INTRODUCTION
Renal involvement is one of the most serious clinical manifestations of systemic lupus erythematosus (SLE), contributing significantly to overall morbidity and mortality. Its prevalence in lupus varies from 31% to 75%, typically presenting within the first year of SLE diagnosis. If present at SLE diagnosis, it is also a major predictor for future disease exacerbations. It has direct and indirect socioeconomic effects, as well as a significant impact on quality-of-life measures, due to both the disease itself and the side effects of therapies. It is important to recognize that lupus kidney disease has an extremely broad spectrum of clinical manifestations, and there is no single standard of care appropriate for all patients with lupus nephritis. Although more recent attempts at clarification of the various histologic patterns and clinical correlations provide useful guidelines in clinical decision-making, such characteristics can vary over time, requiring careful monitoring for progression, response to treatment, as well as complications of therapy.
A 26-year-old female executive presents with a faint malar rash, alopecia, arthralgias, and fevers of 2 months’ duration. Laboratory tests show mild anemia, leukopenia, 2+ proteinuria (1.2 g/day) with granular casts and dysmorphic erythrocytes, hypocomplementemia, high titers anti-nuclear antibody (ANA) and moderate titer anti-dsDNA. The 24-hour creatinine clearance and serial blood pressure determinations are normal.
CLINICAL PRESENTATION AND DIAGNOSIS
Renal involvement in lupus is highly variable and may occur as any or a combination of the following: occult or “silent,” active nephritis, nephrotic syndrome, rapidly progressive nephritis, and chronic kidney disease. This may follow a protracted course with periods of remissions and exacerbations, and tendency for worse prognosis in certain racial groups.
Because renal involvement in lupus is largely asymptomatic, it is important to specifically elicit symptoms such as foamy urine (proteinuria) and edema, and monitor closely for new-onset or worsening hypertension.
Laboratory Tests
Laboratory tests are used to assess the degree of glomerular inflammation and renal function. The urinalysis is the most important and cost-effective method to detect and monitor lupus nephritis. For accurate results, a fresh midstream clean-catch urine specimen, preferably the first morning urine sample, must be expeditiously processed and examined at the clinic or laboratory particularly for dipstick protein and sediments. Hematuria with dysmorphic erythrocytes ( Fig. 10-1 ) indicates inflammatory glomerular or tubulointerstitial disease, granular casts reflect proteinuria, cellular (red blood cell, white blood cell, mixed cellular) casts ( Fig. 10-2 ) reflect nephritic states, and broad and waxy casts reflect chronic renal damage. Serum creatinine alone crudely reflects renal function, and more precise evaluation should include estimation of glomerular filtration rate (GFR) by 24-hour creatinine clearance measurement, or calculating from formulas such as the traditional Cockroft-Gault, or the Modification of Diet in Renal Disease study formula, the latter being less precise but more closely approximating GFR changes in older subjects. Several clinical laboratories now routinely incorporate formula-based GFR estimates with serum creatinine values. Once a patient demonstrates significant proteinuria (>300–500 mg/day) or has a urinary dipstick proteinuria (+1 or greater), the measurement of the protein to creatinine (P/C) ratio should be performed on a random urine sample. Random urine P/C ratio is highly sensitive (92%–97%) and specific (87%–94%), and correlates well with 24-hour urinary protein. Because of diurnal variations, urinary P/C ratios obtained at certain timed collections (3–6 PM and 6 AM–6 PM) were shown to be more reliable than spot urine samples, and may be more convenient for the patient than a 24-hour collection.
Measurements of complement components are useful in evaluating the extent of glomerular inflammation. SLE patients with renal involvement were more frequently found to have markedly reduced serum levels of C3 and C4 than patients with extrarenal involvement only. Moreover, low C3 levels were predictive of persistently active glomerular disease and associated with progression to end-stage renal disease (ESRD). Detection of high titers anti-dsDNA is useful not only in the diagnosis of SLE, but also suggests high risk for renal disease flares, especially when associated with low levels of serum complement.
Levels of plasma and urinary cytokines or chemokines such as monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule-1, soluble tumor necrosis factor receptor-1 (sTNFR-1), osteoprotegerin, and neutrophil gelatinase-B– associated lipocalin (lipocalin-2) have been shown to correlate with renal disease activity and predict renal flares. Because they are noninvasive and relatively sensitive, these biomarkers provide an attractive tool for monitoring therapeutic response and are being explored for potential use in clinical practice.
Renal Biopsy
Renal biopsies rarely help in the diagnosis of lupus but are useful in determining the treatment choice and prognosis, especially when weighing the benefits versus risks of vigorous immunosuppressive therapy. The morphologic classification of SLE nephritis has evolved over the past 4 decades as more lesions were identified and defined, with the increasing challenge to make each classification and index relevant to clinical practice. The original 1974 World Health Organization (WHO) classification of lupus nephritis ( Table 10-1 ) has been modified and further supplemented by the development of activity and chronicity indices ( Table 10-2 ) of the National Institutes of Health. High activity scores are often reversible with aggressive treatment, whereas high chronicity scores reflect irreversible changes that lack response to immunosuppression. The most current International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification ( Table 10-3 ) incorporates and combines the basic elements of the WHO classification with the activity and chronicity indices and aims to standardize definitions, emphasize clinically relevant lesions, and encourage uniform and reproducible reporting among centers.
| Class | Description |
|---|---|
| Class I | Normal glomeruli (by light microscopy, immunofluorescence and electron microscopy) |
| Class II | Purely mesangial disease |
| Normocellular mesangium by light microscopy but mesangial deposits by immunofluorescence or electron microscopy | |
| Mesangial hypercellularity with mesangial deposits by immunofluorescence or electron microscopy | |
| Class III | Focal proliferative glomerulonephritis (< 50%) |
| Class IV | Diffuse proliferative glomerulonephritis (≥ 50%) |
| Class V | Membranous glomerulonephritis |
| ACTIVITY INDEX (maximum score 24 points) |
| Hypercellularity: endocapillary proliferation compromising glomerular capillary circulation * |
| Leukocyte exudation: polymorphonuclear leukocytes in glomeruli * |
| Karyorrhexis/fibrinoid necrosis (weighted ×2): necrotizing changes in glomeruli † |
| Cellular crescents (weighted ×2): layers of proliferating epithelial cells and monocytes lining Bowman’s capsule † |
| Hyaline deposits: eosinophilic materials lining (wire loops) or PAS-positive filling (hyaline thrombi) in capillary loops * |
| Interstitial inflammation: infiltration of leukocytes (predominantly mononuclear cells) among tubules * |
| CHRONICITY INDEX (maximum score 12 points) |
| Glomerular sclerosis: collapse and fibrosis of capillary tufts † |
| Fibrous crescents: layers of fibrous tissue lining Bowman’s capsule † |
| Tubular atrophy: thickening of tubular basement membranes, tubular epithelial degeneration, with separation of residual tubules * |
| Interstitial fibrosis: deposition of collagenous connective tissue among tubules * |
* Scored on a scale of 0 to 3 representing either absent, mild, moderate and severe lesions, respectively.
† Scored on a scale of 0 to 3 according to presence of lesions in none, <25%, 25-50%, and >50% of glomeruli, respectively.
| Class I | Minimal mesangial lupus nephritis |
| Normal glomeruli by light microscopy, with mesangial immune deposits by immunofluorescence | |
| Class II | Mesangial proliferative lupus nephritis |
| Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits. | |
| A few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy | |
| Class III | Focal lupus nephritis * |
| Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations | |
| Class III(A) | Active lesions: focal proliferative LN |
| Class III(A/C) | Active and chronic lesions: focal proliferative and sclerosing LN |
| Class III(C) | Chronic inactive lesions with glomerular scars: focal sclerosing LN |
| Class IV | Diffuse lupus nephritis † |
| Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) LN when ≥50% of involved glomeruli have segmental lesions, and diffuse global (IV-G) LN when ≥50% of involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft, and includes cases with diffuse wire loop deposits but with little or no glomerular proliferation | |
| Class IV-S(A) | Active lesions: diffuse segmental proliferative LN |
| Class IV-G(A) | Active lesions: diffuse global proliferative LN |
| Class IV-S(A/C) | Active and chronic lesions: diffuse segmental proliferative and sclerosing LN |
| Class IV-G(A/C) | Active and chronic lesions: diffuse global proliferative and sclerosing LN |
| Class IV-S(C) | Chronic inactive lesions with scars: diffuse segmental sclerosing LN |
| Class IV-G(C) | Chronic inactive lesions with scars: diffuse global sclerosing LN |
| Class V | Membranous lupus ephritis |
| Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations | |
| Class V LN may occur in combination with class III or IV in which case both will be diagnosed | |
| Class V LN show advanced sclerosis | |
| Class VI | Advanced sclerosis lupus nephritis |
| ≥ 90% of glomeruli globally sclerosed without residual activity |
* Indicate the proportion of glomeruli with active and with sclerotic lesions.
† Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents.
The usual indications for renal biopsy in lupus nephritis include unexplained hematuria, cellular casts or proteinuria (>0.5 to 1 g/day), or unexplained worsening of renal function. Renal biopsy is also indicated to establish the specific class and severity of lesions, which correlate to some degree with clinical findings and require different approaches to therapy. Patients with established clinical and laboratory evidence of lupus nephritis or nephrotic syndrome may not require a renal biopsy before treatment with cytotoxic drugs. On the other hand, patients with persistent clinically active disease despite previous immunosuppressive treatment may be candidates for renal biopsy.
The pathologist must provide an accurate and detailed description of all the biopsy findings by light microscopy, immunofluorescence and electron microscopy ( Fig. 10-3A to D ), with a summary diagnosis that includes the class (or classes) of lupus nephritis, and percentage of glomeruli with active and chronic lesions. The extent, severity and type of tubulointerstitial and vascular involvement should also be documented and graded. The renal biopsy findings must be interpreted by the clinician in the context of the patient’s clinical presentation, serologic findings and clinical course.
TREATMENT
General Approach
Current strategies for management of lupus nephritis include an induction phase intended to aggressively suppress glomerular inflammation and achieve disease remission, and a maintenance phase, which aims to consolidate and sustain the therapeutic effect. The main issue with the induction phase is the achievement of an effective therapeutic response, whereas the maintenance phase aims toward an acceptable balance between sustaining the therapeutic response and minimizing adverse effects of medications.
Corticosteroids
Corticosteroids, particularly in high doses, have remained the mainstay of therapy for active lupus nephritis. Although there have been no controlled clinical trials proving the benefit of corticosteroids over supportive therapy alone, widespread clinical experience has established its value, especially for active renal disease. For induction therapy or renal flares, it is used at a high daily dose, for example, prednisone 0.5 to 1.0 mg/kg/day, or as pulse intravenous therapy, for example, methylprednisolone 0.5 to 1.0 g/day for 1 to 3 days. The main limitation of corticosteroids consists of a waning of effectiveness over time, with side effects eventually outweighing benefits. Thus, it is common practice to combine corticosteroids with other “steroid-sparing” immunosuppressive regimens during the induction phase, especially for proliferative lupus nephritis. It is also important to prevent or minimize steroid side effects, which further contribute to morbidity, for example, calcium 1.2 g/day plus vitamin D 800 IU/d, bisphosphonates and teriparatide to prevent or treat glucocorticoid-induced osteoporosis (see Chapter 24 ).
Immunosuppressive Regimens
A meta-analysis of early trials showed that the addition of immunosuppressive drugs like cyclophosphamide (CY) or azathioprine (AZA) to corticosteroids lowered the risk of renal insufficiency and dialysis. Since then, effective immunosuppressive therapy has been established in several controlled clinical trials for lupus nephritis. Although most trials have been limited by diverse study variables such as small populations, racial mixtures, and short follow-up, these studies have provided the templates by which physicians make clinical decisions. It is not unusual practice to shift or combine the various regimens, because each management program has to be tailored for the individual patient.
Cyclophosphamide
Early studies have shown the superior efficacy of oral CY over corticosteroids alone in lupus nephritis. However, the higher risks of toxicity like hemorrhagic cystitis and bladder cancer has strongly favored the use of intravenous (IV) CY pulse over oral therapy.
The National Institutes of Health pulse CY regimen ( Table 10-4 ), established in a series of controlled trials over several decades, has provided the standard against which other regimens have been compared. In this regimen, IV-CY pulses are given monthly for 6 months, with the starting dose (0.75–1 g/m 2 ) increased to achieve a white blood cell count nadir between 1500/µL and 4000/µL on day 14. Hydration with forceful diuresis is required, and antiemetics are coadministered. Dexamethasone (oral or IV) or pulse IV methylprednisolone administered immediately before CY also has antiemetic effects. Mesna (20% of total CY dose) may be used to avoid bladder toxicity, especially in patients who cannot tolerate hyperhydration, and leuprolide acetate (3.75 mg subcutaneously 2 weeks before each CY dose) can be used to prevent ovarian failure (special precautions in patients with thrombotic diathesis), or testosterone (100 mg intramuscularly every 2 weeks) to prevent male infertility.
| Initial dose of cyclophosphamide (CY) | Administer 0.75 g/m 2 of body surface area (BSA) if glomerular filtration rate (GFR) is greater than one third of normal value, or 0.5 g/m 2 of BSA if GFR is less than one-third of normal value. |
| Administration of CY | Use 500 ml of 5% dextrose in 0.3% to 0.9% saline, and infuse 250 ml over 1 to 2 hours. To remaining 250 ml, incorporate CY and infuse over 1 to 2 hours. |
| Diuresis | Administer 500 ml of 5% dextrose in 0.3% to 0.9% saline and infuse for ≥ 3 hours (± 250 mL/h). |
| Increase oral fluid intake to 2 liters in 24 hours. | |
| Use diuretics, e.g., furosemide for edema, fluid retention, hypertension or signs and symptoms of impending pulmonary congestion | |
| 2-Mercaptoethane sulfonate sodium (Mesna) [optional] | To minimize the risk of hemorrhagic cystitis, Mesna® orally (with fruit juice) or IV (with infusions), each Mesna dose being 20% of the CY dose |
| Antiemetic therapy | Single dose of dexamethasone (5 to 10 mg) orally or IV, followed by any of the following over the next 1 to 2 days: (a) 5HT3 antagonists, e.g., ondansetron, tropisetron, or granisetron, orally or IV, or (b) oral metoclopramide (watch for extrapyramidal side effects). |
| Antihistamine and benzodiazepine can be used as alternatives | |
| White blood cell (WBC) count monitoring | Measure WBC counts between day 10 and 14 after CY pulse |
| Subsequent CY doses | If nadir WBCs > 4000/µL, increase subsequent dose to a maximum of 1.0 g/m 2 of BSA. If nadir WBCs < 1500/µL, reduce subsequent dose of CY by 0.25 g/m 2 of BSA |
| Pulse timing | Administer CY pulses monthly for six months for induction; may extend to seven months for very active disease. |
| Then administer CY pulses quarterly for maintenance for at least 1 year beyond remission, defined by: inactive urinalysis, reduction of proteinuria to less than nephrotic range (ideally <1 g/day), normalization of serum complement titers (and ideally anti-dsDNA antibodies), and minimal extrarenal lupus activity) |
Extended follow-up of patients who received both methylprednisolone and CY pulses demonstrated greater efficacy of the combination therapy compared with CY alone, without significant risk of toxicity.
The Euro-Lupus nephritis trial (ELNT) compared the high-dose IV-CY regimen (six monthly pulses and two quarterly pulses with doses increased according to the white blood cell count nadir), to a low-dose IV-CY regimen (six fortnightly pulses at a fixed dose of 500 mg), each regimen followed by AZA, in 90 European SLE patients with proliferative glomerulonephritis ( Table 10-5 ). The data showed comparable number of patients who achieved renal remission (54% to 71%) in both regimens, with a trend (but not statistically different) toward more infections in the high-dose group.
| Dose of cyclophosphamide (CY) | 500 mg (fixed dose) |
| Administration of CY | Use 500 mL 5% dextrose in 0.3% to 0.9% saline, infuse 250 ml over 1 to 2 hours. To remaining 250 mL, incorporate 500 mg CY and infuse 1 to 2 hours. |
| Diuresis | Infuse 100 to 500 mL of 5% dextrose in 0.3% to 0.9% saline over 1 to 3 hours. |
| Increase oral fluid intake to 2 liters in 24 hours. | |
| Use diuretics, for example, furosemide for edema, fluid retention, hypertension or signs and symptoms of impending pulmonary congestion | |
| 2-Mercaptoethane sulfonate sodium (Mesna) [optional] | To minimize the risk of hemorrhagic cystitis, give Mesna orally (with fruit juice) or IV (with infusions), each Mesna dose being 20% of the CY dose |
| Antiemetic therapy | Single dose of dexamethasone 5 to 10 mg orally or intravenously, followed by: metoclopramide (10–20 mg orally or IV), or alizapride (50–100 mg orally or IV) |
| If needed, prescribe 5HT3 antagonists such as ondansetron, tropisetron or granisetron over the next 1–2 days | |
| White blood cell (WBC) count monitoring | No need to monitor WBC count |
| Subsequent CY doses | Always 500 mg |
| Timing | Administer CY pulses every 2 weeks for six times (six doses of 500 mg) |
The overall data support the use of high dose steroids, for example, pulse IV methylprednisolone plus CY. The subtle differences in the efficacy, safety, and long-term outcomes of the various CY regimens including the high rate of renal relapse despite intensive therapy, reiterates the need to individualize therapy, closely monitor the patient’s response and treatment side effects, and consider alternative therapies in the patient with severe, aggressive disease.
Alternatives to Pulse Induction Therapy
AZA, a cytotoxic drug mainly used for steroid-sparing and maintenance therapy, has been proposed as an alternative to CY for the induction phase. However, the Dutch Lupus Nephritis study comparing a standard NIH IV-CY regimen (CY arm) with combined AZA (2 mg/kg/day) plus pulse IV methylprednisolone (AZA/MP arm) showed more relapses and doubling of creatinine (albeit unsustained) in the AZA/MP arm at median 5.7 years follow-up. We recommend induction with AZA only in patients with mild disease or those who refuse to risk the side effects of more proven effective agents like CY.
Mycophenolate mofetil (MMF) has recently become an important alternative drug for induction therapy in lupus nephritis. The initial study conducted among Chinese patients with class IV nephritis compared MMF 2 g/day for 6 months decreased to 1 g/day for the next 6 months, with oral CY 2.5 mg/kg/day for 6 months followed by AZA 1.5 mg/kg/day in the next 6 months. At 1 year, MMF was found comparable to CY for inducing remission. However, with longer follow-up, patients treated with MMF relapsed more often than the CY/AZA group (46% versus 17%, respectively). These observations led to a modified protocol using MMF given initially at 2 g/day for 6 months, then 1.5 g/day for 6 months and finally 1 g/day for at least a year before further tapering; CY/AZA was administered as in the first study. Using this modified protocol also in Chinese patients with a median follow-up of 63 months, the complete and partial remission rates were comparable at greater than 90% for both groups. Side effects such as amenorrhea and infections were more common in the CY group.
A multicenter study among 140 SLE patients (56% blacks) with class III to V nephritis compared MMF at initial dose 1 to 3 g/day with the NIH IV CY pulse regimen (IV-CY). At 24 weeks, more patients in the MMF compared with the IV-CY group achieved complete (16% versus 4%) or partial (21% versus 17%) remission. The more recent Aspreva Lupus Management Study (ALMS) trial randomized 370 patients to either MMF (<3 g/day) or IV-CY (0.5–1.0 g/m 2 /month), in combination with prednisone for 24 weeks. Although this trial did not meet its primary endpoint to demonstrate superiority of MMF over IV-CY, MMF appeared more consistently effective across racial/ethnic and geographic groups than IV-CY. It is also important to note that the therapeutic response depended on the dose of MMF, and only about 40% of patients had improvement of proteinuria with MMF doses below 1 g/day. Moreover, MMF was withdrawn from some patients because of adverse side effects, particularly diarrhea and abdominal discomfort. For patients unable to tolerate the recommended doses of MMF, enteric-coated mycophenolate sodium has recently been shown to be a useful alternative. Despite the limited number of patients and short follow-up time, these results support the use of MMF as an alternative for induction therapy in lupus nephritis.
A recent observational study compared leflunomide given at a loading dose of 1 mg/kg/day for 3 days, followed by 30 mg/day in combination with prednisone, to IV-CY at a dose of 0.5 g/m 2 body surface area administered monthly for 6 months as induction therapy in 110 Chinese patients with proliferative lupus nephritis. After 6 months, the total response rate was 73% for both treatment groups, with similar rates of adverse events.
Although IV immunoglobulin (IVIg) therapies have been used successfully with dramatic response in treating clinical manifestations of SLE like refractory thrombocytopenia, the beneficial effects are often of limited duration. Moreover, nephrotoxicity is a potentially serious complication of IVIg therapy, and patients with lupus nephritis who receive IVIg should be adequately hydrated and closely monitored. High-dose immunoablative chemotherapy (HDIC) with autologous hematopoietic stem cell transplantation (HSCT) has been used to treat patients with severe disease refractory to standard immunosuppressive treatment with variable results. A recent trial compared HDIC therapy (200 mg/kg CY administered over 4 days with or without HSCT) with the standard NIH monthly CY pulse therapy, followed by quarterly maintenance dosing over 2 years. Interestingly, the results still showed superior efficacy of the traditional CY regimen over HDIC. A few trials evaluating the role of plasmapheresis in lupus nephritis have shown variable results. Overall, the most impressive results were reported in patients with active disease and minimal scarring, and when combined with high-dose immunosuppressive therapy. At this time, plasmapheresis can be recommended only for patients with renal disease who are resistant to corticosteroid and cytotoxic drug therapy.
The increasing use of biologic agents such as rituximab in clinical practice has fueled the conduct of randomized clinical trials of these agents in lupus nephritis. These are more extensively discussed toward the end of this chapter.
Maintenance Therapy
A sequential study compared IV-CY, AZA, and MMF as maintenance therapy after inducing remission with pulse IV-CY (seven pulses) in 59 patients with lupus nephritis (95% Hispanic or blacks). Response to pulse IV-CY induction occurred in 83%. During maintenance therapy, although there were no significant differences in actuarial renal survival, the 72-month event-free survival (based on a composite endpoint of death and renal failure) was significantly better in both the AZA and the MMF groups than in the IV-CY group, although the small sample size, suboptimal IV-CY doses, and high doses of concomitant corticosteroids may have biased the results in favor of AZA and MMF. Analysis of pooled data on 445 patients in eight controlled trials showed that MMF conferred a significant survival benefit with the ability to induce renal remissions and prevent ESRD comparable to CY, and with a more favorable safety profile. These studies demonstrate that AZA and MMF provide good alternative options for maintenance therapy.
Cyclosporine A (CsA), a calcineurin inhibitor, has been used in lupus nephritis, particularly in those refractory to cytotoxic therapy. In a randomized controlled trial, CsA (2.5 to 4 mg/kg/day) was comparable to AZA (1.5 to 2 mg/kg/day) as induction and maintenance therapy in proliferative lupus nephritis for up to 4 years. Another controlled study of CsA and oral CY in nephritic children with proliferative lupus nephritis and nephrotic syndrome demonstrated a corticosteroid-sparing effect of CsA. Although there is no permanent nephrotoxicity in patients treated with low dose (<5 mg/kg/day) CsA, serum creatinine should be checked at baseline and every 2 to 4 weeks on treatment. For patients who fail to respond to these regimens, other less extensively studied drugs like tacrolimus (FK506) at 0.06 to 0.1 mg/kg/day may be tried, with strict monitoring for adverse effects.
These multiple studies across various centers and different racial groups offer and compare various regimens currently used in lupus nephritis. Obviously, there is no single regimen suitable for all patients. While maintaining some degree of flexibility in the management of individual patients, there is general consensus advocating early aggressive therapy during the “window of opportunity” (induction phase), including liberal use of moderate- to high-dose corticosteroids. During the maintenance phase, the predominant factors likely to affect clinical decisions include patient preference, long-term side effects such as fertility issues, and overall cost-benefit ratio. Patient choices are particularly important, with studies demonstrating an unwillingness of patients to opt for the best therapy (a regimen containing cytotoxic agents) when confronted with the potential side effects. Patients at high risk for ESRD should be counseled not to compromise future health by rejecting timely effective therapy for lupus nephritis. Close monitoring and strict patient adherence are crucial to achieving renal remission and preventing recurrences.
Adjunct Therapies
Patients with lupus nephritis are at heightened risk for accelerated atherosclerosis and cardiovascular events, and it is essential to aggressively control contributory factors such as hypertension and dyslipidemia by both pharmacologic and nonpharmacologic measures such as diet and exercise.
Hypertension, particularly a mean diastolic blood pressure exceeding more than 85 mm Hg, is a strong independent factor for occurrence of arterial thrombosis. Moreover, lupus nephritis patients who achieve optimum blood pressure control have a greater decline in proteinuria. Among the antihypertensive agents, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), either singly or combined, have the additional benefit of reducing proteinuria and slowing the progression of renal disease. Although serum creatinine may increase with these drugs, a mild increase may reflect a reduction in glomerular capillary pressure associated with extended preservation of renal function. The risk of hyperkalemia may be reduced by a loop diuretic and avoidance of potassium-rich foods. Combination antihypertensive regimens are frequently necessary in patients with chronic renal insufficiency, and the ACE inhibitors or ARBs can be effectively combined with other anti-hypertensives including diuretics, calcium channel antagonists, and beta blockers.
Patients with lupus are prone to urinary tract infections (UTI), usually caused by Escherichia coli . Some other associated risk factors include elderly age, previous UTI, thrombocytopenia, leukopenia, and methotrexate treatment. It is also important to distinguish UTI, which predominantly presents as isolated pyuria, from active nephritis which presents with pyuria accompanied by proteinuria and other urine sediments. Lupus nephritis frequently coexists and exacerbates with any infection including UTI.
Dietary protein restriction (0.3 to 0.6 g/kg/day) delays the progression of chronic kidney disease in nondiabetics, including those with lupus nephritis, and decreases the risk of need for dialysis, kidney transplantation, or death. However, a low-protein diet is usually not palatable, making it difficult for most patients to adhere to this dietary prescription. The benefits of a low-protein diet among chronic kidney disease patients (creatinine clearance <60 ml/min) should be weighed against the risk of protein-calorie malnutrition, and these patients should be closely monitored to assess compliance, nutritional status, and progression of kidney disease. On the other hand, the overall benefit and safety of dietary protein restriction or supplementation among patients with nephrotic syndrome (proteinuria >3.5 g/day and hypoalbuminemia) remains uncertain.
Membranous Nephropathy
Membranous lupus nephritis (MLN) represents about 20% of clinically significant renal involvement in lupus. The course and prognosis of MLN is variable, but the coexistence of proliferative changes generally confers a worse prognosis compared with pure membranous lupus nephritis. The effects of adding alternate-month pulse CY (<1 g/m 2 /infusion) or low-dose CsA (<5 mg/kg/day) to alternate-day prednisone in 42 patients with MLN were evaluated in a prospective randomized controlled trial, the results of which support the use of combination prednisone with either pulse CY or CsA over prednisone alone. For patients who cannot receive or tolerate CY, CsA may be an alternative, although extended follow-up has shown remissions to be more enduring with CY than with CsA. A recent open-label study showed tacrolimus at 0.1 to 0.2 mg/kg/day to be effective and safe in the treatment of MLN, with faster resolution of proteinuria and lower risk of lupus flare within 1 year, compared with conventional cytotoxic therapy.
Monitoring Disease Activity
The term “remission” has been used for inactive extrarenal disease, absence of urine sediments even with small amounts of proteinuria (<1g/d), normal serum complement, and low steroid dose requirement (<10 mg/day). Complete renal remission is defined by the Lupus Nephritis Collaborative Group as serum creatinine less than 1.4 mg/dL, inactive urine sediment, and protein excretion less than 330 mg/day. On the other hand, partial remission is defined as a 50% reduction in proteinuria (<1.5 g/day) and stable renal function. Although partial remission in lupus nephritis was associated with a significantly better patient and renal survival compared with no remission, the high rate of relapse with early discontinuation of cytotoxic drug therapy supports the continuation of maintenance treatment for several months beyond remission. Long-term follow-up of patients in the ELNT demonstrated that early response to immunosuppressive therapy predicted good renal outcome in lupus nephritis, enabling early identification of responders versus non-responders to cytotoxic drug therapy.
Nephritic flares with active urine sediment and increasing serum creatinine portend a poor renal prognosis, and must be approached using any of the induction regimens discussed earlier. Milder nephritic flares may be treated less aggressively, but close monitoring is essential with intensification of therapy if patients do not respond promptly. It is also important to identify and control precipitating and exacerbating factors such as infection, dehydration, uncontrolled hypertension, and drugs.
A 33-year-old housewife developed active nephritis 2 years after the diagnosis of SLE. Renal histology disclosed ISN/RPS Class IV-G (A) with activity index 10 and chronicity 3. She achieved partial remission after 6 monthly pulses of CY, and was maintained on azathioprine 100 mg/day. Eighteen months later, she had rapidly progressive glomerulonephritis manifesting as hypertension, proteinuria, oliguria, and azotemia, requiring maintenance hemodialysis. A second biopsy showed ISN/RPS Class VI with activity index 3 and chronicity 10. Two years later, with clinically quiescent disease, she underwent allograft kidney transplantation.
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