http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(3): 453–456 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844293
ORIGINAL ARTICLE
The clinical significance of serial kidney biopsies in lupus nephritis Abdulkareem Omer Alsuwaida
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Department of Medicine, King Saud University, Riyadh, Saudi Arabia Abstract
Keywords
Objectives. Repeated kidney biopsies are increasingly recognized to be pivotal in the management of various phases of lupus nephritis. The aim of this retrospective study was to examine the shift in activity index and chronicity index among International Society of Nephrology/ Renal Pathology Society (ISN/RPS) class patients with lupus nephritis who undergo a triple kidney biopsy. Methods. Eleven patients with lupus nephritis and 3 biopsies each were assessed and reclassified based on ISN/RPS classification. Results. The mean creatinine level increased from 74 (⫾ 38) μmol/l at baseline to 129 (⫾ 116) μmol/l at the second biopsy and to 204 (⫾ 200) μmol/l at the last biopsy. Among 11 kidney biopsies, 7 (63.7%) had a different ISN/RPS class in the second biopsy. The third biopsy showed that six kidney biopsies had a different ISN/RPS class compared to the second biopsy. Even among patients who stayed in the same ISN/RPS class, the second and third biopsies gave a different activity and/or chronicity index. The median activity index (range) was 3.1 (0–14), 4 (0–13) and 3 (0–14) for the first, second and third biopsies, respectively. The median chronicity indices (range) were 2.5 (0–8), 7 (0–8) and 5 (0–10), respectively. Conclusion. My study has shown that lupus nephritis is a shifting disease, and repeated biopsies are a pivotal policy in its management.
Biopsy, Kidney, Nephritis, Systemic lupus erythematosus
Introduction Lupus nephritis has a major impact on the long-term outcome of patients with systemic lupus erythematosus (SLE) [1]. Because of its potentially aggressive and nonstatic nature and relatively low predictive power of clinical and biochemical parameters, thresholds for performing a renal biopsy should be low [2]. The histopathological diagnosis plays a leading role in establishing a prognosis and treatment. Repeat renal biopsies are usually conducted when there is a worsening of renal function or refractoriness to therapy. We have reported the utility of protocol biopsy in determining the remission status of lupus nephritis [3]. This is the first study to report the change in renal histology in three repeated biopsies among patients with lupus nephritis. The objective of this study was to report the utility of serial biopsies among patients with lupus nephritis.
Materials and methods A retrospective review of clinical and histological data of patients with lupus nephritis from 1998 to 2012 was undertaken. Eleven patients were included on the basis of these criteria. The indications for repeated biopsy were persistence of proteinuria and/or worsening of renal function or relapse. Baseline and follow-up biopsies were classified according to the ISN/RPS 2003 classification criteria [4]. Histological slides (hematoxylin/eosin, periodic acid Schiff and Jones’ silver staining) and immunofluorescence Correspondence to: Dr. Abdulkareem Omer Alsuwaida, MD, FRCPC, MSc, Associate Professor, Department of Medicine, King Saud University, P.O. Box 2925 Riyadh 11321, Saudi Arabia. Tel: ⫹ 966-1-4672398. Fax: ⫹ 966-1-4671494. E-mail: [email protected]
History Received 18 December 2012 Accepted 21 May 2013 Published online 18 October 2013
slides (IgG, IgA, IgM, C3, C1q and fibrin) were available for all biopsies. Activity (AIs) and chronicity indices (CIs) were computed according to Austin scoring systems [5]. Statistical analyses Statistical analyses were conducted using SAS software. Comparisons of the clinical, laboratory and pathologic characteristics were performed using the X2 test and Fisher’s exact test for categorical data and the Kruskal–Wallis test and Dunn’s multiple comparisons test for continuous data.
Results The patient group consisted of 10 females and one male. The mean age of the participants was 25.7 years. The baseline characteristics and the presenting clinical manifestations are shown in Table 1. The median time between the first and second biopsy was 2 years and between the second and last biopsy was 3.5 years. The mean creatinine level increased from the baseline value of 74 (⫾ 38) μmol/l to 129 (⫾ 116) μmol/l at the second biopsy and to 204 (⫾ 200) μmol/l at the last biopsy. Proteinuria was also higher at the third biopsy, as shown in Table 2. Prednisolone was started at 0.8 mg per kilogram per day. The daily dose of prednisolone was reduced by 5 mg per day every two weeks until a maintenance dose of 5 mg per day had been reached, at approximately six months. Of 11 patients included in the study, eight patients received intravenous cyclophosphamide for induction at baseline biopsy. Of the eight patients in the intravenous cyclophosphamide group, three patients received six monthly doses of the drug as maintenance while five patients were switched
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Mod Rheumatol, 2014; 24(3): 453–456
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Table 1. Baseline characteristics of patients.
ISN/RPS class shifts 25.7 ⫾ 8.9
Age (years) Clinical manifestation at presentation Malar rash Arthritis Serositis Haematological Discoid rash Oral ulcer Cerebral Photosensitivity Renal disease Hair loss Renal biopsy according to class–no. (%) II III IV V Serum creatinine—μmol/L Median Interquartile range Urine protein–g per 24-hr urine sample Median Interquartile range Serum complement 3–g/L Median Interquartile range Serum complement 4–g/L Median Interquartile range Anti-dsDNA –IU/ml Median Interquartile range Activity index Median Interquartile range Chronicity index Median Interquartile range
4 (36%) 7 (64%) 2 (18%) 2 (18%) 2 (18%) 3 (27%) 2 (18%) 3 (27%) 6 (55%) 2 (18%) 3 (27%) 1 (9%) 6 (55%) 1 (9%) 60 50–93 1.0 0.4–1.9 0.56 0.46–0.84 0.21 0.04–0.39 544 120–1612 2 0–4 2 0–4
Anti-dsDNA, anti-double stranded DNA antibodies (radioimmunoassay, normal: ⬍ 7 U/ml). Normal complement-3 is 0.9–1.8 g/l, and normal complement-4 is 0.1–0.4 g/l. The maximum activity index score is 24, and the maximum chronicity index score is 12.
to azathioprine 1.5 mg per kilogram per day given orally. The mean cumulative dose of cyclophosphamide per patient was 10.3 ⫾ 6.2 gm (Median 8.7 gm). Total of six patients received mycophenolate mofetil 2000 mg per day at the time of second biopsy and were subsequently kept on 500 to 1000 mg per day as maintenance.
Table 3 shows the comparison of the ISN/RPS classifications of 33 biopsies that were assessed. As illustrated in Table 3, seven patients (63.3%) had a different ISN/RPS class at the second biopsy, while at the third biopsy, five patients (45.4%) had a different ISN/RPS class in comparison to the second biopsy. Only four patients (36.6%) continued to have the same baseline ISN/RPS class at the third biopsy. Then the transition according to ISN/RPS II versus III and IV to other classes was analyzed (Table 4). There was a shift in the ISN/RPS class on repeat biopsy in all patients with ISN/RPS class II. Meanwhile, the rate of transition in patients with ISN/RPS III and IV lesions was 14.3% (1/7) in the first repeated biopsy and 28.6% (2/7) in the second repeated biopsy. Activity/chronicity indices As indicated in Table 2, the median activity index was two at baseline, four at the second biopsy and three at the last biopsy (P ⫽ 0.45). There were four patients (36.7%) at the second biopsy and three patients (27.2%) at the third biopsy with no evidence of active disease. The chronicity index significantly worsened over time. The median chronicity indices were 2, 7 and 5 at the first, second and third biopsies, respectively. There were three patients (27%) with advanced disease at the third biopsy. Among the patients with baseline class II, who developed class III or IV in repeat biopsy, the mean activity index increased from 0 to 3 ⫾ 2.7, while the mean chronicity indices increased from 1 ⫾ 1.7 to 6 ⫾ 1. In contrast, when the patients with class III or IV regressed to class II in repeat biopsy, the mean activity index decreased from 2 ⫾ 1.4 to 0. Similarly, the chronicity index also decreased from 7 ⫾ 1.4 to 1.5 ⫾ 2.1 in the repeat biopsy. One patient progressed from class IV to VI with a decrease in the activity index from 6 to 3 and an increase in the chronicity index from 7 to 10.
Discussion Protocol biopsy has been used in renal allograft transplantation to detect subclinical rejections and has been shown to have a significant impact on graft survival [6,7]. Lupus nephritis is an autoimmune disease that may cause significant injury to kidney tissue without been clinically evident as proteinuria or change in serum creatinine. Although there has been significant improvement in
Table 2. Biochemical and histological characteristics of patients at the time of kidney biopsies. Serum creatinine (μmol/L) Mean ⫾ SD Median (range) Urine 24 h protein (g/day) Mean ⫾ SD Median (range) Complement 3 (g/L) Mean ⫾ SD Median (range) Complement 4 (g/L) Mean ⫾ SD Median (range) Activity index Mean ⫾ SD Median (range) Chronicity index Mean ⫾ SD Median (range)
Baseline biopsy
Second biopsy
Third biopsy
P value
74 ⫾ 38 60 (38–172)
129 ⫾ 116 88 (53–459)
204 ⫾ 200 95 (49–521)
0.07
1.13 ⫾ 0.88 1.01 (0.04–2.33)
1.63 ⫾ 1.44 1.21 (0.23–3.29)
2.65 ⫾ 1.9 3.38 (0.131–4.546)
0.25
0.58 ⫾ 0.26 0.56 (0.16–0.87)
1.02 ⫾ 0.43 0.92 (0.7–1.3)
0.853 ⫾ 0.368 0.785 (0.425–1.52)
0.06
0.27 ⫾ 0.26 0.21 (0.01–0.66)
0.32 ⫾ 0.20 0.34 (0.11–0.64)
0.254 ⫾ 0.198 0.183 (0.05–0.63)
0.6
3.1 ⫾ 4.2 2 (0–14)
5 ⫾ 4.3 4 (0–13)
4.9 ⫾ 4.9 3(0–14)
0.45
2.5 ⫾ 2.5 2 (0–8)
5.8 ⫾ 2.3 7 (0–8)
5.3 ⫾ 2.9 5 (0–10)
0.01
P values were calculated using the Kruskal–Wallis test for continuous variables.
The clinical significance of serial kidney biopsies in lupus nephritis
DOI 10.3109/14397595.2013.844293
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Table 3. Histologic changes in ISN/RPS classifications and immunosuppressive therapy at baseline and repeat biopsies for each patient. Patient 1 2 3 4 5 6 7 8 9 10 11
Baseline biopsy (AI/CI) II (0/3) II (1/2) II (0/0) III (3/2) IV (7/4) IV (14/2) IV (2/8) IV (2/1) IV (4/0) IV (1/5) V (0/0)
Treatment PSL PSL PSL PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC
Second biopsy (AI/CI) III (2/7) II (0/0) IV (6/7) IV &V (13/3) III (5/7) IV (10/5) III (1/8) III (4/7) IV (10/7) IV (1/6) II & V (3/6)
Third biopsy Treatment (AI/CI) PSL/CYC IV (7/10) PSL III & V (1/5) PSL/CYC VI (3/10) PSL/AZA IV & V (14/3) PSL/CYC III (1/6) PSL/CYC/AZA IV (10/4) PSL/CYC II (0/0) PSL/CYC IV (2/5) PSL/CYC IV (11/6) PSL/AZA IV (5/6) PSL/AZA II & V (0/3)
Treatment PSL/MMF PSL/MMF PSL/AZA PSL/MMF PSL/AZA PSL/MMF – PSL/MMF PSL/AZA PSL/MMF PSL/MMF
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ISN/RPS class, International Society of Nephrology and Renal Pathology Society; AI, activity index; CI, chronicity index; PSL, prednisolone; CYC, intravenous cyclophosphamide; AZA, azathioprine; MMF, mycophenolate mofetil.
patient survival over the last decade [8], there has been no change in the number of patients who progress to end-stage renal disease [9]. In addition, we have shown that biochemical and serological parameters are poor predictors of disease activity, and a protocol biopsy is the best available method of ascertaining the remission status of lupus nephritis after immunosuppressive treatment [3]. Repeated biopsies are critical among patients who fail to attain complete remission on immunosuppressive therapy. The risk of complications of renal biopsies is minimal with the current standard of using real-time ultrasound performed by a trained clinician [10]. This finding should encourage physicians to have a lower threshold for performing kidney biopsies in patients with lupus nephritis. In practice, repeat kidney biopsy assist both clinicians and patients in making decisions during various phases of lupus nephritis treatment. When are kidney biopsies in lupus nephritis indicated? A baseline biopsy is needed to determine the underling pathology. We have shown in an earlier study that a biopsy during the maintenance phase is critical and more predictive of long-term outcomes than a baseline biopsy [3].A clinician tends to use less aggressive immunosuppressive therapy among ISN/RPS class II patients. However, all patients in our study who were class II had a different renal pathology at repeated biopsy. The majority of patients in our study had a change in either the ISN/RPS class, or disease activity or chronicity indices. In the recent European guidelines on the management of lupus nephritis, a repeat kidney biopsy was recommended for patients who are refractory to immunosuppressive therapy or at relapse [2]. The minimum target was to achieve partial remission within 12 months of treatment. However, almost one-third of patients with lupus nephritis continue to be in partial remission, even
after one year of immunosuppressive treatment [11]. Whether this represents an active disease that needs extended or modified immunosuppressive treatment or simply chronic changes cannot be ascertained without kidney biopsy. Similarly, the renal pathology of lupus nephritis is not limited to ISN/RPS classes. Other pathology, including vascular, tubulointerstitial and podocytopathy, may coexist [12,13]. The coexistence of other renal pathologies can only be assessed by renal biopsy. The standard therapy for active lupus involves use of various immunosuppressive treatments, and clinicians tend to give more immunosuppressive drugs to those with persistence of proteinuria or worsening of renal function. The increase in immunosuppressive drugs will have no effect on patients with inactive disease or the persistence of proteinuria and elevated serum creatinine because of chronic changes. Our study showed that one-quarter to onethird of patients had no active disease on second and third biopsy, respectively. Biomarkers are desperately needed in the management of lupus nephritis. These biomarkers are needed to diagnose the underlying renal pathology, assess disease activity and monitor treatment response. Similarly, biomarkers are necessary for the early diagnosis of renal flares. Large numbers of biomarkers have been studied in lupus nephritis, such as monocyte chemoattractant protein-1, neutrophil gelatinase-associated lipocalin, tumor necrosis factor and others. However, none of them have been validated in largescale studies [14].
Conclusion A repeat renal biopsy provides diagnostic and prognostic information that can assist clinicians in making correct therapeutic decisions in patients with partial response, refractory disease or relapse.
Table 4. Pathological transition stratified by baseline ISN/RPS class.
First repeat biopsy II III & IV IV & V Second repeat biopsy II III/IV III or IV & V VI
Acknowledgements
Baseline biopsy Class II (3)
Class III & IV (7)
We thank Mrs. Aileen Esteibar for her secretarial assistance.
1 2 0
0 6 1
Conflict of interest
0 1 1 1
1 5 1 0
References
ISN/RPS class, International Society of Nephrology and Renal Pathology Society.
None declared.
1. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82:299–308.
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2. Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, 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;71:1771–82. 3. Alsuwaida A, Husain S, Alghonaim M, AlOudah N, Alwakeel J, ullah A, et al. Strategy for second kidney biopsy in patients with lupus nephritis. Nephrol Dial Transplant. 2012;27:1472–8. 4. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65: 521–30. 5. Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TA, Kullick ME, Klippel JH, et al. Prognostic factors in lupus nephritis. Contribution of renal histologic data. Am J Med. 1983;75:382–91. 6. Furness PN, Philpott CM, Chorbadjian MT, Nicholson ML, Bosmans JL, Corthouts BL, et al. Canas C: Protocol biopsy of the stable renal transplant: A multicentre study of methods and complication rates. Transplantation. 2003;76:969–73. 7. Racusen LC. Protocol transplant biopsies in kidney allografts: Why and when are they indicated? Clin J Am Soc Nephrol. 2006;1:144–7.
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8. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54:2550–7. 9. Ward MM. Changes in the incidence of endstage renal disease due to lupus nephritis in the United Sates, 1996–2004. J Rheumatol 2009; 36:63–67. 10. Corapi KM, Chen JL, Balk EM, Gordon CE. Bleeding complications of native kidney biopsy: a systematic review and meta-analysis. Am J Kidney Dis. 2012;60:62–73. 11. Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ; Collaborative Study Group. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephrol. 2008;3:46–53. 12. Yu F, Wu LH, Tan Y, Li LH, Wang CL, et al. Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 international society of nephrology and renal pathology society system. Kidney Int. 2010;77(9):820–9. 13. Markowitz GS, D’Agati VD. Classification of lupus nephritis. Curr Opin Nephrol Hypertens. 2009;18(3):220–5. 14. Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010;2010:638413. doi:10.1155/2010/638413.
ORIGINAL ARTICLE
The clinical significance of serial kidney biopsies in lupus nephritis Abdulkareem Omer Alsuwaida
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Department of Medicine, King Saud University, Riyadh, Saudi Arabia Abstract
Keywords
Objectives. Repeated kidney biopsies are increasingly recognized to be pivotal in the management of various phases of lupus nephritis. The aim of this retrospective study was to examine the shift in activity index and chronicity index among International Society of Nephrology/ Renal Pathology Society (ISN/RPS) class patients with lupus nephritis who undergo a triple kidney biopsy. Methods. Eleven patients with lupus nephritis and 3 biopsies each were assessed and reclassified based on ISN/RPS classification. Results. The mean creatinine level increased from 74 (⫾ 38) μmol/l at baseline to 129 (⫾ 116) μmol/l at the second biopsy and to 204 (⫾ 200) μmol/l at the last biopsy. Among 11 kidney biopsies, 7 (63.7%) had a different ISN/RPS class in the second biopsy. The third biopsy showed that six kidney biopsies had a different ISN/RPS class compared to the second biopsy. Even among patients who stayed in the same ISN/RPS class, the second and third biopsies gave a different activity and/or chronicity index. The median activity index (range) was 3.1 (0–14), 4 (0–13) and 3 (0–14) for the first, second and third biopsies, respectively. The median chronicity indices (range) were 2.5 (0–8), 7 (0–8) and 5 (0–10), respectively. Conclusion. My study has shown that lupus nephritis is a shifting disease, and repeated biopsies are a pivotal policy in its management.
Biopsy, Kidney, Nephritis, Systemic lupus erythematosus
Introduction Lupus nephritis has a major impact on the long-term outcome of patients with systemic lupus erythematosus (SLE) [1]. Because of its potentially aggressive and nonstatic nature and relatively low predictive power of clinical and biochemical parameters, thresholds for performing a renal biopsy should be low [2]. The histopathological diagnosis plays a leading role in establishing a prognosis and treatment. Repeat renal biopsies are usually conducted when there is a worsening of renal function or refractoriness to therapy. We have reported the utility of protocol biopsy in determining the remission status of lupus nephritis [3]. This is the first study to report the change in renal histology in three repeated biopsies among patients with lupus nephritis. The objective of this study was to report the utility of serial biopsies among patients with lupus nephritis.
Materials and methods A retrospective review of clinical and histological data of patients with lupus nephritis from 1998 to 2012 was undertaken. Eleven patients were included on the basis of these criteria. The indications for repeated biopsy were persistence of proteinuria and/or worsening of renal function or relapse. Baseline and follow-up biopsies were classified according to the ISN/RPS 2003 classification criteria [4]. Histological slides (hematoxylin/eosin, periodic acid Schiff and Jones’ silver staining) and immunofluorescence Correspondence to: Dr. Abdulkareem Omer Alsuwaida, MD, FRCPC, MSc, Associate Professor, Department of Medicine, King Saud University, P.O. Box 2925 Riyadh 11321, Saudi Arabia. Tel: ⫹ 966-1-4672398. Fax: ⫹ 966-1-4671494. E-mail: [email protected]
History Received 18 December 2012 Accepted 21 May 2013 Published online 18 October 2013
slides (IgG, IgA, IgM, C3, C1q and fibrin) were available for all biopsies. Activity (AIs) and chronicity indices (CIs) were computed according to Austin scoring systems [5]. Statistical analyses Statistical analyses were conducted using SAS software. Comparisons of the clinical, laboratory and pathologic characteristics were performed using the X2 test and Fisher’s exact test for categorical data and the Kruskal–Wallis test and Dunn’s multiple comparisons test for continuous data.
Results The patient group consisted of 10 females and one male. The mean age of the participants was 25.7 years. The baseline characteristics and the presenting clinical manifestations are shown in Table 1. The median time between the first and second biopsy was 2 years and between the second and last biopsy was 3.5 years. The mean creatinine level increased from the baseline value of 74 (⫾ 38) μmol/l to 129 (⫾ 116) μmol/l at the second biopsy and to 204 (⫾ 200) μmol/l at the last biopsy. Proteinuria was also higher at the third biopsy, as shown in Table 2. Prednisolone was started at 0.8 mg per kilogram per day. The daily dose of prednisolone was reduced by 5 mg per day every two weeks until a maintenance dose of 5 mg per day had been reached, at approximately six months. Of 11 patients included in the study, eight patients received intravenous cyclophosphamide for induction at baseline biopsy. Of the eight patients in the intravenous cyclophosphamide group, three patients received six monthly doses of the drug as maintenance while five patients were switched
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Mod Rheumatol, 2014; 24(3): 453–456
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Table 1. Baseline characteristics of patients.
ISN/RPS class shifts 25.7 ⫾ 8.9
Age (years) Clinical manifestation at presentation Malar rash Arthritis Serositis Haematological Discoid rash Oral ulcer Cerebral Photosensitivity Renal disease Hair loss Renal biopsy according to class–no. (%) II III IV V Serum creatinine—μmol/L Median Interquartile range Urine protein–g per 24-hr urine sample Median Interquartile range Serum complement 3–g/L Median Interquartile range Serum complement 4–g/L Median Interquartile range Anti-dsDNA –IU/ml Median Interquartile range Activity index Median Interquartile range Chronicity index Median Interquartile range
4 (36%) 7 (64%) 2 (18%) 2 (18%) 2 (18%) 3 (27%) 2 (18%) 3 (27%) 6 (55%) 2 (18%) 3 (27%) 1 (9%) 6 (55%) 1 (9%) 60 50–93 1.0 0.4–1.9 0.56 0.46–0.84 0.21 0.04–0.39 544 120–1612 2 0–4 2 0–4
Anti-dsDNA, anti-double stranded DNA antibodies (radioimmunoassay, normal: ⬍ 7 U/ml). Normal complement-3 is 0.9–1.8 g/l, and normal complement-4 is 0.1–0.4 g/l. The maximum activity index score is 24, and the maximum chronicity index score is 12.
to azathioprine 1.5 mg per kilogram per day given orally. The mean cumulative dose of cyclophosphamide per patient was 10.3 ⫾ 6.2 gm (Median 8.7 gm). Total of six patients received mycophenolate mofetil 2000 mg per day at the time of second biopsy and were subsequently kept on 500 to 1000 mg per day as maintenance.
Table 3 shows the comparison of the ISN/RPS classifications of 33 biopsies that were assessed. As illustrated in Table 3, seven patients (63.3%) had a different ISN/RPS class at the second biopsy, while at the third biopsy, five patients (45.4%) had a different ISN/RPS class in comparison to the second biopsy. Only four patients (36.6%) continued to have the same baseline ISN/RPS class at the third biopsy. Then the transition according to ISN/RPS II versus III and IV to other classes was analyzed (Table 4). There was a shift in the ISN/RPS class on repeat biopsy in all patients with ISN/RPS class II. Meanwhile, the rate of transition in patients with ISN/RPS III and IV lesions was 14.3% (1/7) in the first repeated biopsy and 28.6% (2/7) in the second repeated biopsy. Activity/chronicity indices As indicated in Table 2, the median activity index was two at baseline, four at the second biopsy and three at the last biopsy (P ⫽ 0.45). There were four patients (36.7%) at the second biopsy and three patients (27.2%) at the third biopsy with no evidence of active disease. The chronicity index significantly worsened over time. The median chronicity indices were 2, 7 and 5 at the first, second and third biopsies, respectively. There were three patients (27%) with advanced disease at the third biopsy. Among the patients with baseline class II, who developed class III or IV in repeat biopsy, the mean activity index increased from 0 to 3 ⫾ 2.7, while the mean chronicity indices increased from 1 ⫾ 1.7 to 6 ⫾ 1. In contrast, when the patients with class III or IV regressed to class II in repeat biopsy, the mean activity index decreased from 2 ⫾ 1.4 to 0. Similarly, the chronicity index also decreased from 7 ⫾ 1.4 to 1.5 ⫾ 2.1 in the repeat biopsy. One patient progressed from class IV to VI with a decrease in the activity index from 6 to 3 and an increase in the chronicity index from 7 to 10.
Discussion Protocol biopsy has been used in renal allograft transplantation to detect subclinical rejections and has been shown to have a significant impact on graft survival [6,7]. Lupus nephritis is an autoimmune disease that may cause significant injury to kidney tissue without been clinically evident as proteinuria or change in serum creatinine. Although there has been significant improvement in
Table 2. Biochemical and histological characteristics of patients at the time of kidney biopsies. Serum creatinine (μmol/L) Mean ⫾ SD Median (range) Urine 24 h protein (g/day) Mean ⫾ SD Median (range) Complement 3 (g/L) Mean ⫾ SD Median (range) Complement 4 (g/L) Mean ⫾ SD Median (range) Activity index Mean ⫾ SD Median (range) Chronicity index Mean ⫾ SD Median (range)
Baseline biopsy
Second biopsy
Third biopsy
P value
74 ⫾ 38 60 (38–172)
129 ⫾ 116 88 (53–459)
204 ⫾ 200 95 (49–521)
0.07
1.13 ⫾ 0.88 1.01 (0.04–2.33)
1.63 ⫾ 1.44 1.21 (0.23–3.29)
2.65 ⫾ 1.9 3.38 (0.131–4.546)
0.25
0.58 ⫾ 0.26 0.56 (0.16–0.87)
1.02 ⫾ 0.43 0.92 (0.7–1.3)
0.853 ⫾ 0.368 0.785 (0.425–1.52)
0.06
0.27 ⫾ 0.26 0.21 (0.01–0.66)
0.32 ⫾ 0.20 0.34 (0.11–0.64)
0.254 ⫾ 0.198 0.183 (0.05–0.63)
0.6
3.1 ⫾ 4.2 2 (0–14)
5 ⫾ 4.3 4 (0–13)
4.9 ⫾ 4.9 3(0–14)
0.45
2.5 ⫾ 2.5 2 (0–8)
5.8 ⫾ 2.3 7 (0–8)
5.3 ⫾ 2.9 5 (0–10)
0.01
P values were calculated using the Kruskal–Wallis test for continuous variables.
The clinical significance of serial kidney biopsies in lupus nephritis
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Table 3. Histologic changes in ISN/RPS classifications and immunosuppressive therapy at baseline and repeat biopsies for each patient. Patient 1 2 3 4 5 6 7 8 9 10 11
Baseline biopsy (AI/CI) II (0/3) II (1/2) II (0/0) III (3/2) IV (7/4) IV (14/2) IV (2/8) IV (2/1) IV (4/0) IV (1/5) V (0/0)
Treatment PSL PSL PSL PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC PSL/CYC
Second biopsy (AI/CI) III (2/7) II (0/0) IV (6/7) IV &V (13/3) III (5/7) IV (10/5) III (1/8) III (4/7) IV (10/7) IV (1/6) II & V (3/6)
Third biopsy Treatment (AI/CI) PSL/CYC IV (7/10) PSL III & V (1/5) PSL/CYC VI (3/10) PSL/AZA IV & V (14/3) PSL/CYC III (1/6) PSL/CYC/AZA IV (10/4) PSL/CYC II (0/0) PSL/CYC IV (2/5) PSL/CYC IV (11/6) PSL/AZA IV (5/6) PSL/AZA II & V (0/3)
Treatment PSL/MMF PSL/MMF PSL/AZA PSL/MMF PSL/AZA PSL/MMF – PSL/MMF PSL/AZA PSL/MMF PSL/MMF
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ISN/RPS class, International Society of Nephrology and Renal Pathology Society; AI, activity index; CI, chronicity index; PSL, prednisolone; CYC, intravenous cyclophosphamide; AZA, azathioprine; MMF, mycophenolate mofetil.
patient survival over the last decade [8], there has been no change in the number of patients who progress to end-stage renal disease [9]. In addition, we have shown that biochemical and serological parameters are poor predictors of disease activity, and a protocol biopsy is the best available method of ascertaining the remission status of lupus nephritis after immunosuppressive treatment [3]. Repeated biopsies are critical among patients who fail to attain complete remission on immunosuppressive therapy. The risk of complications of renal biopsies is minimal with the current standard of using real-time ultrasound performed by a trained clinician [10]. This finding should encourage physicians to have a lower threshold for performing kidney biopsies in patients with lupus nephritis. In practice, repeat kidney biopsy assist both clinicians and patients in making decisions during various phases of lupus nephritis treatment. When are kidney biopsies in lupus nephritis indicated? A baseline biopsy is needed to determine the underling pathology. We have shown in an earlier study that a biopsy during the maintenance phase is critical and more predictive of long-term outcomes than a baseline biopsy [3].A clinician tends to use less aggressive immunosuppressive therapy among ISN/RPS class II patients. However, all patients in our study who were class II had a different renal pathology at repeated biopsy. The majority of patients in our study had a change in either the ISN/RPS class, or disease activity or chronicity indices. In the recent European guidelines on the management of lupus nephritis, a repeat kidney biopsy was recommended for patients who are refractory to immunosuppressive therapy or at relapse [2]. The minimum target was to achieve partial remission within 12 months of treatment. However, almost one-third of patients with lupus nephritis continue to be in partial remission, even
after one year of immunosuppressive treatment [11]. Whether this represents an active disease that needs extended or modified immunosuppressive treatment or simply chronic changes cannot be ascertained without kidney biopsy. Similarly, the renal pathology of lupus nephritis is not limited to ISN/RPS classes. Other pathology, including vascular, tubulointerstitial and podocytopathy, may coexist [12,13]. The coexistence of other renal pathologies can only be assessed by renal biopsy. The standard therapy for active lupus involves use of various immunosuppressive treatments, and clinicians tend to give more immunosuppressive drugs to those with persistence of proteinuria or worsening of renal function. The increase in immunosuppressive drugs will have no effect on patients with inactive disease or the persistence of proteinuria and elevated serum creatinine because of chronic changes. Our study showed that one-quarter to onethird of patients had no active disease on second and third biopsy, respectively. Biomarkers are desperately needed in the management of lupus nephritis. These biomarkers are needed to diagnose the underlying renal pathology, assess disease activity and monitor treatment response. Similarly, biomarkers are necessary for the early diagnosis of renal flares. Large numbers of biomarkers have been studied in lupus nephritis, such as monocyte chemoattractant protein-1, neutrophil gelatinase-associated lipocalin, tumor necrosis factor and others. However, none of them have been validated in largescale studies [14].
Conclusion A repeat renal biopsy provides diagnostic and prognostic information that can assist clinicians in making correct therapeutic decisions in patients with partial response, refractory disease or relapse.
Table 4. Pathological transition stratified by baseline ISN/RPS class.
First repeat biopsy II III & IV IV & V Second repeat biopsy II III/IV III or IV & V VI
Acknowledgements
Baseline biopsy Class II (3)
Class III & IV (7)
We thank Mrs. Aileen Esteibar for her secretarial assistance.
1 2 0
0 6 1
Conflict of interest
0 1 1 1
1 5 1 0
References
ISN/RPS class, International Society of Nephrology and Renal Pathology Society.
None declared.
1. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82:299–308.
456
A. O. Alsuwaida
Mod Rheumatol Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/11/14 For personal use only.
2. Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, 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;71:1771–82. 3. Alsuwaida A, Husain S, Alghonaim M, AlOudah N, Alwakeel J, ullah A, et al. Strategy for second kidney biopsy in patients with lupus nephritis. Nephrol Dial Transplant. 2012;27:1472–8. 4. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65: 521–30. 5. Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TA, Kullick ME, Klippel JH, et al. Prognostic factors in lupus nephritis. Contribution of renal histologic data. Am J Med. 1983;75:382–91. 6. Furness PN, Philpott CM, Chorbadjian MT, Nicholson ML, Bosmans JL, Corthouts BL, et al. Canas C: Protocol biopsy of the stable renal transplant: A multicentre study of methods and complication rates. Transplantation. 2003;76:969–73. 7. Racusen LC. Protocol transplant biopsies in kidney allografts: Why and when are they indicated? Clin J Am Soc Nephrol. 2006;1:144–7.
Mod Rheumatol, 2014; 24(3): 453–456
8. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54:2550–7. 9. Ward MM. Changes in the incidence of endstage renal disease due to lupus nephritis in the United Sates, 1996–2004. J Rheumatol 2009; 36:63–67. 10. Corapi KM, Chen JL, Balk EM, Gordon CE. Bleeding complications of native kidney biopsy: a systematic review and meta-analysis. Am J Kidney Dis. 2012;60:62–73. 11. Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ; Collaborative Study Group. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephrol. 2008;3:46–53. 12. Yu F, Wu LH, Tan Y, Li LH, Wang CL, et al. Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 international society of nephrology and renal pathology society system. Kidney Int. 2010;77(9):820–9. 13. Markowitz GS, D’Agati VD. Classification of lupus nephritis. Curr Opin Nephrol Hypertens. 2009;18(3):220–5. 14. Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010;2010:638413. doi:10.1155/2010/638413.
