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External validation of the Oxford classification of IgA nephropathy: A retrospective study of 70 patients from Saudi Arabia

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ORIGINAL ARTICLE

External validation of the Oxford

classification of IgA nephropathy: A

retrospective study of 70 patients from

Saudi Arabia

Hala Kfoury

a,

*

, Abdulkareem Alsuwaida

b

, Sufia Hussain

a

,

Noura AlOudah

c

, Fayez Alhejaili

d

, Khaled Alsaad

c

,

Mohammed Alghonaim

b

a

King Saud University, King Khalid University Hospital, Department of Pathology, Saudi Arabia

b

King Saud University, King Khalid University Hospital, Department of Medicine, Saudi Arabia

cKing Abdelaziz Medical City, Department of Pathology, Saudi Arabia d

King Abdelaziz Medical City, Department of Medicine, Saudi Arabia

KEYWORDS IgA nephropathy; Oxford classification; validation

Summary Background/purpose: The validity of the Oxford classification of immunoglobulin (Ig)A nephropathy has not been fully explored in the Arab population. The aim of this study was to assess the validity of this classification in a cohort of adult Saudi patients with histolog-ically proven IgA nephropathy.

Methods: A retrospective review of clinical and histological data of patients with biopsy-proven IgA nephropathy diagnosed between May 1998 and May 2011 was undertaken. The study was conducted at two institutions in Riyadh, Saudi Arabia. A total of 70 patients (46% females) with primary IgA nephropathy were included, with a mean age of 32.2 12.9 years. The me-dian follow-up was 3.5 years. The primary endpoint was decreased renal function, which was defined as 50% decrease in estimated glomerular filtration rate from baseline at last follow up. Results: Higher mesangial score and later stage of segmental glomerulosclerosis showed trends towards correlations with a higher degree of proteinuria and lower estimated glomerular filtra-tion rate at presentafiltra-tion and a higher rate of worsening of renal funcfiltra-tion, but these trends did not reach statistical significance (p> 0.05). However, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis were significantly associated with reduced initial esti-mated glomerular filtration rate and higher initial proteinuria. In multivariate logistic regres-sion, the worsening of renal function was not predicted by any histologic class.

Conclusion: The Oxford classification system is a useful tool that reflects the severity of the initial clinical presentation in Arabs with IgA nephropathy. However, it did not predict long-term renal outcomes.

* Corresponding author. Department of Pathology (78), College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia.

E-mail addresses:[email protected],[email protected](H. Kfoury).

http://dx.doi.org/10.1016/j.hkjn.2014.04.001

1561-5413/Copyrightª 2014, Hong Kong Society of Nephrology Ltd. Published by Elsevier Taiwan LLC. All rights reserved.

Available online atwww.sciencedirect.com

ScienceDirect

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背景: 在阿拉伯人群中,IgA 腎病變的牛津分類法尚未通過充分的驗證。本研究以經過組織學驗證 為 IgA 腎病變的沙烏地阿拉伯成年患者為對象,對此分類法的效度進行了評估。 方法: 是次分析所涉及的個案,是從 1998 年 5 月至 2011 年 5 月間,經切片證實為原發性 IgA 腎 病變的 70 位患者,女性佔 46%,平均年齡 32.2  12.9 歲,均來自沙烏地阿拉伯利雅得的兩家院 所。追蹤期間中位數為 3.5 年,首要終點為腎功能下降,其定義為腎小球濾過速率 (GFR) 估算值 降幅達 50% (相對於基線)。 結果: 分析顯示,環間膜評分偏高、與較晚期節段性腎小球硬化症,均與以下呈現相關的傾向: 基線較嚴重的蛋白尿、基線較低的 GFR 估算值、及追蹤期間較明顯的腎功能惡化,雖然未達統計 學意義 (p > 0.05)。然而,微血管內細胞過多、及腎小管萎縮/間質纖維化,則與基線較嚴重的蛋 白尿、及基線較低的 GFR 估算值呈明顯關聯。在多變項邏輯迴歸分析中,組織學分類並未能預測 腎功能惡化的發生。 結論: 對於阿拉伯的 IgA 腎病變成年患者,牛津分類法可有效反映初期的病情嚴重性,但未能預 測腎功能的長期變化。

Introduction

Immunoglobulin (Ig)A nephropathy is the most common primary glomerulonephritis worldwide.1 Since its descrip-tion in 1968 by Berger,2,3 several reports, reviews, and original articles have evaluated the various aspects of IgA nephropathy at both the clinical and pathological levels.4e7 Their main aim has been to understand its natural history, to evaluate its prognostic parameters, and to classify cases into prognostic categories. Therapeutic regimens may be targeted to optimize their benefits and prevent the pro-gression to end-stage renal disease and/or death. Although the diagnosis of IgA nephropathy is straightforward and based on the immunofluorescence or immunohistochemical finding of dominant or codominant IgA on renal biopsy, the histological features are varied. Different pathological classifications have been offered to address these issues,8,9

and the Oxford classification is one of them.10

The prognostic value of the Oxford classification was validated in a study in the United States.11That study found that the Oxford classification was valuable in predicting the prognosis and outcome of patients with IgA nephropathy and recommended its use. With the necessity of external validation, we assessed the utility of the Oxford classifica-tion in an Arab populaclassifica-tion from two different instituclassifica-tions in the central region of the Kingdom of Saudi Arabia.

Methods

The study was conducted at King Khaled University Hospital (King Saud University) and King Abdulaziz Medical City, in Riyadh, Saudi Arabia. Ethical approval was obtained from the Institutional Review Board of King Saud University. Initially, 125 cases of IgA nephropathy were identified be-tween 1998 and 2011. Fifty-five cases were lost to follow-up. The remaining 70 patients comprised the study popu-lation. Four pathologists reviewed the histology slides as well as the electron photomicrographs of all cases. The review of the renal biopsies included confirmation of the diagnosis and categorization according to the Oxford clas-sification. The initial proteinuria and estimated glomerular filtration rate (eGFR) values at the time of the biopsy were recorded. The primary endpoint was a decreased renal

function, which was defined as at least a 50% decrease in eGFR rate from baseline at last follow-up. All cases that were included were reviewed by the pathologists according to a backbone-reporting format in which detailed descrip-tion of the four constituents (glomeruli, tubules, inter-stitium, and blood vessels) were standardized to maintain homogeneity in reporting. The pathologists were blinded to all of the clinical data.

The number of the globally or segmentally sclerotic glomeruli in each case was counted. The other histological features in each glomerulus, if present, were evaluated, including the cellular, fibrocellular, or fibrous crescents; capsular adhesion; segmental necrosis; mesangial hyper-cellularity; and endocapillary proliferation. The vascular changes, mainly sclerosis and hyalinosis, were also assessed. Subsequently, the cases were organized ac-cording to the Oxford classification based on the mesangial (M), sclerosis (S), endocapillary proliferation (E), and interstitial fibrosis/tubular atrophy (T) scores.10M0 meant that the mesangial proliferation involved <50% of the glomeruli, and M1 meant that >50% of the glomeruli showed mesangial proliferation. The E and S scores were rated either 0 or 1, depending on the absence or presence of endocapillary proliferation or sclerosis, respectively. Interstitial fibrosis and tubular atrophy were scored from 0 to 2, indicating the percentage of interstitial fibrosis and tubular atrophy. The pathological findings, reported as per the Oxford classification, were correlated with proteinuria at the time of the biopsy and the progression of renal disease at the last follow-up, which was defined as a decrease of estimated glomerular filtration rate by 50% from baseline. The four parameters (M, S, E, and T) of the Oxford classification were evaluated separately and tested for their correlation with proteinuria and the progression of the disease.

Statistical analysis

Statistical analyses were conducted by using Predictive Analytical Software version 18.0 (PASW; IBM-SPSS, Chicago, IL, USA). The incidence and prevalence of various glomer-ular diseases were determined. For discrete variables, Pearson’s Chi-square test and Fisher’s exact test were used

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to compare baseline characteristics (e.g., sex and smoking) between patients with or without evidence of kidney dis-ease. The Student t test and Wilcoxon’s rank-sum test for testing of continuous data were used to compare the baseline differences between any two groups for contin-uous measurements (e.g., baseline serum creatinine level and age). Analysis of variance was used to compare means in more than two groups. Regression analysis was used to evaluate factors associated with worsening of renal function.

Results

The characteristics of the 70 patients who met the inclu-sion criteria are given inTable 1. The patients’ mean age at the time of biopsy was 32.2 12.9 years, and 46% were female. Table 1 lists the initial clinical and laboratory characteristics of patients at baseline, prior to the kidney biopsy procedure. Hematuria (either macroscopic or microscopic) was present in 10 patients (18.6%). Eighteen adults had hematuria and proteinuria (not in nephrotic range), and other proteinuria patterns were observed in a smaller portion of the patients (Table 1). The Oxford classification of IgA nephropathy of the cases is shown in

Table 2.

Correlations between pathological lesions and clinical presentation at renal biopsy

Higher mesangial score, later stage of segmental glomer-ulosclerosis, and greater endocapillary hypercellularity were each associated with a higher degree of proteinuria and lower GFR, but these trends did not reach statistical significance (Table 3). Tubular atrophy and interstitial fibrosis, however, were associated with significantly reduced initial eGFR and higher initial proteinuria.

Correlations between pathological lesions and outcome

There were no significant differences between baseline and last eGFR measurement for M-score or E-score. In unad-justed analysis, the S-score [odds ratio (OR) 8.35; confi-dence interval (CI) 1.01e69.57, p Z 0.02] and T-score (OR 2.88; CI 1.22e6.79, p Z 0.03) were significant predictors for worsening renal function. The prevalence of worsening of renal function was 21% in the M0 class and 18.2% in the M1 class (pZ 0.79;Table 4). Worsening renal function was seen in 91.7% of S1 cases in comparison to 56.9% of S0 cases (pZ 0.02). Regarding E scores, 33.3% of E1 cases and 15.7% of E0 cases had worsening renal function (pZ 0.16). Lo-gistic regression analysis showed that no histological parameter was capable of predicting the long-term outcome of worsening of renal function after adjusting for baseline eGFR, hypertension, age, and sex (Table 5).

Discussion

In this article, we assessed the value of the Oxford classi-fication in relation to the clinical characteristics, the extent of proteinuria at the time of the biopsy and the deterioration of renal function of Arab IgA nephropathy patients. We found that tubular atrophy and interstitial fibrosis were associated with a reduced initial eGFR and higher initial proteinuria. Logistic regression analysis Table 1 Baseline clinical and laboratory characteristics of

patients with IgA nephropathy.

Characteristic Value

Age, y 32.2 13

Body mass index, kg/m2 30.7 8.7

Hypertension 27 (39)

Urine protein, g/24-h urine sample 1.98 0.97 Baseline GFR, mL/min 43.43 Duration of symptoms, y 7.80 1.92 Female 33 (47.1) Clinical presentation Asymptomatic hematuria 13 (18.6) Asymptomatic hematuria/proteinuria 18 (25.7) Gross hematuria 10 (14.3) Nephritic syndrome 7 (10) Nephrotic syndrome 2 (2.8) Nephritic-nephrotic 12 (17.1) Azotemia 20 (28.6) Hypertension 22 (31.4) Dialysis requirement 5 (7)

Data are presented as n (%) or mean SD.

Table 2 Distribution of the cohort across various Oxford histological classes. Classification n (%) M0 20 (28.6) M1 50 (71.4) S0 29 (41.4) S1 41 (58.6) E0 53 (75.7) E1 17 (24.3) T0 45 (64.3) T1 17 (24.3) T2 8 (11.4)

Table 3 The relationships between baseline proteinuria and Oxford histological classifications of kidney biopsies. Classification Baseline proteinuria pa

M0 0.57 (0.28e1.28) 0.13 M1 1.44 (0.61e2.56) S0 0.79 (0.24e1.37) 0.09 S1 1.68 (0.57e2.73) E0 0.86 (0.35e1.94) 0.05 E1 1.86 (1.10e4.99) T0 0.62 (0.34e1.19) 0.009 T1 1.79 (1.42e3.69) T2 3.69 (1.25e5.73)

Data are presented as median (IQR).

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showed that no histological parameter was capable of predicting the long-term outcome of worsening renal function after adjusting for baseline eGFR, hypertension, age, and sex. Previous studies have addressed the issue of the typing of IgA nephropathy and the deterioration of eGFR over time.12e15 Whereas the clinical findings, i.e.

proteinuria, play a major role in the progression of the renal disease to end-stage kidney disease,13,16the

patho-logical picture is an independent prognostic parameter in the IgA nephropathy population, as outlined by the original working group and in the validation reports of North American and European studies.10,11,17

The histopathology of IgA nephropathy is heteroge-neous, and the classifications according to the histopatho-logical findings are varied. The Oxford classification is the latest reported classification, and its application and popularity are increasing worldwide as its prognostic value is gradually being revealed through validation studies on different continents. The classifications are divided into two types according to the method used: either a single grade8,9or a semi-quantitative scoring system assessing the glomerular, tubular, interstitial and vascular compartments separately.18e20The advantage of the scoring system is its good correlation with the clinical progression of the pa-tient. It has been noted that these classifications are time consuming, however, especially in centers dealing with a large number of biopsies; hence the advent of a grading system based on a single grade. Furthermore, both grading systems are clinically relevant,16,21e24 but none of the

classifications has proven superiority over arterial pressure or proteinuria at the time of the biopsy.16

The most recent Oxford classification selected four pa-rameters as the main indicators of renal function deteriora-tion: mesangial hypercellularity, endocapillary proliferation, tubular atrophy/interstitial fibrosis and glomerular segmental sclerosis.10 It is also important that the total number of glomeruli and the numbers of glomeruli with endocapillary proliferation, extracapillary proliferation, global glomerulosclerosis, and segmental glomerulosclerosis be reported. The novelty of the current classification is that it takes into account the vertical data related to the clinical progression of the patient, which are not considered in any previous classifications. The consequent possibility of evalu-ating each histological parameter in the light of the last clinical follow-up with the known eGFR and proteinuria hel-ped tremendously in strengthening the value of the Oxford classification because both the IgA Network Group and the Renal Pathology Society worked closely to outline the pa-rameters of the Oxford classification and to validate these different parameters.

Our study is the first report from Saudi Arabia to corre-late the pathological parameters of the Oxford classifica-tion for IgA nephropathy and the progress of the disease. In the multivariate logistic regression, no histologic class predicted the worsening of renal function. Our study is limited by the relatively low number of patients with a relatively short follow up and events. It is likely that a larger study group with a greater number of events and longer follow up would have allowed more definitive con-clusions on the relation of Oxford histological predictors and long term outcome.

The Oxford classification system may be a useful tool that reflects the severity of the initial clinical presentation in Arabs with IgA nephropathy, but it did not predict the long-term renal outcome. Future studies may be needed to properly evaluate the progression of IgA nephropathy in the Arab population and to further assess the usefulness of the Oxford classification.

Conflicts of interest

All authors declare no conflicts of interest.

References

1. Droz D, Kramar A, Nawar T, Noel LH. Primary IgA nephropathy: prognostic factors. Contrib Nephrol 1984;40:202e7.

2. Berger J, Hinglais N. Intercapillary deposits of IgA-IgG. J Urol Nephrol 1968;74:694e5.

3. Berger J. IgA glomerular deposits in renal disease. Transplant Proc 1969;1:939e44.

4. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002; 347:738e48.

5. Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol 2005; 16:2088e97.

6. Berthoux FC, Mohey H, Afiani A. Natural history of primary IgA nephropathy. Semin Nephrol 2008;28:4e9.

7. Feehally J. Predicting prognosis in IgA nephropathy: editorials. Am J Kidney Dis 2001;38:881e3.

8. Lee SMK, Rao VM, Franklin WA, Schiffer MS, Aronson AJ, Spargo BH, et al. IgA Nephropathy: morphologic predictors of progressive renal disease. Hum Pathol 1982;13:314e22.

Table 4 Prevalence of worsening renal function in various Oxford classes.

Oxford class Decrease in GFR of50% pa

M0 4/19 (21.1) 0.79 M1 8/44 (20) S0 29/51 (56.9) 0.02 S1 11/12 (91.7) E0 8/51 (18.9) 0.02 E1 4/12 (33.3) T0 4/38 (10.5) 0.03 T1 4/17 (23.5) T2 4/8 (50)

Data are presented as median (IQR).

a Calculated with the use of Kruskal-Wallis test.

Table 5 Adjusted odds ratios in various Oxford classes for the outcomes of worsening renal function.a

Parameter Odds ratio (95% confidence interval) p M 0.360 (0.074e1.757) 0.206 E 1.852 (0.349e9.832) 0.469 S 1.349 (0.261e6.967) 0.721 T 1.545 (0.228e10.485) 0.655

a The analysis was adjusted for baseline estimated glomerular

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9.Haas M. Histologic subclassification of IgA nephropathy. A clinicopathologic study of 244 cases. Am J Kid Dis 1997;29: 829e42.

10. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. Oxford classification of IgA nephropathy. Kidney Int 2009;76:546e56. 11. Herzenberg AM, Fogo AB, Reich HN, Troyanov S, Bavbek N, Massat AE, et al. Validation of the Oxford classification of IgA nephropathy. Kidney Int 2011;80:310e7.

12. Riansuwan T, Kanjanabuch T, Lewsuwan S, Eiam-Ong S. Clinical characteristics and histopathological findings in 120 IgA ne-phropathy patients in Thailand. J Med Assoc Thai 2006; 89(Suppl. 2):S163e7.

13. Milovanceva-Popovska M, Grcevska L, Dzikova S, Ristovska V, Nikolov V, Polenakovic M. IgA nephropathy: 23 years of follow-up. Prilozi 2006;27:13e27.

14. Walsh M, Sar A, Lee D, Yilmaz S, Benediktsson H, Manss B, et al. Histopathologic features aid in predicting risk for progression of IgA nephropathy. Clin J Am Soc Nephrol 2010;5:425e30.

15. Prakash S, Kanjanabuch T, Austin PC, Croxford R, Hsu CY, Choi AI, et al. Continental variations in IgA nephropathy among Asians. Clin Nephrol 2008;70:377e84.

16. Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting pro-gression in IgA nephropathy. Am J Kidney Dis 2001;38:728e35.

17.Alamartine E, Sauron C, Laurent B, Sury A, Seffert A, Mariat C. The use of the Oxford classification of IgA nephropathy to predict renal survival. Clin J Am Soc Nephrol 2011;6:2384e8. 18.Alamartine E, Sabatier J-C, Guerin C, Berliet JM, Berthoux F.

Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses. Am J Kidney Dis 1991;18:12e9.

19.Kobayashi Y, Hiki Y, Fujii K, Kurokawa A, Tateno S. Moderately proteinuric IgA nephropathy: prognostic prediction of individ-ual clinical courses and steroid therapy in progressive cases. Nephron 1989;53:250e6.

20.Radford Jr MG, Donadio Jr JV, Bergstralh EJ, Grande JP. Pre-dicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997;8:199e207.

21.Frimat L, Brianc¸on S, Hestin D, Aymard B, Mayeux D, Renoult, et al. IgA nephropathy: prognostic classification of end-stage renal failure. Nephrol Dial Transplant 1997;12:2569e75. 22.Daniel L, Saingra Y, Giorgi R, Bouvier C, Pellissier JF, Berland Y.

Tubular lesions determine prognosis in IgA nephropathy. Am J Kidney Dis 2000;35:13e20.

23.Lee HS, Koh HI, Lee HB, Park HC. IgA nephropathy in Korea: a morphological and clinical study. Clin Nephrol 1987;27: 131e40.

24.Kim SW, Han SY, Jo SK, Cha DR, Cho WY, Kim HK, et al. Prog-nosis of IgA nephropathy with Haas classification in Korea (unpublished data). J Am Soc Nephrol 1998;9:92A.

References

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