A survey on manifestations, laboratory findings and pathological renal biopsy-based classification of patients with lupus nephritis – Bui Van Khanh

Journal of military pharmaco-medicine n 0 9-2018 128 A SURVEY ON MANIFESTATIONS, LABORATORY FINDINGS AND PATHOLOGICAL RENAL BIOPSY-BASED CLASSIFICATION OF PATIENTS WITH LUPUS NEPHRITIS Bui Van Khanh1; Nguyen Van Doan1; Nguyen Dang Dung2 SUMMARY Introduction: Lupus nephritis comprises a spectrum of glomerular, vascular, and tubulointerstitial lesions, which has significant racial variations in severity and manifestations. The current International Society of Nephrology/Renal Pathology Society classification (2003) has been successfully improved for the categorization of lupus glomerulonephritis. Methods: This study is a retrospective analysis on clinical manifestations and the pathological features of lupus nephritis. Clinical manifestations and laboratory test were collected and analysed by SPSS 20.0 program. Results: Among the 38 patients with lupus nephritis, 92.1% was female, with the major manifestations being hypertension (47.4%), edema (44.7%), skin malar rash (36.9%), arthritis (57.9%), anemia (81.1%), oral ulcer (21.1%). The mean SLEDAI was 20.58 ± 6.46, and mean serum level of creatinine was 152.86 ± 125.96 µmol/L. Percentage of patients with hypoalbuminemia was 75%. Of the patients involved, 94.4% showed with decrease of C3 complement, 69.4% of C4 complement. The mean 24-hour urine protein was 5.03 ± 4.88 g. 94.4% of the patients had ANA test positive, among which 69.4% positive with anti-dsDNA, and 14.3% positive with anti-Sm autoantibodies. On the basis of this classification, 38 patients with lupus nephritis revealed the following distribution: Class I: 0%; class II: 5.3%; class III: 50%; class IV: 28.9%; class V: 10.5%; combined classes III & IV: 2.6%; and class VI: 2.6%. Conclusions: In patients with lupus nephritis, manifestations and laboratory findings by renal biopsy were clinically valuable in identifying different renal classifications of lupus pathology, which was helpful for diagnosis and treatment guide. * Keywords: Lupus nephritis; Clinical Manifestation; Laboratory finding. INTRODUCTION Renal involvement is one of the most severe complications of systemic lupus erythematosus (SLE) and the clinical presentation of lupus nephritis (LN) is highly variable, ranging from mild asymptomatic proteinuria to rapidly progressive glomerulonephritis [1, 2]. The renal morphological expression can vary considerably among patients or within an individual over time [3, 4]. Performing renal biopsies to accurately determine the prognosis and to guide treatment in LN patients is greatly needed. Recently, 1. Bachmai Hospital 2. Vietnam Military Medical University Corresponding author: Nguyen Dang Dung (dzungmd@yahoo.com) Date received: 30/08/2018 Date accepted: 16/11/2018 Journal of military pharmaco-medicine n 0 9-2018 129 the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN was proposed [5]. However, very few publications are currently available concerning the demographic, clinical, and pathological features of LN in Vietnam [8]. Therefore, this study aimed to: Assess the clinical and basic laboratory features of patients with biopsy-proven LN according to ISN/RPS 2003 classification, renal pathological activity, and chronicity index of the patients. SUBJECTS AND METHODS 1. Subjects. Patients with LN who underwent renal biopsy between 2015 and 2017 in the Center of Allergy and Clinical Immunology, Bachmai Hospital, were included in this study. All patients met the American College of Rheumatology (ACR) revised criteria for the classification of SLE [3]. For inclusion, patients had to have adequate renal biopsy samples for histological diagnosis, including > 10 glomeruli. Consequently, data of 38 patients were available in the study. 2. Methods. * Study design: This is a retrospective analysis on clinical manifestations and the pathological features of renal biopsy of LN patients. * Data collection: For included patients, clinical records and laboratory parameters at the time of biopsy were collected. Renal biopsy- confirmed LN cases were classified according to the 2003 ISN/RPS classification [3]. Data regarding immunofluorescence images were available for 100% of the patients. Activity indices (AIs) and chronicity indices (CIs) were calculated accordingly. In addition, the following parameters were collected: Demographic data (sex, age), extrarenal SLE manifestations, SLEDAI, anti-dsDNA antibody, anti-nuclear antibodies, anti-Sm antibody, and hematological and biochemical parameters (including CBC, hemoglobin, serum levels of urea, creatinine, albumin, and complement). Nephrotic syndrome was defined as a simultaneous existence of generalized edema, an increase in the proteinuria of ≥ 3.5 g/24 hours and a decrease in serum albumin to ≤ 30 g/L. * Statistical analysis: Data with normal distribution and non- normal distribution were presented as mean ± SD and median and range, respectively. Categorical variables were presented as percentage. All statistical evaluations were performed using the SPSS Program, version 20.0 RESULTS AND DISCUSSION 1. Baseline demographic, clinical and laboratory features of the patients at the time of renal biopsy. Renal involvement is a frequent and serious organ manifestation of SLE and is also a major cause of mortality and morbidity, especially when it occurs as proliferative LN. Our study was conducted on 38 patients. Journal of military pharmaco-medicine n 0 9-2018 130 Table 1: The characteristics of patients (n = 38). Variables Value [mean ± SD, or n (%)] Age 31.24 ± 12.41 < 20 years 6 (15.8) 20 - 39 years 27 (71.1) ≥ 40 5 (13.2) Females 35 (92.1) Edema present 17 (44.7) Hypertension 18 (47.4) Malar rash 14 (36.8) Oral ulcer 8 (21.1) Arthritis 22 (57.9) SLEDAI 20.58 ± 6.46 Table 2: Baseline laboratory features of the patients. Variable Value [mean ± SD, or n (%)] Hb < 120 g/L (n = 37) 31 (83.8) Leukopenia (WBC < 4 G/L) (n = 37) 8 (21.6) Thrombocytopenia (PLT < 100 G/l) (n = 37) 6 (16.2) Hypoalbuminemia (albumin < 30 g/L) (n = 36) 27 (75.0) Creatinin (µmoL/L) (n = 36) 152.86 ± 125.96 Cholesterol (mmoL/L) (n = 30) 6.45 ± 2.28 Decreased C3 (n = 36) 34 (94.4) Decreased C4 (n = 36) 25 (69.4) Positive ANA (n = 36) 34 (94.4) Positive anti-dsDNA (n = 36) 25 (69.4) Positive anti-Sm (n = 21) 3 (14.3) Urine protein 24 hours (g/24 hrs) (n = 38) 5.03 ± 4.88 Hematuria present (n = 33) 32 (97.0) Most of the patients with lupus glomerulonephritis were female, accounting for 92.1%, which is similar to those of other authors [6, 7, 8, 9]. The mean age of patients with lupus glomerulonephritis at the time of biopsy was 31.24 ± 12.41 years, the most common age group was 20 - 40 years, which was similar to that reported by Hamid Nasri et al with mean age of their patients being 32.7 ± 12 years. Hypertension, edema, malar rash, arthritis and oral ulcer were the most manifestation at the time of renal biopsy. It was implied that LN does not only have manifestation of renal damage, but also other organs. It was further demonstrated by high SLEDAI being 20.58 ± 6.46. In patients with SLE and renal disease, the presence of haematuria, proteinuria, hypoalbuminemia, low C3, C4, and positive anti-dsDNA may positively predict proliferative LN. Although renal biopsies remain the best way of diagnosis of LN, clinicians in ereas where renal biopsies are not available may use these clinical findings and other laboratory tests as alternatives for diagnosis of LN. This may help guiding proper therapy. 2. Histopathological features of biopsies. * The classification of renal biopsy of lupus nephritis by ISN/RPS: Class I: 0 patient; class II: 2 patients (5.3%); class III: 15 patients (50.0%); class IV: 12 patients (28.9%); class V: 4 patients (10.5%); class VI: 1 patient (2.6%); mix class III + IV, IV + V: 1 patient (2.6%). The ISN/RPS lupus nephritis class III and IV occurred more frequently than other classes of LN. Journal of military pharmaco-medicine n 0 9-2018 131 Renal biopsy plays an important role in the diagnosis and management of LN, which provides information about kidney damage, activity levels, as well as chronic kidney disease of injury. Our study results were mainly attributable to class III and class IV, similar to those in other studies [8], where class III was higher, which was not consistent with studies rescues in the area [8]. This difference may be explained by the choice of biopsy patients, primarily in patients with severe clinical manifestations such as edema, elevated 24-hour proteinuria. Another factor contributing to this explanation is that most of patients in our study went to hospital when it was relatively late for diagnosis and treatment, leading to more severe renal damage. Classes I and II were low which is also explained by our selection of patients with a renal biopsy, focusing only on those with severe clinical and urinalysis, according to the medical literature. Abnormalities in clinical and urinalysis were less common in LN classes I and II [1]. Table 3: The characteristics of subclasses III and IV. A A/C C Total Class n % n % n % n % III 13 65.0 4 20.0 3 15.0 20 100 S 3 42.8 4 57.2 0 0 7 100 IV G 2 50.0 2 50.0 0 0 4 100 The characteristics of LN subclasses III and IV have shown that the majority of subclasses were active. Classes III and IV of LN are often associated with subclasses A or A/C, and are less common in subclass C alone, suggesting that the glomerular injury is continuous, resulting in a pathological glomerulosclerosis. Percentage of class V of LN (10.5%) was followed by kidney damage in class III and IV, which was lower than that reported by other groups, such as the Japanese authors 15.6%, USA 29.4%, UK 18.9% [8]. This may possibly be due to our small number of patients. In our study, only 1 patient (2.6%) was of class VI of LN, which was relatively low in percentage, possibly be due to the choice of patients. Class VI kidney damage is end-stage renal disease, with complete fibrosis of more than 90% of glomerular, which leads to clinical end- stage renal disease such as chronic renal failure, anuria. In these patients, we do not indicate a kidney biopsy. Other authors have also reported that the prevalence of kidney damage in class VI is very low, being 1% by Japan authors, 3.3% in the United States and 0.6% in the United Kingdom [8]. * Activity index (n = 32): Type 1 (0 - 8): 26 patients (81.25%); type 2 (9 - 16): 6 patients (18.75%); type 3: (17 - 24): 0 patient. Mean activity index (AI) value: 5.91 ± 3.21. Journal of military pharmaco-medicine n 0 9-2018 132 The AI of the study was mainly found in mild (81.3%) and moderately active (18.8%) groups, with an average activity index of 5.91 ± 3,21, which is the same to that of Pham Hoang Ngoc Hoa (6.53 ± 4.66) [1], suggesting that the majority of patients having been evaluated for renal biopsy were flare disease, and consistent with clinical manifestations such as elevated urinary proteinuria or clinical edema. * Chronicity index (n =32): Type 1 (≤ 1): 14 patients (43.8%); type 2 (2 - 3): 13 patients (40.6%): type 3 (≥ 4): 5 patients (15.6%). Mean chronic index (CI) value: 1.94 ± 1.46. The most common CI was the mild CI (43.8%), with an average CI of 1.94 ± 1.46, which was lower than that of Pham Hoang Ngoc Hoa (2.21 ± 2.57) [1]. Table 4: Results of immunofluorescence staining of renal biopsies in LN (n = 38). Immunofluorescence staining positive n % IgG 36 94.7 IgM 17 44.7 IgA 25 65.8 C3 32 84.2 C4 9 23.7 C1q 35 92.1 Full-house 4 10.5 The percentage of positive immunofluorescence stained markers were high with IgG and C1q, C3, and IgA, IgM, C4. Of 38 patients undergoing renal biopsy, 10.5% showed all 6 markers (IgG, IgM, IgA, C3, C4, C1q deposition at gromeruli) positive by immuno- fluorescense staining. Characteristics of fluorescent immuno- staining are important for the differential diagnosis of lupus glomerulonephritis versus other nephropathy. Our study found that 100% of patients were positive for at least one immunological marker, and 10.5% of patients were positive for all immunological markers, of which IgG and C1q showed very high positive rates of 94.7% and 92.1%, respectively. The results of this study are similar to that of Pham Hoang Ngoc Hoa et al [1]. CONCLUSION This study indicates that clinical and laboratory fundings at renal biopsy are clinically valuable in identifying different renal classifications of lupus pathology, activity, and chronicity index. Our results suggest that patients with class III and IV had signicantly higher proportions of microscopic hematuria, proteinuria, impaired renal function, anemia, hypoalbuminemia, and positive anti-DNA antibody. All of these findings correlated well with high activity index and chronicity index of lupus pathology. REFERENCES 1. Phạm Hoàng Ngọc Hoa, Nguyễn Văn Hưng. Apply the classification of International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 in diagnosis of LNitis. Hochiminh Medicine. 2015, Vol. 19, No. 5. 2. Adeel Zubair, Marianne Frieri. Lupus nephritis: Review of the literature. Curr Allergy Asthma Rep. 2013, 13, pp.580-586. 3. Bevra H. Hahn, Maureen A. McMahon, Alan Wilkinson et al. American College of Rheumotology Guidelines for screening, treatment, and management of LN. Arthritis Care and Research. 2012, 64, pp.797-808. Journal of military pharmaco-medicine n 0 9-2018 133 4. Jan J. Weening, Vivette D. D’Agati, Melvin M. Schwartz et al. The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited. JASN. 2004, February 1, 2, Vol. 15, No. 2, pp.241-250. 5. George K Bertsias, Maria Tektonidou, ZahirAmoura et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 2012, 71, pp.1771-1782. 6. Hamid Nasri, Ali Ahmadi, AzarBaradaran et al. Clinicopathological correlations in lupus nephritis; a single center experience. J Nephropathol. 2014, 3 (3), pp.115-120. 7. Hitoshi Yokoyama, Hiroshi Okuyama, Hideki Yamaya. Clinicopathological insights into lupus glomerulonephritis in Japanese and Asians. Clin Exp Nephrol. 2011, 15, pp.321- 330. 8. IG Okpechi et al. Clinicopathological insights into lupus nephritis in South Africans: A study of 251 patients. Lupus. 2012, 21, pp.1017-1024. 9. Z Wang et al. Clinicopathological characteristics of familial SLE patients with LN. Lupus. 2009, 18, pp.243-248.