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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 6  |  Page : 1314-1320
Clinical outcomes of nephrotic syndrome in immunoglobulin a nephropathy

Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea

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Date of Web Publication18-Dec-2017


Immunoglobulin A (IgA) nephropathy can be complicated by the nephrotic syndrome in rare cases. Although corticosteroid therapy should be recommended in such cases, the response to steroid treatment has been variable, and spontaneous remission also has been reported without steroid treatment in some cases. We report a retrospective analysis of our experience on the clinical outcomes of nephrotic syndrome in patients with IgA nephropathy, in the nephrology department of a provincial hospital in South Korea. Thirty-three patients with biopsy-proven IgA nephropathy with nephrotic syndrome were enrolled between March 1990 and March 2013. We analyzed data according to demographic, clinical, and laboratory records. The mean follow-up duration was 62 ± 45 months (10–204) in 33 patients. Complete remission occurred in 10 steroid-users and two steroid-nonusers. Partial remission occurred in seven steroid-users, and eight steroid-nonusers. During follow-up, six patients showed progressive deterioration of renal function. Among the IgA nephropathy patients with nephrotic syndrome, 36% and 45% of patients had complete and partial remission, respectively. Steroid treatment may effectively reduce proteinuria. However, spontaneous remission occurs in some cases.

How to cite this article:
Jeong EG, Hyoun S, Lee SM, An WS, Kim SE, Son YK. Clinical outcomes of nephrotic syndrome in immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl 2017;28:1314-20

How to cite this URL:
Jeong EG, Hyoun S, Lee SM, An WS, Kim SE, Son YK. Clinical outcomes of nephrotic syndrome in immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2023 Feb 2];28:1314-20. Available from: https://www.sjkdt.org/text.asp?2017/28/6/1314/220876

   Introduction Top

Immunoglobulin A (IgA) nephropathy is the most common primary glomerular disease in Korea and the world and is known as an important cause of end-stage renal disease. Approximately 25%–30% of patients progress slowly to end-stage renal disease and require renal replacement therapy within 20–25 years after the onset of symptoms.[1],[2] Clinical manifestations are diverse, and include asymptomatic urine abnormalities such as gross hematuria followed by upper respiratory infection, persistent mild proteinuria, or considerable amount of proteinuria and hematuria. However, the prevalence of nephrotic syndrome or nephrotic range proteinuria is relatively rare.[1],[2] Minimal change disease of the nephrotic syndrome occurs in less than 5% of patients with IgA nephropathy. It is unclear whether this is a variant type of IgA nephropathy or a variant type of minimal change disease of the nephrotic syndrome. In a recent study, the assertion that each independent disease of IgA nephropathy and minimal change disease occurs at the same time has been raised. This is defined as minimal change disease with nephrotic syndrome that is accompanied by mesangial IgA deposit.[3],[4],[5],[6],[7] High-dose steroid therapy is recommended when IgA nephropathy is accompanied by minimal change disease with nephrotic syndrome, with heavy proteinuria.[8] Nevertheless, several cases of spontaneous remission without steroid therapy, and only supportive care, have been reported.[3],[9] Therefore, studies on clinical outcomes and the treatment of nephrotic syndrome in IgA nephropathy are needed.[8],[9],[10]

We report our experience in treating patients with nephrotic syndrome in IgA nephropathy.

   Methods Top

Patients and data collection

This study was approved by the Medical Research Committee and Ethics Committee of the College of Medicine, Dong-A University, Korea. From March 1990 to March 2013, we included 33 patients with a follow-up of more than 6 months duration from, among 55 cases of idiopathic IgA nephropathy, which were confirmed through renal biopsy and presented with the clinical features of nephrotic syndrome such as generalized edema, proteinuria (>3.0 g/24 h), serum albumin level <3.5g/dL, and hyperlipidemia. Exclusion criteria using detailed clinical history, physical examination, and laboratory findings were patients with Henoch–Schönlein purpura, systemic erythematous lupus, and chronic liver disease.

Patients were divided into two groups. The 18 patients in the steroid-user group were treated with high-dose steroids after diagnosis. In contrast, the 15 patients in the supportive care group did not receive any steroids and only received supportive treatment including medications for blood pressure control and renin–angiotensin–aldosterone system (RAAS) blockade (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers), as well as a low protein and low salt diet. Four of 15 patients did not use steroid therapy owing to low glomerular filtration rate (eGFR) (<50 mL/min/1.73 m2), two of 15 patients achieved partial remission within six months of supportive care. Nine patients refused immunosuppressive treatment.

Patients on steroid therapy received oral prednisolone 40–60 mg/day for four or eight weeks before the dose was slowly tapered. A reduction of proteinuria to <1.0 g/day was designated as a response, and the complete correction of the biochemical findings, including the absence of proteinuria (<0.3 g/day), was considered as complete remission. Partial remission was defined as the reduction in proteinuria by >50% from baseline and <3.5 g/day. Relapse of the nephrotic syndrome was defined as the recurrence of significant proteinuria (more than 1.0 g/day). Patients on renal replacement therapy were defined as having end-stage renal disease (ESRD).

Laboratory measurements

Demographic and clinical data were reviewed retrospectively for age, sex, medical history, presenting symptoms, medications, time to remission, and follow-up duration. We collected laboratory data including complete blood count, serum blood urea nitrogen (BUN), creatinine, albumin, and total cholesterol levels, as well as 24-h urinary protein excretion, and urinary protein-to-creatinine ratio. The eGFR was calculated using the four-variable Modification of Diet in Renal Disease study formula.[11]

Ultrasound-guided renal biopsy was performed, and the specimens were used for light, immunofluorescent, and electron microscopy examinations. All pathology cases were reported based on the Haas classification system.[12]

   Statistical Analysis Top

Statistical analysis was performed using the the Statistical Package for the Social Sciences for Windows version 12.0 (SPSS Inc., Chicago, IL, USA). Data were expressed as mean with standard division. Results were analyzed using t-test and ANOVA. Variables between the two groups were compared using Chi-square test. Statistical significance was defined as a P <0.05.

   Results Top

Clinical features of patients upon admission

Among the 1040 patients with biopsy-proven primary glomerulonephritis in Dong-A Univer-sity Hospital who were admitted from March 1990 to March 2013, IgAN was present in 534 patients (51.3%). Among the 534 patients with biopsy-proven IgAN, nephrotic syndrome was present in 55 patients (10.2%). Three patients who progressed to ESRD within six months after renal biopsy and 19 patients who could not be followed up were excluded. The 33 study participants consisted of 16 men and 17 women, and the mean age at the time of diagnosis was 44 ± 16 years. The mean follow-up period was 62 ± 45 months (10–204) in both groups and 57 ± 53 (10–204) and 68 ± 53 months (range 27–126) in the steroid-user and supportive therapy groups, respectively.

The mean systolic blood pressures on admission were 131 ± 25 mm Hg and 123 ± 21 mm Hg in the steroid-user and supportive therapy groups, respectively. The mean diastolic blood pressures were 84 ± 14 mm Hg and 82 ± 12 mm Hg in the steroid-user and supportive therapy groups, respectively. The systolic blood pressure was relatively higher in the steroid-user group (P = 0.05).

There were no significant differences in the mean levels of serum hemoglobin, BUN, and eGFR between the two groups. The mean 24-h urine protein was 5.2 ± 2.7 g in both groups, and 5.8 ± 3.3 g and 4.4 ± 1.2 g in the steroid-user and supportive therapy groups, respectively. There were no statistically significant differences between the two groups. The levels of serum albumin and cholesterol were 2.7 ± 0.6 mg/dL and 304 ± 91 g/dL in the steroid-user group, and 3.1 ± 4.0 mg/dL and 241 ±70 g/dL in the supportive care group, respectively. There were statistically significant differences in serum albumin (P = 0.02) and cholesterol (P = 0.04) levels between the two groups [Table 1].
Table 1: Baseline characteristics of the patients.

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Renal biopsy findings

All patients had a renal biopsy at the nephrotic stage. According to Haas classification, nine (27%) of the 33 patients were identified as having diffuse proliferative (Subclass IV) lesions, the most frequent subclass. The steroid-user group had five cases (28%) each of advanced chronic (Subclass V) and minimal histologic (Subclass I) lesions and showed the highest frequency of these subclasses. In the supportive care group, the highest to lowest was according to diffuse proliferative (Subclass IV), focal proliferative (Subclass III), and advanced chronic (Subclass V) [Table 1].

Clinical outcomes

In the steroid-user group, 10 (55%) and seven (39%) patients achieved complete and partial remission, respectively. In the supportive care group, two (13%) and eight patients (53%) achieved complete and partial remission, respectively. The steroid-user group had a higher response rate compared to the supportive care group. During the observation period, the serum creatinine and albumin levels did not show any significant differences between the two groups. The 24-h urine protein level and eGFR were 0.9 ± 1.2 g/day and 72 ± 29 (mL/min/1.73 m2) in the steroid group, and 2.2 ± 1.2 g/day and 48 ± 36 (mL/min/1.73 m2) in the supportive care group, respectively. At the last follow-up, there were statistically significant differences in serum creatinine (P = 0.01). However, albumin level between the two groups (P = 0.09) were not significantly different. During the observation period, one patient (6%) and five patients (33%) in the steroid and supportive care groups progressed to end-stage renal failure, respectively (P = 0.04) [Table 2].
Table 2: Clinical outcomes of the patients.

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Clinical characteristics of patients in complete remission

Among the 33 study participants, 12 (36%) patients reached complete remission. The required period involved approximately 3.3 ± 0.9 months (range 2–5) and 8.5 ± 2.1 months (range 7–10) in the steroid and supportive care groups, respectively. According to the Haas classification, there were 4, 1, 2, 1, and 2 cases of histologic subclasses I, II, III, IV, and V in the steroid group, respectively. In the supportive care group, the two patients who achieved complete remission had Subclass IV lesions. The eGFR was classified according to the chronic kidney disease stages of the Kidney Disease Outcomes Quality Initiative guideline and we compared the first and final stage of chronic kidney disease (CKD). After 65 ± 43 months (range 14–129) of follow-up, there were four and five cases of CKD stage 1 and 2 from the original three cases each of CKD stage 1 and 2, respectively, in the steroid group. In the supportive care group, both patients remained in CKD stage 2 after 50 ± 25 months (range 32–67). Two patients had recurrence in the steroid group. In these cases, proteinuria within the nephrotic range recurred within two and three months after discontinuing steroid, respectively. Nevertheless, they obtained complete remission after steroid therapy was resumed.

Clinical characteristics of patients with a partial response

Seven out of the 18 (39%) and eight of the 15 (53%) patients in the steroid and supportive care groups, respectively, achieved partial remission. The mean period necessary to achieve partial remissions were 4.3 ± 2.3 months (range 2–9), and 6.3 ± 3.0 months (range 3–11) in the steroid and supportive groups, respectively. Histologic findings in the steroid group were classified as Subclass I (1 case), Subclass II (1 case), Subclass IV (3 cases), and Subclass V (2 cases). In the supportive care group, there was one case of subclass 1, one case of subclass II, two cases of subclass III and IV, and one case of subclass V. One case had insufficient glomerular tissue sample from renal biopsy and could not be classified histologically. During the 51 ± 69 months (range 10–204) of follow-up in the steroid group, one and two out of the original three patients remained in CKD Stages 1 and 2, respectively. One case each progressed to the next stage and were added each to the original three cases of CKD Stages 2 and 3, respectively. Out of the four original CKD Stage 3 cases, only three remained. One patient who started treatment at CKD Stage 4 of the disease recovered renal function after treatment and was reclassified as CKD Stage 2. A temporary rise to the nephrotic range of proteinuria occurred in 1 patient in the supportive care group, which subsequently spontaneously decreased during the follow-up period.

The clinical characteristics of the patients who progressed to the end-stage renal disease

In the steroid group, one patient who was in histologic Subclass V and CKD stage 4 at the time of diagnosis progressed to ESRD within 18 months of follow-up. In the supportive care group, five patients progressed to the ESRD within 78 ± 39 months (range 37–120). Two and one patients were classified as CKD stage 2 and 3 at the time of starting treatment, respectively.

   Discussion Top

Idiopathic IgA nephropathy is the most common glomerular disease in the world. It advances slowly to ESRD and eventually requires renal replacement therapy. The accumulative incidence of ESRD occurs in 14–39% of patients within 20 years.[2] The risk of progressive renal disease depends on the presence of hypertension, proteinuria over 1 g/day, hyalinosis, crescent lesions, and the histopathological type, as well as the degree of kidney tissue damage. Isolated asymptomatic hematuria without proteinuria or hypertension does not require any medications. However, in patients with hypertension or proteinuria over 1 g/day, RAAS blockade, such as those involving the inhibition of angiotensin-converting enzymes or angiotensin II receptor blocker based treatment, is known to have a renoprotective function and acts by reducing blood pressure and proteinuria.[13],[14],[15] The amount of proteinuria, from minor to heavy, in IgA nephropathy determines the prognosis of patients. Nephrotic range of proteinuria, at the time of first onset, is known to be relatively rare.[5],[11] Nephrotic syndrome that is accompanied by IgA nephropathy does not respond well to steroid treatment. Histopathologically, proliferative lesions are common. When combined with hypertension, this finally progresses to end-stage renal disease.[16],[17],[18] Nevertheless, a study which focused on the clinical and histopathological findings of IgAN associated with nephrotic syndrome, identified 12 IgAN patients who presented with nephrotic syndrome of short duration and relatively mild glomerular lesions and experienced spontaneous remission.[19] In a prospective study, although steroid treatment of IgAN with nephrotic syndrome were mostly ineffective, 80% of patients with mild histological lesions experienced remission with steroid therapy.[5] Thus, the selective use of steroids is recommended. However, recent studies reported that patients who were treated conservatively (i.e., blood pressure control, low salt diet, low protein diet, and inhibition of RAAS (angiotensin converting enzyme inhibitor or angiotensin II receptor blocker) and without immunosuppressive agents such as steroids, showed spontaneous remission. However, the clinical course remains unclear.[7],[8],[9]

This research was conducted to analyze the clinical features of IgAN accompanied with nephrotic syndrome. In our study, complete remission, defined as proteinuria of less than 0.3 g/day was observed in 12 out of 33 patients. Ten of these patients were in the steroid-user group. In addition, unlike the previous reports, patients with CKD stages 3 and 4 had responded well to steroid treatment. Even patients with relatively advanced phases of pathologic findings, as determined by the Haas classification, showed complete remission. Partial remission defined as proteinuria of less than 3.5 g/day was observed in 15 patients. Patients with partial remission showed similar clinical findings between the steroid user and symptomatic therapy groups. In both groups, despite the relatively advanced histological biopsy findings (5 cases of subclass IV, 3 cases of subclass V), the amount of proteinuria reduced after an average of 4.3 months (range 2–9) in steroid group, and after the average of 6.3 months (range 3–11) in the supportive care group, respectively. In this study, during the total mean follow-up period of 62 months (range 10–204), six patients progressed to end-stage renal failure requiring renal replacement therapy. In particular, five patients were in supportive care group and the incidence of end-stage renal failure was higher in the supportive care group. Patients, who progressed to end-stage renal failure, had high blood pressure at the time of visit (except for 1 case) and showed advanced histologic findings of more than Haas subclass III (except for 2 cases who could not be confirmed histopathologically). In addition, two patients in the supportive care group with CKD stage 2 at the time of visit progressed to end-stage renal failure during the 120 months and 53 months in the follow-up observation period. Although the mean blood pressure was lower in the steroid group, the 24-h urine protein was significantly higher in symptomatic therapy group. The other clinical findings showed similarities between the two groups. At the end of the observation period, renal function and 24-h urine protein showed a significant difference between the two groups.

In conclusion, the use of steroids in the treatment of IgA nephropathy accompanied with nephrotic syndrome can be beneficial. Nevertheless, the symptomatic therapy only group also reached partial and complete remission. Therefore, selective use of steroid therapy is recommended and more research is required to determine the influencing factors and prognostic predictors affecting the pathology of IgA nephropathy that is accompanied by the nephrotic syndrome.

   Disclosure Top

This study was supported by research fund from Dong-A University.

Conflict of interest: None declared.

   References Top

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Wu G, Katz A, Cardella C, Oreopoulos DG. Spontaneous remission of nephrotic syndrome in IgA glomerular disease. Am J Kidney Dis 1985;6:96-9.  Back to cited text no. 3
Lai KN, Lai FM, Chan KW, et al. An overlapping syndrome of IgA nephropathy and lipoid nephrosis. Am J Clin Pathol 1986;86: 716-23.  Back to cited text no. 4
Choi J, Jeong HJ, Lee HY, et al. Significance of mesangial IgA deposition in minimal change nephrotic syndrome: A study of 60 cases. Yonsei Med J 1990;31:258-63.  Back to cited text no. 5
Matsukura H, Miya K, Arai M, Miyawaki T, Inaba S. Minimal change variants with mesangial IgA deposits. Clin Nephrol 2007;68:337-8.  Back to cited text no. 6
Westhoff TH, Waldherr R, Loddenkemper C, et al. Mesangial IgA deposition in minimal change nephrotic syndrome: Coincidence of different entities or variant of minimal change disease? Clin Nephrol 2006;65:203-7.  Back to cited text no. 7
Sinnassamy P, O'Regan S. Mesangial IgA deposits with steroid responsive nephrotic syndrome: Probable minimal lesion nephrosis. Am J Kidney Dis 1985;5:267-9.  Back to cited text no. 8
Han SH, Kang EW, Park JK, et al. Spontaneous remission of nephrotic syndrome in patients with IgA nephropathy. Nephrol Dial Transplant 2011;26:1570-5.  Back to cited text no. 9
Kim JH, Kim H, Hong SM, et al. Spontaneous remission of nephrotic syndrome in IgA nephropathy. Kidney Res Clin Pract 2010;29:371-5.  Back to cited text no. 10
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266.  Back to cited text no. 11
Haas M. Histologic subclassification of IgA nephropathy: A clinicopathologic study of 244 cases. Am J Kidney Dis 1997;29:829-42.  Back to cited text no. 12
Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the reninangiotensin system? Kidney Int 1994;45:861-7.  Back to cited text no. 13
Remuzzi A, Perticucci E, Ruggenenti P, et al. Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy. Kidney Int 1991;39:1267-73.  Back to cited text no. 14
Remuzzi A, Perico N, Sangalli F, et al. ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy. Am J Physiol 1999;276:F457-66.  Back to cited text no. 15
Rodicio JL. Idiopathic IgA nephropathy. Kidney Int 1984;25:717-29.  Back to cited text no. 16
Lai KN, Lai FM, Ho CP, Chan KW. Corticosteroid therapy in IgA nephropathy with nephrotic syndrome: A long-term controlled trial. Clin Nephrol 1986;26:174-80.  Back to cited text no. 17
Hood SA, Velosa JA, Holley KE, Donadio JV Jr. IgA-IgG nephropathy: Predictive indices of progressive disease. Clin Nephrol 1981;16:55-62.  Back to cited text no. 18
Kim SM, Moon KC, Oh KH, et al. Clinicopathologic characteristics of IgA nephropathy with steroid-responsive nephrotic syndrome. J Korean Med Sci 2009;24 Suppl:S44-9.  Back to cited text no. 19

Correspondence Address:
Young Ki Son
Department of Internal Medicine, Dong-A University, 3Ga-1, Dongdaeshin-Dong, Seo-Gu, Busan, 602-715
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.220876

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