 14%, and in less should be sought and, if present, treated with . 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 primary . 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 . 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. Ju¨rgen 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: ϩ49 241 80 89530; Fax: cal clinical scenarios encountered in Is Very Benign, and Does Not Need ϩ49 241 80 82446; E-mail: juergen.floege@rwth- IgAN patients: that is, the coincidental Treatment aachen.de 1 discovery of minor urinary abnormali- In autopsy series and zero-hour allo- Copyright © 2011 by the American Society of ties (the majority); the typical patient graft ,2 glomerular IgA deposits Nephrology

J Am Soc Nephrol 22: 1785–1794, 2011 ISSN : 1046-6673/2210-1785 1785 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 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 Add immunosuppression for at least 3–6 months No immunosuppression (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 - 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 Ͻ50% 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 , 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 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 - ● Control 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 (, warfarin, or Level 2 recommendations dipyridamole were used), often com- ● Restrict NaCl intake/institute therapy bined with immunosuppression, and ● Control fluid intake were retrospective and nonrandom- ● Non–dihydropyridine calcium-channel blocker therapy ● Control each component of the ized. At present, no recommendation ● antagonist therapy on the use of such drugs is possible in ● Beta-blocker therapy IgAN patients. ● Smoking cessation , combined with im- ● 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 D deficiency sillectomy reduces proteinuria from ● Control hyperphosphatemia and hyperparathyroidism; in animal models and in human 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 ; NSAID, non-steroidal anti-inflammatory . 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 far24 clude their small size, nonrandomized will be KDIGO recommendations (as op- noted a better preservation of renal nature, and nonsystematic -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 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 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 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 markedly ex- ceeded the threshold of2gofmethylpred- 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- . 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) 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) that, during the 6-month run-in phase, Overview of a case with sclerotic and atrophic changes. Right-sided glomerulus with 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 Ͻ0.75 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- 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 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 mScNephrol Soc Am J 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, 22: plus oral prednisone 0.5 mg/kg for 9 months, and then 30 kg/day per month) then reduced by 5–10 2

7519,2011 1785–1794, every other day for 6 months mg/m 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 if hypertensive in all patients in all patients follow-up during follow-up Key outcome in steroid Ten-year renal survival (ϭabsent Significant reduction in No benefit in the steroid Mean annual loss of GFR 6.2 Significantly fewer group versus control doubling of serum ), 53% proteinuria but not group versus placebo at 2 ml/min in controls versus 0.6 patients with a 50% 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 ϩ 10 mg (end of year 2) ϩ oral maximum, 80 mg/d for 4 weeks maximum, 80 mg/d for 4 weeks oral 1.5 mg/kg www.jasn.org 1.5 mg/kg per tapered to alternate steroid at 1 tapered to alternate steroid at 1 per day for 6 months g Nephropathy IgA day for 3 months, and then oral mg/kg until end of year 2) ϩ oral mg/kg until end of year 2) ϩ 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) ϩ (heparin years) ϩ warfarin ϩ dipyridamole followed by warfarin and dipyridamole)

Control regimen Supportive therapy only Supportive therapy ϩ anticoagulants Above regimen without azathioprine Same as shown in Table 2 36 REVIEW BRIEF (see above) 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 1789 Comment Study included pediatric patients only Study included pediatric patients only Therapeutic regimens and outcomes in controlled trials in IgAN patients. RAS, renin-angiotensin system. 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 ,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 .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

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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 (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 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 from the history and such patients eases.80 The treatment of secondary IgAN should receive supportive therapy. In is primarily directed against the underlying 1. Waldherr R, Rambausek M, Duncker WD, AKI associated with macroscopic hema- primary disease. In particular, in patients Ritz E: Frequency of mesangial IgA deposits turia, a repeat is indicated if with alcoholic liver disease, 80% of the pa- in a non-selected autopsy series. Nephrol Dial Transplant 4: 943–946, 1989 81 renal function does not improve within a tients exhibit glomerular IgA deposits, 2. Suzuki K, Honda K, Tanabe K, Toma H, Nihei few days to differentiate acute tubular but progressive IgAN is very rare. A discus- H, Yamaguchi Y: Incidence of latent mesan- necrosis with intratubular erythrocyte sion of current therapeutic concepts in He- gial IgA deposition in renal allograft donors casts from crescentic and/or necrotizing noch-Scho¨nlein is beyond the in Japan. Kidney Int 63: 2286–2294, 2003 IgAN. The former again requires sup- scope of our review. The reader is referred 3. Szeto CC, Lai FM, To KF, Wong TY, Chow KM, Choi PC, Lui SF, Li PK: The natural 82–84 portive care only; macrohematuria lon- to recent reviews. history of nephropathy ger than 10 days, older age, and de- among patients with hematuria and minimal creased baseline GFR are clinical proteinuria. Am J Med 110: 434–437, 2001 predictors of incomplete recovery from 4. Nieuwhof C, Kruytzer M, Frederiks P, van Breda Vriesman PJ: Chronicity index and AKI.74 RECURRENT IgAN IN THE TRANSPLANT PATIENT mesangial IgG deposition are risk factors for In case series of crescentic and/or ne- hypertension and renal failure in early IgA crotizing IgAN and either AKI or a rap- nephropathy. Am J Kidney Dis 31: 962–970, idly progressive course, there was a None of the currently available immuno- 1998 seeming benefit from treatment analo- suppressive drugs used after renal trans- 5. Shima Y, Nakanishi K, Kamei K, Togawa H, gous to ANCA-associated plantation can prevent the histologic re- Nozu K, Tanaka R, Sasaki S, Iijima K, Yo- 8,85 shikawa N: Disappearance of glomerular IgA (steroids and cyclophosphamide).75–78 currence of IgAN. There is also no clear evidence that the choice of immu- deposits in childhood IgA nephropathy Limitations of all these studies include showing diffuse mesangial proliferation after the lack of controls and their usually ret- nosuppression after renal transplanta- 2 years of combination/prednisolone ther- rospective nature. Such rare patients tion affects the clinical manifestation or apy. Nephrol Dial Transplant 26: 163–169, 8 can also have anti-GBM or course of recurrent IgAN. 2011 6. Yoshikawa N, Iijima K, Matsuyama S, Suzuki ANCAs and probably should be treated Relative consensus exists that patients with recurrent IgAN should mainly re- J, Kameda A, Okada S, Nakamura H: Repeat analogously to Goodpasture’s syndrome or renal biopsy in children with IgA nephropa- ANCA vasculitis, respectively. ceive optimized supportive care. A small thy. Clin Nephrol 33: 160–167, 1990 case series86 reported that without renin- 7. Cuevas X, Lloveras J, Mir M, Aubia J, Masra- mon J: Disappearance of mesangial IgA de- The Patient with Overt Nephrotic angiotensin blockade 4 out of 4 patients posits from the kidneys of two donors after Syndrome with recurrent IgAN progressed to end- stage renal disease compared with 3 out transplantation. Transplant Proc 19: 2208– Although nephrotic-range proteinuria is 2209, 1987 not uncommon in IgAN patients, partic- of 9 in the group treated with an ARB. 8. Floege J: Recurrent IgA nephropathy after ularly those with poorly controlled hy- Whether patients with recurrent IgAN renal transplantation. Semin Nephrol 24: pertension, a complete nephrotic syn- should also receive a tonsillectomy, as 287–291, 2004 suggested by a recent small Japanese trial, 9. Reich HN, Troyanov S, Scholey JW, Cattran drome is distinctly uncommon. In such DC: Remission of proteinuria improves prog- is currently unresolved.30 cases, coincidental IgAN with minimal- nosis in IgA nephropathy. J Am Soc Nephrol change nephropathy should be excluded 18: 3177–3183, 2007 by electron and, if present, 10. D’Amico G: Natural history of idiopathic IgA nephropathy and factors predictive of dis- treatment should be analogous to mini- ACKNOWLEDGMENTS ease outcome. Semin Nephrol 24: 179–196, mal-change disease. A small randomized 2004 controlled trial from 1986 suggests that We thank Lee Hebert, The Ohio State Univer- 11. 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