|Year : 2017 | Volume
| Issue : 1 | Page : 12-16
Is renal biopsy always necessary to start immunosuppressive therapy in lupus nephritis?
Vasudevan Chelliah, V Balaraman, S Ilango, S Ramesh, V Kannan Bhaba, D Shivakumar
Department of Nephrology, Kilpauk Medical College and Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||23-Feb-2017|
Department of Nephrology, Kilpauk Medical College and Hospital, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objective: Most of the patients with proliferative lupus nephritis (LN) have high titer of anti-dsDNA antibody and low complement levels. In this study, we tried to predict proliferative LN with serological profile.
Methods: This prospective study was conducted in fifty pateints with known systemic lupus erythematosus (SLE) with laboratory evidence of LN (proteinuria, microscopic hematuria, or increased serum creatinine). Serological profile (anti-dsDNA, C3, and C4) and renal biopsy were done in all patients.
Results: Of 50 patients, 35 had Class IV (70%), 7 Class II (14%), 4 Class V (8%), and 4 had Class IV and V (8%) on renal biopsy. Totally, 39 (78%) patients had proliferative LN (Class IV and Class IV and V). The prevalence of anti-dsDNA, low C3, and low C4 was 97.1%, 68%, and 74% with LN and 97.4%, 84.6%, and 87.2% with proliferative LN (P < 0.001), respectively. About 72% (28 of 39 patients) with proliferative LN had the combination of anti-dsDNA positivity, low C3, and low C4 levels. However, whoever had the combination of anti-dsDNA positivity, low C3, and low C4 showed only proliferative LN on biopsy. Positive predictive value was 100% (P < 0.05). None of the patients with Class II or Class V (nonproliferative LN) had this combination of serology.
Conclusion: In this study, it was found that proliferative LN can be predicted by serological profile alone. Thus it might be argued that immunosuppressive therapy (steroids and mycophenolate mofetil) may be started without renal biopsy in a known SLE patient with laboratory evidence of LN and positive serology; however, robust studies are required.
Keywords: Anti-dsDNA, complement, lupus nephritis, renal biopsy
|How to cite this article:|
Chelliah V, Balaraman V, Ilango S, Ramesh S, Bhaba V K, Shivakumar D. Is renal biopsy always necessary to start immunosuppressive therapy in lupus nephritis?. Indian J Rheumatol 2017;12:12-6
|How to cite this URL:|
Chelliah V, Balaraman V, Ilango S, Ramesh S, Bhaba V K, Shivakumar D. Is renal biopsy always necessary to start immunosuppressive therapy in lupus nephritis?. Indian J Rheumatol [serial online] 2017 [cited 2017 Apr 26];12:12-6. Available from: http://www.indianjrheumatol.com/text.asp?2017/12/1/12/199121
| Introduction|| |
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the involvement of multiple organ systems. Women of childbearing age group between 15 and 45 years are more commonly affected. Female to male ratio is 10:1.,,, The gender predominance is less pronounced in children and elderly individuals. Lupus nephritis (LN) is more severe in children and males and is less likely in elderly individuals.,,, LN is one of the common manifestations of SLE. It is a frequent and potentially life-threatening complication of SLE.,,,,, Almost 50%–60% of patients with SLE have clinically significant renal involvement at the time of diagnosis. Organ damage is mediated by tissue binding autoantibodies and immune complexes. Antinuclear antibody (ANA) is the most sensitive test for SLE and is present in more than 90% of patients but not specific for SLE. Anti-dsDNA is a more specific but less sensitive marker of SLE. High titer of anti-dsDNA correlates with disease activity and especially with LN.,,, Serum levels of complements C3 and C4 are usually decreased in active SLE and in active LN. Most of the patients with active proliferative LN have high titer of anti-dsDNA and low C3 and C4 levels.,,,,,
Nowadays, renal biopsy is recommended in almost all patients who have clinical or laboratory evidence of renal involvement to determine the histological class of LN and thereby to plan therapy. According to ISN/RPS 2003 classification, there are six classes of LN, Classes I to VI: Minimal mesangial, mesangial proliferative, focal, diffuse, membranous, and advanced sclerosing lupus nephritides, respectively. However, the requirement of renal biopsy has not been studied scientifically. Dr. Glassock had written in his editorial comment in Journal of American Society of Nephrology that “the marginal value of renal biopsy (with classification of the lesions found) is minimal over and above clinical evaluation (age, sex, race, duration of disease, blood pressure, extra renal manifestations) and the application of simple, noninvasive laboratory tests (serum creatinine, urinalysis, urine protein excretion, hemoglobin concentration, complement component levels, auto-antibody serology) in estimating prognosis and guiding therapy. Aggressive immunosuppressive therapy of LN (steroids and cytotoxic agents) in this modern era is associated with high levels of initial responsiveness (partial or complete remission) and narrowed the gap between individual categories of LN with respect to long-term prognosis.” Primary objective of this study was to appraise the need for renal biopsy in LN.
| Methods|| |
This prospective study was conducted in a tertiary care hospital from January 2011 to December 2013 to evaluate the correlation between serological profile (anti-dsDNA, low C3, and low C4) and histopathology of LN and to define the positive predictive value (PPV) of anti-dsDNA and low complement levels with proliferative LN. ANA-positive female SLE patients between 15 and 45 years with any one of the three abnormalities, proteinuria (protein creatinine ratio (PCR) >0.5), microscopic hematuria (≥3 red blood cells/hpf), or increased serum creatinine (>1.2 but <1.8 mg/dl), were included in the study. Male SLE patients, patients below 15 and above 45 years, ANA-negative lupus patients, and patients with serum creatinine >1.8 were excluded from the study.
A pro forma was used to collect the demographic and clinical details of the patients. Serological profile and percutaneous ultrasonography-guided renal biopsy were done in all patients. Anti-dsDNA antibody was done by Crithidia luciliae DNA-based indirect immunofluorescence method. Serum complement levels C3 and C4 were done by nephelometric method. Biopsy samples were analyzed by LM and IF methods. The correlation between serological profile and histopathology was assessed. Data analysis was performed using SPSS 17 Software is produced by SPSS Inc., later acquired by IBM in 2009. Univariate analysis was performed by Chi-square test. Multivariate analysis was carried out by logistic regression method. Receiver operating characteristic (ROC) curve analysis was also performed.
Necessary approvals were obtained from the ethics committee of our institution. Informed written consent was obtained from all patients prior to their enrollment in this study.
| Results|| |
In our study, 50 female SLE patients were included in the study. Of 50 patients, 25 were in the age group of 15–25 years, 17 in 26–35 years, and 8 were in 36–45 years. Thirty-five patients (70%) had Class IV LN, 7 (14%) Class II, 4 (8%) Class V, and 4 patients (8%) had Class IV and V on renal biopsy [Table 1]. No one had Class III LN in our study. Thirty-nine patients (78%) had proliferative LN (Class IV and Class IV and V). Only 17 (34%) had increased serum creatinine. Sixteen (45.7%) of 35 patients with class IV and 1 (25%) of 4 patients with Class V had increased serum creatinine. None of the patients with Class II and Class IV and V had increased serum creatinine (P = 0.047).
|Table 1: It shows individual class of Lupus nephritis and number of patients on renal biopsy|
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Of 50 patients 41 (82%) had anti-dsDNA positivity. Thirty-four (97.1%) of 35 patients with Class IV, all the 4 patients (100%) with Class IV and V, 1 of 7 patients with Class II, and 2 of 4 patients with Class V LN had anti-dsDNA positivity. Thirty-eight of 39 patients with proliferative LN had anti-dsDNA positivity (P < 0.001). Of 50 patients with LN, 34 (68%) had low C3 level in serum. Twenty-nine of 35 patients with Class IV, all the 4 patients with Class IV and V, and 1 of 4 patients with Class V LN had low C3 level in serum. However, none of the patients with Class II LN had low C3 level. Thirty-three of 39 patients with proliferative LN had low C3 level (P < 0.001). Of 50 patients with LN, 37 (74%) had low C4 level in serum. Thirty of 35 patients with Class IV, all the 4 patients with Class IV and V, and 3 of 4 patients with Class V LN had low C4 level in serum. However, none of the patients with Class II LN had low C4 level. Thirty-four of 39 patients with proliferative LN had low C4 level (P < 0.001).
Logistic regression analysis was used to analyze the correlation between all the three variables in serology (anti-dsDNA positivity, low C3, and low C4) and proliferative form (Class IV and Class IV and V) of LN. All the three variables, positive anti-dsDNA, low C3, and low C4 independently predicted proliferative LN well [Table 2].
|Table 2: Logistic regression analysis shows individual correlation of serological markers with proliferative lupus nephritis (P<0.05)|
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Of 39 patients with proliferative LN, 28 (72%) had the combination of positive anti-dsDNA, low C3, and low C4 levels in serum. However, none of the patients with Class II and Class V LN had similar combination of serology. All these three serological markers had significant correlation with proliferative LN (Class IV, 'IV and V'), and positive predictive value (PPV) of all these three serological markers together for proliferative LN was 100% (P < 0.05) [Table 3]. Whoever had the combination of anti-dsDNA positivity, low C3 and low C4 showed only proliferative LN on renal biopsy. ROC curve also shows the importance of these parameters in the diagnosis of proliferative LN [Figure 1].
|Table 3: PPV of all three serological markers Anti dsDNA, low C3, low C4 for proliferative lupus nephritis is 100%|
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|Figure 1: The interpretation shows that (1) Receiver operating characteristic curve for laboratory parameters in diagnosis of lupus nephritis has superior benefits compared with the diagonal of no benefit. (2) Low C3 would give the best balance with sensitivity and false positivity rate|
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The study was approved by the local ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.
| Discussion|| |
Most of the patients with active proliferative LN have high titers of anti-dsDNA and low serum complement levels.,, In diffuse proliferative LN, the deposited immune complexes comprise nuclear antigens (e.g., DNA) and high-affinity complement fixing IgG antibodies., Localization of immune complexes in the glomeruli leads to activation of complement cascade and complement-mediated injury. High anti-dsDNA antibody titer correlates well with clinical activity and flare of LN., Serum levels of total hemolytic component (CH50) and complement components C3 and C4 are often decreased in patients with active SLE and active LN., Both C3 and C4 are decreased or the C4 alone is preferentially decreased in LN. Serial monitoring of complement levels, if declining, helps in predicting a flare in LN, and normalization of decreased levels is often associated with improved renal outcome. Low C4 and normal C3 levels reflect hereditary C4 deficiency.
We studied 50 ANA-positive female SLE patients with the evidence of LN (proteinuria, microscopic hematuria, or increased serum creatinine) to evaluate the correlation between serological profile and histopathology of LN. Nakano et al. reported that 83.8% (31 of 37 patients) of patients had class IV LN on biopsy. In our study, 70% (35 patients) had class IV and 8% (4 patients) had combined class IV and V. Totally, 78% (39 of 50 patients) had proliferative LN. Salwa Ibrahim and Ahmed Fayed reported renal impairment in 85% of the patients with LN. In our study, it was 34% (17 of 50 patients). Nakano et al. found that 67% (25 of 37) of patients with proliferative LN had renal insufficiency. In our study, 41% (16 of 39) of patients with proliferative LN had increased serum creatinine. Pradhan et al. reported high prevalence of anti-nucleosomal (88%) and anti-dsDNA (80%) antibodies in SLE patients with active proliferative LN. However, it was not statistically significant between LN group and non-LN group (P > 0.05). Bigler et al. also reported high prevalence of anti-dsDNA antibodies (94.3%) in SLE patients with active proliferative LN and it was statistically significant when compared to non-LN group (P < 0.001). Gonzalo et al. reported that 84.5% (49 of 58 patients) with proliferative LN had anti-dsDNA positivity. In our study, the prevalence of anti-dsDNA was 97.1% in LN and 97.4% (38 of 39 patients) in proliferative LN (P < 0.001). In a study conducted by Franco et al., the prevalence of hypocomplementemia was 91.4% with Class IV LN (P = 0.05). Gonzalo et al. also reported high prevalence (91.2%) of hypocomplementemia with proliferative LN. In our study, C3 level was low in 68% of patients with LN and 84.6% with proliferative LN (P < 0.001). C4 level was low in 74% of patients with LN and 87.2% with proliferative LN (P < 0.001). Austin and Illei quoted that anti-dsDNA was commonly absent with variable hypocomplementemia in membranous LN and anti-dsDNA positivity with hypocomplementemia in proliferative LN. In our study, 72% (28 of 39 patients) of the patients with active proliferative LN (Class IV, 'IV and V') had the combination of anti-dsDNA positivity, low C3, and low C4 levels, but none of the patients with Class II or Class V LN (nonproliferative LN) had this combination of serology. All these three combined serological markers had a significant correlation with proliferative LN (Class IV, 'IV and V'), and the PPV was 100% (P < 0.05). Whoever had the combination of anti-dsDNA positivity, low C3, and low C4 levels showed only proliferative LN in biopsy.
Definitely, in this era, biopsy has so many additional advantages. There are a variety of other renal lesions that can be seen in patients with SLE in addition to typical immune complex glomerulonephritis. These include acute tubulointerstitial nephritis (almost always seen with concurrent glomerular disease), vascular disease (e.g., thrombotic microangiopathy, antiphospholipid nephropathy, or vasculitis), drug-induced lupus, lupus podocytopathy, and concurrent renal disease unrelated to lupus (e.g., diabetes).
However, in this study, we found that proliferative LN can be predicted by serological profile alone. Thus it might be argued that immunosuppressive therapy (steroids and mycophenolate mofetil) may be started without renal biopsy in a known SLE patient with laboratory evidence of LN and positive serology. The caveat, however is that even we start immunosuppressive therapy without biopsy initially based on serology and other lab parameters, at one point of time, patients may need biopsy if the treatment fails or to assess prognosis.
This study has several limitations such as small sample size, lack of anti-dsDNA antibody titer measurement, lack of subclassification of proliferative LN based on activity and chronicity indices, absence of patients with class III LN, and proliferative LN was not categorized as with or without crescents. Another limitation was exclusion of patients with serum creatinine of >1.8 mg/dl from the study. Our logic for this was that if the serum creatinine is more than 1.8 mg/dl, the chance of getting chronic lesions in biopsy is more and starting immunosuppressive therapy (steroids and MMF) without biopsy would not be justifiable.
Though, our study raises the question that in at least some patients with LN renal biopsy may not be necessary; however, in the want of robust studies in this area and the potential life-threatening nature of LN, no recommendations of any kind can be made based on the present study.
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Conflicts of interest
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| References|| |
West SG, Achenbach GA, Edelstein CL. Renal involvement in systemic lupus erythematosus. In: Schrier RW, editor. Diseases of the Kidney and Urinary Tract. 8th
ed., Ch. 65. Lippincott: Williams & Wilkins; 2007. p. 1673.
Appel GB, Jayne D. Lupus nephritis. In: Johnson R, Floege J, Feehaly J, editors. Comprehensive Clinical Nephrology. St. Louis: Elsevier; 2010.
Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358:929-39.
Rus V, Maury EE, Hochberg MC. The epidemiology of SLE. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus. 7th
ed. Philadelphia: Lippincott Williams and Wilkins; 2007. p. 34-43.
Waldman M, Appel GB. Update on the treatment of lupus nephritis. Kidney Int 2006;70:1403-12.
Appel GB, D'Agati VD. Lupus nephritis-pathology and pathogenesis. In Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus. 7th
ed. Philadelphia: Lippincott Williams and Wilkins; 2007. p. 1094-112.
Appel GB, D'Agati V. Renal involvement in systemic lupus erythematosus. In: Massary S, Glassock R, editors. Text of Kidney Disease. St. Louis: Williams and Wilkins; 2000. p. 787-97.
Bomback AS, Appel GB. Updates on the treatment of lupus nephritis. J Am Soc Nephrol 2010;21:2028-35.
Tutuncu ZN, Kalunian KC. The definition and classification of SLE. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus. 7th
ed. Philadelphia: Lippincott Williams and Wilkins; 2007. p. 16-21.
Waldman M, Madaio MP. Pathogenic autoantibodies in lupus nephritis. Lupus 2005;14:19-24.
Ng KP, Manson JJ, Rahman A, Isenberg DA. Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus. Arthritis Rheum 2006;55:900-4.
Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al
. Classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241-50.
Glassock RJ. Reclassification of lupus glomerulonephritis: Back to the future. J Am Soc Nephrol 2004;15:501-3.
Ponticelli C, Zucchelli P, Moroni G, Cagnoli L, Banfi G, Pasquali S. Long-term prognosis of diffuse lupus nephritis. Clin Nephrol 1987;28:263-71.
Markowitz GS, D'Agati VD. Classification of lupus nephritis. Curr Opin Nephrol Hypertens 2009;18:220-5.
Nasr SH, D'Agati VD, Park HR, Sterman PL, Goyzueta JD, Dressler RM, et al.
Necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity. Clin J Am Soc Nephrol 2008;3:682-90.
D'Agati VD, Barry Stokes M. Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjogren's syndrome, and rheumatoid arthritis. In: Jennette CJ, Olson L, Schwartz MM, editors. Pathology of the Kidney. 5th
ed. Philadelphia: Lippincott-Raven; 1998.
Laitman RS, Glicklich D, Sablay LB, Grayzel AI, Barland P, Bank N. Effect of long-term normalization of serum complement levels on the course of lupus nephritis. Am J Med 1989;87:132-8.
Walport MJ. Complement. Second of two parts. N Engl J Med 2001;344:1140-4.
Nakano M, Ueno M, Hasegawa H, Watanabe T, Kuroda T, Ito S, et al.
Renal haemodynamic characteristics in patients with lupus nephritis. Ann Rheum Dis 1998;57:226-30.
Ibrahim S, Fayed A. The incidence of biopsy-proven glomerulonephritis in Cairo University, Egypt: A 5-year study. NDT Plus 2009;2:431-2.
Pradhan VD, Patwardhan MM, Ghosh K. Anti-nucleosome antibodies as a disease marker in systemic lupus erythematosus and its correlation with disease activity and other autoantibodies. Indian J Dermatol Venereol Leprol 2010;76:145-9.
Bigler C, Lopez-Trascasa M, Potlukova E, Moll S, Danner D, Schaller M, et al.
Antinucleosome antibodies as a marker of active proliferative lupus nephritis. Am J Kidney Dis 2008;51:624-9.
Gonzalo E, Toldos O, Martínez-Vidal MP, Ordoñez MC, Santiago B, Fernández-Nebro A, et al.
Clinicopathologic correlations of renal microthrombosis and inflammatory markers in proliferative lupus nephritis. Arthritis Res Ther 2012;14:R126.
Franco C, Yoo W, Franco D, Xu Z. Predictors of end stage renal disease in African Americans with lupus nephritis. Bull NYU Hosp Jt Dis 2010;68:251-6.
Austin HA, Illei GG. Membranous lupus nephritis. Lupus 2005;14:65-71.
[Table 1], [Table 2], [Table 3]