Lupus nephritis remains a common complication and major determinant of outcome in systemic lupus erythematosus (SLE).1 Survival of patients with lupus nephritis has significantly improved over the last decades due to increasing treatment options than in the past. However, the optimal treatment of lupus nephritis is still a challenge to the clinician.2–4
It is clear that avoidance of flares is important for long-term prognosis of lupus nephritis and its treatment regimens include an induction phase aimed to induce remission of the disease in a short time and a maintenance phase to preserve the remission on the long term.5 Also, it has been well recognized that renal biopsy is the gold standard for assessing renal activity and hence guiding the treatment.6 There are several pathological classes of lupus nephritis, each of them has different clinical behavior and probably immunopathogenesis. The pathological class of lupus nephritis may change from one to a different class during a disease flare. Therefore, repeat renal biopsy has been attracted much attention and its clinical relevance has been evaluated by a number of studies.7–10 However, whether a repeat renal biopsy is helpful for each patient with suspicion of renal flare remains controversy.
Here we retrospectively evaluated 44 patients with lupus nephritis in whom renal biopsy was performed at the first hospitalization and was repeated one or more times during follow-up. The purpose of the study was to verify the histopathological patterns in different clinical settings and their contribution to guiding treatment.
Patients who were hospitalized between January 1995 and June 2011 were selected from the database of the patient pathology registration at the Renal Division of Nanfang Hospital. Inclusion criteria were a diagnosis of lupus nephritis and two or more renal biopsies. The patients were excluded if the data were not complete. Forty four patients were included on the basis of these criteria. All patients fulfilled the American College of Rheumatology diagnostic criteria for SLE. The study was approved by the Clinical Research Ethical Committee of the Nanfang Hospital.
Collection of clinical data
Data were collected on the patient's demographic characteristics and clinical manifestations based on medical record. The lab values such as serum creatinine, albumin, urea, proteinuria, complement levels (C3 and C4), anti-double strand DNA antibody titer, and the disease activity of SLE as represented by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) on the day of renal biopsy were extracted by an independent physician. To verify the accuracy of chart abstraction, an independent abstractor re-evaluated the above information.
Evaluation of renal pathology
Renal biopsy was evaluated according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis.11 The activity index (AI) and chronicity index (CI) of each biopsy were scored by standard methods.12 All biopsies were assessed by two renal pathologists (Wang GB and Jia N) by light microscopy. ISN/RPS classifications between the first and the second biopsy were compared. If biopsy specimens were classified according to WHO classification (class I, normal kidney; class II, mesangial proliferation; class III, focal and segmental proliferative glomerulonephritis; class IV, diffuse proliferative glomerulonephritis; class V, membranous glomerulonephritis; and class VI, sclerosing glomerulonephritis), they were reassessed according to the ISN/RPS classifications and the new classification were compared. If patients had more than two biopsies, the second and third, as well as third and fourth, biopsies were paired. Thus, the last biopsy performed before the repeat biopsy served as the reference biopsy.
Therapy and definitions
After the renal biopsy, all patients were followed for at least 6 months. The clinical management was decided by individual nephrologists. In general, patients were treated with prednisolone alone, or together with cyclosporin A, oral cyclophosphamide (CTX), intravenous CTX, tacrolimus or mycophenolate mofetil (MMF) according to established protocols. Therapeutic response to induction immunosuppression was assessed at 12 weeks after treatment and classified into complete remission, partial remission, and no response, as defined previously.7 Nephrotic proteinuria was defined by a daily urine protein excretion of 3.5 g/d or greater. Nonnephrotic proteinuria was defined as a urinary protein excretion between 0.2 and 3.4 g/d. Worsening of renal function was defined as an increase in plasma creatinine level caused by either a slow or fast increase in plasma creatinine level of at least 50% greater than the basal value. Relapse was defined as an increase in disease activity which required an increase in the prednisolone dose. Increased immunosuppression was defined as an induction treatment with MMF or CTX plus high dose of prednisone. Decreased immunosuppression was defined as a treatment with low dose prednisone as maintenance treatment or withdraw of the maintenance treatment.
Indications for repeated renal biopsy
Renal biopsy was repeated on the basis of one of these three clinical indications: improvement of renal disease but persistence of non-nephrotic proteinuria; persistent or relapsing nephrotic syndrome; worsening of renal function; and relapse. Four patients were scheduled to receive the renal biopsy to assess the efficacy of leflunomide treatment.13
Data were analyzed using SPSS 13.0 for Windows®. The continuous variables were presented as the mean ± standard deviation (SD) or the median and interquartile ranges where appropriate. Categorical variables are presented as percentages. For the univariate analysis, we compared two groups using the Student's t test when normally distributed, and the Mann-Whitney test when not. The Pearson χ2 test and the Kruskal-Wallis test were applied for analysis of nominal and ordinal variables, respectively. Two-sided P values <0.05 were considered statistically significant.
Characteristics of patients at first renal biopsy
We identified 44 SLE patients with serial renal biopsies. In total, there were 94 renal biopsies: 39 patients had two biopsies, 4 had three, and 1 had four. Their baseline demographic and clinical data at the time of the first renal biopsy were summarized in Table 1.
In total, there were 50 pairs of renal biopsies. Their ISN/RPS classification was listed in Table 2. Overall, the ISN/RPS class of the repeat biopsy was the same as that of the reference biopsy in only 18 pairs (36%). Thus, rate of pathological transition was 64%.
We further analyzed the pathological transition stratified by biopsy indication. As shown in Table 3, the rate of transition was also very common: 68.8% in patients received repeated biopsy due to persistent non-nephrotic proteinuria, 60% in patients due to nephrotic proteinuria, and 71.4% in patients due to worsening of renal function. Even though the rate of transition in patients with worsening of renal function had a trend to be highest, they remained statistically insignificant. Meanwhile, the rate of transition in patients received biopsy due to lupus relapse was lower when compared with total cohort (45.5% vs. 64%, P <0.05). The number of patients received biopsy due to extra-renal manifestation and research was limited. Their transition rate seemed to be high.
There is an argument that conversion from one proliferative form to another (e.g. class III to class IV) would not be helpful since treatment guidelines usually do not differentiate between them.8 We then analyzed the transition according to pure membranous, proliferative, and mix lesion. The changes from proliferative to membranous or mix lesions and vice versa between the reference and repeat biopsies were shown in Table 4. In 17 instances (17/50, 34%), the reference biopsy and the repeat biopsy showed proliferative lesions. The rate of transition in patients with proliferative lesion was 35% (9/26). In 13 cases (13/50, 26%), the reference biopsy and the repeat biopsy showed mix lesion. The rate of transition in patients with mix lesions was 23.0% (3/16). Meanwhile, three cases with pure membranous lesion on reference biopsy all switched to mix lesions (100%, 3/3). This indicates that class switch were more prevalent in patients with membranous lesion. One patient with prolieferative lesion in the reference biopsy showed extensive glomeruloscrerosis.
A comparison of clinical characteristics between the reference and repeat biopsy was made to see whether there was a difference in clinical characteristics associated with the pathology alteration. As shown in Table 5, the level of complement C3 was increased and SLEDAI was significantly decreased at the time of repeat biopsy. Meanwhile, the chronic index of renal pathology was increased. This data suggest that there was only difference in clinical and pathological activity after the reference biopsy. To identify whether the clinical characcteristics could predict pathological transition, we made the comparison between patients with and without pathological conversion. As shown in Table 6, there was no difference in clinical characteristics in patients with and without pathological transition, suggesting the clinical characteristics could not predict the pathological transition.
Therapeutic decisions after repeated renal biopsies
One of the most important reasons to perform a repeat biopsy is to decide on a treatment strategy in patients with lupus nephritis. We evaluated the alterations in treatment regimen after repeat biopsy. The treatment regimen 3-6 months prior to the repeat biopsy was set as the baseline. As shown in Table 7, in 33 instances (66%), the treatment regimen after repeat biopsy was the same as that before repeat biopsy. This suggested that 34% of patients had a change in their treatment regimen after the repeat biopsy. For patients who were planed to receive an increased immunosuppression before repeat biopsy, ten (55.5%) did. Meanwhile, five cases (26.7%) remained the baseline treatment and 3 (16.7%) received a decreased immunosuppression therapy. For patients who were planed to continue the baseline treatment, 14 (60.8%) did. Five cases enhanced and 4 case reduced the immunosuppression. All patients who were planed to reduce immunosupression were actually treated with the same way as that before repeat biopsy, suggesting reduced immunosuppression therapy could be made without repeat biopsy.
This retrospective study investigated the pathological transition and alteration of treatment regimen based on repeat biopsy in patients with lupus nephritis with the hope of finding the clinical value of repeat biopsy. Our results added additional evidence to support the early reports that pathological conversion was very prevalent in patients with lupus nephritis. However, the transitions became less prevalent when they were analyzed according to pure membranous, proliferative, and mix lesion. In addition, our data found 34% of patients had their treatment regimen changed after a repeat biopsy. Thus, repeat biopsy might be helpful to identify the patients who need unnecessary increased immunosuppression therapy.
Repeat biopsy has been advised for patients with a suspected flare of lupus nephritis to determine the most effective treatment as well as the prognosis and potential pathogenesis.12,14,15 The pathological conversion, a characteristic of lupus nephritis, has been observed in a serial renal biopsy according to the old WHO classification14 and recently the ISN/RPS classification.11 The transitions were variable ranged from 49% to 75% according to the different patient population and criteria used.7,8,14 Consistent with early reports, our data also found that pathological transition in lupus nephritis was very common (64%). However, the transitions became less prevalent when they were analyzed according to purely membranous, proliferative, and mix lesion. This analysis is clinical relevant since current treatment regimens do not differentiate between classes III and IV nephritis16 and treatment options for membranous lupus nephritis is still under investigation.17–19 In these patients, the transitions in patients with proliferative and mix lesion were 35% and 23.0%, respectively. Meanwhile, three cases with pure membranous lesion on reference biopsy all switched to mix lesions. This information suggests that clinically relevant class switches were more frequent in patients with non-proliferative lesions in the reference biopsy. Thus, repeat biopsy appears to be helpful in patients with non-proliferative lesions in the original biopsy. In accordance with early reports,7 the pathological conversion could not be predicted by baseline clinical, biochemical, or pathological parameters.
Several studies have investigated the clinical significance of repeat biopsy in patients with lupus nephritis.7,8,14 It has been argued that conversion from one proliferative form to another (e.g. class III to class IV) does not influence the choice of treatment regimen since treatment guidelines usually do not differentiate between them. Thus, a repeat biopsy becomes unnecessary if transition to another proliferative form and these forms receive the same treatment. In addition, the proliferative lesions on the original biopsy rarely switch to a pure non-proliferative one during a lupus flare.8 Some authors suggested that the need for repeat biopsies in renal flares may depend on the pathological class in the original biopsy and are not always necessary.8,9 However, a study in Italy showed that repeat biopsy could significantly influence the therapeutic decisions.10 The alteration in treatment regimens, an increase or decrease in immunosuppression therapy, occurred in 77% of patients after the repeat biopsy.10 In our study, we found overall 34% of patients had a change in their treatment regimen after the repeat biopsy. For patients who were supposed to receive the enforced immunosuppression, repeat biopsy seemed to be more useful because only 55.5% of them actually did and the remaining patients received the same treatment as the baseline or even a decreased immunosuppression therapy after the repeat biopsy. Considering the potential toxicity of the available treatments, repeat biopsy is a reliable way to identify the patients who need unnecessary increased immunosuppression therapy.
Several limitations of the present study need to be addressed. First, the small sample size of our study does not allow subgroup comparison between different histological classes of lupus nephritis be reliable. It is important to bear the mind that there was a wide range of agreement on scoring histopathological characteristics of lupus nephritis.20 Thus, a subgroup of histological class might be classified into another subgroup due to different specialized observer. Second, we did not address the prognostic value of repeat biopsy due to lack of data on long term follow up. Third, the choices of treatment regimens after a repeat biospy (e.g. increased imumnosupression or decreased immunosupression) were largely dependent on the individual nephrologist. Unfortunately, there is no widely acknowledged guideline for the choice of treatment after a repeat biopsy. Finally, whether alteration of treatment regimen after a repeat biopsy will translate into improved prognosis remains unknown. It is also presently unclear whether treatment regimens affect pathological transition. Further studies are thus required.
In summary, we found a change in the histological class of lupus nephritis was common. The transitions became less common when the pathological patterns were analyzed according to purely membranous, proliferative, and mix lesion. Repeat renal biopsy is useful for guiding the treatment and to avoid unnecessary increased immunosuppression therapy when there is lupus flare with potential renal involvement.
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