Renal and patient survival in lupus nephritis : the impact of conventional and novel immunosuppressive treatments

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Renal and patient survival in lupus nephritis : the impact of conventional and novel immunosuppressive treatments

Yap, Yat-hin, Desmond; 葉逸軒 Yap, Y. D. [葉逸軒]. (2013). Renal and patient survival in lupus nephritis : the impact of conventional and novel immunosuppressive treatments. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5333557 2013

http://hdl.handle.net/10722/207609

The author retains all proprietary rights, (such as patent rights) and the right to use in future works.

RENAL AND PATIENT SURVIVAL IN LUPUS NEPHRITIS – THE IMPACT OF CONVENTIONAL AND NOVEL IMMUNOSUPPRESSIVE TREATMENTS

By

Yap Yat Hin Desmond MBBS (HKU), MRCP (UK), FHKCP, FHKAM

A thesis submitted for the degree of

DOCTOR OF MEDICINE In The Faculty of Medicine The University of Hong Kong Hong Kong China October 2013

Abstract of thesis entitled

RENAL AND PATIENT SURVIVAL IN LUPUS NEPHRITIS – THE IMPACT OF CONVENTIONAL AND NOVEL IMMUNOSUPPRESSIVE TREATMENTS

Submitted by Yap Yat Hin Desmond for the degree of Doctor of Medicine at the University of Hong Kong in October 2013

Lupus nephritis (LN) is an important clinical manifestation of systemic lupus erythematosus (SLE) and contributes significantly to patient morbidity and mortality. In the era of effective immunosuppressive treatments, the clinical outcomes of LN patients have substantially improved, and the 10-year patient and renal survival rates were 98.2% and 98.0% respectively. With prolonged patient survival, infection (50.0%), cardiovascular disease (20.8%) and malignancy (12.5%) but not uncontrolled disease, have emerged as the leading causes of death in LN patients. The strongest predictor of mortality in LN patients, however, was endstage renal disease (ESRD) as indicated by a high standardized mortality ratio of 26.1 which doubled that of cardiovascular disease and history of malignancy. Despite the improved patient outcomes, conventional treatment such as cyclosphosphamide (CTX) was associated with significant toxicities and suboptimal long-term renal prognosis and hence alternative immunosuppressive agents with anti-fibrotic properties such as mycophenolate mofetil (MMF) and proliferation signal inhibitors (PSI) warrants further investigation. In Chinese patients with proliferative LN, corticosteroids and MMF as initial therapy conferred favorable long-term outcomes, with 10-year patient and renal survival of 91% and 86% respectively. This regimen, when used as continuous induction-maintenance treatment, is 2

efficacious and well-tolerated, and the continuation of MMF treatment for at least 24 months was associated with significantly lower risk of relapse when compared to treatment for shorter duration. As the severity of tubulointerstitial fibrosis can be attenuated by growth factors with anti-fibrotic properties such as bone morphogenetic protein 7 (BMP7), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), studies were conducted in NZB/W F1 mice to investigate the impact of treatment on intra-renal expression of growth factors pertinent to fibrosis. Methylprednisolone (MP) combined with either MMF or CTX have resulted in increased BMP7 and reduced HGF and VEGF in the renal parenchyma, reduced fibrosis, and improved clinical parameters, compared with MP alone. The data also suggested that the increase in BMP7, a potentially anti-fibrotic cytokine, was observed earlier in the mice treated with MMF compared with those treated with CTX. Our preliminary clinical experience also suggested that PSI combined with corticosteroids may serve as an efficacious and well-tolerated immunosuppressive regimen in human LN, especially in patients with MMF intolerance or history of malignancy. These observations have important implications on the choice of therapy for the treatment of proliferative LN. As for membranous LN, our pilot results suggested that corticosteroids combined with either MMF or tacrolimus can be effective treatment options for patients with significant proteinuria, while each regimen exhibits distinct efficacy and tolerability profiles. In conclusion, the results from the studies included in this thesis show the magnitude of benefit conferred by novel immunosuppressive treatment regimens for LN on renal and patient survival, and on the associated intra-renal mechanisms pertaining to fibrosis.

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Table of Contents Acknowledgement .................................................................................................................... 7 Declaration................................................................................................................................ 8 Contributions to medical literature ........................................................................................ 9 Abbreviations ......................................................................................................................... 11 List of Figures and Illustrations ........................................................................................... 14 List of Tables .......................................................................................................................... 17 CHAPTER

I.

BACKGROUND

AND

LITERATURE

REVIEW:

CLINICAL

MANIFESTATION, PATHOLOGY AND PATHOGENESIS OF LUPUS NEPHRITIS .................................................................................................................................................. 19 1.1. Epidemiology and clinical manifestations of lupus nephritis .................................................... 20 1.1.1.

Epidemiology of systemic lupus erythematosus and lupus nephritis .............................. 20

1.1.2. Clinical manifestations of lupus nephritis ........................................................................... 24 1.2. Overview of different classes of lupus nephritis and their clinico-pathological correlations .... 25 1.2.1. Histopathological classifications of lupus nephritis - the WHO vs. ISN/RPS 2003 classifications ................................................................................................................................ 25 1.2.2. Clinico-pathological correlation and outcomes according to different classes of lupus nephritis......................................................................................................................................... 29 1.3. Pathogenesis of systemic lupus erythematosus and lupus nephritis .......................................... 32 1.3.1. Role of genetic factors ........................................................................................................ 32 1.3.2. Role of cytokines ................................................................................................................ 34 1.3.3. Role of T- and B-lymphocytes ............................................................................................ 37 1.3.4. Role of autoantibodies ........................................................................................................ 39 4

1.3.5. Mechanism of inflammation and fibrosis in lupus nephritis ............................................... 42 1.3.6. Animal model for the study of lupus nephritis.................................................................... 46 1.4. Aims and significance of thesis ................................................................................................. 49

CHAPTER II. FACTORS THAT AFFECT RENAL AND PATIENT SURVIVAL IN LUPUS NEPHRITIS – IMPACT OF CONVENTIONAL IMMUNOSUPPRESSIVE TREATMENT ........................................................................................................................ 50 2.1. Evolution of immunosuppressive treatment in lupus nephritis and the treatment outcomes ..... 51 2.1.1 Induction treatment for proliferative lupus nephritis ........................................................... 51 2.1.2. Maintenance treatment for proliferative lupus nephritis ..................................................... 58 2.1.3. Treatment for membranous lupus nephritis ........................................................................ 59 2.2. Survival analysis and causes of mortality in lupus nephritis patients ........................................ 61 2.2.1 Introduction .......................................................................................................................... 61 2.2.2. Patients and methods........................................................................................................... 62 2.2.3. Results ................................................................................................................................. 66 2.3. Long-term outcome of patients with proliferative lupus nephritis treated with corticosteroids and mycophenolate mofetil ............................................................................................................... 74 2.3.1. Introduction ......................................................................................................................... 74 2.3.2. Patients and Methods .......................................................................................................... 75 2.3.3. Results ................................................................................................................................. 79 2.4. Discussion .................................................................................................................................. 88 2.5. Conclusion ................................................................................................................................. 97

CHPATER III. EMERGING TREATMENTS FOR LUPUS NEPHRITIS AND DATA FROM ANIMAL STUDIES.................................................................................................. 98 5

3.1 Introduction ................................................................................................................................. 99 3.2. In vivo studies to compare the effect of mycophenolate mofetil and cyclophosphamide, together with methylprednisolone on clinical and histological parameters of lupus nephritis ....... 102 3.2.1. Introduction ....................................................................................................................... 102 3.2.2. Materials and methods ...................................................................................................... 104 3.2.3. Results ............................................................................................................................... 110 3.2.4. Discussion ......................................................................................................................... 114 3.2.5. Conclusion ........................................................................................................................ 118 3.3. Proliferation Signal Inhibitors as a novel treatment for lupus nephritis .................................. 129 3.3.1. Introduction ....................................................................................................................... 129 3.3.2. Patients and methods......................................................................................................... 131 3.3.3. Results ............................................................................................................................... 133 3.3.4. Discussion ......................................................................................................................... 135 3.3.5. Conclusion ........................................................................................................................ 137 3.4. Mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome ......................................................................................................................... 142 3.4.1. Introduction ....................................................................................................................... 142 3.4.2. Patient and methods .......................................................................................................... 145 3.4.3. Results ............................................................................................................................... 149 3.4.4. Discussion ......................................................................................................................... 151 3.4.5. Conclusion ........................................................................................................................ 156

CHAPTER IV. GENERAL DISCUSSION AND OVERALL CONCLUSION ............. 162 REFERENCES ..................................................................................................................... 174 6

Acknowledgement

This thesis is a research output stemmed from the concerted efforts of many colleagues in the department. I would like to take this opportunity to extend my heartfelt gratitude to them.

First of all, I would like to express my sincerest thanks to my supervisor Professor Chan Tak Mao. He had been my mentor since I commenced my Nephrology training. I am much indebted to this inspiring teacher who had significantly influenced my clinical practice, attitudes and research directions. Secondly, I would like to convey my heartiest appreciation to my co-supervisor Dr. Susan Yung, who has helped me through the animal studies and also the various aspects of this thesis. I would also like to acknowledge the members of the Nephrology team who have assisted me in the clinical studies and colleagues from other divisions who have given constructive advice and encouragement throughout the writing of this thesis.

Last but not least, I would also like to thank my family who had fostered me to become a responsible doctor and a keen researcher. Tremendous credits should be directed to my wife Maggie as well as my little daughter Giselle who had provided unconditional support and patience during the preparation of this thesis. Without their care and tolerance, this piece of work would have never been accomplished.

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Declaration

I declare that, except where specially stated in the acknowledgement, the studies mentioned in this thesis represent my own work and has not been submitted as an exercise for a degree in any other university or college.

Yap Yat Hin Desmond

8

Contributions to medical literature

Works from the studies presented in this thesis have been published or accepted for publication in the following peer-reviewed journals:

Original Publications 1.

Yap DY, Ma MK, Mok MM, Tang CS, Chan TM. Long-term data on corticosteroids and mycophenolate mofetil treatment in lupus nephritis. Rheumatology (Oxford) 2013; 52: 480-6.

2.

Yap DY, Ma MK, Tang SC, Chan TM. A preliminary experience of using Proliferation Signal Inhibitors (PSI) in lupus nephritis. Nephrology (Carlton) 2012; 17: 676-80.

3.

Yap DY, Tang SC, Ma MK, Lam MF, Chan TM. Survival analysis and causes of mortality in patients with lupus nephritis. Nephrol Dial Transplant 2012; 27: 3248-54.

4.

Yap DY, Tang SC, Chan TM. A pilot 24-month study to compare mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome. Nephrology (Carlton) 2012; 17: 352-7.

5.

Mok CC, Yap DY*, Navarra SV, Liu ZH, Zhao MH, Lu L, Takeuchi T, Avihingsanon Y, Yu XQ, Lapid EA, Lugue-Lizardo LR, Sumethkul V, Shen N, Chen SL, Chan TM; Asian Lupus Nephritis Network (ALNN). Overview of Lupus Nephritis Management Guidelines and Perspective from Asia. Nephrology (Carlton) 2013 [Epub ahead of print] (*co-first author)

Works from the studies presented in this thesis have also been presented in abstract form in the following international conferences:

9

1.

Yap DY, Ma MK. Mok MM, Chan TM. Long term outcomes of lupus nephritis patients treated with corticosteroids and mycophenolate mofetil. [Abstract presented at the American Society of Nephrology Kidney Week 2012]

2.

Yap DY, Tang CS, Ma MK, Tse KC, Lam MF, Chan TM. Causes of death in patients with severe lupus nephritis. [Abstract presented at 12th Asian Pacific Congress of Nephrology, Seoul, June 2011]

3.

Yap DY, Tang CS, Ma MK, Tse KC, Lam MF, Chan TM. Survival and mortality in patients with lupus nephritis. [Abstract presented at 9th International Congress of Systemic Lupus Nephritis, Vancouver, June 2010]

10

Abbreviations

ACR

American College of Rheumatology

AZA

Azathioprine

BANK1

B-cell scaffold protein with ankyrin repeats 1

BLK

B-lymphoid tyrosine kinase

BLys

B-Lymphocyte Stimulator

BMP7

Bone morphogenetic protein 7

CNI

Calcineurin inhibitors

CR

Complete remission

CTX

Cyclophosphamide

CYA

Cyclosporin A

DNASE1

Deoxyribonuclease 1

DPLN

Diffuse proliferative lupus nephritis

EMT

Epithelial-to-mesenchymal transition

ESRD

End stage renal disease

EULAR

European League Against Rheumatism

FASL

Fas Ligand

FCGR

Fc fragment of IgG low affinity receptor

FSP-1

Fibroblast specific protein 1

GWAS

Genome wide association study

HCQ

Hydroxychloroquine

HGF

Hepatocyte growth factor

HLA

Human leukocyte antigen

IFN

Interferon 11

IL

Interleukin

IMPDH

Inosine monophosphate dehydrogenase

IRF5

Interferon regulator factor 5

ISN

International Society of Nephrology

ITGAM

Integrin alpha M

KDIGO

Kidney Disease: Improving Global Outcomes

LN

Lupus nephritis

MLN

Membranous lupus nephritis

MMF

Mycophenolate mofetil

MMP-2

Matrix-metalloproteinase 2

MP

Methylprednisolone

PAI-1

Plasminogen activator inhibitor-1

PDCD1

Programmed cell death 1

PR

Partial remission

PSI

Proliferation signal inhibitors

PTEC

Proximal tubular epithelial cells

PTPN22

Protein tyrosine phosphatase non-receptor type 22

RPS

Royal Pathology Society

SLE

Systemic lupus erythematosus

SLEDAI

Systemic lupus erythematosus disease activity index

SMR

Standardized mortality ratio

STAT4

Signal transducer and activator of transcription 4

TAC

Tacrolimus

TGF-

Transforming growth factor-beta

TNF-

Tumor necrosis factor-alpha 12

TNFRSF6

Tumor necrosis factor receptor superfamily member 6

TREX1

Three prime repair exonuclease 1

VEGF

Vascular endothelial growth factor

WHO

World Health Organization

13

List of Figures and Illustrations

Figure 1.1. Prevalence of SLE in different Asian countries. .............................. 22 Figure 1.2. Schematic diagram showing the pathogenesis of lupus nephritis. . 34 Figure 1.3. Schematic diagram showing the interaction between various immune cells and cytokines involved in the pathogenesis of SLE. ............ 37 Figure 1.4. Schematic diagram showing possible mechanisms through which anti-dsDNA antibodies bind to the glomerular basement membrane and resident renal cells.......................................................................................... 41 Figure 1.5. Schematic diagram showing the cellular events in the pathogenesis of renal fibrosis. .............................................................................................. 42

Figure 2.1. Histological classes of 230 Chinese patients with lupus nephritis. . 70 Figure 2.2. Kaplan-Meier plot of patient survival in 230 Chinese patients with lupus nephritis. ............................................................................................... 71 Figure 2.3. The causes of mortality in 230 Chinese patients with lupus nephritis. .......................................................................................................................... 72 Figure 2.4. (A) Kaplan-Meier plot of renal survival in 230 patients with lupus nephritis. (B) Kaplan-Meier plot of renal survival in patients with Class III/IV lupus nephritis +/- membranous features vs. Class V lupus nephritis. .......................................................................................................................... 73 Figure 2.5. Renal survival (A) and patient survival (B) in 65 proliferative lupus nephritis patients treated with prednisolone and MMF as induction then maintenance immunosuppression. ............................................................... 85

14

Figure 2.6. Longitudinal data on serum creatinine (A), estimated glomerular filtration rate (B), proteinuria (C) and anti-dsDNA (D) in 65 proliferative lupus nephritis patients who received prednisolone and MMF as induction then maintenance immunosuppressive treatment. ..................................... 86 Figure 2.7. Relapse-free survival and the impact of MMF treatment duration in patients with proliferative lupus nephritis treated with prednisolone and MMF continuously from the induction phase to the long-term maintenance phase. ............................................................................................................... 87

Figure 3.1. Overall survival of NZB/W F1 mice with or without immunosuppressive treatment. ................................................................... 119 Figure 3.2. Serum urea levels of NZB/W F1 mice with or without immunosuppressive treatment. ................................................................... 120 Figure 3.3. Serum creatinine levels of NZB/W F1 mice with or without immunosuppressive treatment. ................................................................... 121 Figure 3.4. Urine albumin-to-creatinine ratio (ACR) of NZB/W F1 mice with or without immunosuppressive treatment. ..................................................... 122 Figure 3.5. The serum anti-DNA antibodies level of NZB/W F1 mice with or without immunosuppressive treatment. ..................................................... 123 Figure 3.6. Histologic changes in renal specimens obtained from NZB/W F1 mice with or without immunosuppressive treatment. .............................. 124 Figure 3.7. Expression of BMP7 in renal specimens obtained from NZB/W F1 mice with or without immunosuppressive treatment. .............................. 125 Figure 3.8. Expression of HGF in renal specimens obtained from NZB/W F mice with or without immunosuppressive treatment. .............................. 126 15

Figure 3.9. Expression of VEGF in renal specimen obtained from NZB/W F1 mice with or without immunosuppressive treatment. .............................. 127 Figure 3.10. Vascular expression of VEGF obtained from renal specimens from NZB/W F1 mice with or without immunosuppressive treatment. ........... 128 Figure 3.11. Longitudinal profile of proteinuria, serum albumin (A) and serum creatinine (B) in 16 patients with MLN and nephrotic range proteinuria at baseline randomized to treatment with Pred+MMF (n=7) or Pred+TAC (n=9) .............................................................................................................. 161

16

List of Tables

Table 1.1. Risk factors for progressive renal failure in lupus nephritis. ........... 23 Table 1.2. Predictors for remission in patients with lupus nephritis ................. 23 Table 1.3. Predictors for relapse in lupus nephritis. ........................................... 24 Table 1.4. Original WHO classification of lupus nephritis (1974). .................... 26 Table 1.5. Modified WHO classification of lupus nephritis (1982; modified in 1995) ................................................................................................................ 27 Table 1.6. International Society of Nephrology/Royal Pathology Society (ISN/RPS) classification of Lupus Nephritis (2003) .................................... 28

Table 2.1. KDIGO guidelines for the initial treatment of proliferative lupus nephritis. ......................................................................................................... 53 Table 2.2. Baseline characteristics of 230 Chinese patients with lupus nephritis. .......................................................................................................................... 68 Table 2.3. Causes of mortality according to the era of diagnosis in 230 Chinese patients with lupus nephritis. ........................................................................ 69 Table 2.4. Baseline characteristics of 65 proliferative lupus nephritis patients treated with corticosteroids and MMF as induction and maintenance immunosuppression. ...................................................................................... 83 Table 2.5. Adverse events experienced by 65 proliferative lupus nephritis patients while on maintenance treatment with MMF, AZA or CNI. ......... 84

Table 3.1. Baseline characteristics of lupus nephritis patients who have been 17

treated with Proliferation Signal Inhibitors (PSI) for induction therapy (A) or maintenance immunosuppression (B). .................................................. 138 Table 3.2. Longitudinal laboratory data in five* lupus nephritis patients treated with Proliferation Signal Inhibitors (PSI) as induction therapy (A) or maintenance immunosuppression (B). ....................................................... 140 Table 3.3. Longitudinal lipid profile of five lupus nephritis patients treated with Proliferation Signal Inhibitors (PSI) as induction (A) or maintenance immunosuppression (B). .............................................................................. 141 Table 3.4. Baseline characteristics of 16 patients with MLN and nephrotic range proteinuria randomized to treatment with Pred+MMF (n=7) or Pred+TAC (n=9). ............................................................................................................. 157 Table 3.5. Achieved MMF dose and trough TAC blood level in 16 patients with MLN and nephrotic range proteinuria treated with Pred+MMF (n=7) or Pred+TAC (n=9) ........................................................................................... 158 Table 3.6. Outcome of 16 patients with MLN and nephrotic range proteinuria after treatment with Pred+MMF (n=7) or Pred+TAC (n=9) for 24 months. ........................................................................................................................ 159 Table 3.7. Adverse events in 16 patients with MLN and nephrotic range proteinuria treated with Pred+MMF (n=7) or Pred+TAC (n=9). ........... 160

18

CHAPTER I. BACKGROUND AND LITERATURE REVIEW:

CLINICAL MANIFESTATION, PATHOLOGY AND PATHOGENESIS

OF LUPUS NEPHRITIS

19

1.1. Epidemiology and clinical manifestations of lupus nephritis

1.1.1. Epidemiology of systemic lupus erythematosus and lupus nephritis

Systemic lupus erythematosus (SLE) is a severe autoimmune disorder characterized by immunological abnormalities leading to multi-system dysfunction. The incidence, prevalence, disease activity and prognosis of SLE vary between ethnicities (Danchenko et al. 2006; Osio-Salido and Manapat-Reyes 2010; Jakes et al. 2012). For instance, a higher prevalence was observed in patients of Afro-American and Asian descendants than the Caucasians (Johnson et al. 1995; Feng 2007). The prevalence of SLE in Asia ranges between 50 to 100 per million population and hence confers a significant disease burden in this locality (Feng 2007) (Figure 1). In Hong Kong, the prevalence and annual incidence of SLE are estimated to be 0.1% and 6.7 per 100,000 populations respectively (Mok 2011).

The survival of SLE patients is influenced by medical factors such as the extent of organ involvement, efficacy and toxicities of immunosuppressive therapy, timing of diagnosis and proper management of treatment-related complications as well as non-medical factors such as ethnicity, educational level, and socio-economic status (Kaslow and Masi 1978; Kaslow 1982; Ward 2004). Survival analysis published over the past few decades have shown an overall trend of improvement in patient survival, most notably in the reduction of early mortality, while excessive mortality compared with the general population was still observed (Bernatsky S 2006; Urowitz et al. 2008). Data from the 1970s to 1980s showed that SLE was associated with substantial mortality in Asian countries and the 5-year patient survival rates were only 60-70% (Feng 2007). With progress in the immunosuppressive therapy and supportive medical care, recent series in Europe, USA and Asia had reported significant 20

progress in the long-term survival of SLE patients, with 10-year patient survival rates up to 80-90% (Cervera et al. 2003; Kasitanon N 2006; Mok 2011).

Among the various clinical presentations of SLE, lupus nephritis (LN) is one of the most common and severe organ manifestations. Renal involvement occurs in over 60% of patients with SLE and contributes significantly to morbidity and mortality (Golbus and McCune 1994; Ward et al. 1996; Bomback and Appel 2010; Saxena et al. 2011). Asian SLE patients have higher rates of renal involvement (21-65% at diagnosis and 40-82% at follow-up) when compared to Caucasians (Jakes et al. 2012) and may also present with more severe nephritis than patients of other ethnic origins (Saxena et al. 2011). In SLE patients, renal damage confers negative impact on patient outcomes and many previous studies had identified the risk factors for progressive renal failure in LN (Berden 1997; Moroni et al. 2004) (Table 1.1). Among these risk factors, lack of remission and repeated relapse are coined as more crucial determinants for progressive renal insufficiency. In this context, previous studies have reported that Caucasians, older age at presentation, milder renal manifestations and early commencement of treatment (50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) when >50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft IV-S(A) or IV-G(G): Purely active lesions: diffuse segmental or global proliferative LN IV-S(A/C) or IV-G (A/C): Active and chronic lesions: diffuse segmental or global proliferative and sclerosing LN IV-S(C) or IV-G(C): Inactive with glomerular scars: diffuse segmental or global sclerosing LN

Class V

Membranous LN# Global or segmental subepithelial immune deposits or their morphologic sequelae by LM and by IF or EM, with or without mesangial alterations

Class VI

Advanced sclerosing LN >=90% of glomeruli globally sclerosed without residual activity

LM= Light microscopy; IF= immunofluorescence; EM= electron microscopy *

#

Indicate the proportion of glomeruli with active and with sclerotic lesions Indicate the proportion of glomeruli with fibrinoid necrosis and with cellular crescents Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions May occur in combination with III or IV in which case both will be diagnosed, may show advanced sclerosis

28

1.2.2. Clinico-pathological correlation and outcomes according to different classes of lupus

nephritis

Serial biopsies and long-term follow-up of SLE patients indicate that the different classes of LN exhibit distinct natural history and clinical patterns, and that transformation from one major class to another can occur. Due to historical reasons, many data regarding the clinico-pathological correlations of different classes of LN were referenced to the WHO classifications. The following discussion reviewed the clinic-pathological correlations and outcomes of different classes of LN.

ISN/RPS Class I and II lupus nephritis ISN/RPS class I or II LN patients run similar clinical courses and outcomes. Patients with class I LN (minimal mesangial LN) usually have subclinical disease. Likewise, class II LN (mesangial proliferative LN) is also infrequently associated with overt renal disorder, and usually have inactive urinary sediments (Appel et al. 1978; Appel et al. 1987; Berden 1997; Cameron 1999). Proteinuria is generally mild and seldom exceeds 1g/day. Unless they transformed into the proliferative forms, patients with class I or II LN usually have favorable renal prognosis. In some rare cases, patients may behave like minimal change nephropathy and this entity is now coined as “lupus podocytopathy” (Dube et al. 2002; Hertig et al. 2002; Kraft et al. 2005). Typically, these patients present with sudden onset of heavy proteinuria and renal biopsy reveals findings of class I or II LN with marked podocyte effacement on electron microscopy. These patients may have repeated relapses of nephrotic syndrome. The exact pathogenic mechanism of this disease entity remained obscure. Similar to minimal change nephropathy, patients with lupus podocytopathy respond favorably to corticosteroids.

29

ISN/RPS Class III and IV lupus nephritis The clinical manifestations of ISN/RPS Class III (focal proliferative) and Class IV (diffuse proliferative) LN are often indistinguishable. In the WHO classification, some authors have suggested that pathogenetic heterogeneities exist between Class III (>50%) and IV LN due to their difference in histological findings and serological abnormalities (Najafi et al. 2001; Schwartz et al. 2008). WHO Class III (>50%) LN shows severe focal segmental lesions similar to those seen with vasculitis, has less glomerular immune deposits and relatively higher serum complement levels, while the abundance of glomerular immune deposition and depressed serum complements level suggest a more immune complex-mediated mechanism in WHO Class IV LN. However, the difference between Class III and IV LN in ISN/RPS histological classification is determined by the percentage of glomeruli involved, and such distinction is quantitative rather than qualitative and is prone to sampling errors. Therefore, in clinical practice, patients with Class III or IV are often managed quite similarly. Patients with Class III or IV LN usually have proteinuria with active urinary sediment and serological activity, coupled with variable degree of renal dysfunction. The clinical course of Class III LN can be quite protean. Patients with mild proliferation involving a small percentage of the glomeruli on their biopsies have favorable outcomes and 1 g/day, or deteriorating renal function. Re-biopsies were performed in most, but not all, subsequent renal flares. Histological classification of biopsy findings was based on the 1982 WHO classification for LN until 2004, when the ISN/RPS classification was adopted (Weening et al. 2004). Biopsy performed before 1982 were reviewed by the same renal pathologist and re-classified according to the ISN/RPS 2003 classifications.

In the late 1960s and 1970s, patients with active LN were treated with high dose corticosteroids with or without AZA. Standard immunosuppressive treatment protocols were adopted since the late 1980s. Patients with Class III (focal proliferative) or Class IV (diffuse proliferative) LN were given induction immunosuppressive treatment that comprised corticosteroids with either CTX or MMF for six months, followed by low-dose prednisolone combined with either AZA or MMF as long-term maintenance immunosuppression. Mixed 62

Class III+V or Class IV+V LN were treated as for Class III or IV LN respectively. Patients with pure Class V LN and proteinuria 2g/day were given initial immunosuppression as for Class IV LN for six months and those with persistent proteinuria >2g/day were treated with low-dose prednisolone and TAC. Class II (mesangial) LN was treated with prednisolone 30 mg/d, which was then tapered gradually, with or without AZA for steroid-sparing.

Dyslipidemia was managed with dietary control before HMG CoA-reductase inhibitors were available in our centre in 1988. After 1988, management was in accordance with the National Cholesterol Education Program, Adult Treatment Panel (NCEP-ATP) guidelines [NCEP-ATP I: 1988-92; NCEP-ATP II: 1993-2001]. From 2002, the NCEP-ATP III guidelines (LDL 1g/day were prescribed angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers prior to the addition of CNI. The target systolic and diastolic blood pressure was 110-130 mmHg and 70-85 mmHg respectively.

Patients were followed at 2- to 14-week intervals depending on their clinical status. Any clinically significant events and adverse reactions to medications were documented during each clinic visit. The blood pressure, pulse rate, urine dipstick results, complete blood counts, renal and liver function tests, anti-dsDNA, complement levels and urinalysis were also monitored during every outpatient visit. Anti-dsDNA titre was determined with an in-house ELISA and complement levels were measured by nephelometric methods (Synchron LXR, Beckman Coulter, USA). Urinary protein excretion, fasting sugar and lipid profile were assessed at 6-month intervals.

Study outcomes The primary objective was to evaluate the long-term renal outcomes, including renal survival (i.e. free from endstage renal failure), serum creatinine levels, and doubling of baseline serum creatinine. Other parameters examined included disease flares, patient survival and tolerability profile. Complete response was defined as decrease in urine protein excretion to 0.5 to 1g/day and/or rise in serum creatinine by >15% compared with baseline that was not explained by other factors such as drug nephrotoxicity, with or without serological activity, and with histological confirmation. Extra-renal flare referred to a measurable increase in disease activity in organ systems other than the kidney, involving new or worsened clinical findings and laboratory measurements that are clinically significant and required change of treatment (Ruperto et al. 2011). Patients with Class III or IV LN relapse received another course of corticosteroids and MMF induction as stated previously. Treatment of extra-renal flares was according to the local standard of care, mostly with an escalation of prednisolone. The glomerular filtration rate was estimated with the MDRD (Modification of Diet in Renal Disease Study) equation validated in Chinese patients (Ma et al. 2006).

Statistical analysis Continuous variables were expressed as mean ± standard deviations unless otherwise specified and compared by t-test or Mann-Whitney U test where appropriate. Categorical variables were compared by Pearson χ2 test or Fisher exact test. Relapse-free survival was estimated by Cox-regression models while the patient and renal survival rates were assessed by actuarial analysis and compared by log rank test. Proportionality assumption was tested by plotting log [-log (survival function)] against time (Parmar and Machin 1995). Mixed models analysis was employed to detect time effect and the significance of between-group difference for each of the continuous variable with repeated measures over time (Latour et al. 1996). This method has the advantage of handling missing values. Between-group difference of least squares means was computed for each parameter. Akaike’s information criterion was used to 77

assess the model fitness (Littell et al. 1996; McQuarrie and Tsai 1998). All statistical analyses were performed with PASW for Windows 18.0 (SPSS Inc, Chico, IL) and two sided p

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