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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM ASIA - AFRICA  
Year : 2019  |  Volume : 30  |  Issue : 2  |  Page : 501-507
Clinical and histopathological profile of lupus nephritis and response to treatment with cyclophosphamide: A single center study


Department of Nephrology, Gauhati Medical College and Hospital, Gauhati, Assam, India

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Date of Submission15-May-2018
Date of Acceptance08-Jul-2018
Date of Web Publication23-Apr-2019
 

   Abstract 


Lupus nephritis (LN) is an immune-complex glomerulonephritis that is usually manifested by proteinuria, active urinary sediment, hypertension, and renal failure. The objective of this study is to study the clinical and histopathological profile of LN and the response to treatment with cyclophosphamide. This was a retrospective study conducted in a tertiary care center in Assam, India, where 176 LN patients who underwent renal biopsy were included. The presenting features, laboratory parameters such as proteinuria, hematuria, and the histopathological class of the patients were studied. Among the 176 patients, 89.8% were female and 10.2% were male and maximum patients (61.3%) were in the age group of 20–40 years. Pedal edema was present in 100% of the patients, decreased urine output in 43.7%, malar rash in 38%, joint pain in 42%, hair loss in 63%, hypertension in 41.4%, oral ulcers in 31.8%, seizures in 17%, psychosis in 13%, hematuriain 78.4%, anemia in 72.1%, thrombocytopenia in 51.1%, and leukopenia in 31.7% of patients. The anti-nuclear antibody was positive in all patients and anti-dsDNA was positive in 70.5% of the patients. The most common histopathological type was class IV (50%), followed by class III (17.6%). One hundred and two patients received intravenous cyclophosphamide as initial treatment of whom, 40 received the Eurolupus regimen and 62 received the NIH regimen. The number of patients who underwent remission in both the regimen was compared. The response rate of initial treatment with cyclophosphamide in the Eurolupus group was 62.5% and in the NIH group was 64.5% (P >0.05). Majority of the patients had proliferative LN in this study, of which class IV was the most common. Proliferative LN, if not detected and treated early, leads to poor outcome in terms of patient and renal survival. Hence, patients with systemic lupus erythematosus should be evaluated for kidney involvement and treated accordingly for better outcome.

How to cite this article:
Sharma M, Das HJ, Doley PK, Mahanta PJ. Clinical and histopathological profile of lupus nephritis and response to treatment with cyclophosphamide: A single center study. Saudi J Kidney Dis Transpl 2019;30:501-7

How to cite this URL:
Sharma M, Das HJ, Doley PK, Mahanta PJ. Clinical and histopathological profile of lupus nephritis and response to treatment with cyclophosphamide: A single center study. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 21];30:501-7. Available from: http://www.sjkdt.org/text.asp?2019/30/2/501/256857



   Introduction Top


Lupus nephritis (LN) is immune-complex glomerulonephritis (GN) that is a common and serious feature of systemic lupus erythematosus (SLE), which itself is defined by a combination of clinical and laboratory features.[1],[2]

The American College of Rheumatology (ACR) criteria for the diagnosis of SLE have been widely used in both epidemiologic and treatment studies. The peak incidence of lupus is 15 to 45 years, with women outnumbering men by 10:1. The incidence of renal involvement varies depending on the populations studied, the diagnostic criteria for kidney disease, and whether involvement is defined by renal biopsy or clinical findings. Approximately 25% to 50% of lupus patients will have the clinical renal disease at onset while as many as 60% of adults with SLE will develop the renal disease during their course.[3],[4],[5],[6],[7] Although LN may affect all structures of the kidney, glomerular involvement has been the best-studied component and correlates well with the presentation, course, and treatment. The systematic classification systems for LN are based on glomerular involvement. The currently used International Society of Nephrology (ISN)/ Renal Pathology Society (RPS) classification refines and clarifies some of the deficiencies of the previous WHO classification,[8] and has improved inter-observer reproducibility and the predictive value of LN biopsies.[9],[10] The ISN classification is shown in [Table 1].
Table 1: Classification of lupus nephritis using the ISN/RPS 2004 classification.

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Patients with diffuse GN and severe focal and membranous GN are at higher risk for progressive renal insufficiency.[11] Cyclophosphamide, in combination with glucocorticoids, is used to treat severe LN.[12] LN is usually manifested by proteinuria, active urinary sediment, hypertension, and renal failure. The objective of this study is to study the clinical and histopathological profile of LN and the response to treatment with cyclophosphamide.


   Methods Top


This was a retrospective study conducted in a tertiary care center in Assam, India, where 176 LN patients who underwent renal biopsy were included. All patients fulfilled the ACR classification criteria for SLE. The presenting features, laboratory parameters such as proteinuria, microscopic hematuria and the histological class of the patients were studied. One hundred and two patients received intravenous (i.v.) cyclophosphamide as initial treatment of which 40 received the Eurolupus regimen and 62 received the NIH regimen. In the Eurolupus regimen, patients received 500 mg of cyclophosphamide every two weeks for six doses and in the NIH regimen the patients received 0.5 g/m2 of cyclophosphamide monthly for six doses. The number of patients who underwent remission in both the regimen were compared. Complete and partial remission was defined according to the kidney disease: improving global outcomes guidelines.[13] Complete remission is defined as return of serum creatinine (SCr) to previous baseline, plus a decline in the urinary protein-creatinine ration (uPCR) to <500 mg/g. Partial remission is defined as stabilization (±25%), or improvement of SCr, but not to normal, plus a ≥50% decrease in uPCR. If there was nephrotic-range proteinuria (uPCR ≥3000 mg/g), improvement requires a ≥50% reduction in uPCR, and auPCR <3000 mg/g.


   Results Top


The total number of patients included in the study was 176 of which 158 were female and 18 were male. The majority of the patients were in the age group of 20–40 years. The age and sex distribution of the patients are shown in [Table 2] and [Table 3].
Table 2: Age distribution of the study patients.

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Table 3: Sex distribution of the study patients

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Regarding the presenting features, pedal edema was present in 92% of the patients, decreased urine output in 60.8%, malar rash in 38%, joint pain in 42%, hair loss in 63%, hypertension in 41.4%, oral ulcer in 31.8%, seizures in 17%, and psychosis in 13%. Microscopic hematuria was present in 78.4%, anemia in 72.1%, thrombocytopenia in 51.1%, and leukopenia in 31.7% of the patients. The anti-nuclear antibody (ANA) was positive in all patients and anti-dsDNA in 70.4%. The presenting clinical and laboratory features are shown in [Table 4] and [Table 5].
Table 4: Clinical and laboratory parameters of the patients.

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Table 5: Anti-nuclear antibody and anti-dsDNA status in the patients.

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On renal biopsy, the most common class found was class IV in 50% of patients followed by class III in 17.6%, class V in 9%, class II in 8.5%, class IV + V in 7.9%, and class III + V in 6.8% of patients. The distribution of the renal biopsy findings is shown in [Table 6].
Table 6: Distribution of class of lupus nephritis in the study patients.

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The amount of proteinuria in different class of LN was studied and is shown in [Table 7].
Table 7: Amount of proteinuria in different classes of lupus nephritis.

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One hundred and two patients received i.v. cyclophosphamide as initial treatment of whom, 40 received the Eurolupus regimen and 62 received the NIH regimen. No significant difference was found in the response rates in the two groups after the initial treatment. The number of patients with either complete or partial response is shown in [Table 8].
Table 8: Response rate of the Eurolupus and NIH regimen.

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The adverse effects of the two regimens were also compared. The adverse effect studied was the gastrointestinal adverse effects, hair loss, infections, and menstrual abnormalities. Although there was a slight difference in the adverse effects in the two groups, the differences were not found to be significant. The adverse effects are shown in [Table 9].
Table 9: Adverse effects of the Eurolupus and NIH regimen.

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   Discussion Top


The present study was a retrospective study where 176 patients of LN were included of which, 89.8% were females. There was a preponderance of female patients in the study. This finding is similar to most of the studies of SLE that have shown a predominance of females.[14],[15],[16] Most of the patients were in the age group of 20–40 years. In this study, pedal edema was the most common presenting feature. Austin et al[17] and Neumann[18] also found pedal edema to be the most common feature in LN. Hypertension was detected in 41.4% in the present study. Shobha et al[16] found hypertension in 25% of patients and Esdaile et al,[14] in 81.5% of patients.

The most common class of LN was found to be class IV in 50% of patients followed by class III in 17.6%, class V (9%), and class II (8.5%). This was similar to the study conducted by Biswas et al,[19] who also found class IV to be the most common followed by class III. A study of 150 patients by Neumann et al[18] found class IV (53%) to be the most common followed by class III (17%), class V (14%), and class II (10%). Pollak et al[20] found class IV (37%) to be the most common followed by class II (26%), class III (19%), and class V (15%). Shobha et al[16] found class IV (40.6%) to be most common followed by class II (28.1%), class III (21.9%), and class V (9.4%). The present study and all the studies mentioned above found class IV to be the most common lesion.

The Eurolupus Nephritis trial compared low dose cyclophosphamide with standard dose cyclophosphamide (NIH regimen) with regard to efficacy and adverse effects.[21] They randomized 90 patients with diffuse or focal proliferative LN, or membranous plus proliferative disease, to receive either standard six monthly pulses of cyclophosphamide (0.5 to 1g/m2) followed by every third monthly infusions or to a shorter treatment course consisting of 500 mg of i.v. cyclophosphamide every two weeks for six doses (total dose, 3 g), followed by azathioprine maintenance therapy (2 mg/kg/ day). Both regimens were found to be equally effective. The episodes of severe infection were more than twice as frequent in the high-dose group, but it was not statistically significant. The present study examined the response rate after the initial treatment, i.e., after six pulses of cyclophosphamide in the Eurolupus and NIH regimen and found no significant difference in the response rate in the two groups.

There was no significant difference in the adverse effects in the two groups in the present study. Lesliane et al[22] in their study also did not find any significant difference in the adverse effects in high- and low-dose cyclophosphamide regimen.


   Conclusion Top


SLE is an important cause of morbidity in this part of the country, which commonly involves the kidneys. Majority of the patients had proliferative LN in this study, of which class IV was the most common. Proliferative LN if not detected and treated early leads to poor outcome in terms of patient and renal survival. Hence, patients with SLE should be evaluated for kidney involvement and treated accordingly for better outcome. Regarding treatment, both the regimen of cyclophosphamide was found to be equally effective in the present study with no significant difference in adverse effects.



 
   References Top

1.
Davidson A, Aranow C. Pathogenesis and treatment of systemic lupus erythematosus nephritis. Curr Opin Rheumatol 2006;18:468-75.  Back to cited text no. 1
    
2.
Contreras G, Roth D, Pardo V, Striker LG, Schultz DR. Lupus nephritis: A clinical review for practicing nephrologists. Clin Nephrol 2002;57:95-107.  Back to cited text no. 2
    
3.
Appel GB, Jayne D, Rovin BH. Lupus nephritis. In: Johnson RJ, Feehally J, Floege J, editors. Comprehensive Clinical Nephrology. 5th ed. Philadelphia: Saunders; 2015.  Back to cited text no. 3
    
4.
Appel GB, D’Agati VD. Lupus nephritis – Pathology and pathogenesis. In: Wallace DJ, Hahn BH, editors. Dubois’ Lupus Erythe-matosus. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 1094-112.  Back to cited text no. 4
    
5.
Tutuncu ZN, Kalunian KC. The definition and classification of SLE. In: Wallace DJ, Hahn BH, editors. Dubois’ Lupus Erythematosus. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 16-21.  Back to cited text no. 5
    
6.
Rus V, Maury EE, Hochberg MC. The epidemiology of SLE. In: Wallace DJ, Hahn BH, editors. Dubois’ Lupus Erythematosus. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 34-43.  Back to cited text no. 6
    
7.
Harley IT, Kaufman KM, Langefeld CD, Harley JB, Kelly JA. Genetic susceptibility to SLE: New insights from fine mapping and genome-wide association studies. Nat Rev Genet 2009;10:285-90.  Back to cited text no. 7
    
8.
Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521-30.  Back to cited text no. 8
    
9.
Markowitz GS, D’Agati VD. The ISN/RPS 2003 classification of lupus nephritis: An assessment at 3 years. Kidney Int 2007;71:491-5.  Back to cited text no. 9
    
10.
Furness PN, Taub N. Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis-a UK-wide study. Am J Surg Pathol 2006;30:1030-5.  Back to cited text no. 10
    
11.
Navaneethan SD, Viswanathan G, Strippoli GF. Treatment options for proliferative lupus nephritis: An update of clinical trial evidence. Drugs 2008;68:2095-104.  Back to cited text no. 11
    
12.
Houssiau FA. Cyclophosphamide in lupus nephritis. Lupus 2005;14:53-8.  Back to cited text no. 12
    
13.
KDIGO Glomerulonephritis Work Group. Clinical practice guidelines for glomerulonephritis. Kidney disease: Improving global outcomes. Kidney Int Suppl 2012;2:139-274.  Back to cited text no. 13
    
14.
Esdaile JM, Levinton C, Federgreen W, Hayslett JP, Kashgarian M. The clinical and renal biopsy predictors of long-term outcome in lupus nephritis: A study of 87 patients and review of the literature. Q J Med 1989;72:779-833.  Back to cited text no. 14
    
15.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7.  Back to cited text no. 15
    
16.
Shobha V, Prakash R, Arvind P, Tarey SD. Histopathology of lupus nephritis: A singlecenter, cross-sectional study from Karnataka, India. Internet J Rheumatol Clin Immunol 2014;2:OA3.  Back to cited text no. 16
    
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Austin HA 3rd, Boumpas DT, Vaughan EM, Balow JE. Predicting renal outcomes in severe lupus nephritis: Contributions of clinical and histologic data. Kidney Int 1994;45:544-50.  Back to cited text no. 17
    
18.
Neumann K, Wallace DJ, Azen C, et al. Lupus in the 1980s: III. Influence of clinical variables, biopsy, and treatment on the outcome in 150 patients with lupus nephritis seen at a single center. Semin Arthritis Rheum 1995;25: 47-55.  Back to cited text no. 18
    
19.
Biswas RS, Bhattacharjee B. Clinical and histological profile of lupus nephritis patients attending in a tertiary care center. J Integr Nephrol Androl 2015;2:81-4.  Back to cited text no. 19
  [Full text]  
20.
Pollak VE, Pirani CL, Schwartz FD. The natural history of the renal manifestations of systemic lupus erythematosus. J Lab Clin Med 1964;63:537-50.  Back to cited text no. 20
    
21.
Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: The euro-lupus nephritis trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46: 2121-31.  Back to cited text no. 21
    
22.
Castro-Santana LE, Colón M, Molina MJ, Rodríguez VE, Mayor AM, Vilá LM. Efficacy of two cyclophosphamide regimens for the treatment of lupus nephritis in Puerto Ricans: Low vs. standard dose. Ethn Dis 2010;20:S1-116-21.  Back to cited text no. 22
    

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Correspondence Address:
Manjuri Sharma
Department of Nephrology, Gauhati Medical College and Hospital, Guwahati - 781 032, Assam
India
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DOI: 10.4103/1319-2442.256857

PMID: 31031386

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