Current status of lupus nephritis

Introduction

Systemic lupus erythematosus (SLE) is a chronic, debilitating autoimmune disorder that involves multiple organ systems either simultaneously or sequentially with relapsing and remitting course. The word lupus is a Latin term which means wolf. 'Lupus' has been used since the middle ages by the Romans to describe the ulcerative lesions of the skin in lupus patients, which resemble to those caused by a wolf bite. William Osler first described nephritis as a component of SLE1. Lupus nephritis (LN) is one of the common complications in patients with SLE and influences overall outcome of these patients. About two-thirds of patients with SLE have renal disease at some stage which is a leading cause of mortality in these patients2. Manifestations of LN vary from asymptomatic urinary abnormalities to rapidly progressive crescentic glomerulonephritis to end-stage renal disease (ESRD). Multiple randomized controlled trials (RCTs) have been conducted worldwide which have added evidence to therapeutic armamentarium with improved patient outcome and reduced drug toxicity. The low-dose intravenous (iv) cyclophosphamide (CYC) as induction agent followed by azathioprine (AZA) as maintenance therapy especially in less severe LN is outcome of studies conducted in Europe and India345. The equal outcomes with mycophenolate and CYC even in severe LN have broadened the choice for clinician in managing patients with severe LN6.

Classification criteria for systemic lupus erythematosus

The diagnosis of SLE is clinically supported by serology and histopathology. In the absence of diagnostic criteria, clinicians use classification criteria proposed by various research organizations from time to time to appropriately manage these patients. The American College of Rheumatology (ACR) revised classification criteria for SLE published in 19827 and subsequently revised in 19978 (Table I) have been in widespread use. Although in clinical use for over a decade, the 1997 criteria have not been validated unlike 19829 criteria and have a few shortcomings, such as duplication of terms for cutaneous lupus (malar rash and photosensitivity) and omission of other lupus manifestations such as myelitis and biopsy proven LN. To address these shortcomings, the Systemic Lupus International Collaborating Clinics (SLICC) (an international group of SLE researchers) developed and validated new classification criteria9. A total of 17 criteria were identified. The SLICC (Table 1) criteria for SLE classification requires (i) fulfilment of at least four criteria, with at least one clinical criterion and one immunologic criterion or (ii) the presence of LN with positive antinuclear antibody (ANA) or anti-double-stranded DNA (dsDNA) antibodies. In the validation set, the SLICC Classification criteria resulted in fewer misclassifications and had greater sensitivity but less specificity9. Amezcua-Guerra et al10 compared 1997 ACR and 2012 SLICC criteria and found their performance similar in uncontrolled life scenario.

Table I American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinic (SLICC) criteria for systemic lupus erythematosus

Pathogenesis of systemic lupus erythematosus and lupus nephritis

The pathogenesis of SLE and LN is a result of interplay of multiple factors, notably genetic, epigenetic and environmental factors. It is characterized by loss of self-tolerance which leads to polyclonal antibody activation classically manifesting as positive ANA and full-house pattern on immunofluorescence in renal biopsy specimen1112. In the early stage of disease, innate immune system activates T-cells and activators of B-cells which all lead to activation of adaptive immune response11. T-cells including type 1 T-helper (T_H1) cells and T_H17 drive the systemic and intra-renal activation of B-cells1314. B-cells after activation by either T-cells or innate immune system generate various autoantibodies and cytokines15. More than 10 genome-wide association studies (GWAS) conducted so far in multiple ethnicities to identify genetic loci linked with SLE have collectively identified >50 genes associated with SLE. It also includes patients with LN16. Some of these genes breach immune tolerance and produce autoantibodies such as anti-dsDNA, which might act along with genes that augment innate immune signalling to generate effector leucocytes and release of inflammatory mediators and other autoantibodies that together initiate renal assault1718. The genes implicated in genesis of LN include B lymphoid tyrosine kinase (BLK), human leucocyte antigen-antigen D related (HLA-DR), Signal Transducer and Activator of Transcription 4(STAT4) and toll-like receptor 9 (TLR9)1819.

Lupus nephritis definition and classification

The ACR lupus classification criteria define LN by proteinuria >0.5 g/day or a urinary protein/creatinine ratio (UPCR) of >0.5 or urinary protein greater than 3+ by dipstick analysis or urinary cellular casts of more than five cells per high-power field (in the absence of urinary tract infection)8. The term LN encompasses diverse patterns of renal injury encountered in patients of SLE, through immune-mediated mechanism20. Besides an immune complex-mediated glomerular disease, most patients often have tubulointerstitial and vascular changes such as fibrinoid necrosis and thrombotic microangiopathy (TMA)21. The World Health Organization (WHO) in 1974 gave classification of LN based entirely on glomerular lesions, and subsequently, it underwent repeated transformations till we had the most accepted classification given by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS)2022. The most significant outcome of ISN/RPS classification was high inter and intra-observer reproducibility with flipside being its failure to give adequate representation to extraglomerular lupus lesions. The extraglomerular lesions of LN are caused by immune- and non-immune-mediated mechanisms and significantly influence disease outcome. Lupus podocytopathy is a recently described entity, seen in the subset of patients of lupus presenting with nephrotic syndrome, with kidney biopsy showing only mild mesangial expansion without peripheral capillary wall immune deposits. The pathophysiology of nephrotic syndrome here is based on fusion of foot processes of glomerular visceral epithelial cells as seen in minimal change disease (MCD). In a large cohort study of 3750 kidney biopsies of LN patients, lupus podocytopathy was found in 1.33 per cent biopsies23.

Role of kidney biopsy in lupus nephritis

Despite the presence of clinical criteria, LN remains a histopathological diagnosis. The kidney biopsy provides an unequivocal diagnosis of LN. It provides evidence for disease prognosis, activity, chronicity and planning of therapy. As the therapy of LN consists of potentially toxic drugs, it may be harmful to venture into the treatment without definitive diagnosis. A given patient of SLE with features suggestive of renal involvement may have extraglomerular features of SLE such as TMA or non-lupus renal disease or drug-induced interstitial nephritis all with different management and outcomes. Hence, kidney biopsy is considered sine qua non in the management of LN. The usual indications for performing the first kidney biopsy are proteinuria >500 mg/day, active urine sediment (≥5 red blood cells or white blood cells per high-power field, mostly dysmorphic without evidence of infection) or rising serum creatinine242526. The current approach to treating LN and studying new therapeutic modalities is largely guided by ISN/RPS, classification (Table II).

Table II International Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification of lupus nephritis (LN)

Drugs used in treatment of lupus nephritis

Evidence-based treatment for lupus nephritis

Guidelines developed by organizations such as the Kidney Disease: Improving Global Outcome (KDIGO), ACR and the European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) are important and handy to use242526. Overall, immunosuppressive treatment should be guided by renal biopsy, and treatment aimed at complete renal response (proteinuria <0.5 g/24 h with normal or near normal renal function). According to ISN/RPS classification of LN22, Class I, Class II (with proteinuria <3 g/day) and Class VI LN do not need any treatment from renal point of view but should be treated as per extrarenal indications. All these major guidelines advise immunosuppression with either CYC or MMF combined with steroids in Class III/IV LN. ACR guidelines25 advocate to prefer MMF in Class III/IV LN, especially in African Americans and Hispanics. The KDIGO24 and EULAR26 guidelines advise dose target for MMF of 3 g/day, whereas ACR recommends 3 g/day for non-Asians and 2 g/day for Asians. Euro lupus regimen is recommended as alternate to MMF by EULAR/ERA-EDTA in severe LN, whereas ACR recommends Euro lupus regimen in patients of European descent. Both ACR and EULAR/ERA-EDTA recommend the use of steroids plus MMF in Class V LN with nephrotic range proteinuria whereas KDIGO recommends to choose any of CYC/MMF/AZA/CNI along with steroids in Class V LN. Steroids as per MCD are advised for the treatment of lupus podocytopathy, which has ultra-structural homology with MCD. There is evidence to use either of MMF or CYC in severe/crescentic LN, albeit with longer experience for later agent. The treatment of LN is summarized in Table III.

Table III Suggested algorithm of treatment of lupus nephritis (LN)

Refractory and relapsing lupus nephritis

Despite the use of aggressive immunosuppression, a few patients of LN may not respond. Around 20-70 per cent of patients with LN are reported to be resistant to first-line immunosuppressive therapy84. There is no uniformly accepted definition for resistant/refractory LN. According to EULAR/ERA-EDTA26, changing to an alternative drug is recommended for the patients who do not achieve partial response after 6-12 months, or complete response after two years of treatment. It is also suggested to switch to an alternative agent if there are signs of deterioration in the very early course of therapy. Such an alternative agent could be RTX alone or in combination with other immunosuppression or any one of the extended courses of CYC or CNI or plasmapheresis or multitarget therapy84. LN is a relapsing disease. Renal relapse/flare is defined by return of active urine sediment or proteinuria more than 0.5 g/day or worsening serum creatinine. The average rate of renal relapse after reduction or cessation of immunosuppression varies from 5 to 15/100 patient years, in different series within first five years of attaining remission85. Relapses should be treated with the same induction agent that was effective on previous occasion unless contraindicated (high dose CYC) and to consider repeat renal biopsy if there is uncertainty about diagnosis or chronicity of disease.

Treatment of LN should be continued up to one year after complete remission before tapering it off. According to KDIGO24, serial measurements of proteinuria and serum creatinine are most important biomarkers to monitor progress of LN, and resolution of proteinuria is most important predictor of kidney survival. Besides this, during each visit, patients should be regularly monitored for body weight, blood pressure, estimated glomerular filtration rate (GFR), serum albumin, urinary sediment, serum C3 and C4, serum anti-dsDNA antibody levels and complete blood cell count. Patients should be initially followed up every 2-4 wk for 3-6 months and then every 3-6 months for the rest of life. Antiphospholipid antibodies and lipid profile should be measured at baseline and then periodically. Clinically lupus can either be in a chronic, quiescent or a relapse/flare. EULAR task force advises to use any of the available lupus disease indices such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the British Isles Lupus Assessment Group scale, the Safety of Estrogen in Lupus Erythematosus - National Assessment - SLEDAI, the European Consensus Lupus Activity Measure (ECLAM) or the Systemic Lupus Activity Measure (SLAM) to monitor lupus disease activity.

Ancillary treatment in lupus nephritis

According to KDIGO24 and EULAR/ERA-EDTA26, all patients with LN should receive HCQ unless contraindicated. According to EULAR/ERA-EDTA, all patients with LN should receive ACE/ARB if UPCR >50 mg/mmol or hypertensive, statins if low-density lipoprotein cholesterol (LDL-C) >100 mg/dl, acetyl-salicylic acid if positive for antiphospholipid antibodies, oral anticoagulant if antiphospholipid antibody syndrome (APLAS) or nephrotic syndrome with serum albumin <2 g/dl. Patients should also be vaccinated with non-live vaccine as appropriate for risk and age. They should also receive supplement of calcium and vitamin D with continuous vigil for metabolic bone disease. Patients with LN and TMA or diffuse alveolar haemorrhage should receive plasmapheresis. Sun exposure mainly ultraviolet light (UV) is a well-known factor leading to flare of cutaneous lupus; however, sun exposure has also been found to be associated with exacerbation of non-cutaneous lupus including LN in various anecdotal reports86. The proposed mechanism for such a phenomenon is increased breakdown of epidermal DNA by exposure to UV light which enhances its antigenicity leading to more antibody formation and immune-mediated organ damage. Hence, people with LN are also advised sun protection in the form of sunscreens, wide-brimmed hats and full-sleeved shirts.

Antiphospholipid antibody syndrome (APLAS) and lupus nephritis

APLAS is characterized by the presence of antiphospholipid antibodies, recurrent thrombotic events and/or foetal loss. Patients with SLE have considerably higher thrombotic events than the general population. The major contributor for pro-thrombotic state in SLE is antiphospholipid antibodies; however, other traditional factors such as hyperlipidaemia, ageing, diabetes, hypertension, smoking, male sex, disease activity and drugs such as corticosteroids also add, initiate or propagate the pro-thrombotic state of SLE24. SLE is the most common cause of APLAS. The antiphospholipid syndrome nephropathy (APSN) is a classical feature of renal involvement with APLAS and it is characterized by microthrombi in acute phase followed by evidence of recanalization and fibrous intimal hyperplasia in chronic APSN. APSN can occur in patients with SLE with or without LN. The presence of aPL antibodies is associated with worse renal outcomes. Similarly, around 20-30 per cent of patients with SLE have histopathological lesions consistent with APSN. The biopsy diagnosis becomes necessary in such a scenario as treatment of APSN is anticoagulation whereas LN will require immunosuppression26.

Pregnancy in lupus nephritis

SLE most commonly affects women in their childbearing age. Pregnancy in lupus is associated with increased risk of preeclampsia, premature labour, thromboembolic events, infections, increased haematological and LN flare in mother and increased risk of intrauterine growth retardation, neonatal lupus and preterm birth87. The presence of Ro and La antibodies is associated with increased risk of congenital heart block (CHB) and requires frequent surveillance in pregnancy. The CHB usually develops during 18-24 wk of gestation87. According to EULAR/ERA-EDTA and KDIGO, pregnancy may be planned in stable patients with inactive lupus and UPCR <50 mg/mmol, for the preceding six-months, with GFR that should preferably be >50 ml/min. Drugs such as CYC, MMF, ACEI and ARB should not be used in pregnancy. Acceptable drugs during pregnancy are HCQ, low-dose prednisone, AZA and CNI. The treatment should not be reduced in preconception period and during pregnancy. The patient should be continuously followed up every four weeks in the first half of pregnancy and then every 1-2 wk during latter half of pregnancy. Acetylsalicylic acid should be considered to reduce the risk of preeclampsia. The use of HCQ has been found helpful in reducing various maternal and foetal complications in pregnant lupus patients2426.

End-stage renal disease (ESRD) in lupus nephritis

Progression of LN to ESRD is usually associated with remission of extrarenal features of SLE in most of the patients88. Approximately 10-30 per cent of the patients with LN reach ESRD over 15 years despite aggressive treatment8990. According to the recent US data, the overall rates of ESRD in LN have stopped increasing over the last decade91. According to EULAR/ERA-EDATA26, the outcome of patients with LN-associated ESRD on haemodialysis (HD) or peritoneal dialysis is comparable, though HD is associated with vascular thrombosis-related complications, especially with antiphospholipid antibodies and increased rate of infections in later modality. Renal transplant offers the best rehabilitation for most lupus patients with ESRD91. The allograft survival rates in lupus and non-lupus transplant recipients are similar. Transplantation should be performed once lupus is quiescent, for at least six (3-12) months. The results are better for living-donor92 though those with antiphospholipid antibodies have a higher graft failure risk. Post-renal transplant recurrence of LN is uncommon (2-11%) and usually does not compromise long-term graft outcome26909293.

Conclusion

With the current treatment, LN has evolved from incurable to a disease which can be controlled with trade-off between improved outcomes and therapy-related adverse events. Objective criteria for renal biopsy assessment and their utilization for the treatment have made therapy almost similar worldwide though lupus is known to behave differently across races and ethnicities. Low-dose iv CYC or MMF has been suggested as an induction agent for proliferative LN along with tapering course of steroids. However, high-dose iv CYC or MMF may be preferred in patients with crescentic LN associated with loss of GFR. Target dose of MMF of 2 g/day during induction and 1g/day during maintenance may be adequate for patients of the Indian subcontinent. AZA and MMF have performed almost equally as maintenance agent, both in safety and efficacy outcome parameters in various studies across the globe. AZA has been suggested as maintenance agent as it offers advantage of being cheap and is safe for use in pregnancy. Multitarget therapy can be an option in patients with resistant LN. Biologicals, especially RTX although still off the shelf as induction agent, can be used for resistant LN. Overall, treatment has to be individualized, multidisciplinary and holistic to prevent loss of organ function. Still, we need new, safe and specific drugs and uniform disease and outcome-related definitions so that knowledge across the world can be put to an optimal use.