IgA肾病治疗进展

Current Therapy for IgA Nephropathy Ju¨rgen Floege and Frank Eitner Division of Nephrology and Immunology, RWTH University of Aachen, Aachen, Germany Although IgA nephropathy (IgAN) is the most common noninfectious glomeru- lonephritis worldwide, there are remark- ably few randomized controlled trials and very rarely do patient numbers ex- ceed 200. Consequently, most guidelines relating to IgAN in the KDIGO Clinical Practice Guideline for Glomerulonephritis (to be published in late 2011) will be based on a low to very low level of evi- dence and, in many cases, suggestions cannot even be offered. Thus, the major- ity of patients will continue to be treated based largely onopinion. This reviewwill attempt to incorporate evidence-based recommendations, but it will also cover areas founded exclusively on opinion. We have based the review on four classi- cal clinical scenarios encountered in IgAN patients: that is, the coincidental discovery of minor urinary abnormali- ties (the majority); the typical patient who requires close follow-up and treat- ment; atypical manifestations including overt nephrotic syndrome, acute or rap- idly progressive kidney injury, or sec- ondary forms of IgAN; and finally recur- rent IgAN after renal transplantation. A synopsis of our suggested approach is given in Figure 1. Supportive care throughout the manuscript refers to measures listed in Table 1, which are not specific for IgAN and which have been shown to retard progression of chronic glomerular diseases. THE SILENT MAJORITY Most IgAN Likely Goes Unnoticed, Is Very Benign, and Does Not Need Treatment In autopsy series1 and zero-hour allo- graft biopsies,2 glomerular IgA deposits are detected in 5 to 20% of all cases. Full- blown IgANwith glomerular IgA plusC3 deposits as well as mesangioproliferative changes were noted in 1.6% of Japanese graft kidneys before implantation.2 Thus, the majority of patients with IgAN must run a clinically inconspicuous course and spontaneous remissions of the dis- ease must exist. Indeed, in Chinese IgAN patients with isolated microhematuria followed for up to 12 years, microhema- turia disappeared in 14%, and in less than one third, proteinuria increased above 1 g/d or GFR fell.3 Repeat biopsy studies confirm that glomerular changes, including IgA deposits, can completely disappear spontaneously or after treat- ment in both native4–6 and transplanted kidneys.7,8 These studies have two im- portant clinical implications: IgAN—at least in early stages—can be spontane- ously reversible and patients with iso- lated urinary abnormalities, particular those in whom IgAN has been con- firmed, need to be followed long-term, as there may be progressive disease in ap- proximately 30%. Although such long- term follow-up is often recommended, especially in young patients, at least in our experience it is rarelymaintained through- out the necessary 10 or more years. Auto- Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Ju¨rgen Floege, Department of Nephrology and Clinical Immunology, RWTH Uni- versity Hospital Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. Phone: �49 241 80 89530; Fax: �49 241 80 82446; E-mail: juergen.floege@rwth- aachen.de Copyright © 2011 by the American Society of Nephrology ABSTRACT IgA nephropathy (IgAN) is a very common glomerulonephritis worldwide. In this review, we discuss therapeutic options in four clinical scenarios encountered in patients with IgAN: first is the patient with minor urinary abnormalities where the mainstay of treatment is long-term, regular follow-up to detect renal progression and hypertension. Second is the typical patient presenting with microhematuria, significant but non-nephrotic proteinuria, hypertension, and variable degrees of renal failure. Here the mainstay of treatment is optimized supportive care. If this does not lower proteinuria below 1 g/d, corticosteroid monotherapy may be effective, as long as the GFR is above 50 ml/min. There is insufficient data to advocate the use of other immunosuppressive drugs or even combination therapy in such patients. Third is the atypical patient with overt nephrotic syndrome, or acute or rapidly progressive kidney injury where a possible vasculitic form of IgAN should be sought and, if present, treated with immunosuppression. In other atypical patients with secondary IgAN, treatment should target the underlying primary disease. And fourth is the transplanted patient with recurrent IgAN where the mainstay of treatment is optimized supportive care. J Am Soc Nephrol 22: 1785–1794, 2011. doi: 10.1681/ASN.2011030221 BRIEF REVIEW www.jasn.org J Am Soc Nephrol 22: 1785–1794, 2011 ISSN : 1046-6673/2210-1785 1785 mated reminder systems might provide some help here. THE TYPICAL PATIENT WITH IgAN Proteinuria, Hypertension, and GFR Are Key Determinants of the Type of Treatment The degree of proteinuria is one of the strongest predictors of outcome in IgAN.9–11 The risk for renal failure in- creases with higher proteinuria. Vice versa, lowering proteinuria markedly de- creases risk regardless of whether the ini- tial proteinuria is mild or in the ne- phrotic range.9,11 Whereas most studies use a proteinuria cutoff of 1 g/d, above which increased risk for renal failure de- velops,9–11 others contend that an in- creased risk starts above 0.5 g/d.12 Fur- thermore, it unresolved, which is the best predictor, proteinuria at initial presenta- tion or the level maintained over the first year or at year 1.12 Uncontrolled hyper- tension has an additive effectwithprotein- uria in driving progression of disease.9,11 The third consistent indicator of risk is a decrease in GFR at presentation.10 This is expected since loss of renal function likely identifies the subgroup of IgAN patients who are already progressive. Finally, renal prognosis is worse in obese IgAN pa- tients,13,14 possibly related to superim- posed obesity-related renal changes.15 Nonsurgical weight loss can indeed lead to a reduction of proteinuria.16 In terms of histologic parameters (Figure 2), the IgAN Oxford classifica- tion17,18 may offer important advances by providing evidence that not only chronic fibrotic changes, particularly glomerulosclerosis and tubulointersti- tial fibrosis, but also mesangial and en- docapillary hypercellularity predict prognosis. Various validation studies, such as the VALIGA study of the Euro- pean Renal Association (ERA-EDTA), are ongoing. Whether it is beneficial to base clinical decisions on this classifica- tion system, in particular, the novel pa- rameters of mesangial and endocapillary hypercellularity, has not yet been tested. Finally, how the presence of cellular cres- cents in a patient who does not exhibit a rapidly progressive (vasculitic) course of IgAN should ultimately affect treatment modality is unresolved. There is relative consensus, however, that crescents in �50% of the glomeruli in an otherwise stable patient should not automatically prompt immunosuppression since insti- tution of adequate supportive therapy may indeed lead to resolution of cres- cents. One Size Fits All: Optimized Supportive Therapy Is the Cornerstone for All Patients at Risk of Progression There is no doubt that an optimized sup- portive regimen constitutes the corner- Optimize supportive therapy Nephrotic syndrome or RPGNGFR < 30–50 ml/min Continue supportive therapy for at least 3–6 months Add corticosteroid, if proteinuria > 1g/day or progressive GFR-loss despite blood pressure control Add immunosuppression Continue supportive therapy No immunosuppression (except if RPGN) LOW RISK (minor urinary abnormalities, GFR normal, no hypertension) MODERATE TO HIGH RISK (proteinuria > 0.5–1 g/d and/or GFR reduced and/or hypertension) ACUTE OR RAPID GFR LOSS AKI due to macro- hematuria or other common cause Supportive therapy BIOPSY-PROVEN, PRIMARY IgAN Proteinuria >0.5–1 g/day GFR normal or slowly , but > 30–50 ml/min Monitor annually for at least 10 years Continue supportive therapy alone, if proteinuria < 1g/day and GFR-decline < 30%/6 months Figure 1. Synopsis of suggested therapeutic approaches to patients with IgAN depending on the clinical setting. BRIEF REVIEW www.jasn.org 1786 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 1785–1794, 2011 stone of any therapeutic approach to IgAN patients at risk for progression. In fact, this will be the only area where there will be KDIGO recommendations (as op- posed to suggestions with lower degree evidence). These measures are summa- rized in Table 1. In view of space limita- tions, we will not discuss this issue in de- tail. The reader is referred to excellent reviews on this topic.19–21 Of note, most randomized trials in IgAN suffer from lack of optimized and comprehensive supportive care. We therefore initiated the STOP-IgAN trial,22 which will test in high-risk IgAN patients whether immu- nosuppression exerts an added benefit after the supportive therapy has been op- timized over 6 months. We recently fin- ished recruitment and data are expected by 2014. Nonestablished and Controversial Nonimmunosuppressive Treatment Approaches In a meta-analysis of fish oil therapy in patients with IgAN, no statistically sig- nificant benefit was noted, although there was a 75% probability of at least a minor effect.23 Long-term follow-up of the largest randomized trial so far24 noted a better preservation of renal function in the fish oil group. In a smaller Italian randomized trial in pro- teinuric IgAN patients with preserved renal function, proteinuria decreased by 75% in the fish oil group but re- mained stable in controls;25 however, a tendency of the control group toward worse prognostic features at baseline (numerically lower mean GFR, higher proteinuria, and more men) was nota- ble. Essentially no side effects were noted. In contrast, another more re- cent randomized trial failed to detect a benefit from fish oil;26 whether this was related to a slightly higher baseline proteinuria in the fish oil group re- mains unresolved. At present, fish oil in IgAN is literally a matter of taste. Antiplatelet and anticoagulant drugs are mostly used in Asia for the treatment of IgAN. A small random- ized trial suggested benefit from dipy- ridamole (75 mg three times daily and warfarin [INR 1.3 to 1.5]) compared with no treatment, but angiotensin- converting enzyme (ACE) inhibitors were avoided in these patients.27 Most other studies on this topic suffer from the fact that antiplatelet therapy was not standardized (aspirin, warfarin, or dipyridamole were used), often com- bined with immunosuppression, and were retrospective and nonrandom- ized. At present, no recommendation on the use of such drugs is possible in IgAN patients. Tonsillectomy, combined with im- munosuppression, in patients at risk for progressive IgAN, is mostly recom- mended in Japan, based largely on ret- rospective data.28,29 A recent small Jap- anese study in transplanted patients with recurrent IgAN30 reports that ton- sillectomy reduces proteinuria from 880 to 280 mg/d, whereas little change was noted in a non–operated control group. Another recent Japanese study in primary IgAN also reports that ton- sillectomy combined with immuno- suppression is more effective in induc- ing remission of proteinuria and/or hematuria than immunosuppression alone.31 Limitations of both studies in- clude their small size, nonrandomized nature, and nonsystematic renin-ang- iotensin blockade. Given that other studies have been unable to document a benefit in IgAN patients who are Caucasian,32,32a we feel that an ade- quately powered randomized con- trolled trial will be required before tonsillectomy can be routinely re- commended in the care of IgAN pa- tients. An exception may be when there is a clear temporal relationship be- tween tonsillitis episodes and bouts of macrohematuria. A recent Finnish study investigated the relationship between alcohol con- sumption and progression of IgAN.33 Better kidney function was associated with light-to-moderate alcohol con- sumption after correction for hyper- tension and 24-hour protein excretion. Light consumption (one drink per day) in women and moderate consumption (1 to 3 drinks per day) in men appears optimal. Although this certainly does Table 1. Supportive therapy of IgAN Level 1 recommendations ● Control blood pressure (sitting systolic BP in the 120s) ● ACE inhibitor or ARB therapy with uptitration of dosage or combination ACE inhibitor and ARB therapy ● Avoid dihydropyridine calcium-channel blockers unless needed for BP control ● Control protein intake Level 2 recommendations ● Restrict NaCl intake/institute diuretic therapy ● Control fluid intake ● Non–dihydropyridine calcium-channel blocker therapy ● Control each component of the metabolic syndrome ● Aldosterone antagonist therapy ● Beta-blocker therapy ● Smoking cessation ● Allopurinol therapy ● Empiric NaHCO3 therapy, independent of whether metabolic acidosis is present or not Other measures to retard IgAN progression ● Avoid NSAIDs altogether, or no more than once or twice weekly at most ● Avoid prolonged severe hypokalemia ● Avoid phosphate cathartics ● Ergocalciferol therapy to correct vitamin D deficiency ● Control hyperphosphatemia and hyperparathyroidism; in animal models and in human studies, controlling hyperphosphatemia slows CKD progression Recommended supportive therapy options in patients with, or at risk of, progressive IgAN (modified after reference 20). The goal is to implement all level 1 recommendations and as many level 2 recommendations as feasible. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; NSAID, non-steroidal anti-inflammatory drug. BRIEF REVIEWwww.jasn.org J Am Soc Nephrol 22: 1785–1794, 2011 IgA Nephropathy 1787 not establish a causal or even therapeu- tic relationship, patients should be made aware of these findings. Proteinuric Patients, Despite Optimized Supportive Care, Should Be Given a 6-Month Course of Corticosteroids If GFR Is Above 50 ml/min Three randomized controlled trials have shown that a 6-month course of cortico- steroids in IgAN patients with relatively preserved renal function, and a GFR above 50ml/min, can reduce proteinuria and decrease the risk of subsequent renal failure.34–37Whereas corticosteroid ther- apy in the first trial consisted of com- bined pulse and oral steroids, a purely oral regimen was used in the subsequent trials and appeared effective as well (Ta- ble 2). In contrast, in a smaller United States trial,26 using a much longer but strictly alternating steroid regimen, no benefit was noted at 2 years (Table 2). Similarly, a low-dose corticosteroid reg- 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 ofmethylpred- nisolone administered within 3 months, abovewhich the incidenceof 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 IgANpatients where corticosteroid pulse therapy as well as ACE-inhibitor therapy 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 of patients whowould have ended up in a low-risk category with ACE inhibitor treatment alonewere assigned additional immunosuppression.44 In our own on- going STOP-IgAN study,22 we noted that, during the 6-month run-in phase, which is meant to uptitrate renin-angio- tensin blockers to their maximum anti- proteinuric effect, proteinuria decreased to�0.75 g/d in most patients with IgAN (unpublished data). A pragmatic approach suggests first optimizing supportive therapy in IgAN patients at risk for progression (see above). If this is not sufficient to lower proteinuria below about 1 g/d, patients should be offered a 6-month trial of cor- ticosteroids as long as their GFR is higher than 50 ml/min (Figure 1). Table 2 sug- gests that strictly alternating or low-dose corticosteroid therapy is ineffective. It is unresolved which of the three high-dose daily regimens is more beneficial. The longest follow-up data are available for BA DC FE Figure 2. The range of histologic findings in IgA nephropathy with an evaluation based on the Oxford classification.17,18 All sections are PAS stains. (A) Glomerulus without mesangial proliferation and matrix increase (M0 with the majority of glomeruli showing this phenotype). (B) Glomerulus with segmental mesangial hypercellularity (arrow) (M1 with the majority of glomeruli showing such a phenotype). (C) Endocapillary hypercellu- larity (E1). (D) Glomerulus with segmental necrosis and extracapillary proliferation. (E) Overview of a case with sclerotic and atrophic changes. Right-sided glomerulus with segmental glomerulosclerosis and a focal adhesion (arrow) surrounded by increased interstitial matrix and tubules with segmental dedifferentiation (tubular atrophy) (S1 for glomerular sclerosis and T1 for tubular atrophy and interstitial fibrosis). (F) Higher mag- nification of the glomerulus illustrated in Figure 2E with segmental glomerulosclerosis and an adhesion (arrow) (S1). BRIEF REVIEW www.jasn.org 1788 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 1785–1794, 2011 Ta b le 2 . C or ti co st er oi d m on ot he ra p y Tr ia l P o zz i et al ., It al y3 7 ,3 6 K at af uc hi et al ., Ja p an 3 8 H o g g et al ., U ni te d St at es 2 6 M an no et al ., It al y3 5 Lv et al ., C hi na 3 4 C o rt ic o st er o id re g im en In tr av en ou s m et hy lp re d ni so lo ne 1 g /d fo r 3 co ns ec ut iv e d ay s at th e b eg in ni ng of m on th s 1, 3, an d 5, p lu s or al p re d ni so ne 0. 5 m g /k g ev er y ot he r d ay fo r 6 m on th s O ra lp re d ni so lo ne 20 m g /d ta p er ed to 5 m g /d at 18 m on th s O ra lp re d ni so ne ev er y ot he r d ay 60 m g /m 2 fo r 3 m on th s, th en 40 m g /m 2 fo r 9 m on th s, an d th en 30 m g /m 2 fo r 12 m on th s O ra lp re d ni so ne fo r 6 m on th s (1 m g /k g /d ay fo r 2 m on th s, th en re d uc ed b y 0. 2 m g / kg /d ay p er m on th ) O ra lp re d ni so ne fo r 6– 8 m on th s (0 .8 –1 m g /k g / d ay fo r 2 m on th s, th en re d uc ed b y 5– 10 m g ev er y 2 w k) C o nt ro l re g im en Su p p or tiv e on ly D ip yr id am ol e Pl ac eb o Su p p or tiv e on ly Su p p or tiv e on ly R A S b lo ck ad e 14 % at b as el in e, al lo w ed d ur in g fo llo w -u p 2% at b as el in e; al lo w ed d ur in g fo llo w -u p En al ap ril if hy p er te ns iv e Ra m ip ril in al lp at ie nt s C ila za p ril in al lp at ie nt s K ey o ut co m e in st er o id g ro up ve rs us co nt ro l Te n- ye ar re na ls ur vi va l( � ab se nt d ou b lin g of se ru m cr ea tin in e) , 53 % in co nt ro ls ve rs us 97 % in th e st er oi d g ro up Si g ni fic an t re d uc tio n in p ro te in ur ia b ut no t ES RD fr eq ue nc y N o b en ef it in th e st er oi d g ro up ve rs us p la ce b o at 2 ye ar s M ea n an nu al lo ss of G FR 6. 2 m l/m in in co nt ro ls ve rs us 0. 6 m l/m in in th