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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2019  |  Volume : 30  |  Issue : 4  |  Page : 803-811
Spectrum of glomerulonephritis in Egyptian patients with rheumatoid arthritis: A University Hospital experience


1 Department of Internal Medicine, Nephrology Unit, Cairo University, Cairo, Egypt
2 Department of Pathology, Cairo University, Cairo, Egypt
3 Department of Internal Medicine, Rheumatology and Immunology Unit, School of Medicine, Cairo University, Cairo, Egypt

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Date of Submission03-Feb-2018
Date of Decision18-Apr-2018
Date of Acceptance26-Apr-2018
Date of Web Publication27-Aug-2019
 

   Abstract 


Rheumatoid arthritis (RA) is accompanied by a variety of nephropathies. It is often difficult to distinguish between disease-associated and drug-associated renal diseases. Three hundred and seventy-six RA patients with renal involvement were included in our study; they were subjected to full history and clinical examination, kidney function, 24-h urinary protein, and kidney biopsy. All our patients were on methotrexate, low dose steroids, and nonsteroidal anti-inflammatory drugs, in addition to the previous medications. About 79.3%, 20.7%, 6.9%, and 5.9% of our patients were on leflunomide, hydroxychloroquine, etanercept, and infliximab, respectively. Renal presentation was in the form of nephrotic syndrome (33.5%), persistent subnephrotic proteinuria (12.2%), persistent proteinuria and recurrent hematuria (13.3%), acute nephritis (23.9), recurrent hematuria (7.4%), and creatinine >1.5 mg/dL (10.6%). Renal biopsies were glomerular amyloidosis (28.1%), mesangioproliferative (19.1%), membranous (6.1%), crescent (16.8%), focal segmental glomerulosclerosis (18.6%), and minimal changes (11.7%). There was a statistically significant difference in the incidence of membranous nephritis between patients who took leflunomide, and hydroxychloroquine and those did not. Etanercept in our study seems not to be related to any form of renal involvement, while infliximab is related to focal segmental sclerosis and amyloidosis of tubulointerstitial type. Kidney involvement in RA is not a rare complication. Any type of histopathological changes can be present, with amyloidosis on top of the list. Hydroxychloroquine and leflunomide are accused in membranous nephropathy. Infliximab is associated with focal segmental sclerosis and amyloidosis of tubulointerstial type, and etanercept appear to be safe as regards kidney affection.

How to cite this article:
Fayed A, Shaker A, Hamza WM, Wadie M. Spectrum of glomerulonephritis in Egyptian patients with rheumatoid arthritis: A University Hospital experience. Saudi J Kidney Dis Transpl 2019;30:803-11

How to cite this URL:
Fayed A, Shaker A, Hamza WM, Wadie M. Spectrum of glomerulonephritis in Egyptian patients with rheumatoid arthritis: A University Hospital experience. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 18];30:803-11. Available from: http://www.sjkdt.org/text.asp?2019/30/4/803/265455



   Introduction Top


Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with articular and extra-articular manifestation, and it may be associated with systemic effects.[1] Etiology of RA remains unknown. Although the impact of genetic factors is obvious, the genetic basis is not sufficient to explain the triggering of the immune insult in RA patients.[2]

RA is associated with a variety of different kidney disorders. The reported prevalence of kidney disease in patients with RA ranges from 5% to 50%, reflecting wide variations in the diagnostic criteria and definitions of renal disease. Furthermore, different study designs can affect the percent of renal affection.[3]

Regardless of the traditional cardiovascular risk factors for developing chronic kidney disease (CKD) and glomerulonephritis (GN) still RA patients had a higher risk of developing CKD and GN. This increased risk may be related to GN, chronic inflammation, comorbidities, and renal toxicity of any rheumatic drugs.[4]

Improvement of clinical and laboratory parameters in rheumatoid kidney affection was achieved in most cases after drug withdrawal and in some cases with immunosuppressant.[5] In patients with amyloid deposition, etanercept treatment reduced proteinuria as well as serum amyloid A. Furthermore, it entailed a decrease in serum creatinine (Cr) in patients with Cr values <2.0 mg/dL at the onset of amyloidosis.[6]


   Patient and Methods Top


Cairo University Hospital is a major hospital and a tertiary referral center serving patients from Cairo and also patients referred from all other governorates of Egypt. We obtained the hospital records of 1896 RA patients for whom a diagnosis was confirmed and fulfilling the 2010 ACR/EULAR RA Classification Criteria between June 2009 and July 2017. Of these RA patients, 376 developed renal affection throughout the follow-up duration. These patients with renal complications were subjected to full history and clinical examination, kidney function, 24-h urinary protein, and kidney biopsy was obtained, and we analyzed the results of these renal biopsies.

All renal biopsy specimens were evaluated by both light and immune fluorescence microscopes by specialized nephropathology team in the pathology department according to the following standard methods.

Light microscopy

Briefly, kidney biopsy specimens were fixed in buffered formalin, dehydrated in graded alcohols, and embedded in paraffin using standard techniques. Serial 3-mm thick sections were cut and treated with hematoxylin and eosin, Jones methenamine silver, Masson’s trichrome, or periodic acid–Schiff reagent. Pathological diagnosis of granulomatous interstitial nephritis depended on detection of interstitial nephritis, in which the inflammatory infiltrate contained at least one aggregate of epithelioid histiocytes admixed with lymphocytes with or without multi-nucleated giant cells. To differentiate amyloid from other hyaline deposits, Red Congo stain was used. Amyloid material has high affinity for Congo red stain and if present; amyloid deposits have a characteristic green birefringence when examined with polarized light.

Immunofluorescence microscopy

Samples were transported in Michel media, washed in buffer, and frozen in a cryostat. Sections, cut at 5 mm, were rinsed in buffer and reacted with fluorescein-tagged polyclonal rabbit antihuman antibodies to IgG, IgA, IgM, C3, C4, C1q, fibrinogen, k or l light chains (Dako, Carpenteria, CA; Kent Laboratories, Bellingham, WA, USA) for 1 h and rinsed; a cover slip was applied using aqueous mounting media.


   Statistical Analysis Top


Data were coded and entered using the Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM Corp., Armonk, NY, USA). Data were summarized using mean, standard deviation (SD), median, minimum and maximum in quantitative data, and using frequency (count) and relative frequency (percentage) for categorical data. For comparing categorical data, Chi-square test was performed. Exact test was used instead when the expected frequency is <5. P <0.05 were considered as statistically significant.


   Results Top


Our study included 376 RA with kidney affection, 180 females, 196 males, age range from 24 to 62 years with a mean of 42.3 ± 8.78, disease duration range from 13 to 56 months with a mean of 31.2% ± 7.96.25% of them were smokers. About 23.9% of our patients were diabetics, 31.4% of our patients were hypertensive, and 17.3% of our patients had interstitial lung disease.

All our patients were on methotrexate with a dose ranging from 12.5 mg/w to 25 mg/w, low dose steroid 7.5 mg/d, and nonsteroidal anti-inflammatory drugs (NSAIDs), in addition to the previous medication 79.3% of our patients were on leflunomide, 20.7% were on hydroxy-chloroqine, 6.9% were on etanercept, 5.9% were on infliximab.

Renal affection of our patients started before treatment initiation in 10.4%, and in 89.6% after starting treatment. Renal presentation in our patients were as follows; nephrotic syndrome (NS) was present in 33.5%, persistent subnephrotic proteinuria was present in 12.2%, persistent proteinuria and recurrent hematuria was present in 13.3%, acute nephritis was present in 23.9%, recurrent hematuria after the exclusion of urological causes was present in 7.4%, and impaired renal function with Cr >1.5 mg/dL was present in 10.6% [Figure 1].
Figure 1: Renal presentation in our patients.

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As regards laboratory findings, the mean and SD of Cr was 1.46 ± 1.31 mg/dL, serum calcium mean and SD was 8.17 ± 0.62 mg/dL, serum phosphorus mean and standard deviation (S)D was 3.9 ± 0.81 mg/dL, hemoglobin mean and SD was 10.2 ± 2.7g/dL, serum albumin mean and SD was 3.22 ± 0.49 mg/dL, 24-h urinary protein mean and SD was 2.8 ± 1.08 g/dL. Hematuria was found in 7.4% of our patients; 23.9 % of our patients had casts in urine.

Renal biopsy of our patients revealed the following:

  1. Glomeular affection: 28.1% of our patients had amyloidosis, 19.1% of our patients had mesangioproliferative affection, 6.1% of our patients had membranous affection, crescent form was found in 16.8% of our patients, 18.6% of our patients had focal segmental glomerulosclerosis (FSGS), and minimal change picture was found in 11.7% of our patients [Table 1].
  2. Tubulointerstitial affection: 17% of our patients had amyloidosis, 2.1% of our patients had acute nephritis, 3.5% of our patients had chronic nephritis, acute tubular necrosis (ATN) was found in 4.3% of our patients, and 38.8% of our patients had interstitial fibrosis and tubular atrophy (IF/TA was mild in 50% of them, moderate in 42.5% of them, and marked affection was found in 7.5%) [Table 2].
  3. Vascular affection: 13% of our patients had amyloidosis, 17.6% of our patients had arterial hyalinosis, 2.9% of our patients had thrombotic microangiopathy, vasculitis was found in 4.8% of our patients, and 9.9% of our patients had arterial intima fibrosis [Table 1].
Table 1: Renal biopsy results.

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Table 2: Comparison between glomerular lesions in patients on leflunomide and those without and patients on hydroxychloroquine and those without.

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Renal affection of our patients started before treatment initiation in 10.4%. About 61.5% of this subset of patients had crescentic form, 15.4% had amyloidosis, 7.8% had mesangio-proliferative affection, 5.1% had membranous affection, 5.1% had FSGS, and minimal changes was found in 5.1% of this subset of patients.

Persistent subnephrotic proteinuria was present in 12.2%. About 82.6% of this subset of patients had minimal changes, while FSGS was found in 17.4% of this subset of patients. Persistent proteinuria and recurrent hematuria were present in 13.3%. About 100% of this subset of patients had mesangioproliferative affection.

Crescentic GN was found in 16.8% of our patients. Sixty-three percent of this subset of patients had cellular crescents. Twenty-seven percent had fibrocellular crescents. Fibrous crescents were found in 10% of this subset of patients. About 71.4% of this subset of patients was antineutrophil cytoplasmic antibodies (ANCA) negative, while 15.9% of this subset of patients had ANCA-c and 12.7% had ANCA-p. C3 and C4 were done in 100% of this subset of patients which were consumed in 6.3% of this subset of patients.

About 28.1% of our patients had amyloi-dosis. The average age in these subsets of the patient was 41.9 (24–62 ± 8.9).

There was a statistically significant difference in the incidence of membranous nephro-pathy between patients who took leflunomide and those who did not also we found the same result in patients taking hydroxychloroquine where there was statistically significant difference in the incidence of membranous nephro-pathy between patients who took hydroxy-chloroquine and those who did not [Table 2].

Etanercept in our study seems not to be related to any form of renal affection, while infliximab seems to be related to focal segmental sclerosis and amyloidosis of tubulo-interstial type, as there was statistically significant difference in the incidence of focal segmental sclerosis and amyloidosis of tubulo-interstial type between patients who took infliximab and those not [Table 3].
Table 3: Comparison between patients on infliximab and those without.

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   Discussion Top


RA is a widespread disease and its renal involvement, is relatively common, and it is clinically significant because it worsens the course of the primary disease and mortality.[7]

In RA kidney is the most common affected organ with clinical presentation characterized by proteinuria (often nephrotic range) and micro-hematuria followed by chronic renal failure. This condition is well known as a rheumatoid nephropathy (rheumatoid GN), which is mediated by an immunological inflammation and by the nephrotoxic effects of numerous drugs which are usually used in treatment of RA, such as NSAID[8] This is consistent with our study where our patients present with NS, persistent subneph-rotic proteinuria, persistent proteinuria with recurrent hematuria , acute nephritis, recurrent hematuria, and impaired renal function with Cr >1.5 mg/dL, with the most common presentation was the NS. NS represent about one-third of renal affection in our patients.

RA and renal disease often coincide with each other. The renal toxicity of antirheumatic drugs (for example, NSAID or cyclosporine toxicity), secondary renal disease which induced by the chronic inflammatory process (especially renal amyloidosis) and potentially, renal manifestations of the primary disease process, are an important differential diagnoses.[9] In this study, most of our patients started to develop renal affection mainly after starting RA treatment by 89.6%, and hence, this may raise the possibility of the major role of the medication in renal affection, we study the effect of different medication added to baseline treatment of methotrexate, low dose steroids, and NSAIDs to detect the role of other anti-rheumatic drugs when added to them.

The era of modern medicine, patients are exposed to a wide variety of drugs for diagnostic and therapeutic purposes. Unfortunately, many of these agents cause adverse drug effects accompanied with systemic toxicity, including impairment of renal function. Nephrotoxicity results in serious clinical syndromes.[10] Leflu-nomide has, in contrast to many other disease-modifying agents in RA, no known renal side effects. Leflunomide has been incriminated once as causing IgA GN[11] and anti-glomerular basement membrane disease in two RA patients.[12] Leflunomide in this study was related to membranous kidney affection in RA patients. Chloroquine and the chemically related hydroxychloroquine are antimalarials used to treat patients with rheumatic disorders. The incidental morphologic consequence of chloroquine usage, in the form of accumulation of lipid inclusions in podocytes, has been documented. In 2003, a case describing significant deterioration of renal function due to a high cumulative dose of the drug was described.[13] Hydroxychloroquine in the study was related to membranous kidney affection. These findings warrant close follow-up of kidney function to those kept on these medications for long time.

Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine in many chronic inflammatory diseases, including RA; include etanercept, a soluble TNFα receptor; infliximab a chimeric monoclonal IgG1 anti- TNFα antibody.[14] Stokes et al suggested the pathogenic role for anti-TNF-α agents in induction of RA-related nephropathy. Taken together, the clinical, serologic, and pathologic findings in their cases suggest a pathogenic role for anti-TNF-α therapy-related immune dysregulation.[15] In our study, we found that patients on etanercept had no kidney affection while those on infliximab develops focal segmental sclerosis and amylodosis of tubulo-interstitial type, and this may be due to ethnic variation and patient types.

A study of renal biopsy specimens indicated that mesangial GN is the predominant histo-pathologic finding in RA, followed by amyloi-dosis, membranous nephropathy, focal prolife-rative GN, minimal-change nephropathy and acute interstitial nephritis.[16] AA amyloidosis is one of most severe complications of RA. It leads to rapid end-stage renal failure; renal dialysis is often unable to prevent early death.[17] In our study, we found different types of renal affection the most common presentation in our study was amylodosis either the golmerular one followed by mesangial proli-ferative, followed by amylodosis the tubulo-interstial type, followed by arteriolar hylanosis. In our study, renal biopsies were glomeular amyloidosis (28.1%), Mesangioproliferative (19.1%), membranous (6.1%), crescent (16.8%), FSGS (18.6%), and minimal changes (11.7%), tubulointerstial amyloidosis (17%), acute nephritis (2.1%), chronic nephritis (3.5%), ATN (4.3%), IF (38.8%), and TA (IF/TA was mild in 50% of them, moderate in 42.5% of them, and marked affection was found in 7.5%), vascular amyloidosis (13%), arterial hylanosis (17.6%), thrombotic microangiopathy (2.9%), vasculitis (4.8%), and arterial intima fibrosis (9.9%).


   Conclusion Top


Kidney involvement in RA is not a rare complication. Any type of histopathological changes can present with amylodiosis on top of the list. Hydroxychloroquine and leflunomide is accused in membranous nephropathy. Infliximab is associated with focal segmental sclerosis and amyloidosis of tubulointerstial type and eteneracept appear to be safe as regards kidney affection.


   Ethical Committee Approval Top


The local ethical committee of the Internal Medicine Department, School of Medicine, Cairo University, approved this work.


   Human and Animal Rights Top


All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.


   Informed consent Top


Informed consent was obtained from all individual participants included in the study.

Conflict of interest: None declared.



 
   References Top

1.
Cimmino MA, Parisi M, Moggiana G, Mela GS, Accardo S. Prevalence of rheumatoid arthritis in Italy: The Chiavari study. Ann Rheum Dis 1998;57:315-8.  Back to cited text no. 1
    
2.
Morovic-Vergles J. Pathophysiology of rheumatoid arthritis. Reumatizam 2003;50:15- 7.  Back to cited text no. 2
    
3.
Hickson LJ, Crowson CS, Gabriel SE, McCarthy JT, Matteson EL. Development of reduced kidney function in rheumatoid arthritis. Am J Kidney Dis 2014;63:206-13.  Back to cited text no. 3
    
4.
Chiu HY, Huang HL, Li CH, et al. Increased risk of chronic kidney disease in rheumatoid arthritis associated with cardiovascular complications – A national population-based cohort study. PLoS One 2015;10:e0136508.  Back to cited text no. 4
    
5.
Giordano A, Cencioni L, Salvo DP, Berrettini M. Membranous nephropathy secondary to rheumatoid arthritis occurring during anti- TNFalpha therapy and responsive to second-line treatment with rituximab. G Ital Nefrol 2011;28:214-8.  Back to cited text no. 5
    
6.
Nakamura T, Higashi S, Tomoda K, Tsukano M, Shono M. Etanercept can induce resolution of renal deterioration in patients with amyloid A amyloidosis secondary to rheumatoid arthritis. Clin Rheumatol 2010;29:1395-401.  Back to cited text no. 6
    
7.
Icardi A, Araghi P, Ciabattoni M, Romano U, Lazzarini P, Bianchi G. Kidney involvement in rheumatoid arthritis. Reumatismo 2003;55:76- 85.  Back to cited text no. 7
    
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Galesic K, Prkacin I, Tisljar M, Vergles JM. Renal involvement in patients with rheumatoid arthritis. Reumatizam 2009;56:30-5.  Back to cited text no. 8
    
9.
Anders HJ, Vielhauer V. Renal co-morbidity in patients with rheumatic diseases. Arthritis Res Ther 2011;13:222.  Back to cited text no. 9
    
10.
Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005;294:813-8.  Back to cited text no. 10
    
11.
Kemp E, Nielsen H, Petersen LJ, et al. Newer immunomodulating drugs in rheumatoid arthritis may precipitate glomerulonephritis. Clin Nephrol 2001;55:87-8.  Back to cited text no. 11
    
12.
Bruyn GA, Veenstra RP, Halma C, Grond J. Anti-glomerular basement membrane antibody-associated renal failure in a patient with leflunomide-treated rheumatoid arthritis. Arthritis Rheum 2003;48:1164-5.  Back to cited text no. 12
    
13.
Müller-Höcker J, Schmid H, Weiss M, Dendorfer U, Braun GS. Chloroquine-induced phospholipidosis of the kidney mimicking Fabry’s disease: Case report and review of the literature. Hum Pathol 2003;34:285-9.  Back to cited text no. 13
    
14.
Klinkhoff A. Biological agents for rheumatoid arthritis: Targeting both physical function and structural damage. Drugs 2004;64:1267-83.  Back to cited text no. 14
    
15.
Stokes MB, Foster K, Markowitz GS, et al. Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 2005;20: 1400-6.  Back to cited text no. 15
    
16.
Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum 1995;38:242-7.  Back to cited text no. 16
    
17.
Gertz MA, Kyle RA. Secondary systemic amyloidosis: Response and survival in 64 patients. Medicine (Baltimore) 1991;70:246- 56.  Back to cited text no. 17
    

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Correspondence Address:
Ahmed Fayed
Department of Internal Medicine, Nephrology Unit, School of Medicine, Cairo University, Cairo
Egypt
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DOI: 10.4103/1319-2442.265455

PMID: 31464236

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