Updated Oxford classification and the international study of kidney disease in children classification: application in predicting outcome of Henoch-Schönlein purpura nephritis

Data of 292 HSPN patients diagnosed by the Kidney Disease Center of the First Affiliated Hospital of Zhejiang University between August 2004 and November 2015 were retrieved. Criteria for a renal biopsy was HSPN patients who had active urinary sediments (proteinuria or hematuria) with or without impairment of glomerular filtration rate. Inclusive criteria included: aged ≥14 years; a history of palpable purpuric eruption, with or without involvement of gastrointestinal tract or joints; biopsy-proven HSPN. Exclusion criteria was as follows: inadequate number of glomeruli (< 8) in biopsy, concomitant with cirrhotic liver disease, IgA-dominant infection associated glomerulonephritis, human immunodeficiency virus associated IgA nephropathy, anti-neutrophil cytoplasmic antibody associated vasculitis, hepatitis B virus associated nephritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus and other autoimmune diseases. Levels of antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), anti-glomerular basement antibody together with complements were collected to exclude autoimmune disease.

Of these 292 patients, 11 patients were lost to follow-up, and another 6 patients were excluded because of biopsy inadequacy (< 8 glomeruli), the remaining 275 patients were the basis of our study. The study protocols conformed to the provisions of the Declaration of Helsinki. The Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University approved the protocols (Reference number: 2017678).

Medical records of the patients were reviewed to obtain clinical data at the time of biopsy and during the course of follow-up. The data included age, gender, blood pressure, urine protein excretion based on 24-h urine collection, serum creatinine (Scr) and estimated glomerular filtration rate (eGFR). Also, the use of immunosuppressant drugs was assessed. The mean arterial pressure (MAP) was calculated by the equation MAP = (2 × diastolic pressure + systolic pressure)/3, while the eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.

Renal biopsy of all patients were graded according to the International Study of Kidney Disease in Children classification [8]: (I) minimal glomerular alterations; (II) mesangial proliferation; (IIIa) focal or (IIIb) diffuse proliferation or sclerosis with < 50% crescents; (IV) mesangial proliferation or sclerosis with 50–75% crescents; (V) mesangial proliferation or sclerosis with > 75% crescents; (VI) membranoproliferative-like lesion. Patients were divided into three groups: Group ISKDC-G0 included ISKDC grade I and II, Group ISKDC-G1 included ISKDC grade III, and ISKDC-G2 included ISKDC grade IV, V and VI. Pathologic findings in these renal biopsies were then re-evaluated with the updated Oxford classification MEST-C scoring system [12]:(1) mesangial proliferation (M): mesangial score < 0.5 (M0), or > 0.5(M1); (2) endocapillary hypercellularity (E): absent (E0) or present (E1); (3) segmental glomerulosclerosis (S): absent (S0) or present (S1); (4) tubular atrophy/ interstitial fibrosis (T): 0–25% (T0), 25–50% (T1), > 50% (T2); (5)cellular/ fibrocellular crescents (C): absent (C0), 0–25% (C1), ≥25% (C2). Group T1 and T2 were merged because there were only 2 patients scored T2. One experienced renal pathologist who was blinded to the case histories evaluated all renal pathology.

The primary renal endpoint was defined as ≥30% reduction of eGFR from baseline in 2 years, doubling of Scr or ESRD. ESRD was defined by reaching an eGFR of <15 ml/min/1.72m² or requiring maintaining renal replacement therapy for more than 3 months.

Statistical analysis was performed by IBM SPSS 22.0 (IBM, Chicago, IL, USA). Normal distributed data were expressed as mean ± standard deviation, and comparisons were tested by Student’s t test. Non-normal distributed data were expressed as median(interquartile range), and compared by the Mann-Whitney U-test. Chi-square χ² test, Fisher’s exact test and non-parametric test were used to compare categorical variables. We used one-way ANOVA and R x C contingency table for comparison of three groups. Student-Newman-Keuls test was used to further compare between two groups. To evaluate the association between the classifications and renal endpoint, we used univariate analysis and multivariate Cox regression model, defining the day of renal biopsy as starting point, and the result was presented with hazard ratios (HR). P < 0.05 was considered significant.

The study sample comprised 275 HSPN patients. At the time of biopsy, their mean age was 33 ± 17 years, and 52.0% were male. All of the patients were the Han population. During a median follow-up of 56(30,86) months, 30(10.9%) patients reached renal endpoints including more than 30% decrease in baseline eGFR in 2 years (11 patients), doubling in Scr (7 patients) and ESRD (12 patients). Comparations between patients with or without renal endpoints were shown in Table 1. There were no significant differences in age and extrarenal manifestations, but patients reaching endpoints had a higher male proportion, higher average MAP (100 ± 9 mmHg vs 94 ± 11 mmHg, p = 0.012), higher Scr level [103.0 (74.8217.8) μmol/L vs 63.0 (53.0,78.0) μmol/L, p < 0.001] and lower eGFR level [67.4 (30.1, 115.4) ml/min/1.73m² vs 121.2 (92.6, 140.1)ml/min/1.73m², p < 0.001], and more proteinuria [2.7 (1.0, 5.0) g/24 h vs 1.12 (0.6, 2.7) g/24 h, p < 0.001]. Angiotensin converting enzyme inhibitor (ACEI) / angiotensin II receptor blocker (ARB) and immunosuppressants were prescribed in our patients. A percentage of 72.7% of patients received immunosuppressive therapy; the percentage was same in patients with or without renal endpoints. However, patients with endpoints received a higher proportion of steroids combining with intravenous cyclophosphamide or mycophenolate mofetil (18/24 vs 83/176, p = 0.019), probably correlating with a higher severity of the disease.

The detailed pathologic features (including the severity of mesangial proliferation, the proportion of glomeruli with each pathologic lesion, and the proportion of interstitial inflammation) in patients with or without renal endpoints were shown in Table 2. A greater proportion of glomeruli with crescents (p < 0.001), and higher percentages of tubular atrophy (p = 0.013) and tubulointerstitial inflammation (P = 0.004) were observed in patients reaching renal endpoints. Immunofluorescence deposition feature is provided in Additiobnal file 1: Table S1

Distribution of the patients categorized by the ISKDC classification and the updated Oxford classification was presented in Table 3. There were 101(36.7%) patients graded ISKDC II, 148(53.8%) patients graded IIIa, 17(6.2%) patients graded IIIb, 8(2.9%) patients graded IV, and only 1(0.4%) patients graded V. No patient was graded I or VI. By the updated Oxford classification, M1, E1, S1, T1/T2 were observed in 41(14.9%), 82(29.8%), 149(54.2%), 8(2.9%) patients respectively. Additionally, there were only 6 patients graded T1, and 2 patients graded T2, so we merged them in a group (T1/T2) for analysis. With regards to crescents, 141(51.3%) patients scored C1 and 35(12.7%) patients scored C2. For renal outcomes, the percentage of patients reaching renal endpoints increased with the increasing grade from ISKDC-G0, G1 to G2 (4.9, 12.7, 44.4% respectively, p < 0.001), and those in M1, E1, S1, T1/T2, C1 or C2 groups of the updated Oxford classification were 12.1, 15.8, 12.7, 25, 13.4% or 20%, respectively.

Correlations between clinical data and pathologic classifications were shown in Table 4. According to the ISKDC classification, with the increase of classification from ISKDC G0, G1 to G2, patients had more daily urine protein (p < 0.05), higher Scr level (p < 0.05) and lower eGFR level (p < 0.05). According to the updated Oxford classification, no significant difference in MAP, proteinuria, eGFR and Scr levels was found between M0 and M1 group; patients in E1 group had more daily urine protein than E0 group (p < 0.001); patients in S1 group had higher MAP level (p = 0.003), higher Scr level (p < 0.001) and lower eGFR level (p < 0.001) than those in S0 group; patients in T1/T2 group had higher Scr level (p = 0.001) and lower eGFR level (p = 0.001) than those in T0 group; both patients in C1 group (Crescents 0–25%) and C2 group (Crescents ≥25%) had more daily urine protein (p < 0.05), higher Scr level (p < 0.05) and lower eGFR level (p < 0.05) than those in C0 group; furthermore, patients in C2 group have more proteinuria than C1 group.

Survival analysis was shown in Table 5. By the univariate Cox regression analysis, E1(P = 0.038), S1(p = 0.005), T1/T2(p < 0.001) and C1/C2(p = 0.005) were risk factors for renal endpoints. In multivariate model, variants including age, 24-h proteinuria, eGFR, and pathologic features (E1, S1, T1/T2 and C1/C2) were analyzed; and S1 lesion (HR = 4.086 95%CI = 1.111–15.026, p = 0.034) and more proteinuria (HR = 1.191, 95%CI = 1.012–1.401, p = 0.035) were independently risk factors for renal endpoints.