The Differences in Etiology and Treatment of IgA Nephropathy in Korea

H.S. Lee’s grading system developed in 1987 by incorporating mesangial proliferation, segmental lesion, crescent, and interstitial fibrosis showed good correlation with proteinuria, hypertension, and impaired renal function at the time of biopsy. Interestingly, episodes of macroscopic hematuria which is a favorable factor for renal progression in Korea were less frequent in patients with higher grade of this system [28].

Some modification of H.S. Lee’s grading system with particular emphasis on crescent, segmental sclerosis, and global sclerosis which implicate, respectively, active necrotizing glomerular inflammation, podocyte depletion, and resultant irreversible glomerular damage correlated well with patients’ age, CCr, 24-h urinary protein, and the prevalence of hypertension in dose-dependent manner. Moreover, this grading system predicted renal progression independent of clinical risk findings such as initial renal function and proteinuria, whereas the Hass classification did not [32].

Class IV/V lesions of WHO classification were a prognostic factor of renal progression independent of renal insufficiency (serum creatinine ≥1.4 mg/dL) and heavy proteinuria [33].

These studies suggest that specific histological features such as mesangial proliferation, crescent, segmental sclerosis, and advanced tubulointerstitial lesions rather than the whole system of histological classification were suggested to be significant prognostic factors independent of clinical features even before the introduction of Oxford classification.

After the Oxford classification was introduced as a new histological classification system for IgAN in 2009, several studies were performed to validate the usefulness of this classification in Korean patients.

All studies identified T1 and T2 lesions, namely, advanced tubulointerstitial lesions, as a predictor of renal progression independent of clinical findings in multivariable analysis [34–36]. T1 and T2 were also predictors of renal progression in posttransplant IgAN [37]. These findings confirmed the well-established prognostic importance of tubulointerstitial lesion in essentially all glomerular diseases including IgAN.

E1 was associated with more frequent prescription of steroid in studies where steroid was infrequently used, i.e., 18 % and 11 % of subjects of study, respectively [35, 36]. But in one study in which 38 % of patients had received steroid, S1 but not E1 was associated with the more frequent use of steroid [34]. RAS blockade treatment was more frequent in patients with M1 [34, 36]. Thus, at least in current situation, where the prescription of immunosuppressive drugs is largely dependent on the decision of individual physician without agreed guideline for immunosuppressive treatment, the reported relationship of specific Oxford lesions with steroid treatment be viewed with the consideration for criteria by which steroid was used in a specific study.

The frequency of M1, S1, E1, T1, and T2 increased along with the increasing grade of WHO classification [34] and also showed correlation with Hass classification in patients with posttransplant IgAN [37]. All MEST variables, especially S and E, correlated with activity index in semiquantitative classification, but only S and T showed relationship with chronic index [34]. Hass and Oxford classifications were comparable in providing additive predictive value for renal progression to known clinical parameters such as proteinuria and eGFR [36], but Oxford classification was superior to Haas classification in posttransplant IgAN [37]. Thus, pre-existing pathological grading systems of IgAN such as WHO and Hass classification could provide useful prognostic information as much as Oxford classification, but Oxford classification is superior to old systems in the convenience in clinical application and consistency in interpretation of pathologic findings by different pathologists.

Similar to conclusion from Oxford group, a retrospective analysis of 430 patients in which 18.8 % of patients had crescent showed that crescent was not a prognostic factor for renal progression independent of clinical findings and T lesion although patients with crescent had higher UPCR, lower eGFR, lower serum albumin level, and more prescription of RAS blockade and glucocorticoid treatment during follow-up. Because the patients in this study had a relatively good basal eGFR of 80.5 ± 24.1 ml/min/1.73 m², this study could not give the answer about the prognostic significance of crescent in patients having worse eGFR <30 ml/min/1.73 m² as Oxford classification could not [38]. But in posttransplant IgAN, 4-year graft survival after biopsy was 30.0 % in patients having crescents compared with 70.8 % patients without crescents despite the enhanced immunosuppression in the former group. Moreover, IgAN was the cause of graft failure in 66.7 % of patients with crescents, whereas IgAN was the cause of graft failure in only 13.6 % of patients without crescents [39]. Thus, the prognostic significance of crescent in IgAN remained to be defined especially in patients with low basal eGFR and/or patients on the immunosuppressive therapy at the time of renal biopsy.

Although the excellent prognosis is taken for granted for patients presenting with normotension, normal renal function, and normal or low-grade proteinuria, this does not apply to all such patients.

IgAN constituted 33.3 % (n = 52) of 156 patients who underwent renal biopsy due to isolated hematuria without proteinuria, hypertension, and azotemia. During a follow-up of mean duration of 31.6 ± 14.1 months, five patients with IgAN developed proteinuria and/or hypertension and/or eGFR <60 ml/min/1.73 m² [40].

In a retrospective analysis of 153 patients with IgAN presenting with benign clinical manifestation, i.e., proteinuria <0.5 g/day, normotension, and eGFR >60 ml/min at the time of renal biopsy, 31 % (n = 36) of patients achieved clinical remission defined as disappearance of microscopic hematuria, proteinuria <0/2 g/day, and normal renal function. But 11 patients developed proteinuria >1 g/day, three patients showed greater than 50 % increase in serum creatinine, and six patients developed ESRD. Interstitial fibrosis at renal biopsy and hypoalbuminemia were independent risk factors for the development significant proteinuria and renal progression [41].

Out of 1,076 patients, typical nephrotic syndrome was observed in 100 (10.2 %) patients, 93 of whom presented with generalized edema at initial presentation. Histologically only four patients showed typical minimal change disease-like features, and C3 deposition was observed in 91 % of patients. A total of 48 patients achieved complete remission, spontaneously in 24 patients and by immunosuppressive treatment in another 24 patients. Partial response and no response occurred in 32.0 % and 20.0 % of patients, respectively. During the median follow-up of 45.2 months, the doubling of serum creatinine occurred in 24 % of nephrotic patients compared with 7.1 % in non-nephrotic patients. In patients with nephrotic syndrome, the risk for reaching the doubling of serum creatinine was highest for patients with no response followed by partial response (HR 14.49, 95 % CI 1.14–183.76, p = 0.04 and HR 215, 95 % CI 15–2983, p < 0.001 respective for partial response and nonresponse compared with complete response). The prognosis of complete responder was excellent with only two patients reaching the doubling of serum creatinine during follow-up. In 24 patients having spontaneous complete remission, Haas IV or V classifications were observed in 11 patients. Female sex, initial serum creatinine <1.2 mg/dL, and more than 50 % reduction of proteinuria within 3 months after the onset of nephrotic syndrome were associated with likelihood of attaining spontaneous remission [4].

Among 581 patients with IgAN, 48 patients (8.3 %) presented with nephrotic syndrome. Of 25 patients who received high-dose corticosteroid, 12 patients achieved complete remission of nephrotic syndrome. Seven episodes of relapse in five patients occurred during the tapering of corticosteroids, six of which respond well to reintroduction of high-dose steroid with complete remission. Compared with nonresponders, responders were characterized by clinical features similar to minimal change disease, i.e., rapid onset of edema, higher weight gain, higher proteinuria, lower serum albumin, and lower serum creatinine, and pathological features of lower histological grade and lower mesangial IgA deposition. While none of 12 responders did not progress to ESRD, 38 % of nonresponders to steroid and 43 % of patients who did not receive steroid treatment reached ESRD [42].

Collectively, these studies suggest that about 10 % of IgAN patients present with nephrotic syndrome in which there are considerable heterogeneity in histopathology, clinical course, response to treatment, and prognosis. Prognosis of nephrotic patients was largely determined by the reduction of proteinuria spontaneously or by steroid treatment.

Because the level of residual proteinuria attained spontaneously or by treatment was a major determinant of renal progression irrespective of risk factors at initial presentation such as eGFR, blood pressure, proteinuria, and histological findings, the optimal target for the reduction of proteinuria is always an important topic in IgAN.

In a retrospective analysis of 500 patients, the risk for developing 50 % decline in eGFR increased markedly in patients with 1.0 g/g ≤ TAP (time-averaged proteinuria) ≥2.99 g/g (HR 25.0, 95 % CI 3.17–197.0, p = 0.002) and TAP ≥3.0 (HR 244.07, 95 % CI 27.09–2198.98, p < 0.001) compared with patients with TAP <0.3 g/g. Although there was no difference in the development of 50 % decline in eGFR or ESRD between the patients with time-averaged proteinuria during clinical course (TAP) <0.3 g/g and patients with 0.3 g/g ≤ TAP ≥ 0.3–0.99 g/g, eGFR slope was lower in patients with TAP <0.3 g/g than patients with 0.3≤ TAP ≥0.99 (−0.41 ± 1.68 vs. −0.73 ± 2.82 ml/min/1.73 m²/year, p = 0.03) [43].

In another retrospective study of 125 patients, the risk for reaching to eGFR <15 ml/min/1.73 m² increased by tenfolds in patients with residual proteinuria after treatment >1.0 g/day compared with the patients with residual proteinuria <0.3 g/day. Although statistically insignificant probably due to relatively small numbers of patients, eGFR slope in patients with residual proteinuria of 0.3–0.99 was larger than patients with residual proteinuria <0.3 g/day (−1.24 ± 1.25 vs. −1.06 ± 1.69 ml/min/1.73 m²/year, p = 0.580). The relapse of proteinuria more than 1 g/day, which occurred 5.2 ± 3.2 years after the initiation of treatment, was more frequent in patients with residual proteinuria of 0.3–0.99 g/day than patients with proteinuria <0.3/day (41.5 % vs. 26.3 %, p = 0.025) [44].

These studies suggest that the maintenance of proteinuria <1 g/day as recommended by KDIGO was a reasonable therapeutic target in renal protection, but the attainment of proteinuria <0.3 g/day might provide additional renal protection especially in young and otherwise healthy patients in whom a long life span is expected.

Angiotensin-converting enzyme inhibitor (ACEI) decreased proteinuria from 3.85 ± 2.54 g/day to 1.68 ± 1.91 g/day in 24 patients in which five of whom proteinuria decreased below 0.5 g/day. ACEI also decreased the proteinuria of ten patients whose baseline proteinuria was greater than 3 g/day from 4.89 ± 1.43 g/day to 1.38 ± 1.21 g/day [45]. Insertion/deletion polymorphism of ACE gene did not influence the anti-proteinuric effect of ACEI [46].

In a trial of 4 weeks of washout period followed by 12 weeks of active treatment in which patients were randomized to once-daily losartan 50 mg/day or amlodipine 5 mg/day without any dietary restriction, all but one patient treated by losartan showed reduction in proteinuria, whereas proteinuria slightly increased in patients treated by amlodipine without no difference in blood pressure attained during the trial. Proteinuria decreased by 42.7 % from baseline after 4 weeks treatment of losartan and further reduced by 54.4 % after 12 weeks of treatment (2.3 ± 1.5 g/day, 1.4 ± 1.4 g/day, and 1.1 ± 1.2 g/day, respectively, at baseline, 4 weeks, and 12 weeks after treatment). No treatment-induced change in CCr was noted in both groups. Whereas there were no difference in serum level of TGF-ß between normal volunteer and patients with IgAN, urinary TGF-ß and reflecting renal production of TGF-ß were 20-folds higher in patients with IgAN than in normal control. Losartan but not amlodipine decreased urinary TGF-ß, but there was neither relationship between urinary TGF-ß level and proteinuria nor between decrement of urinary TGF-ß and reduction of proteinuria by losartan [47].

A crossover trial of once-daily candesartan 4 mg or placebo over 12 weeks on 19 patients who had been stably maintained on 5–7,5 mg of ramipril for at least 6 months showed the reduction of proteinuria from 4.1 ± 0.3 g/day at placebo period to 3.1 ± 0.3 g/day at combination period without change in blood pressure, serum potassium level, and renal function [48]. The addition of candesartan reduces urinary TGF-β level by 28.9 ± 6.0 %, but the reduction in proteinuria did not correlate with the reduction in urinary TGF-β level [49]. Although the combination of low dose of ACEI and angiotensin receptor blocker (ARB) reduced the proteinuria further in IgA patients having high basal proteinuria >3.0 g/day, the reduction rate in proteinuria by addition of ARB was only 12.3 ± 4.5 %, and residual proteinuria remained high in this study.

In posttransplant IgAN, more than 50 % reduction of proteinuria by enalapril was observed in 71.4 % of patients without segmental sclerosis but only 28.6 % of patients having segmental sclerosis suggestive of the inhibitory effect of segmental sclerosis on the anti-proteinuric effect of ACEI in these patients [50].

A retrospective analysis of 167 patients with IgAN biopsied in author’s hospital revealed that the presence of crescents in glomeruli reduces the anti-proteinuric effects of RAS blockade administered for 1 year in the multivariable analysis adjusted for multiple factors including basal proteinuria, eGFR, and other histological features. In this study, most of reduction in proteinuria occurred within 3 months after RAS blockade, but further reduction of proteinuria was observed until 1 year after RAS blockade (Fig. 10.1) (unpublished results).

In the comparison between 914 IgAN patients without RAS blockade and 831 patients with RAS blockade, the rate of doubling of creatinine, ESRD, and death was higher in patients without RAS blockade (Fig. 10.2) despite the older age, lower basal eGFR, and higher prevalence of hypertension in the patients treated with RAS blockade. Interestingly, the protective effect of RAS blockade against death was significant in patients having DD genotype of insertion/deletion polymorphism of ACE (unpublished results).

Collectively, ACEI or ARB significantly reduced proteinuria in patients with IgAN with favorable long-term effects on the survival of patient as well as the kidney. The combination of ACEI and ARB further reduced the proteinuria with the further reduction of urinary TGF-β secretion. The most degree of anti-proteinuric effect of RASB was attained within 3 months after the administration of drug, but further lowering of proteinuria was observed until 1 year after treatment. Higher basal proteinuria before RASB especially more than 3 g/day and the presence of crescent or segmental sclerosis in renal biopsy decreased the proteinuria-lowering effect of RASB. Although DD genotype of ACE gene did not influence the anti-proteinuric effect of RASB, the patient’s survival benefit was prominent in patients with DD genotype.

In an open label trial conducted on 50 adult patients, daily administration of 1 mg/kg of oral prednisolone for 2 months followed by tapering over 4 months on the top of ARB treatment improved mean eGFR significantly from 80.2 ± 22.7 ml/min/1.73 m² at baseline to 93.0 ± 41.2 ml/min/1.73 m² and decreased UPCR 2.21 ± 2.0 g/g at baseline to 0.7 ± 0.7 g/g at 6 months after treatment. In addition the corticosteroid therapy also decreased the extent of hematuria including 16 patients in whom hematuria completely disappeared. The serum IgA level also decreased after treatment. Seven patients (14 %) who developed more than 20 % decrease in eGFR despite the corticosteroid therapy were characterized by lower eGFR, higher systolic blood pressure, and more frequent presence of crescent at baseline. Especially, the basal proteinuria of these patients was higher than respondent patients (UPCR 3.92 ± 2.00 g/g vs. 1.93 ± 1.88 g/g) in whom residual proteinuria after treatment was also higher (UPCR 1.63 ± 1.00 g/g vs. 0.61 ± 0.59 g/g) [51].

Similar regimen of oral prednisolone or deflazacort on the top of RAS blockade with good blood control also increased CCr by 11.5 ± 16.4 ml/min and decreased 24-h urine proteinuria by 4.4 ± 5.5 g/day and increased serum albumin level by 1.1 ± 2.3 g/dL in a retrospective analysis of 136 patients despite the relatively high basal proteinuria of 5.8 ± 5.6 g/day. Because the follow-up duration was short and too widely distributed and mean residual proteinuria after treatment was more than 1 g/day (1.4 ± 2.3 g/day), actual benefit of this treatment need more long-term follow-up to be confirmed [52].

The effect of intravenous pulse administration of 500 mg of methylprednisolone every 2 weeks for 6 months without accompanying oral corticosteroid administration improved the rate of eGFR decline in the 22 patients who had already progressed more than CKD 3 stage(−0.93 ± 0.87 vs. 0.14 ± 0.99 ml/min/1.73 m²/month, respectively, before and after treatment p = 0.007). Ten-month dialysis-free survival after treatment was 100 % in patients with basal eGFR ≥30 ml/min/1.73 m² and 53 % in patients with eGFR <30 ml/min/1.73 m² suggesting more prominent reno-protective effect of this intermittent steroid pulse therapy in patients having more preserved renal function before treatment. Contrary to other corticosteroid treatment, this treatment did not reduce albuminuria (UACR before and after treatment 1.71 ± 1.60 mg/g vs. 1.48 ± 1.07 mg/g) although albuminuria did not actually increase during follow-up [53].

A retrospective analysis showed that one of the main reasons for worse renal survival in IgAN than in Henöch-Schönlein purpura was earlier (durations between biopsy and steroid start: HSP vs. IgAN 9.6 ± 14.8 months vs. 25.3 ± 17.8 months) and more frequent use of steroid (HSP vs. IgAN 40.2 % vs. 14.2 %) in Henöch-Schönlein purpura. In fact, no difference in renal revival was observed between IgAN and Henöch-Schönlein purpura when matched baseline factors including steroid treatment. In fact, eGFR decreased 83.4 ml/min/1.73 m² to 58.5 mml/min/1.73 m², and UPCR increased from 1.1 to 2.2 g/g in IgAN patients before the initiation of steroid implicating that earlier and more liberal steroid use might improve the prognosis of IgAN patients [54].

In author’s hospital, corticosteroid was used in 44 (15.7 %) out of 281 patients with IgAN. Compared with patients treated by RASB only, the patients to which corticosteroid was administered were characterized by lower eGFR (85.70 ± 31.55 vs. 75.14 ± 26.29 ml/min/1.73 m²), higher UPCR (1.65 ± 1.55 vs. 2.80 ± 1.97 g/g), lower serum albumin (4.01 ± 0.39 vs. 3.76 ± 0.46 g/dL), higher percentage of glomeruli showing segmental sclerosis (8.26 ± 8.08 vs. 13.75 ± 12.26 %), and more frequent presence of advanced tubulointerstitial lesions (17.5 vs. 38.6 %). Modified Pozzi’s regimen in which 500 mg instead of 1,000 mg of methylprednisolone was administered reduced proteinuria and the degree of hematuria and stabilized eGFR which had been decreasing before treatment (Fig. 10.3). The effects on the reduction of proteinuria and the stabilization of eGFR of modified Pozzi’s regimen were similar between the patients whose eGFR before treatment was above and below 50 ml/min/1.73 m², but the extent of reduction of hematuria was greater in patients with pretreatment eGFR ≥50 ml/min/1.73 m² than those with pretreatment eGFR <50 ml/min/1.73 m². Out of 38 patients, five patients required more than two courses of corticosteroid treatment due to increased proteinuria and/or acceleration of eGFR decline after initial treatment (unpublished results).

Collectively, although there have been no settled indications for corticosteroid treatment and no agreed method of administration of corticosteroid in IgAN before the introduction of KDIGO guideline in Korea, corticosteroid treatment was effective in reducing proteinuria and inducing the improvement or stabilization of renal function even in patients with already decreased eGFR before treatment.

A double-blind randomized trial of tacrolimus (clinicaltrial.gov identifier NCT01224028) in adult IgAN patients with UACR of 0.3−3.0 mg/g in which introduction or intensification of RAS blockade is difficult owing to further lowering of blood pressure demonstrated that the initial administration of tacrolimus of 0.1 mg/kg/day adjusted to trough level of 5−10 ng/ml for 8 weeks followed by halving the dose for remaining 8 weeks reduced albuminuria greater than placebo (reduction rate of UACR: 60.2 ± 28.2 %, 62.2 ± 33.9 %, 48.5 ± 29.8 %, and 55.5 ± 24.0 %, respectively, at 4, 8, 12, and 16 weeks after tacrolimus vs. 6.8 ± 32.2 %, 2.5 ± 35.9 %, 12.7 ± 34.2 %, and 21.9 ± 30.6 %, respectively, at 4, 8, 12, and 16 weeks after placebo). Characteristically, anti-proteinuric effect of tacrolimus was most prominent when eGFR mostly decreased from baseline, and the difference in the reduction of proteinuria between tacrolimus and placebo became unapparent after halving dose of tacrolimus in patients on ARB, suggesting hemodynamic mechanism in anti-proteinuric effects of tacrolimus [55].

The combination of cyclosporine A adjusted to trough serum level of 100−200 ng/dL for 8−12 months with prednisolone of 1−2 mg/kg/day for 4 weeks followed by gradual tapering reduced 24-h urine protein from 107.1 ± 35.1 mg/m²/h to 7.4 ± 2.4 mg/m²/h in pediatric patients. At last follow-up, proteinuria was normalized in nine patients (64.3 %) including six patients in whom hematuria also disappeared. In the follow-up biopsies after completion of cyclosporine A, histological grading of Hass classification improved in seven patients (50 %), remained the same in three patients (21 %) and aggravated in four patients (29 %), two of whom showed the clinical improvement despite the worsening of histological findings. The degree of mesangial IgA deposition in immunofluorescence examination decreased in 50 % of patients [56].

Collectively, calcineurin inhibitors could be used for the reduction of proteinuria instead of RAS blockades in patients who are intolerable to RAS blockade due to excessive lowering of blood pressure or in patients already under corticosteroid treatment for further reduction of proteinuria. The mechanism of anti-proteinuric effect of calcineurin inhibitor might be hemodynamic or non-hemodynamic depending on the clinical context where this drug is used.

A retrospective study demonstrated that the daily administration of 50 mg of sulodexide, an oral formulation of mixture of heparan sulfate and dermatan sulfate, for 11.1 ± 2.7 months reduced the UPCR from 1.5 ± 0.6 g/g at baseline to 1.1 ± 0.7 g/g at the end of follow-up in 20 patients who had been maintained on RAS blockade with stable blood pressure more than 2 years. A quarter of patients showed more than 50 % reduction in proteinuria, and 40 % of patients showed UPCR less than 1 g/g at final follow-up. Interestingly, the anti-proteinuric effects of sulodexide were greater in patients with larger basal proteinuria [57].

Encouraged by anti-proteinuric effect in diabetic nephropathy of sulodexide, a multicenter randomized double-blind trial of daily administration of 50 mg and 150 mg of sulodexide for 6 months was conducted on 104 patients who had been maintained on RAS blockade with stable blood pressure. Although there were no differences in the primary outcome, i.e., more than 50 % reduction of UPCR, between treatment groups (12.5 % in placebo, 4.0 % in 75 mg of sulodexide, and 21.4 % in 150 mg of sulodexide), 150 mg of sulodexide significantly reduced the log UPCR of the patients within group from 6.38 ± 0.77 to 5.98 ± 0.94 in time-dependent manner (p = 0.045). The relatively low basal UPCR of 0.6−0.8 g/g and short duration of treatment might contribute to the negative results in this study [58].

Collectively, these studies suggested that the long-term administration of sulodexide might be effective in reducing proteinuria in patients with relatively high basal proteinuria.

No studies of omega-3 fatty acid in Korean patients with IgAN were published. Actually a double-blind, placebo-controlled, multicenter phase 3 trial of omega-3 fatty acid in IgAN patients with decreased renal function has been completed (clinicaltrial.gov identifier NCT 00549692), but the results are not yet published.