Reference
Molecule
Number of patients
Polymorphism
Vs. normal control
F/U duration (months)
Renal progression
Biology
Lim et al. [22]
Clara cell secretory protein
N = 267
G38A
No difference
103.8 ± 52.6
AA genotype
Anti-inflammatory
Multicenter
HR 2.34, 95 % CI 1.19–4.64
Immunomodulatory
P = 0.014 (MV)
Jung et al. [20]
Chymase
N = 261
CMA rs1800875
No difference
103.2 ± 52.6
AA/AG genotype
Alternative enzyme for synthesis of angiotensin II
Single center
HR 2.351
95% CI 1.414–3.908
P = 0.001 (MV)
Jung et al. [20]
Chymase
N = 261
CMA rs1800876
No difference
103.2 ± 52.6
CC/CT genotype
Alternative enzyme for synthesis of angiotensin II
Single center
χ 2 = 4.45
P = 0.035 (UV)
Yoon et al. [23]
CD14
N = 216
159C/T
No difference
86.0 ± 51.1
CC genotype
Inflammatory responses to microorganism
Single center
HR 3.2
95 % CI 1.2–8.8
P = 0.025 (MV)
Kim et al. [18]
Angiotensinogen
N = 238
AGT M235T
No difference
102.4 ± 47.0
TT genotype
Component of renin-angiotensin system
Multicenter
HR 5.704
95% CI 1.578–20.618
P = 0.008
Lim et al. [25]
Transforming growth factor (TGF)-β1
N = 108, single center
C509T
Difference
At least 36
TT genotype
Anti-inflammatory
Poor
Profibrotic activity
Renal outcome
P = 0.042 (UV)
HR 2.202
P = 0.138 (MV)
Yoon et al. [21]
Angiotensin II type 2 receptor
N = 480
A1818T
No difference
30.3 ± 3.3
TT/AT genotype
Counter-regulatory to the vasoconstrictor action of angiotensin II type 1 receptor
Multicenter
HR 0.221
95% CI
0.052–0.940
P = 0.041
Lim et al. [24]
Megsin
N = 260
C2093T
No difference
103.0 ± 52.4
TT genotype
Serpin
HR 3.52
Superfamily
95 % CI 1.69–7.34
Progressive mesangial matrix expansion
P = 0.001 (MV)
CT genotype
HR 2.15
95 % CI 1.30–3.57
P = 0.003 (MV)
Lim et al. [24]
Megsin
N = 260
C2180T
No difference
103.0 ± 52.4
CC genotype
Serpin superfamily
HR 4.05
95 % CI 1.93–8.51
Progressive mesangial matrix expansion
P < 0.001 (MV)
CT genotype
HR 2.35
95 % CI 1.40–3.94
P = 0.001 (MV)
Lim et al. [24]
Megsin
N = 260
2093T-2180C
No difference
103.0 ± 52.4
2093 T-2180C haplotype
Serpin superfamily
Multicenter
Haplotype
HR 2.01
95 % CI 1.44–2.81
Progressive mesangial matrix expansion
P < 0.001 (MV)
GO et al. [26]
Klotho
N = 973
G395A
N/A
50.0 ± 27.8
GA + AA genotype
Related to aging
Multicenter
ESRD
Atherosclerosis
P = 0.04 (UV)
Endothelial dysfunction
Yoon et al. [19]
ACE + PAF-AH
N = 191
ACE I/D
No difference
87.3 ± 50.0
DD + DI&CT + TT
Angiotensin II-forming enzyme
Single center
C1136T
HR 4.5
Enzyme degrading PAF
95 % CI 1.6–12.7
P = 0.0039 MV)
Lee et al. [27]
EPHX2
N = 401
R287Q
No difference
74.4
GG genotype
Determines epoxyeicosatrienoic acid (EET) concentration
Single center
ESRD
HR 1.83
95 % CI 1.13–2.96
P = 0.014 (MV)
With regard to gene polymorphism of renin-angiotensin-aldosterone system, specific single nucleotide polymorphism (SNP) in angiotensin II type 1 receptor [18], aldosterone synthase, [18] and insertion/deletion polymorphism of angiotensin-converting enzyme [19] were not related to the progression of IgAN. While M235T SNP of angiotensinogen was related to renal progression only in male patients [18], specific SNP of chymase [20] and angiotensin II type 2 receptor [21] were related to renal progression in both sexes.
Gene polymorphism of molecules related to inflammation such as Clara cell secretory protein [22], CD 14 [23], and platelet-activating factor acetylhydrolase [19] and molecules related to extracellular matrix deposition such as megsin [24] and TGF-β [25] were associated with renal progression. Gene polymorphism affecting the activity of epoxide hydrolase which hydrolyze epoxyeicosatrienoic acid was associated with renal survival [26]. Interestingly, specific SNPs of klotho gene – an antiaging gene – were related to patients’ survival as well as renal survival [27].
10.1.6 Role of Complements
The activations of alternative and lectin pathway of complements by nephritogenic polymeric IgA1 molecules are known to play an important role in the pathogenesis of IgAN.
10.1.6.1 Alternative Pathway
Mesangial deposition of C3, one of the hallmarks of the activation of alternative pathway, was observed in 73.9 % of 142 Korean patients with IgAN. While C3 deposition was observed in only 53 % of patients with histologically early stage of IgAN, it was observed in 100 % of patients with advanced stage [28].
Decreased level of serum C3 lower than normal and strong mesangial C3 deposition ≥2+ degree were observed in 19.2 % and 18.8 % of 343 patients, respectively. This strong C3 mesangial deposition was associated with low serum C3 level, mesangial hypercellularity, and advanced tubulointerstitial lesions. Importantly both C3 hypocomplementemia and strong mesangial C3 deposition were independent risk factor for the doubling of serum creatinine independent of basal eGFR, proteinuria, and tubulointerstitial lesions [29].
These studies suggest that the activation of alternative pathway of complements occurs in systemic circulation as well as local mesangial area and contributes significantly to the progression of IgAN.
10.1.6.2 Other Pathways
In 23 IgAN patients, glomerular C4d staining and tubular C4d staining were observed in 56.5 % and 47.8 % of patients, respectively, whereas no C4d staining was observed in tubular basement membrane, peritubular capillary, and vascular structure. The glomerular C4d staining was related to albuminuria and tubular C4d staining to higher grade of WHO classification. Tubular deposition of C4d without any co-deposition of immunoglobulin suggested the activation of lectin pathway although clear proofs were lacking [30].
Out of 221 IgAN, 8.1 % of patients had mesangial C1q staining which is a marker of activation of classic complement pathway. The co-deposition of IgG was more frequently observed in C1q(+) patients than propensity score matched C1q(−) patients (38.9 % vs. 8.3 %). C1q(+) was an independent determinant of rate of GFR loss between C1q(+) and matched C1q(−) patients [31].
These studies suggest that the activation of lectin and classic pathway of complement contribute to renal damage in some subset of patients with IgAN.
10.2 Treatment and Prognosis
10.2.1 Role of Renal Biopsy Findings in Predicting Renal Outcome
IgAN is characterized by highly variable clinical courses and the differences in response to a specific therapy resulting in highly variable renal outcome within individual patients. Even though proteinuria is generally regarded as the best predictor of renal outcome, there are substantial numbers of the patients with no proteinuria at presentation who ultimately show renal progression. Hence, many studies about the correlation between renal biopsy findings and renal progression have been performed to define a role of renal pathology for prediction of renal outcomes beyond clinical parameters.
10.2.1.1 Pathologic Grading Systems Before the Introduction of Oxford Classification
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.
10.2.1.2 Validation Studies 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.
10.2.2 Significance of Proteinuria in Treatment and Prognosis
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