Utility of a repeat renal biopsy in lupus nephritis: a single centre experience

Utility of a repeat renal biopsy in lupus nephritis: a single centre experience Abstract Background The role of repeat renal biopsy in lupus nephritis (LN) to guide treatment or predict prognosis has been controversial. We assessed glomerular and tubulointerstitial histological characteristics of serial renal biopsies, correlations with clinical variables and the impact on subsequent management. Methods Out of a large single-centre cohort of 270 biopsy-proven LN patients, 66 (24%) had serial biopsies. LN classes based on glomerular pathology were defined according to the International Society of Nephrology/Renal Pathology Society 2003 classification, while tubulointerstitial pathologies were evaluated using the revised Austin’s semi-quantitative scoring system. Results LN class transitions from proliferative (III and IV) to non-proliferative classes (II and V) were uncommon (n = 4, 7.7%), while non-proliferatives frequently switched to proliferative classes (n = 12, 63.2%) and were more likely to receive increased immunosuppression (P = 0.040). Biochemical or serological variables could not predict these histopathological transitions. Tubulointerstitial score (mean ± standard deviation) progressed from 2.69 ± 2.03 on reference to 3.78 ± 2.03 on repeat biopsy (P = 0.001). Serum creatinine levels correlated with the degree of tubular atrophy on both reference (r = 0.33, P = 0.048) and repeat biopsy (r = 0.56, P < 0.001), and with interstitial scarring (r = 0.60, P < 0.001) on repeat biopsy. Greater interstitial inflammation on reference biopsy was associated with advanced interstitial scarring on repeat biopsies (r = 0.385, P = 0.009). Conclusions Repeat renal biopsy is an important tool to guide management, in particular in those with initial class II or V who flare. Although class transitions cannot be predicted by clinical parameters, serum creatinine level correlates with the degree of tubulointerstitial damage. lupus nephritis, repeat biopsy, tubulointerstitial changes INTRODUCTION Renal biopsy plays a crucial role in the diagnosis of lupus nephritis (LN) [1]. However, its clinical relevance in subsequent renal flares has been subject to debate. Up to 60% of patients with systemic lupus erythematosus (SLE) develop renal involvement during the course of the disease and despite the increasing variety of immunosuppressive treatment options, response is often incomplete and relapses remain common. There has been no clear consensus on relapse definition but the majority of studies define flares as either proteinuric, based on a rise of protein excretion, or nephritic, based on urinary sediment [2]. Both types of flare are known to add to the overall cumulative damage in LN and hence often lead to escalation of treatments, which may potentially have toxic effects [3]. The proliferative classes (classes III and IV) require immunosuppression while the evidence is not strong for the other classes. Some authors have advocated that since patients with proliferative lesions on their first biopsy rarely switch to a pure non-proliferative nephritis during a flare, immunosuppression can be escalated without performing a repeat renal biopsy [4]. However, other studies have suggested that clinical flares do not always correspond to proliferative lesions on repeat biopsy and class transitions may be common [5, 6]. Furthermore, there may be features on repeat renal biopsies such as tubular atrophy and tubulointerstitial scarring that flag high risk groups for renal failure who may not respond well to immunosuppression. Current guidelines do not seem to have robust recommendations for indications of repeat renal biopsies. While the joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) guideline proposes repeat renal biopsies for those with worsening or non-responding renal disease despite 1-year of immunosuppressive treatment [7], the Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends considering repeat renal biopsies in patients showing worsening renal function in the 3 months of induction treatment or in the absence of complete remission after 12 months of maintenance treatment [8]. Both guidelines suggest considering a repeat renal biopsy during nephritis flare if there is a suspicion of class transition or there is uncertainty in differentiating activity from chronic damage, or to detect an alternative pathology. In this study, we aimed to evaluate the histological characteristics of repeat renal biopsies and whether a repeat biopsy may be an important tool in guiding therapeutic decisions in terms of optimizing immunosuppressive treatment. MATERIALS AND METHODS Patients and study design This retrospective study was carried out at a tertiary lupus centre within a large university hospital, Barts Health NHS Trust, UK. All patients fulfiled at least four of the American College of Rheumatology revised classification criteria for SLE [9]. Renal biopsies LN classes based on glomerular pathology were defined according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification [10]. Eight patients had more than two biopsies, in those cases the last biopsy performed before the repeat biopsy served as reference biopsy. Classes III, IV and combinations with V were considered proliferative classes, while classes I, II and V were considered non-proliferative. LN class II (mesangial proliferative LN) was grouped with classes I and V because of its relatively benign nature. Interstitial inflammation was scored semi-quantitatively according to the revised Austin’s scoring system using a grading system of 0–3 (0, normal; 1, mild <25%; 2, moderate between 26 and 50%; 3, severe >50% of the interstitium affected) [11]. Using a similar method, chronicity indices (0–12) were calculated and included scores for glomerular sclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. Treatment Individual nephrologists and rheumatologists decided the choice of immunosuppressive treatment. We considered a treatment change when the immunosuppressive treatment dose was changed or a new induction treatment was initiated. Statistical analysis Descriptive analyses were performed on the clinical and histological data. Continuous variables are shown as means ± standard deviation (SD) or medians with interquartile range (IQR), and were analysed using one-way ANOVA or Mann–Whitney U tests. For categorical variables Pearson’s chi test was used, and data are shown as percentages. Spearman’s rank-order correlation was run to determine relationship between clinical variables and histological findings. All statistical analyses were performed using SPSS software version 22 for Mac; P-values <0.05 were considered statistically significant. RESULTS Patient characteristics A total of 285 SLE patients underwent a renal biopsy. Of those, 270 had histological evidence of LN, while 15 patients (5.2%) had an alternative diagnosis including focal segmental glomerulosclerosis (FSGS, n = 4), normal (n = 2), thrombotic microangiopathy (n = 2), acute tubular necrosis (n = 2), hypertensive glomerulosclerosis (n = 2), thin membrane nephropathy (n = 1), small vessel vasculitis (n = 1) and fibrillary glomerulonephritis (n = 1). We identified 66 LN patients (24.5%) with two or more renal biopsies; however, 7 patients were excluded from the final analysis as the initial biopsy was done elsewhere. In total, 130 renal biopsies were analysed. The baseline characteristics at first biopsy comparing LN patients with or without repeat biopsy are shown in Table 1. The median time between initial and repeat biopsies was 32 months (IQR, 13–80 months). Patients with repeat kidney biopsies were significantly younger at both SLE (26 versus 31 years, P = 0.007) and LN diagnosis (28 versus 34 years, P = 0.001) compared with those with no repeat biopsy. Regarding histopathological classes, proliferative classes with or without membranous component were the most frequent (n = 44, 73.4%). One case of FSGS was felt most likely to be secondary to LN based on clinical presentation and serological evidence of active SLE, in addition to the histological findings. Table 1 Baseline demographics and characteristics of LN patients with or without repeat renal biopsy   Total (n = 270)  Without repeat biopsy (n = 204)  With repeat biopsy (n = 66)  P-value  Gender, n (%)           Male  41 (15.2)  30 (14.7)  12 (18.2)  0.498   Female  228 (84.8)  174 (85.3)  54 (81.8)  Ethnicity, n (%)           African/Afro-Caribbean Black  116 (43.0)  78 (38.2)  38 (57.6)  0.069   White Caucasian  53 (19.6)  44 (21.6)  9 (13.6)   South Asian  56 (20.7)  44 (21.6)  12 (18.2)   Oriental Asian  13 (4.8)  10 (4.9)  3 (4.5)   Other/mixed race  32 (11.9)  28 (13.7)  4 (6.1)  Age (years), mean (SD)           at SLE diagnosis  29 (11.8)  31 (11.6)  26 (11.7)  0.007   at LN diagnosis  32 (12.1)  34 (12.1)  28 (11.1)  0.001  Serology, n (%)           ANA positive  210/223 (94.2)  155/163 (95.1)  55/60 (91.7)  0.333   ENA antibody positive  143/213 (67.8)  103/154 (66.9)  40/59 (67.8)  0.899   RNP antibody positive  83/213 (39.2)  61/154 (39.6)  22/59 (37.3)  0.756   Sm antibody positive  56/213 (26.4)  39/154 (25.3)  17/59 (28.8)  0.605   Ro antibody positive  84/213 (39.8)  61/154 (39.6)  23/59 (39.0)  0.933   aPL antibody positive  51/176 (29.0)  36/128 (28.1)  15/48 (31.3)  0.684  Initial renal histology class (ISN/RPS 2003), n (%)           I  2/238 (0.8)  2/179 (1.1)  0  0.725   II  26/238 (10.9)  18/179 (10.1)  8/59 (13.6)   III/IV  133/238 (55.9)  98/179 (54.7)  35/59 (59.3)   V  45/238 (18.8)  37/179 (20.7)  8/59 (13.6)   III/IV and V  31/238 (13.0)  23/179 (12.8)  8/59 (13.6)   VI  1/238 (0.4)  1/179 (0.6)  0    Total (n = 270)  Without repeat biopsy (n = 204)  With repeat biopsy (n = 66)  P-value  Gender, n (%)           Male  41 (15.2)  30 (14.7)  12 (18.2)  0.498   Female  228 (84.8)  174 (85.3)  54 (81.8)  Ethnicity, n (%)           African/Afro-Caribbean Black  116 (43.0)  78 (38.2)  38 (57.6)  0.069   White Caucasian  53 (19.6)  44 (21.6)  9 (13.6)   South Asian  56 (20.7)  44 (21.6)  12 (18.2)   Oriental Asian  13 (4.8)  10 (4.9)  3 (4.5)   Other/mixed race  32 (11.9)  28 (13.7)  4 (6.1)  Age (years), mean (SD)           at SLE diagnosis  29 (11.8)  31 (11.6)  26 (11.7)  0.007   at LN diagnosis  32 (12.1)  34 (12.1)  28 (11.1)  0.001  Serology, n (%)           ANA positive  210/223 (94.2)  155/163 (95.1)  55/60 (91.7)  0.333   ENA antibody positive  143/213 (67.8)  103/154 (66.9)  40/59 (67.8)  0.899   RNP antibody positive  83/213 (39.2)  61/154 (39.6)  22/59 (37.3)  0.756   Sm antibody positive  56/213 (26.4)  39/154 (25.3)  17/59 (28.8)  0.605   Ro antibody positive  84/213 (39.8)  61/154 (39.6)  23/59 (39.0)  0.933   aPL antibody positive  51/176 (29.0)  36/128 (28.1)  15/48 (31.3)  0.684  Initial renal histology class (ISN/RPS 2003), n (%)           I  2/238 (0.8)  2/179 (1.1)  0  0.725   II  26/238 (10.9)  18/179 (10.1)  8/59 (13.6)   III/IV  133/238 (55.9)  98/179 (54.7)  35/59 (59.3)   V  45/238 (18.8)  37/179 (20.7)  8/59 (13.6)   III/IV and V  31/238 (13.0)  23/179 (12.8)  8/59 (13.6)   VI  1/238 (0.4)  1/179 (0.6)  0  Clinical presentation at time of repeat biopsy Clinical indications for repeating the renal biopsies were known in 64 cases, and included either suspected flare (n = 50, 78.1%), of which 45 had worsening proteinuria with or without rising serum creatinine (90%) and 5 had rising serum creatinine without change in proteinuria (10%), or lack of treatment response (21.9%, n = 14, where the reason was reduction of proteinuria by <50% in most, but also including 4 patients who were dialysis-dependent despite treatment). Clinical variables including the level of proteinuria, serum creatinine and albumin concentrations, and lupus activity markers were similar at first and repeat biopsies (Table 2). Table 2 Clinical characteristics at reference and repeat biopsies   Reference renal biopsy  Repeat renal biopsy  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  4.90 (1.54–8.75)  5.00 (2.10–10.90)  0.848   Serum creatinine (μmol/L)  106 (66–220)  133 (75–234)  0.322   Serum albumin (g/L)  29 (23–34)  29 (24–34)  0.723  Lupus activity markers, n (%)         Raised dsDNA  21/28 (75)  18/28 (64.3)  0.383   Low C3  18/29 (62.1)  14/29 (48.3)  0.291   Low C4  17/33 (51.5)  20/33 (60.6)  0.457    Reference renal biopsy  Repeat renal biopsy  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  4.90 (1.54–8.75)  5.00 (2.10–10.90)  0.848   Serum creatinine (μmol/L)  106 (66–220)  133 (75–234)  0.322   Serum albumin (g/L)  29 (23–34)  29 (24–34)  0.723  Lupus activity markers, n (%)         Raised dsDNA  21/28 (75)  18/28 (64.3)  0.383   Low C3  18/29 (62.1)  14/29 (48.3)  0.291   Low C4  17/33 (51.5)  20/33 (60.6)  0.457  dsDNA, double-stranded DNA; C3, complement 3; C4, complement 4. Histopathological transitions The distribution of the ISN/RPS classes at reference and repeat biopsies is shown in Table 3. Overall, of the 71 repeat biopsies, histological transition occurred in 53.5% (n = 38); however, the transition was clinically significant (proliferative to non-proliferative or vice versa) in a much smaller proportion of the cases (22.5%, n = 16). When the reference biopsies were classified as proliferative (classes III, IV or combination with V), histological change to non-proliferative classes only occurred in 4 (7.7%, in one case class IV to class II suggesting disease regression rather than transformation, and in three cases classes IV and V), while when the reference biopsy showed non-proliferative lesion transitions to proliferative classes occurred in 12 (63.2%). Illustrative characteristic histopathological findings on reference and repeat biopsies are shown in Figure 1. Table 3 Histological transitions Reference kidney biopsy ISN/RPS class  Repeat kidney biopsy ISN/RPS class, n (%)   II  III  IV  V  III + V  IV + V  VI  II (n = 9)  2 (22.2)  1 (11.1)  4 (44.4)  0  0  1 (11.1)  1 (11.1)  III (n = 14)  0  6 (42.9)  3 (21.4)  0  0  5 (35.7)  0  IV (n = 26)  1 (3.8)  0  13 (50)  3 (11.5)  1 (3.8)  7 (26.9)  1 (3.8)  V (n = 9)  0  0  0  4 (44.4)  3 (33.3)  2 (22.2)  0  III+V (n = 5)  0  0  1 (20.0)  0  2 (40.0)  2 (40.0)  0  IV+V (n = 7)  0  0  0  0  0  6 (85.7)  1 (14.3)  FSGS (n = 1)  0  0  1 (100.0)  0  0  0  0  Reference kidney biopsy ISN/RPS class  Repeat kidney biopsy ISN/RPS class, n (%)   II  III  IV  V  III + V  IV + V  VI  II (n = 9)  2 (22.2)  1 (11.1)  4 (44.4)  0  0  1 (11.1)  1 (11.1)  III (n = 14)  0  6 (42.9)  3 (21.4)  0  0  5 (35.7)  0  IV (n = 26)  1 (3.8)  0  13 (50)  3 (11.5)  1 (3.8)  7 (26.9)  1 (3.8)  V (n = 9)  0  0  0  4 (44.4)  3 (33.3)  2 (22.2)  0  III+V (n = 5)  0  0  1 (20.0)  0  2 (40.0)  2 (40.0)  0  IV+V (n = 7)  0  0  0  0  0  6 (85.7)  1 (14.3)  FSGS (n = 1)  0  0  1 (100.0)  0  0  0  0  Bold type indicates non-proliferative to proliferative transitions; italic indicates proliferative to non-proliferative transitions. FIGURE 1 View largeDownload slide Example of a patient with (A) non-proliferative class (class V) on first and (B) mixed proliferative (class III + V) on repeat biopsy. FIGURE 1 View largeDownload slide Example of a patient with (A) non-proliferative class (class V) on first and (B) mixed proliferative (class III + V) on repeat biopsy. We compared clinical variables at time of repeat biopsy in those initially presenting with non-proliferative LN classes (Table 4). We found no difference in clinical characteristics (serum creatinine, albumin, proteinuria, lupus activity markers including dsDNA and complements) in patients with and without histological transitions to proliferative classes, indicating that class switch cannot be predicted by clinical variables. Table 4 Histopathological transitions from non-proliferative to proliferative classes are not predictable by clinical variables   Repeat kidney biopsy       Non-proliferative  Proliferative  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  1.9 (1.7–1.9)  1.9 (0.8–11.3)  0.548   Serum creatinine (μmol/L)  64.0 (60.0–238.0)  86.0 (81.0–143.0)  0.876   Serum albumin (g/L)  32.0 (28.0–38.0)  32.5 (26.8–39.5)  1.000  Lupus activity markers, n (%)         Raised dsDNA  1/4 (25)  5/6 (83.3)  0.165   Low complements (C3 or C4)  3/4 (75)  7/8 (87.5)  0.584    Repeat kidney biopsy       Non-proliferative  Proliferative  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  1.9 (1.7–1.9)  1.9 (0.8–11.3)  0.548   Serum creatinine (μmol/L)  64.0 (60.0–238.0)  86.0 (81.0–143.0)  0.876   Serum albumin (g/L)  32.0 (28.0–38.0)  32.5 (26.8–39.5)  1.000  Lupus activity markers, n (%)         Raised dsDNA  1/4 (25)  5/6 (83.3)  0.165   Low complements (C3 or C4)  3/4 (75)  7/8 (87.5)  0.584  dsDNA, double-stranded DNA; C3, complement 3; C4, complement 4. Therapeutic decisions after repeat renal biopsy When the biopsy was repeated due to lack of clinical response (n = 14), there was no alteration of immunosuppressive therapy in nine (64.3%, in one case there was a switch from class IV to II, while none of the others showed class transition), while immunosuppression was reduced in one (no class switch), discontinued in one (class 6 on repeat biopsy), escalated in two (14.3%; of those one showed no class change and was treated with cyclophosphamide, and one showed transition from class V to mixed class IV + V receiving cyclophosphamide and rituximab) and was unknown in one. In cases of suspected flare (n = 50), treatment remained unchanged in 6 cases (12%), was stopped in 1 (2%), escalated in 37 (74%) and was unknown in 6 (12%). The choice of treatment was: 22 cyclophosphamide, 9 mycophenolate mofetil, 5 rituximab and 1 azathioprine. Comparing treatment decisions between those with or without histological transition, all patients (n = 9, 100%) with class transition from non-proliferative to proliferative LN classes received escalation of immunosuppression, as opposed to 60% (n = 3) without class switch (P = 0.040). In those who presented with a proliferative class on reference biopsy, only two patients showed class transition to a non-proliferative class (both patients switching from class IV to class V LN, and despite the less aggressive nature of the LN both received a new immunosuppressive drug regimen). In those with proliferative lesions on both reference and repeat biopsies, treatment escalation occurred in 21 (80.8%). There was no difference in the rate of treatment escalation in case of transition from one proliferative class to another compared with those without proliferative class switch (87.5%, n = 7 versus 77.8%, n = 14, respectively, P = 0.562). Tubulointerstitial damage and correlation with clinical variables We compared tubulointerstitial lesions between reference and repeat biopsies (Figure 2). There was a progression in both tubular atrophy (mean score ± SD of 1.00 ± 0.80 to 1.47 ± 0.87, P = 0.001) and interstitial scarring (mean score ± SD of 0.89 ± 0.80 to 1.51 ± 0.90, P < 0.001), but not in inflammatory cell infiltration (mean score ± SD of 0.8 ± 0.9 to 0.8 ± 0.7, P = 1.000). The mean total tubulointerstitial score (±SD) has progressed from 2.69 ± 2.03 to 3.78 ± 2.03 (P = 0.001). FIGURE 2 View largeDownload slide Tubulointerstitial pathology. Graphs (A), (C) and (E) are showing the severity of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis, respectively; the numbers represent the percentage of cases in each severity group. Graphs (B), (D) and (F) illustrate the progression of the mean scores of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis by the time of repeat biopsy. FIGURE 2 View largeDownload slide Tubulointerstitial pathology. Graphs (A), (C) and (E) are showing the severity of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis, respectively; the numbers represent the percentage of cases in each severity group. Graphs (B), (D) and (F) illustrate the progression of the mean scores of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis by the time of repeat biopsy. There was a positive correlation between serum creatinine level and the severity of tubular atrophy at time of both reference (r = 0.33, P = 0.048) and repeat biopsies (r = 0.56, P < 0.001). In addition, serum creatinine at time of repeat biopsy showed a strong correlation with interstitial scarring (r = 0.60, P < 0.001) (Figure 3). We found no association between any of the other clinical variables and the tubulointerstitial pathology. FIGURE 3 View largeDownload slide Correlation of renal function with tubulointerstitial lesions. Correlation is demonstrated between serum creatinine and tubular atrophy (A, r = 0.597, P < 0.001) and interstitial fibrosis (B, r = 0.562, P < 0.001) at time of repeat renal biopsies. FIGURE 3 View largeDownload slide Correlation of renal function with tubulointerstitial lesions. Correlation is demonstrated between serum creatinine and tubular atrophy (A, r = 0.597, P < 0.001) and interstitial fibrosis (B, r = 0.562, P < 0.001) at time of repeat renal biopsies. A trend was identified between the severity of interstitial inflammation on reference biopsy and the amount of tubular atrophy and interstitial scarring on repeat biopsies (r = 0.349, P = 0.19; r = 0.385, P = 0.009, respectively). The mean chronicity index (CI ± SD) increased from 3.58 ± 2.64 to 5.11 + 2.96 by the time of repeat biopsies. Patients with proliferative histopathology on initial biopsy had higher CI at both the reference (4.03 ± 2.48 versus 2.57 ± 2.79, proliferatives versus non-proliferatives, mean score ± SD, P = 0.047) and repeat biopsies (5.77 ± 2.94 versus 3.64 ± 2.53, proliferatives versus non-proliferatives, mean score ± SD, P = 0.019). Treatment decisions did not seem to be influenced by the progression of CI (treatment escalation in 60.9% versus 61.1%, increased CI versus stable/reduced CI, respectively, P = 0.982). DISCUSSION The aim of this retrospective analysis was to clarify the utility of repeat renal biopsies in LN in routine clinical practice. In our large LN cohort, 24.5% had a repeat biopsy with histological transitions occurring in 53.5%. Previous studies have reported a class change in 25–75%, the lower rates being reported in protocol biopsies performed at 6 months, relatively shortly after induction treatment [4, 6, 12–15]. It has been argued that class transitions from one proliferative form to another have no meaningful therapeutic consequences; however, histopathological changes from proliferative to non-proliferative classes and vice versa are of considerable interest in terms of guiding treatment. Our study shows that class transition from proliferative to non-proliferative classes are infrequent (7.7%). A few studies have reported high transition rates (over 60%) from proliferative to non-proliferative classes, often showing disease regression to class I or II [5, 16, 17]; however, these transition rates were observed on protocol renal biopsies and were likely the results of successful treatment. In the context of renal flares, class transitions from proliferative to pure non-proliferative classes are less common. Our proliferative to non-proliferative conversion rate of 7.7% is lower than the 24% in the study by Greloni et al. [6] but even lower conversion rates were published in two other studies. Daleboudt et al. [4] found during relapse, only 1 of 43 patients with proliferative LN switched to a pure non-proliferative class (2.3%), while in Alsuwaida’s [18] protocol biopsy study this kind of transition was completely absent 12–18 months after induction treatment. Even though our data suggest repeat renal biopsies may be unnecessary in those initially presenting with LN classes III/IV (± class V), there are conflicting data in similarly small cohorts in the literature. Larger cohorts or registries are required to further examine this. In contrast, class changes from the non-proliferative group were prevalent, 63.2% switching to a proliferative class, suggesting that repeat renal biopsies can be particularly valuable in guiding therapy in the group who flare whose initial biopsy shows class I, II or V. Overall, 86.4% of repeat biopsies led to a change in treatment regimens during suspected flare. Since the histopathological transitions were unpredictable based on the clinical parameters studied, it is likely that without the biopsy all patients would have had their treatment increased on clinical suspicion of LN flare. In all the scenarios exhibiting histopathological transition from non-proliferative to proliferative classes the immunosuppressive treatment was escalated, and with 78% starting a new induction treatment, either cyclophosphamide or mycophenolate mofetil. In patients with lack of treatment response, repeat renal biopsies led to treatment escalation in 15%, while in 85% treatment remained unchanged, reduced or stopped. Overall, the repeat biopsy avoided the unnecessary increase of potentially toxic drugs in 30% of the cohort. We observed a progression in chronicity scores on repeat kidney biopsies. This phenomenon has been described in both early and late protocol repeat biopsy studies as well as on biopsies performed in the context of flares [4, 5, 12, 19]. In spite of the progression in chronicity, it did not seem to have an influence on treatment decisions in this cohort. Tubulointerstitial disease is frequent in LN with immune deposits being present in up to one-third of patients [20, 21]. Lesions including interstitial infiltration, tubular atrophy and interstitial fibrosis are all independent risk factors for LN renal outcome [22]. Nevertheless, the widely used 2003 ISN/RPS classification system, differentiating six classes of LN, is purely based on glomerular pathology, and does not take into consideration other kidney compartments such as vasculature, tubules or interstitium. In our cohort there was an increase in the extent of tubular atrophy and interstitial fibrosis on repeat biopsies, without any difference in inflammatory cellularity. These findings are in line with previous studies, showing progression of glomerulosclerosis, tubular atrophy and interstitial scarring [12]. We found that serum creatinine levels showed good correlation with the severity of tubular atrophy on both the reference and repeat biopsies, and interstitial scarring on repeat biopsies. Correlation was also demonstrated between the amount of interstitial inflammation on reference biopsies and the severity of tubular atrophy and interstitial scarring on repeat biopsies, suggesting a possible prognostic role. On protocol repeat renal biopsies, the degree of interstitial inflammation positively correlated with the serum creatinine level at the time of initial biopsy but not at the end of follow-up period, and there was a strong correlation between renal survival and interstitial inflammation on repeat biopsy [18]. A limitation of this study is that data on urinary sediments was incompletely recorded and hence this could not be analysed as a potential clinical marker to identify class transitions from non-proliferative to proliferative classes. However, active sediment does not reliably differentiate class III or IV proliferative LN from class II LN. Renal biopsy is not without risk; however, the overall rate of major complications is less than 1% [23]. Apart from their use for guiding treatment during flares, repeat renal biopsies can also allow us to identify alternative diagnoses and recognize non-LN renal disease. We showed that 5.2% of biopsied SLE patients had an alternative renal diagnosis, including FSGS, acute tubular necrosis, hypertensive glomerulosclerosis, small vessel vasculitis, thin membrane nephropathy and fibrillary glomerulonephritis. The management of these disorders is largely distinct from LN treatment, and diagnoses based solely on clinical presentation without performing a kidney biopsy could have led to treatment error. In summary, in our cohort of LN, histological transition occurred in over half of repeat biopsies undertaken for clinical flare or failure of remission. Transition from proliferative classes to non-proliferative classes was unusual but the reverse was common. We found no clinical or biochemical variable that predicted class transition and hence would propose a low threshold for repeat biopsy in patients with clinically active renal disease, particularly those whose original histology is class II or V. We found that creatinine level correlated with chronic histopathological changes and hence is a useful prognostic marker. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Hsieh YP, Wen YK, Chen ML. The value of early renal biopsy in systemic lupus erythematosus patients presenting with renal involvement. Clin Nephrol  2012; 77: 18– 24 Google Scholar CrossRef Search ADS PubMed  2 Moroni G, Quaglini S, Maccario M et al.   “Nephritic flares” are predictors of bad long-term renal outcome in lupus nephritis. Kidney Int  1996; 50: 2047– 2053 Google Scholar CrossRef Search ADS PubMed  3 Sidiropoulos PI, Kritikos HD, Boumpas DT. Lupus nephritis flares. Lupus  2005; 14: 49– 52 Google Scholar CrossRef Search ADS PubMed  4 Daleboudt GM, Bajema IM, Goemaere NN et al.   The clinical relevance of a repeat biopsy in lupus nephritis flares. Nephrol Dial Transplant  2009; 24: 3712– 3717 Google Scholar CrossRef Search ADS PubMed  5 Esdaile JM, Joseph L, MacKenzie T et al.   The pathogenesis and prognosis of lupus nephritis: information from repeat renal biopsy. Semin Arthritis Rheum  1993; 23: 135– 148 Google Scholar CrossRef Search ADS PubMed  6 Greloni G, Scolnik M, Marin J et al.   Value of repeat biopsy in lupus nephritis flares. Lupus Sci Med  2014; 1: e000004 Google Scholar CrossRef Search ADS PubMed  7 Bertsias GK, Tektonidou M, Amoura Z et al.   Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis  2012; 71: 1771– 1782 Google Scholar CrossRef Search ADS PubMed  8 Kidney Disease: Improving Global Outomes (KDIGO) Glomerulonephritis Work Group (2012). KDIGO clinical practice guidelines for glomerulonephritis. 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Chin Med J  2012; 125: 2890– 2894 Google Scholar PubMed  16 Gunnarsson I, Sundelin B, Heimburger M et al.   Repeated renal biopsy in proliferative lupus nephritis—predictive role of serum C1q and albuminuria. J Rheumatol  2002; 29: 693– 699 Google Scholar PubMed  17 Lee HS, Mujais SK, Kasinath BS et al.   Course of renal pathology in patients with systemic lupus erythematosus. Am J Med  1984; 77: 612– 620 Google Scholar CrossRef Search ADS PubMed  18 Alsuwaida AO. Interstitial inflammation and long-term renal outcomes in lupus nephritis. Lupus  2013; 22: 1446– 1454 Google Scholar CrossRef Search ADS PubMed  19 Zickert A, Sundelin B, Svenungsson E et al.   Role of early repeated renal biopsies in lupus nephritis. Lupus Sci Med  2014; 1: e000018 Google Scholar CrossRef Search ADS PubMed  20 O'Dell JR, Hays RC, Guggenheim SJ et al.   Tubulointerstitial renal disease in systemic lupus erythematosus. 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All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Utility of a repeat renal biopsy in lupus nephritis: a single centre experience

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
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10.1093/ndt/gfx019
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Abstract

Abstract Background The role of repeat renal biopsy in lupus nephritis (LN) to guide treatment or predict prognosis has been controversial. We assessed glomerular and tubulointerstitial histological characteristics of serial renal biopsies, correlations with clinical variables and the impact on subsequent management. Methods Out of a large single-centre cohort of 270 biopsy-proven LN patients, 66 (24%) had serial biopsies. LN classes based on glomerular pathology were defined according to the International Society of Nephrology/Renal Pathology Society 2003 classification, while tubulointerstitial pathologies were evaluated using the revised Austin’s semi-quantitative scoring system. Results LN class transitions from proliferative (III and IV) to non-proliferative classes (II and V) were uncommon (n = 4, 7.7%), while non-proliferatives frequently switched to proliferative classes (n = 12, 63.2%) and were more likely to receive increased immunosuppression (P = 0.040). Biochemical or serological variables could not predict these histopathological transitions. Tubulointerstitial score (mean ± standard deviation) progressed from 2.69 ± 2.03 on reference to 3.78 ± 2.03 on repeat biopsy (P = 0.001). Serum creatinine levels correlated with the degree of tubular atrophy on both reference (r = 0.33, P = 0.048) and repeat biopsy (r = 0.56, P < 0.001), and with interstitial scarring (r = 0.60, P < 0.001) on repeat biopsy. Greater interstitial inflammation on reference biopsy was associated with advanced interstitial scarring on repeat biopsies (r = 0.385, P = 0.009). Conclusions Repeat renal biopsy is an important tool to guide management, in particular in those with initial class II or V who flare. Although class transitions cannot be predicted by clinical parameters, serum creatinine level correlates with the degree of tubulointerstitial damage. lupus nephritis, repeat biopsy, tubulointerstitial changes INTRODUCTION Renal biopsy plays a crucial role in the diagnosis of lupus nephritis (LN) [1]. However, its clinical relevance in subsequent renal flares has been subject to debate. Up to 60% of patients with systemic lupus erythematosus (SLE) develop renal involvement during the course of the disease and despite the increasing variety of immunosuppressive treatment options, response is often incomplete and relapses remain common. There has been no clear consensus on relapse definition but the majority of studies define flares as either proteinuric, based on a rise of protein excretion, or nephritic, based on urinary sediment [2]. Both types of flare are known to add to the overall cumulative damage in LN and hence often lead to escalation of treatments, which may potentially have toxic effects [3]. The proliferative classes (classes III and IV) require immunosuppression while the evidence is not strong for the other classes. Some authors have advocated that since patients with proliferative lesions on their first biopsy rarely switch to a pure non-proliferative nephritis during a flare, immunosuppression can be escalated without performing a repeat renal biopsy [4]. However, other studies have suggested that clinical flares do not always correspond to proliferative lesions on repeat biopsy and class transitions may be common [5, 6]. Furthermore, there may be features on repeat renal biopsies such as tubular atrophy and tubulointerstitial scarring that flag high risk groups for renal failure who may not respond well to immunosuppression. Current guidelines do not seem to have robust recommendations for indications of repeat renal biopsies. While the joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) guideline proposes repeat renal biopsies for those with worsening or non-responding renal disease despite 1-year of immunosuppressive treatment [7], the Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends considering repeat renal biopsies in patients showing worsening renal function in the 3 months of induction treatment or in the absence of complete remission after 12 months of maintenance treatment [8]. Both guidelines suggest considering a repeat renal biopsy during nephritis flare if there is a suspicion of class transition or there is uncertainty in differentiating activity from chronic damage, or to detect an alternative pathology. In this study, we aimed to evaluate the histological characteristics of repeat renal biopsies and whether a repeat biopsy may be an important tool in guiding therapeutic decisions in terms of optimizing immunosuppressive treatment. MATERIALS AND METHODS Patients and study design This retrospective study was carried out at a tertiary lupus centre within a large university hospital, Barts Health NHS Trust, UK. All patients fulfiled at least four of the American College of Rheumatology revised classification criteria for SLE [9]. Renal biopsies LN classes based on glomerular pathology were defined according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification [10]. Eight patients had more than two biopsies, in those cases the last biopsy performed before the repeat biopsy served as reference biopsy. Classes III, IV and combinations with V were considered proliferative classes, while classes I, II and V were considered non-proliferative. LN class II (mesangial proliferative LN) was grouped with classes I and V because of its relatively benign nature. Interstitial inflammation was scored semi-quantitatively according to the revised Austin’s scoring system using a grading system of 0–3 (0, normal; 1, mild <25%; 2, moderate between 26 and 50%; 3, severe >50% of the interstitium affected) [11]. Using a similar method, chronicity indices (0–12) were calculated and included scores for glomerular sclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. Treatment Individual nephrologists and rheumatologists decided the choice of immunosuppressive treatment. We considered a treatment change when the immunosuppressive treatment dose was changed or a new induction treatment was initiated. Statistical analysis Descriptive analyses were performed on the clinical and histological data. Continuous variables are shown as means ± standard deviation (SD) or medians with interquartile range (IQR), and were analysed using one-way ANOVA or Mann–Whitney U tests. For categorical variables Pearson’s chi test was used, and data are shown as percentages. Spearman’s rank-order correlation was run to determine relationship between clinical variables and histological findings. All statistical analyses were performed using SPSS software version 22 for Mac; P-values <0.05 were considered statistically significant. RESULTS Patient characteristics A total of 285 SLE patients underwent a renal biopsy. Of those, 270 had histological evidence of LN, while 15 patients (5.2%) had an alternative diagnosis including focal segmental glomerulosclerosis (FSGS, n = 4), normal (n = 2), thrombotic microangiopathy (n = 2), acute tubular necrosis (n = 2), hypertensive glomerulosclerosis (n = 2), thin membrane nephropathy (n = 1), small vessel vasculitis (n = 1) and fibrillary glomerulonephritis (n = 1). We identified 66 LN patients (24.5%) with two or more renal biopsies; however, 7 patients were excluded from the final analysis as the initial biopsy was done elsewhere. In total, 130 renal biopsies were analysed. The baseline characteristics at first biopsy comparing LN patients with or without repeat biopsy are shown in Table 1. The median time between initial and repeat biopsies was 32 months (IQR, 13–80 months). Patients with repeat kidney biopsies were significantly younger at both SLE (26 versus 31 years, P = 0.007) and LN diagnosis (28 versus 34 years, P = 0.001) compared with those with no repeat biopsy. Regarding histopathological classes, proliferative classes with or without membranous component were the most frequent (n = 44, 73.4%). One case of FSGS was felt most likely to be secondary to LN based on clinical presentation and serological evidence of active SLE, in addition to the histological findings. Table 1 Baseline demographics and characteristics of LN patients with or without repeat renal biopsy   Total (n = 270)  Without repeat biopsy (n = 204)  With repeat biopsy (n = 66)  P-value  Gender, n (%)           Male  41 (15.2)  30 (14.7)  12 (18.2)  0.498   Female  228 (84.8)  174 (85.3)  54 (81.8)  Ethnicity, n (%)           African/Afro-Caribbean Black  116 (43.0)  78 (38.2)  38 (57.6)  0.069   White Caucasian  53 (19.6)  44 (21.6)  9 (13.6)   South Asian  56 (20.7)  44 (21.6)  12 (18.2)   Oriental Asian  13 (4.8)  10 (4.9)  3 (4.5)   Other/mixed race  32 (11.9)  28 (13.7)  4 (6.1)  Age (years), mean (SD)           at SLE diagnosis  29 (11.8)  31 (11.6)  26 (11.7)  0.007   at LN diagnosis  32 (12.1)  34 (12.1)  28 (11.1)  0.001  Serology, n (%)           ANA positive  210/223 (94.2)  155/163 (95.1)  55/60 (91.7)  0.333   ENA antibody positive  143/213 (67.8)  103/154 (66.9)  40/59 (67.8)  0.899   RNP antibody positive  83/213 (39.2)  61/154 (39.6)  22/59 (37.3)  0.756   Sm antibody positive  56/213 (26.4)  39/154 (25.3)  17/59 (28.8)  0.605   Ro antibody positive  84/213 (39.8)  61/154 (39.6)  23/59 (39.0)  0.933   aPL antibody positive  51/176 (29.0)  36/128 (28.1)  15/48 (31.3)  0.684  Initial renal histology class (ISN/RPS 2003), n (%)           I  2/238 (0.8)  2/179 (1.1)  0  0.725   II  26/238 (10.9)  18/179 (10.1)  8/59 (13.6)   III/IV  133/238 (55.9)  98/179 (54.7)  35/59 (59.3)   V  45/238 (18.8)  37/179 (20.7)  8/59 (13.6)   III/IV and V  31/238 (13.0)  23/179 (12.8)  8/59 (13.6)   VI  1/238 (0.4)  1/179 (0.6)  0    Total (n = 270)  Without repeat biopsy (n = 204)  With repeat biopsy (n = 66)  P-value  Gender, n (%)           Male  41 (15.2)  30 (14.7)  12 (18.2)  0.498   Female  228 (84.8)  174 (85.3)  54 (81.8)  Ethnicity, n (%)           African/Afro-Caribbean Black  116 (43.0)  78 (38.2)  38 (57.6)  0.069   White Caucasian  53 (19.6)  44 (21.6)  9 (13.6)   South Asian  56 (20.7)  44 (21.6)  12 (18.2)   Oriental Asian  13 (4.8)  10 (4.9)  3 (4.5)   Other/mixed race  32 (11.9)  28 (13.7)  4 (6.1)  Age (years), mean (SD)           at SLE diagnosis  29 (11.8)  31 (11.6)  26 (11.7)  0.007   at LN diagnosis  32 (12.1)  34 (12.1)  28 (11.1)  0.001  Serology, n (%)           ANA positive  210/223 (94.2)  155/163 (95.1)  55/60 (91.7)  0.333   ENA antibody positive  143/213 (67.8)  103/154 (66.9)  40/59 (67.8)  0.899   RNP antibody positive  83/213 (39.2)  61/154 (39.6)  22/59 (37.3)  0.756   Sm antibody positive  56/213 (26.4)  39/154 (25.3)  17/59 (28.8)  0.605   Ro antibody positive  84/213 (39.8)  61/154 (39.6)  23/59 (39.0)  0.933   aPL antibody positive  51/176 (29.0)  36/128 (28.1)  15/48 (31.3)  0.684  Initial renal histology class (ISN/RPS 2003), n (%)           I  2/238 (0.8)  2/179 (1.1)  0  0.725   II  26/238 (10.9)  18/179 (10.1)  8/59 (13.6)   III/IV  133/238 (55.9)  98/179 (54.7)  35/59 (59.3)   V  45/238 (18.8)  37/179 (20.7)  8/59 (13.6)   III/IV and V  31/238 (13.0)  23/179 (12.8)  8/59 (13.6)   VI  1/238 (0.4)  1/179 (0.6)  0  Clinical presentation at time of repeat biopsy Clinical indications for repeating the renal biopsies were known in 64 cases, and included either suspected flare (n = 50, 78.1%), of which 45 had worsening proteinuria with or without rising serum creatinine (90%) and 5 had rising serum creatinine without change in proteinuria (10%), or lack of treatment response (21.9%, n = 14, where the reason was reduction of proteinuria by <50% in most, but also including 4 patients who were dialysis-dependent despite treatment). Clinical variables including the level of proteinuria, serum creatinine and albumin concentrations, and lupus activity markers were similar at first and repeat biopsies (Table 2). Table 2 Clinical characteristics at reference and repeat biopsies   Reference renal biopsy  Repeat renal biopsy  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  4.90 (1.54–8.75)  5.00 (2.10–10.90)  0.848   Serum creatinine (μmol/L)  106 (66–220)  133 (75–234)  0.322   Serum albumin (g/L)  29 (23–34)  29 (24–34)  0.723  Lupus activity markers, n (%)         Raised dsDNA  21/28 (75)  18/28 (64.3)  0.383   Low C3  18/29 (62.1)  14/29 (48.3)  0.291   Low C4  17/33 (51.5)  20/33 (60.6)  0.457    Reference renal biopsy  Repeat renal biopsy  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  4.90 (1.54–8.75)  5.00 (2.10–10.90)  0.848   Serum creatinine (μmol/L)  106 (66–220)  133 (75–234)  0.322   Serum albumin (g/L)  29 (23–34)  29 (24–34)  0.723  Lupus activity markers, n (%)         Raised dsDNA  21/28 (75)  18/28 (64.3)  0.383   Low C3  18/29 (62.1)  14/29 (48.3)  0.291   Low C4  17/33 (51.5)  20/33 (60.6)  0.457  dsDNA, double-stranded DNA; C3, complement 3; C4, complement 4. Histopathological transitions The distribution of the ISN/RPS classes at reference and repeat biopsies is shown in Table 3. Overall, of the 71 repeat biopsies, histological transition occurred in 53.5% (n = 38); however, the transition was clinically significant (proliferative to non-proliferative or vice versa) in a much smaller proportion of the cases (22.5%, n = 16). When the reference biopsies were classified as proliferative (classes III, IV or combination with V), histological change to non-proliferative classes only occurred in 4 (7.7%, in one case class IV to class II suggesting disease regression rather than transformation, and in three cases classes IV and V), while when the reference biopsy showed non-proliferative lesion transitions to proliferative classes occurred in 12 (63.2%). Illustrative characteristic histopathological findings on reference and repeat biopsies are shown in Figure 1. Table 3 Histological transitions Reference kidney biopsy ISN/RPS class  Repeat kidney biopsy ISN/RPS class, n (%)   II  III  IV  V  III + V  IV + V  VI  II (n = 9)  2 (22.2)  1 (11.1)  4 (44.4)  0  0  1 (11.1)  1 (11.1)  III (n = 14)  0  6 (42.9)  3 (21.4)  0  0  5 (35.7)  0  IV (n = 26)  1 (3.8)  0  13 (50)  3 (11.5)  1 (3.8)  7 (26.9)  1 (3.8)  V (n = 9)  0  0  0  4 (44.4)  3 (33.3)  2 (22.2)  0  III+V (n = 5)  0  0  1 (20.0)  0  2 (40.0)  2 (40.0)  0  IV+V (n = 7)  0  0  0  0  0  6 (85.7)  1 (14.3)  FSGS (n = 1)  0  0  1 (100.0)  0  0  0  0  Reference kidney biopsy ISN/RPS class  Repeat kidney biopsy ISN/RPS class, n (%)   II  III  IV  V  III + V  IV + V  VI  II (n = 9)  2 (22.2)  1 (11.1)  4 (44.4)  0  0  1 (11.1)  1 (11.1)  III (n = 14)  0  6 (42.9)  3 (21.4)  0  0  5 (35.7)  0  IV (n = 26)  1 (3.8)  0  13 (50)  3 (11.5)  1 (3.8)  7 (26.9)  1 (3.8)  V (n = 9)  0  0  0  4 (44.4)  3 (33.3)  2 (22.2)  0  III+V (n = 5)  0  0  1 (20.0)  0  2 (40.0)  2 (40.0)  0  IV+V (n = 7)  0  0  0  0  0  6 (85.7)  1 (14.3)  FSGS (n = 1)  0  0  1 (100.0)  0  0  0  0  Bold type indicates non-proliferative to proliferative transitions; italic indicates proliferative to non-proliferative transitions. FIGURE 1 View largeDownload slide Example of a patient with (A) non-proliferative class (class V) on first and (B) mixed proliferative (class III + V) on repeat biopsy. FIGURE 1 View largeDownload slide Example of a patient with (A) non-proliferative class (class V) on first and (B) mixed proliferative (class III + V) on repeat biopsy. We compared clinical variables at time of repeat biopsy in those initially presenting with non-proliferative LN classes (Table 4). We found no difference in clinical characteristics (serum creatinine, albumin, proteinuria, lupus activity markers including dsDNA and complements) in patients with and without histological transitions to proliferative classes, indicating that class switch cannot be predicted by clinical variables. Table 4 Histopathological transitions from non-proliferative to proliferative classes are not predictable by clinical variables   Repeat kidney biopsy       Non-proliferative  Proliferative  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  1.9 (1.7–1.9)  1.9 (0.8–11.3)  0.548   Serum creatinine (μmol/L)  64.0 (60.0–238.0)  86.0 (81.0–143.0)  0.876   Serum albumin (g/L)  32.0 (28.0–38.0)  32.5 (26.8–39.5)  1.000  Lupus activity markers, n (%)         Raised dsDNA  1/4 (25)  5/6 (83.3)  0.165   Low complements (C3 or C4)  3/4 (75)  7/8 (87.5)  0.584    Repeat kidney biopsy       Non-proliferative  Proliferative  P-value  Biochemical variables, median (IQR)       Proteinuria (g/day)  1.9 (1.7–1.9)  1.9 (0.8–11.3)  0.548   Serum creatinine (μmol/L)  64.0 (60.0–238.0)  86.0 (81.0–143.0)  0.876   Serum albumin (g/L)  32.0 (28.0–38.0)  32.5 (26.8–39.5)  1.000  Lupus activity markers, n (%)         Raised dsDNA  1/4 (25)  5/6 (83.3)  0.165   Low complements (C3 or C4)  3/4 (75)  7/8 (87.5)  0.584  dsDNA, double-stranded DNA; C3, complement 3; C4, complement 4. Therapeutic decisions after repeat renal biopsy When the biopsy was repeated due to lack of clinical response (n = 14), there was no alteration of immunosuppressive therapy in nine (64.3%, in one case there was a switch from class IV to II, while none of the others showed class transition), while immunosuppression was reduced in one (no class switch), discontinued in one (class 6 on repeat biopsy), escalated in two (14.3%; of those one showed no class change and was treated with cyclophosphamide, and one showed transition from class V to mixed class IV + V receiving cyclophosphamide and rituximab) and was unknown in one. In cases of suspected flare (n = 50), treatment remained unchanged in 6 cases (12%), was stopped in 1 (2%), escalated in 37 (74%) and was unknown in 6 (12%). The choice of treatment was: 22 cyclophosphamide, 9 mycophenolate mofetil, 5 rituximab and 1 azathioprine. Comparing treatment decisions between those with or without histological transition, all patients (n = 9, 100%) with class transition from non-proliferative to proliferative LN classes received escalation of immunosuppression, as opposed to 60% (n = 3) without class switch (P = 0.040). In those who presented with a proliferative class on reference biopsy, only two patients showed class transition to a non-proliferative class (both patients switching from class IV to class V LN, and despite the less aggressive nature of the LN both received a new immunosuppressive drug regimen). In those with proliferative lesions on both reference and repeat biopsies, treatment escalation occurred in 21 (80.8%). There was no difference in the rate of treatment escalation in case of transition from one proliferative class to another compared with those without proliferative class switch (87.5%, n = 7 versus 77.8%, n = 14, respectively, P = 0.562). Tubulointerstitial damage and correlation with clinical variables We compared tubulointerstitial lesions between reference and repeat biopsies (Figure 2). There was a progression in both tubular atrophy (mean score ± SD of 1.00 ± 0.80 to 1.47 ± 0.87, P = 0.001) and interstitial scarring (mean score ± SD of 0.89 ± 0.80 to 1.51 ± 0.90, P < 0.001), but not in inflammatory cell infiltration (mean score ± SD of 0.8 ± 0.9 to 0.8 ± 0.7, P = 1.000). The mean total tubulointerstitial score (±SD) has progressed from 2.69 ± 2.03 to 3.78 ± 2.03 (P = 0.001). FIGURE 2 View largeDownload slide Tubulointerstitial pathology. Graphs (A), (C) and (E) are showing the severity of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis, respectively; the numbers represent the percentage of cases in each severity group. Graphs (B), (D) and (F) illustrate the progression of the mean scores of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis by the time of repeat biopsy. FIGURE 2 View largeDownload slide Tubulointerstitial pathology. Graphs (A), (C) and (E) are showing the severity of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis, respectively; the numbers represent the percentage of cases in each severity group. Graphs (B), (D) and (F) illustrate the progression of the mean scores of tubular atrophy, inflammatory cell infiltration and interstitial fibrosis by the time of repeat biopsy. There was a positive correlation between serum creatinine level and the severity of tubular atrophy at time of both reference (r = 0.33, P = 0.048) and repeat biopsies (r = 0.56, P < 0.001). In addition, serum creatinine at time of repeat biopsy showed a strong correlation with interstitial scarring (r = 0.60, P < 0.001) (Figure 3). We found no association between any of the other clinical variables and the tubulointerstitial pathology. FIGURE 3 View largeDownload slide Correlation of renal function with tubulointerstitial lesions. Correlation is demonstrated between serum creatinine and tubular atrophy (A, r = 0.597, P < 0.001) and interstitial fibrosis (B, r = 0.562, P < 0.001) at time of repeat renal biopsies. FIGURE 3 View largeDownload slide Correlation of renal function with tubulointerstitial lesions. Correlation is demonstrated between serum creatinine and tubular atrophy (A, r = 0.597, P < 0.001) and interstitial fibrosis (B, r = 0.562, P < 0.001) at time of repeat renal biopsies. A trend was identified between the severity of interstitial inflammation on reference biopsy and the amount of tubular atrophy and interstitial scarring on repeat biopsies (r = 0.349, P = 0.19; r = 0.385, P = 0.009, respectively). The mean chronicity index (CI ± SD) increased from 3.58 ± 2.64 to 5.11 + 2.96 by the time of repeat biopsies. Patients with proliferative histopathology on initial biopsy had higher CI at both the reference (4.03 ± 2.48 versus 2.57 ± 2.79, proliferatives versus non-proliferatives, mean score ± SD, P = 0.047) and repeat biopsies (5.77 ± 2.94 versus 3.64 ± 2.53, proliferatives versus non-proliferatives, mean score ± SD, P = 0.019). Treatment decisions did not seem to be influenced by the progression of CI (treatment escalation in 60.9% versus 61.1%, increased CI versus stable/reduced CI, respectively, P = 0.982). DISCUSSION The aim of this retrospective analysis was to clarify the utility of repeat renal biopsies in LN in routine clinical practice. In our large LN cohort, 24.5% had a repeat biopsy with histological transitions occurring in 53.5%. Previous studies have reported a class change in 25–75%, the lower rates being reported in protocol biopsies performed at 6 months, relatively shortly after induction treatment [4, 6, 12–15]. It has been argued that class transitions from one proliferative form to another have no meaningful therapeutic consequences; however, histopathological changes from proliferative to non-proliferative classes and vice versa are of considerable interest in terms of guiding treatment. Our study shows that class transition from proliferative to non-proliferative classes are infrequent (7.7%). A few studies have reported high transition rates (over 60%) from proliferative to non-proliferative classes, often showing disease regression to class I or II [5, 16, 17]; however, these transition rates were observed on protocol renal biopsies and were likely the results of successful treatment. In the context of renal flares, class transitions from proliferative to pure non-proliferative classes are less common. Our proliferative to non-proliferative conversion rate of 7.7% is lower than the 24% in the study by Greloni et al. [6] but even lower conversion rates were published in two other studies. Daleboudt et al. [4] found during relapse, only 1 of 43 patients with proliferative LN switched to a pure non-proliferative class (2.3%), while in Alsuwaida’s [18] protocol biopsy study this kind of transition was completely absent 12–18 months after induction treatment. Even though our data suggest repeat renal biopsies may be unnecessary in those initially presenting with LN classes III/IV (± class V), there are conflicting data in similarly small cohorts in the literature. Larger cohorts or registries are required to further examine this. In contrast, class changes from the non-proliferative group were prevalent, 63.2% switching to a proliferative class, suggesting that repeat renal biopsies can be particularly valuable in guiding therapy in the group who flare whose initial biopsy shows class I, II or V. Overall, 86.4% of repeat biopsies led to a change in treatment regimens during suspected flare. Since the histopathological transitions were unpredictable based on the clinical parameters studied, it is likely that without the biopsy all patients would have had their treatment increased on clinical suspicion of LN flare. In all the scenarios exhibiting histopathological transition from non-proliferative to proliferative classes the immunosuppressive treatment was escalated, and with 78% starting a new induction treatment, either cyclophosphamide or mycophenolate mofetil. In patients with lack of treatment response, repeat renal biopsies led to treatment escalation in 15%, while in 85% treatment remained unchanged, reduced or stopped. Overall, the repeat biopsy avoided the unnecessary increase of potentially toxic drugs in 30% of the cohort. We observed a progression in chronicity scores on repeat kidney biopsies. This phenomenon has been described in both early and late protocol repeat biopsy studies as well as on biopsies performed in the context of flares [4, 5, 12, 19]. In spite of the progression in chronicity, it did not seem to have an influence on treatment decisions in this cohort. Tubulointerstitial disease is frequent in LN with immune deposits being present in up to one-third of patients [20, 21]. Lesions including interstitial infiltration, tubular atrophy and interstitial fibrosis are all independent risk factors for LN renal outcome [22]. Nevertheless, the widely used 2003 ISN/RPS classification system, differentiating six classes of LN, is purely based on glomerular pathology, and does not take into consideration other kidney compartments such as vasculature, tubules or interstitium. In our cohort there was an increase in the extent of tubular atrophy and interstitial fibrosis on repeat biopsies, without any difference in inflammatory cellularity. These findings are in line with previous studies, showing progression of glomerulosclerosis, tubular atrophy and interstitial scarring [12]. We found that serum creatinine levels showed good correlation with the severity of tubular atrophy on both the reference and repeat biopsies, and interstitial scarring on repeat biopsies. Correlation was also demonstrated between the amount of interstitial inflammation on reference biopsies and the severity of tubular atrophy and interstitial scarring on repeat biopsies, suggesting a possible prognostic role. On protocol repeat renal biopsies, the degree of interstitial inflammation positively correlated with the serum creatinine level at the time of initial biopsy but not at the end of follow-up period, and there was a strong correlation between renal survival and interstitial inflammation on repeat biopsy [18]. A limitation of this study is that data on urinary sediments was incompletely recorded and hence this could not be analysed as a potential clinical marker to identify class transitions from non-proliferative to proliferative classes. However, active sediment does not reliably differentiate class III or IV proliferative LN from class II LN. Renal biopsy is not without risk; however, the overall rate of major complications is less than 1% [23]. Apart from their use for guiding treatment during flares, repeat renal biopsies can also allow us to identify alternative diagnoses and recognize non-LN renal disease. We showed that 5.2% of biopsied SLE patients had an alternative renal diagnosis, including FSGS, acute tubular necrosis, hypertensive glomerulosclerosis, small vessel vasculitis, thin membrane nephropathy and fibrillary glomerulonephritis. The management of these disorders is largely distinct from LN treatment, and diagnoses based solely on clinical presentation without performing a kidney biopsy could have led to treatment error. In summary, in our cohort of LN, histological transition occurred in over half of repeat biopsies undertaken for clinical flare or failure of remission. Transition from proliferative classes to non-proliferative classes was unusual but the reverse was common. We found no clinical or biochemical variable that predicted class transition and hence would propose a low threshold for repeat biopsy in patients with clinically active renal disease, particularly those whose original histology is class II or V. We found that creatinine level correlated with chronic histopathological changes and hence is a useful prognostic marker. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Hsieh YP, Wen YK, Chen ML. The value of early renal biopsy in systemic lupus erythematosus patients presenting with renal involvement. Clin Nephrol  2012; 77: 18– 24 Google Scholar CrossRef Search ADS PubMed  2 Moroni G, Quaglini S, Maccario M et al.   “Nephritic flares” are predictors of bad long-term renal outcome in lupus nephritis. Kidney Int  1996; 50: 2047– 2053 Google Scholar CrossRef Search ADS PubMed  3 Sidiropoulos PI, Kritikos HD, Boumpas DT. Lupus nephritis flares. Lupus  2005; 14: 49– 52 Google Scholar CrossRef Search ADS PubMed  4 Daleboudt GM, Bajema IM, Goemaere NN et al.   The clinical relevance of a repeat biopsy in lupus nephritis flares. 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Nephrology Dialysis TransplantationOxford University Press

Published: Mar 1, 2018

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