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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 6  |  Page : 1349-1355
Factors associated with relapse of lupus nephritis: A single center study of 249 cases


1 Department of Medicine A, Charles Nicolle Hospital; Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
2 Faculty of Medicine of Tunis, University of Tunis El Manar; Laboratory of Renal Pathology LR00SP01, Charles Nicolle Hospital, Tunis, Tunisia

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Date of Web Publication18-Dec-2017
 

   Abstract 


This is a retrospective cohort study over 20 years (1990–2013) that included all patients with biopsy-proven lupus nephritis (LN) followed up at our nephrology department. We aimed to determine the clinicobiologic predictors of flare-up of LN. Flare was defined as an increase in systemic lupus erythematosus (SLE) disease activity index (SLEDAI) score of at least four points. Clinical manifestations and laboratory parameters were assessed and the SLEDAI score was determined for each patient. We included patients with SLE who fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE. A total of 249 patients including 227 females and 22 males with a median age at diagnosis of 34.32 years (range 16–69) were studied. The mean follow-up duration was 122.4 ± 27 months. Renal symptoms included hypertension in 40%, nephrotic syndrome in 30%, and renal failure in 69.4% of the cases. Class IV and class III nephritis (ISN/RPS) were observed in 44.9% and 24% of the patients, respectively. On univariate analysis, flare predictors were age <30 years (P = 0.02), lymphocytopenia (P = 0.002), the presence of diffuse proliferative LN (P = 0.009), and discontinuation of immunosuppressive therapy (P = 0.004). Our study suggests that these markers should be monitored routinely as prognostic parameters in SLE to characterize patients who are at risk and who should be followed more closely.

How to cite this article:
Hajji M, Harzallah A, Kaaroud H, Barbouch S, Hamida FB, Abdallah TB. Factors associated with relapse of lupus nephritis: A single center study of 249 cases. Saudi J Kidney Dis Transpl 2017;28:1349-55

How to cite this URL:
Hajji M, Harzallah A, Kaaroud H, Barbouch S, Hamida FB, Abdallah TB. Factors associated with relapse of lupus nephritis: A single center study of 249 cases. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Dec 7];28:1349-55. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1349/220863



   Introduction Top


The course of systemic lupus erythematosus (SLE) is variable and characterized by recurrent disease flares. SLE flares are defined as an increase in disease activity, requiring alternative treatment or intensification of therapy.[1] Flares or relapses of SLE are observed in 27%–66% of patients.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11] The variability of incidence of renal flare is due to differences in definitions of flare, induction and maintenance therapies used and duration of follow-up in different studies. Morbidity associated with renal flares is due both to the kidney damage secondary to lupus nephritis (LN) and treatment-related toxic effects. Flares represent a significant problem and are associated with impaired renal survival. We conducted this analysis to identify predictors of SLE flare in our population.


   Methods Top


Patients

We conducted an analysis of retrospectively collected data of 249 adult patients with biopsy-proven LN between January 1990 and December 2013. All biopsies were examined by two expert nephropathologists. Histologic features of activity and chronicity were determined as well as the degree of severity in each biopsy report. The demographics, clinical presentation, histopathology, treatment specifications, and follow-up variables were collected.

In the late 1970s and 1980s, patients with active nephritis were treated with high-dose corticosteroids with or without azathioprine. Standard immunosuppressive treatment protocols were adopted in the late 1990s. Patients with Class III (focal proliferative) or Class IV (diffuse proliferative) LN were given induction immunosuppressive treatment that comprised corticosteroids and either cyclophosphamide or mycophenolate mofetil (MMF) (available since 2005) for six months, followed by low-dose prednisolone and either azathioprine or MMF as long-term maintenance immunosuppression [Table 1]. Mixed Class III + Class V or Class IV + Class V nephritis were treated as for Class III or Class IV, respectively. Intravenous cyclophosphamide was given monthly at a dose of 500–1000 mg/m2 for six doses. Oral cyclophosphamide was not used. The target dose of MMF during the induction phase was 2 g/day. Patients with pure Class V (membranous) LN and proteinuria of <2 g daily were treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
Table 1: Therapeutic protocol for diffuse lupus nephritis followed in our nephrology department.

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Definitions

All patients satisfied diagnostic criteria for LN which is defined as clinical and laboratory manifestations that meet American College of Rheumatology criteria (persistent proteinuria >0.5 g/day or greater than 3+ by dipstick, and/ or cellular casts including red cell, hemoglobin, granular, tubular, or mixed).[12] An additional criterion is a renal biopsy demonstrating immune complex-mediated glomerulonephritis compatible with LN.[13] All renal lesions were classified according to the International Society of Nephrology/Renal Pathology Society (ISN/ RPS) classification.[14] Renal biopsies performed before 2004, were reviewed and reclassified by our nephropathologists according to the ISN/ RPS classification to ensure homogenecity.

Glomerular filtration rate (GFR) was estimated by the formula of modification of diet in renal disease.[15] Renal failure was defined as estimated GFR (eGFR) <60 mL/ min/1.73 m2.[16] End-stage renal disease (ESRD) was defined as an eGFR <15 mL/min/m2 or the need to start dialysis.[16] Nephrotic syndrome was defined as proteinuria greater than 3 g in 24-h urine and serum albumin <30 g/L.[17] We adopted the SLE disease activity index (SLEDAI) definition of flare.[18] We applied the term complete remission to patients who achieved a normalization in renal function and proteinuria: a reduction in proteinuria to essentially normal levels 0.3 to 0.5 g/day,[1],[8],[19],[20],[21],[22] with a normalization of serum creatinine level.[1],[21] Partial remission was defined as a decrease in serum creatinine of 25% from baseline values and a reduction of 50% in baseline proteinuria to 1.5 g/day.[23]


   Statistical Analysis Top


Univariate analysis using the Log-rank test was used to investigate predictors for renal flare, and prognostic analyses were performed using Statistical Package for the Social Sciences (SPSS) version 20.0 software (SPSS Inc., Chicago, IL, USA). P <0.05 was considered statistically significant.


   Results Top


Baseline characteristics of the 249 patients are presented in [Table 2]. Of the 249 patients, 47 (18.8%) achieved complete remission that persisted for the next 10 years without any flare. In the other 202 patients (81.1%), one or more renal flares occurred during the follow-up. In 89 of them (44%), only proteinuric flares developed. Nephrotic syndrome was noted in 30.1% of patients with renal flare. Thirty patients (14.8%) developed one or more nephrotic flares. Clinical indications for biopsies were persistent nonnephrotic proteinuria and/ or hematuria (n = 103, 50.9%), persistence of, or relapsing, nephrotic syndrome (n = 61, 30.1%), and worsening of renal function (n = 30, 14.8%). We do not have data on the cause that motivated rebiopsy in the remaining eight cases. Out of the 202 repeat biopsies, pathological transition occurred related to the previous biopsy in 20 cases (10%) [Table 3]. We could not assess change in 10 of the rebiopsies because of unknown previous biopsy results. Chronic histologic renal lesions were frequent in our patients, with, respectively, interstitial sclerosis, tubular atrophy, and atherosclerosis in 75.9%, 59.8%, and 29.7% of the patients. A predominance of histologic chronicity markers was found in 20 cases (10%). [Table 3] shows the treatment instituted in 148 patients with renal flare (59.4%) (class IV and class IV + V of ISN/RPS). We noted discontinuation of treatment in 85 cases (42% among patients presenting with flares). Overall, 88 out of 148 patients who received treatment (59.4%) achieved partial remission and 44 (29.7%) achieved complete remission after treatment of renal flare. After a median follow-up of 122.4 ± 27 months, 76 patients (30.5%) had normal renal function. Eighty-two patients (47.3%) reached ESRD and 17 of them died (20.7%).
Table 2: Baseline characteristics of the study population (n = 249).

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Table 3: Class changes in repeat biopsies.

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Of the remaining 54 patients, three of them (1.2%) did not receive treatment due to progression to class VI histopathology; 13 patients (5.2%) were lost to follow-up or had follow-up for <6 months after the renal flare, and response to treatment was classified as unknown.

A correlation analysis of the prevalence of flares [Table 4] revealed that flare predictors were age <30 years (P = 0.02) and diffuse proliferative LN (P = 0.009). A significant association with lymphopenia (P = 0.002) was also identified, but not with anemia or thrombocytopenia. The occurrence of flares was not significantly associated with erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level and with immunological markers (antibodies against dsDNA or complement fixation titer). Discontinuation of immunosuppressive therapy correlated with renal flare (P = 0.004). The main complications developed by our patients consisted of avascular femoral necrosis in 11 patients (4.4%), herpes zoster in 24 patients (9.6%), pneumonia in 33 patients (13.2%), cardiac infarct in five patients (2%), peptic ulcer in nine patients (3.6%), diabetes in 71 patients (28.5%), and cancer in three patients (1.2%).
Table 4: Association of laboratory markers (SLEDAI) with lupus flares.

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   Discussion Top


In our study, we adopted the SLEDAI activity score, as it has been shown to be reliable and reproducible.[18] The SLEDAI score increases by an average of three points in a flare.[24] On univariate analysis, we found that the risk of renal flare was significantly associated with age <30 years, lymphocytopenia, the presence of diffuse proliferative LN on renal biopsy, and discontinuation of immunosuppressive therapy. Many studies have tried to identify the clinical or histological factors that could predict the risk of renal flares in patients with LN. Factors identified are high activity score (>9) on initial renal biopsy,[7] age < 29 years at onset of renal disease,[7],[8],[25] male gender, and presence of arterial hypertension at presentation.[14] Treatment with steroids alone,[26] with a delay of more than five months from the onset of nephritis to initiation of cyclophosphamide therapy[8] and a short duration of highdose intravenous cyclophosphamide therapy,[3] has also been found to be significantly associated with the development of renal flares.

Many definitions for renal flares in patients with SLE have been used in different studies.[5],[11],[23] Renal flares can be subdivided into proteinuric or nephritic flares. The EULAR (European League Against Rheumatism) consensus statement also defines an extrarenal flare which affects one or more nonrenal body systems in patients with SLE.[27] Renal flares are detrimental to renal function in patients with severe LN. El Hachmi et al[28] found that 37% of their patients with LN experienced at least one renal flare after a mean follow-up of 40 months. As illustrated by our study and shown in others studies as well, flares of nephritis were associated with a poorer renal outcome.[29],[30],[31] Consistent with other studies, lymphocytopenia was found to be significantly associated with SLE flare. In addition to lymphocytopenia, anemia and ESR have been shown in other studies as the best predictors of flares.[32],[33] However, it was not the case in our series.

Renal biopsy, which was performed on all our patients, remains the gold standard for the diagnosis of renal flares. With equivocal clinical and renal findings associated with persistent serological activity, a renal biopsy should be performed to detect whether active LN is present.[34] Increasing proteinuria of >1 g/day might indicate the onset of active proliferative LN, transformation to class V membranous LN, the onset of lupus podocytopathy, or chronic kidney damage.[35] That is why, the distinction between flare-related glomerular diseases and nonimmunological causes of increased proteinuria can only be made by performing a renal biopsy and is important as each of these diagnoses has a different prognosis and requires different therapy.[36] SLE flares cause cumulative damage that may lead to deterioration of renal function as well as toxicity due to the additional immunosuppression[37].

Our therapeutic approach consisted of an induction therapy followed by low-dose maintenance therapy, whenever a renal flare was diagnosed. We followed the same therapeutic schedule for induction and for flares [Table 3]. Controlled trials have shown that the risk of renal flares can be significantly reduced by prolonged administration of intravenous cyclophosphamide pulses[3] or in severe cases by a combination of high-dose cyclophosphamide and intravenous methylprednisolone pulses.[4] Steinberg and Decker[38] reported the success of cyclophosphamide when compared with azathioprine or placebo for inducing remission over a 10-week period in a randomized trial of 38 patients during the mid-1970s. Other studies suggest that good clinical results may be achieved even with a low cumulative dose of intravenous cyclophosphmide.[39] Among the treatment regimens studied by Austin et al,[40] reduced rates of ESRD were reported in patients who received intravenous cyclophosphamide and glucocorticoids compared with glucocorticoid monotherapy.

The present study has some limitations, especially because of its long duration and the changes in therapy over this period. However, this current study represents, to our knowledge, the first prognostic study in a large cohort focusing on factors associated with relapse of LN in Tunisia.


   Conclusion Top


The prognosis of LN has improved in recent years, but in the long-term, many patients may suffer from complications related either to SLE or to its treatment. Prevention and early diagnosis of lupus flare may be considered important therapeutic goals. Thus, careful monitoring of patients in remission and adherence to therapy are crucial for obtaining optimal survival and renal function in patients with LN.

Conflict of interest: None declared.



 
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Correspondence Address:
Meriam Hajji
Department of Medicine A, Charles Nicolle Hospital, Tunis
Tunisia
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DOI: 10.4103/1319-2442.220863

PMID: 29265046

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