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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 4  |  Page : 801-807
Protocol renal biopsy in patients with lupus nephritis: A single center experience


1 Department of Nephrology, Institute of Postgraduate Medical Education and Research, Kolkata, India
2 Department of Medicine, Government Medical College, Jammu, India

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Date of Web Publication24-Jun-2014
 

   Abstract 

Renal biopsy plays an indispensable role in the diagnosis and management of patients with lupus nephritis (LN). A number of studies have evaluated the role of a repeat biopsy in case of disease relapse or treatment unresponsiveness. We studied 40 patients with LN with renal biopsies performed at baseline and after six months of therapy. The baseline and protocol biopsies were compared with respect to histological class transformation, crescents, tubular atrophy, interstitial fibrosis and glomerulosclerosis. We also compared serum creatinine, hemog­lobin, systemic lupus erythematosus disease activity index (SLEDAI) scores, 24-h urine protein excretion and C3levels as well as activity index (AI) and chronicity index (CI) at baseline and at six months. Comparison of means was made by paired t test, McNemar test and marginal homogeneity test (multinomial data). Histological class transformation was seen in 10 patients (25%). Intra-class progression to greater chronicity was seen in 10 other patients (25%).There was an increase in glomerulosclerosis, tubular atrophy, interstitial fibrosis and a reduction in cellularity, crescent formation and wire loop lesions in the protocol biopsy. A decline in AI (6.05 vs. 2.50, P <0.001) and SLEDAI scores (8.1 vs. 3.7, P <0.001) and an increase in CI (0.68 vs. 2.52, P <0.001) was observed at the time of protocol biopsy. Our study shows a trend toward greater chronicity in protocol biopsies in LN.

How to cite this article:
Singh A, Ghosh R, Kaur P, Golay V, Pandey R, Roychowdhury A. Protocol renal biopsy in patients with lupus nephritis: A single center experience. Saudi J Kidney Dis Transpl 2014;25:801-7

How to cite this URL:
Singh A, Ghosh R, Kaur P, Golay V, Pandey R, Roychowdhury A. Protocol renal biopsy in patients with lupus nephritis: A single center experience. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Dec 8];25:801-7. Available from: https://www.sjkdt.org/text.asp?2014/25/4/801/135016

   Introduction Top


Systemic lupus erythematosus (SLE) is an autoimmune disease involving the kidneys in up to 60% of patients. [1] Presentation of lupus nephritis (LN) may be quite diverse, ranging from asymptomatic proteinuria to rapidly pro­gressive glomerulonephritis. Histological trans­formation among different classes of LN has been reported; [2] mostly, these are small retros­pective studies based on the old World Health Organization (WHO) classification. Deterio­ration of renal parameters or an increase in proteinuria are the common reasons for ob­taining a repeat renal biopsy in most of these studies. [3] The effects of treatment and the change in the activity index (AI) and the chronicity index (CI) have been evaluated in other studies. [4]

Some studies have assessed the modification in treatment regimen based on findings in the repeat biopsy. [5] It is not un­common for a proliferative lesion on renal biopsy to masquerade clinically as mild di­sease with minimal symptoms, normal renal functions and inactive urinary sediment. This also holds true for a repeat renal biopsy that may show a histological class transformation in the absence of any change in clinical picture and, hence, may warrant a change in the course of treatment.


   Subjects and Methods Top


This study was conducted at the Department of Nephrology, IPGMER, Kolkata, India between January 2010 and March 2012. A total of 40 patients with LN were included in the study.

Inclusion criteria

  1. Newly diagnosed patients with SLE according to the revised American College of Rheumatology (ACR) criteria (2006) [6]
  2. Urine protein excretion more than 500 mg/d
  3. Elevated plasma creatinine level at pre­sentation or declining glomerular filtration rate (GFR)
  4. Microscopic hematuria (more than five dysmorphic red blood cells/high-power field) or one or more red blood cell casts in urinary sediment.


Exclusion criteria

  1. Patients who had been started on immuno-suppressive medication prior to study inclusion
  2. Seriously ill patients, advanced renal fai­lure and life-threatening infections
  3. Pregnant women and children less than one year old.


The following clinical and histological para­meters were analyzed at study entry:

  1. Duration of LN before admission to the study, age at the time of diagnosis, sex, organ manifestation(s), blood pressure, sys­temic lupus erythematosus disease activity index (SLEDAI) score [7]
  2. Serum creatinine level, urine microscopy, 24-h urine protein or spot urinary protein to creatinine ratio, serum albumin level, hemogram and GFR by the modification of diet in renal disease (MDRD) equation [8]
  3. Anti-nuclear antibody (ANA), serum C3 levels, anti-double-stranded DNA (dsDNA) titer
  4. Ultrasound of the kidneys
  5. Histological classification of renal biopsy, AI and CI. [9]


A percutaneous renal biopsy was obtained in all patients at study inclusion using an auto­mated biopsy gun. The specimens were pre­pared for light microscopic and immunofluo-rescence studies. Biopsy specimens were cate­gorized according to the International Society of Nephrology/Renal Pathology Society (ISN/ RPS) classification only when at least 10 glo-meruli were obtained.

Treatment regimens

All patients initially received oral predni-solone (1 mg/kg/d). Pulse intravenous methyl-prednisolone (500 mg/d for 3 days) was admi­nistered in severe cases with rapidly deterio­rating renal function. Depending on the renal histological characteristics, disease activity and overall clinical status, the patients were admi­nistered intravenous pulse cyclophosphamide six monthly. Cyclophosphamide was given at an initial dose of 0.75 g/m [2] body surface area. Prednisolone dose was maintained for six to eight weeks and, subsequently, tapered to a minimal dose required for controlling extra-renal disease.

Parameters studied during the follow-up in­cluded:

  1. Blood counts 10 days after a cyclophos-phamide pulse
  2. Monthly serum creatinine, blood urea ni­trogen, albumin and liver enzyme levels
  3. Monthly routine urine examination, 24-h urine protein or spot urine for protein to creatinine ratio
  4. SLEDAI score, ANA, anti-ds DNA levels and C 3 at the end of six months.


Baseline and protocol renal biopsy at six months were compared for the following para­meters: Transformation to a different histolo-gical ISN/RPS class, changes in the degree of crescent formation and their type as well as extent of endocapillary proliferation, fibrinoid necrosis, wire loop lesions, glomerular leuko­cyte infiltration, karyorrhexis, interstitial in­flammation, degree of glomerulosclerosis, in­terstitial fibrosis and tubular atrophy.

Outcome measures included the following: Complete remission was defined as urinary protein excretion less than 0.3 g per 24-h, with normal urinary sediment, normal serum albu­min concentration and serum creatinine that was 15% or less above the baseline value. [10] Partial remission was defined as urinary pro­tein excretion between 0.3 and 2.9 g per 24-h for patients with baseline nephrotic range pro-teinuria or more than 50% reduction in pro-teinuria for those with baseline sub-nephrotic proteinuria, with a serum albumin concentra­tion of at least 3.0 g/dL and stable renal function. [11] Treatment failure was defined as urinary protein excretion that remained at or above 3 g per 24-h or less than 50% decline in proteinuria from baseline, an increase in the serum creatinine of more than 15% above the baseline or the discontinuation of treatment due to side-effects.


   Statistical Analysis Top


Comparison of variable means was made by the paired t test, ANOVA or McNemar test (binomial data) and marginal homogeneity test (multinomial data). Wilcoxon sign rank test was used to compare the means of the variables that were not having a normal distribution. Bivariate correlation was performed with the Pearson method and by point biserial corre­lation. A P-value of <0.05 was considered sta­tistically significant. SPSS 16 was used for the analysis.


   Results Top


Females constituted 37 of the total 40 pa­tients. Hypertension was present in 47.5% of the patients (19 of 40). Ten patients were taking a single antihypertensive drug, 13 pa­tients were on two drugs and one patient was taking five antihypertensive drugs. Renin angio-tensin blockade was employed in 72.5% of the patients. Hydroxychloroquine was used in 80% of the patients. The demographic features of the study patients are shown in [Table 1].
Table 1: Baseline characteristics of the study subjects.

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Change in the histological class was seen in 10 out of the 40 patients. In addition, there was intra-class progression to features suggestive of greater chronicity in 10 other patients (8 class IV-A LN changed to class IV-C and two patients of class IV-A/C progressed to class IV-C). Regression of histological class was not common, and was seen in one class IV LN changing to class II LN. There was a signi­ficant decline in SLEDAI from a mean of 8.1 to 3.7 over the study period. There was an insignificant trend toward lower serum crea-tinine at the end of six months. Almost all patients had serum albumin values of less than 4 g% both at study baseline and at study com­pletion. However, there was a trend toward an increase in the values from a mean of 2.46 to 2.96 g% over six months, and the difference was significant. We also found a significant decline in erythrocyturia in the study. Thirty percent of the patients had nephrotic range proteinuria at Presentation, and this declined to 5% at six months. Forty-five percent of the patients had a urine protein excretion of less than 500mg in 24-h at the end of six months.

On baseline renal biopsy, it was found that 35of the 40 study patients did not have glome-rulosclerosis. After six months of the study period, 50% of the renal biopsies showed glo-merulosclerosis, with 12.5% of the biopsies showing glomerulosclerosis in more than 25% of the glomeruli. About 33% of the renal biop­sies revealed crescents at baseline, whereas at six months, 22.5% of the biopsies showed cre­scents [Figure 1]. 37.5% of the renal biopsies showed interstitial fibrosis of >25% at six months compared with 10% at baseline [Figure 2]. There was an increase in the intimal hyper-plasia of the vessels at six months, but it was not significant statistically. There was no sig­nificant change in mesangial hypercellularity in the two biopsies. Similarly, there was an insignificant trend toward a reduced number of wire loop lesions in the glomeruli in the biop­sies performed at six months [Table 2]. The histological features at baseline and after six months of follow-up are shown in [Table 3] and [Table 4].
Figure 1: Crescents on renal biopsy at baseline and at six months.

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Figure 2: Tubular atrophy at baseline and at six months.

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Table 2: Comparison of variables in the study group at baseline and six months.

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Table 3: Laboratory and histological parameters at first biopsy and relation to remission.

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Table 4: Laboratory and histological parameters at repeat biopsy and relation to remission.

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Complete remission was seen in 11 of 40 pa­tients (27.5%), partial remission in 15 patients (37.5%) and no response in 14 patients (35%). The CI at six months was significantly lower in patients who achieved complete remission than in patients with no remission. The AI and SLEDAI were also lower in patients achieving complete remission as compared with patients with partial or no remission, although the difference was not significant. Remission rates were higher in patients with lower baseline blood pressure (BP). There was no significant correlation between the outcome and baseline serum albumin, renal functions, AI, CI, C 3 levels, hemoglobin and SLEDAI [Table 5]. A bivariate correlation was performed between the baseline variables and proteinuria at six months. Higher baseline systolic and diastolic BP correlated with increasing proteinuria at six months, whereas higher hemoglobin at base­line was significantly associated with lower proteinuria at follow-up [Table 6]. No corre­lation could be found between the serum crea-tinine at six months and the baseline variables [Table 7].
Table 5: Point biserial correlation between outcome and baseline variables.

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Table 6: Correlation between baseline variables and proteinuria at 6 months.

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Table 7: Correlation between baseline variables and serum creatinine.

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   Discussion Top


The baseline renal biopsies were predomi­nantly of class IV LN (70% patients). Histolo-gical transformation from one class to another was seen in 25% of patients. More pronounced change was a trend toward developing more chronic lesions in patients with class IV LN, seen in 25% of the patients. Class transforma­tion was more common, with a non-prolife-rative lesion on baseline renal biopsy than a baseline class IV lesion. Histological transfor­mation in our study was lesser than has been described in earlier studies. This can be ex­plained by the larger number of class IV LN patients at baseline in our study. Moroni et al [12] described histological class change in 55% of the biopsies. Daleboudt et al [13] had shown a class transformation in 46% of the cases. In their study, they noted that five-sixths of non-proliferative lesions on baseline biopsy had changed to a proliferative lesion on repeat biopsy. Bajaj etal [14] showed class transforma­tion in 40% of renal biopsies. They found that progression within a class was common and was more frequent than class shifts. This ob­servation was also noted in our study. In our study, we found that histological class trans­formation was rarely predictable on the basis of available clinical and laboratory parameters. Esdaile et al [15] showed a decrease in AI and increase in CIin repeat biopsy samples. Similar observations were made by Tang et al [16] in his study. Lehman et al [17] had observed a decline in the disease AI, decrease in proteinuria and improved creatinine clearance during follow-up at the time of second biopsy.

The serum creatinine of the patients at entry was 1.55 mg%, which was higher than the entry creatinine in most other studies (1.1 mg% in the NIH study [18] and 1.2 mg% in the Euro lupus study [19] ).

Tubular atrophy and interstitial fibrosis showed a significant increase over time. In the biopsies performed at six months, there was a reduction in the cellularity and interstitial inflammation. In our study, age of the patient showed correlation with outcome; younger patients achieved lesser remission than the older ones. Short duration of the disease was correlated with a better outcome, although the association did not reach significance.

Patients who had lower baseline systolic and diastolic BP had better remission rates than those with higher values at baseline. The corre­lation was significant. No significant corre­lation was observed between the outcome and SLEDAI, AI, CI, baseline renal functions, he­moglobin, complement levels and cyclophos-phamide dosage. Many investigators have found a correlation of response rates with base­line proteinuria, renal functions, disease acti­vity and histological class. Bogdanovic et al [20] in their study found that nephrotic syndrome and class IV lesions at baseline correlated with an adverse outcome. Pattargarn et al [21] in their study found that hypertension and hematuria correlated with poorer patient survival. Yang et al [22] showed that hypertension, anemia and renal dysfunction at baseline were associated with an increased incidence of renal failure at follow-up.

Our study had certain limitations. Firstly, it is a small study comprising of only 40 patients. Secondly, almost three-fourths of the patients at study entry had class IV LN, and there were very few patients of other histological classes. As a result, the transformation of histological lesions was seen much less frequently than in earlier studies. The entry creatinine in our patients was 1.55 mg%, which might be res­ponsible for lower remission rates and greater progression to chronicity at the end of six months. The study was of short duration (six months) and, hence, it was not possible to correlate the findings of repeat biopsy with long-term patient outcome.

In conclusion, protocol renal biopsies per­formed at six months showed an increase in chronicity, especially within the same histolo-gical class. Histological class transformation was not frequently observed in our study.



 
   References Top

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5.Bajaj S, Albert L, Gladman DD, Urowitz MB, Hallett DC, Ritchie S. Serial renal biopsy in systemic lupus erythematosus. J Rheumatol 2000;27:2822-6.  Back to cited text no. 5
    
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7.Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992;35:630-40.  Back to cited text no. 7
    
8.Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med1999;130:461-70.  Back to cited text no. 8
    
9.Schwartz MM, Lan SP, Bernstein J, Hill GS, Holley K, Lewis EJ. Role of pathology indices in the management of severe lupus glomerulonephritis. Lupus Nephritis Collaborative Study Group. Kidney Int 1992;42:743-8.  Back to cited text no. 9
    
10.Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156-62.  Back to cited text no. 10
    
11.Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: The ALMS study. Rheumatology (Oxford) 2010;49:128-40.  Back to cited text no. 11
    
12.Moroni G, Pasquali S, Quaglini S, et al. Clinical and prognostic value of serial renal biopsies in lupus nephritis. Am J Kidney Dis 1999;34:530-9.  Back to cited text no. 12
    
13.Daleboudt GM, Bajema IM, Goemaere NN, van Laar JM, Bruijn JA, Berger SP. The clinical relevance of a repeat biopsy in lupus nephritis flares. Nephrol Dial Transplant 2009; 24:3712-7.  Back to cited text no. 13
    
14.Bajaj S, Albert L, Gladman DD, Urowitz MB, Hallett DC, Ritchie S. Serial renal biopsy in systemic lupus erythematosus. J Rheumatol 2000; 27:2822-6.  Back to cited text no. 14
    
15.Esdaile JM, Joseph L, MacKenzie T, Kash-garian M, Hayslett JP. The pathogenesis and prognosis of lupus nephritis: Information from repeat renal biopsy. Semin Arthritis Rheum 1993;23:135-48.  Back to cited text no. 15
    
16.Tang Z,Wang Z, Zhang HT, et al. Clinical features and renal outcome in lupus patients with diffuse crescentic glomerulonephritis. Rheumatol Int 2009; 30:45-9.  Back to cited text no. 16
    
17.Lehman TJ, Onel K. Intermittent intravenous cyclophosphamide arrests progression of the renal chronicity index in childhood systemic lupus erythematosus. J Pediatr2000;136:243-7.  Back to cited text no. 17
    
18.Illei GG, Austin HA, Crane M. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135(4):248-57.  Back to cited text no. 18
    
19.Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46(8): 2121-31.  Back to cited text no. 19
    
20.Bogdanoviæ R, Nikoliæ V, Pasiæ S, et al. Lupus nephritis in childhood: A review of 53 patients followed at a single centre. Pediatr Nephrol 2004;19:36-44.  Back to cited text no. 20
    
21.Pattaragarn A, Sumboonnanonda A, Parichati-kanond P, Supavekin S, Suntornpoch V, Vongjirad A. Systemic lupus erythematosus in Thai children: Clinicopathologic findings and outcome in 82 patients. J Med Assoc Thai 2005;88 Suppl 8:S232-41.  Back to cited text no. 21
    
22.Yang LY, Chen WP, Lin CY. Lupus nephritis in children-A review of 167 patients. Pediatrics 1994;94:335-40.  Back to cited text no. 22
    

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Correspondence Address:
Ametashver Singh
Department of Nephrology, Institute of Postgraduate Medical Education and Research, Kolkata
India
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DOI: 10.4103/1319-2442.135016

PMID: 24969191

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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