| Abstract|| |
The most common causes of renal disease in rheumatoid arthritis (RA) are glomerulonephritis (GN), amyloidosis, tubulo-interstitial nephritis, and drug toxicity. Our aim was to evaluate the clinicopathologic correlation of renal lesions and to assess the course and prognosis of renal disease in patients with RA. We conducted a prospective observational study in all adult patients with RA between July 2010 and June 2015. The total number of patients studied was 90, with a female:male ratio of 2.3:1. Mean follow-up duration was 30 ± 6.5 months. About 54 patients (60%) were asymptomatic. The most common symptom was edema legs (30%), followed by oliguria (10%). About 18 patients (20%) presented with the nephrotic syndrome, 15 patients (16.6%) with nephritic syndrome, and 30 (33%) with asymptomatic urinary abnormalities. Chronic kidney disease (CKD) was seen in 48 of 90 patients (53%).The most common renal pathology noted was mesangioproliferative GN followed by membranous nephropathy (MN). IgM with C3 deposits was the most common immunofluorescence pattern observed. Among the patients who had glomerular diseases, complete remission was seen in nine patients, partial remission in 15, and persistent proteinuria in 14. Duration of RA and a high erythrocyte sedimentation rate correlated significantly with persistent proteinuria. Only one patient in the glomerular disease group progressed to dialysis-dependent renal failure. On followup, 11 out of 48 CKD patients showed a significant decrease in estimated glomerular filtration rate and worsened to the next stage of CKD. Renal disease in RA presents with varied renal pathology. MN was seen frequently and was not associated with gold or penicillamine usage. Relatively high incidence of CKD was noted. Hence, it is important to monitor renal function abnormalities periodically in these patients.
|How to cite this article:|
Muthukumar P, Dhanapriya J, Gopalakrishnan N, Dineshkumar T, Sakthirajan R, Balasubramaniyan T. Evaluation of renal lesions and clinicopathologic correlation in rheumatoid arthritis. Saudi J Kidney Dis Transpl 2017;28:44-50
|How to cite this URL:|
Muthukumar P, Dhanapriya J, Gopalakrishnan N, Dineshkumar T, Sakthirajan R, Balasubramaniyan T. Evaluation of renal lesions and clinicopathologic correlation in rheumatoid arthritis. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Jul 16];28:44-50. Available from: http://www.sjkdt.org/text.asp?2017/28/1/44/198118
| Introduction|| |
Rheumatoid arthritis (RA) is a chronic crippling disease that affects various organ systems including the kidney. Renal involvement in RA can be due to the disease itself or drugs used in its treatment. Gold and penicillamine used in the past had been shown to cause secondary membranous nephropathy (MN). Renal disease in RA is usually asymptomatic and detected only on laboratory investigations. In a necropsy series by Boers et al, 132 cases were studied; 26 (19.7%) had urinary abnormalities with normal renal function, and 27 (20.5%) had normal urine with abnormal renal function. RA can affect all components of the kidney including the glomerulus, tubules, interstitium, and the blood vessels. The major causes of renal disease in RA are glomerulonephritis (GN), amyloidosis, tubulointerstitial nephritis, and drug toxicity. MN and tubulointerstitial nephritis occur commonly due to drug toxicity but can occur as a result of the disease itself.
Nakano et al reported 49 cases of MN out of 158 (31%), and Yoshida et al had 16 out of 31 (51.6%). The pathogenesis of MN is complex, and it is worth considering that RA itself can predispose to MN and that drugs might acelerate the development of this lesion. , The most common risk factor for the development of secondary amyloidosis is the duration of RA. The mainstay of management of secondary amyloidosis is the aggressive treatment of RA. The presence of other comorbidities such as hypertension and atherosclerosis also affects the course and prognosis of renal disease. With the invention of newer drugs and biological agents, renal disease as a contributor to mortality has become a rarity. Great emphasis has to be placed on regular and periodic screening for renal involvement in RA. In autopsy studies, the proportion of patients with renal failure ranged from 9 to 27% and of renal amyloid from 8 to 17%. There are very few Indian studies regarding the renal involvement in RA. This study was conducted to evaluate the clinicopathologic correlations of renal lesions and to assess the course and prognosis of renal diseases in RA.
| Materials and Methods|| |
We conducted a prospective observational study in the Department of Nephrology between July 2010 and June 2015. All adult patients with RA (diagnosed by the American College of Rheumatology Revised Criteria for the Classification of RA-1987) with renal symptoms or/and asymptomatic urinary abnormalities with or without renal failure were included in the study. Patients with diabetes mellitus, hepatitis B and C, human immunodeficiency virus, syphilis, systemic lupus erythematosus/ overlap, mixed connective tissue disease, and other diseases known to cause glomerular pathology were excluded from the study.
Detailed history, clinical examination, urine analysis, complete hemogram, blood urea, serum creatinine, electrolytes, blood sugar, and serum complements (C3 and C4) were noted. Rheumatoid factor was assessed by latex agglutination method, and a value of more than 8 IU/mL was considered positive. Antibody to cyclic citrullinated peptides was measured by ELISA, and value more than 6.5 IU/m/L was considered positive. C-reactive protein (CRP) was measured by nephelometry and value more than 6 mg/L was considered positive. Renal biopsy was performed in patients with normal-sized kidneys after obtaining written consent. All patients were followed-up every two weeks. At follow-up, urine analysis, urine protein-creatinine ratio (PCR), hemogram, and serum creatinine were performed.
Definitions for the study
- Microhematuria - more than or equal to five red blood cells per high-power field
- Nephrotic proteinuria - urine PCR >3.5
- Subnephrotic proteinuria - urine PCR between 1 and 3.5
- Complete remission-urine spot PCR <0.3
- Partial remission - urine spot PCR <1 or 50% reduction from baseline value during follow-up
- Chronic kidney disease - estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 for >3 months.
| Statistical Analysis|| |
All the variables were expressed as mean. The data were analyzed by Chi-square test and Fisher's exact probability test. P <0.05 was considered significant.
The Institutional Ethics Committee approval was obtained.
| Results|| |
A total of 90 patients were included in the study with a female:male ratio of 2.3:1. The age group ranged from 18 to 69 years, with mean being 46.2 ± 11.3 years. Most of the individuals were in the third and fourth decades. The mean follow-up duration was 30 ± 6.5 months. Fifty-four patients (60%) were asymptomatic. The duration of RA in our patients varied from 9 months to 32 years. Extra- renal manifestations included early morning stiffness (96%), polyarthritis (90%), joint deformities (54%), and subcutaneous nodules (17%). Baseline characteristics and clinical presentation are given [Table 1].
All the patients were on oral prednisolone 5 to 10 mg per day. The most commonly used nonsteroidal anti-inflammatory drug (NSAID) was oral indomethacin, 2-3 mg per kg per day. About 59 patients were on methotrexate (MTX) therapy and the dose ranged from 7.5 to 20 mg per week. Hydroxychloroquine (HCQ) was used in 35 patients while 22 patients received a combination of HCQ and MTX. Forty-two patients underwent renal biopsy. The most common lesion noted was mesangial proliferative GN, followed by MN. Details of the renal lesions are given in [Table 2].
|Table 2. Renal biopsy findings by light microscopy among patients with rheumatoid arthritis.|
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Interstitial fibrosis with tubular atrophy (varied from 10% to 50%) was noted in five cases. Blood vessels were thickened in 10 patients out of whom; only three had hypertension. Fibrointimal proliferation of blood vessels was seen in four cases. The most common immune-fluorescence (IF) pattern was IgM and C3 (14 patients) followed by IgG, IgM, and C3 (9 patients). Dominant or co-dominant mesangial deposits of IgA were found in four cases. No IF deposits were seen in six patients. Clinicopathologic correlation and renal outcome are given in [Table 3]. Thirty-eight patients who had glomerular disease on biopsy were followed-up. Complete remission was seen in nine patients, partial remission in 15, and persistent proteinuria in 14. Risk factors contributing to persistent proteinuria were analyzed by univariate analysis. Longer duration of the disease (P <0.05) and high erythrocyte sedimentation rate (ESR) (P = 0.0001) at presentation were significantly associated with persistent proteinuria. Age (P = 0.620, gender (P = 0.2), and high CRP (P = 0.10) had no statistical significance.
|Table 3. Clinico-pathological correlation and renal outcome among patients with rheumatoid arthritis.|
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Forty-eight patients presented with chronic kidney disease (CKD) at entry into study. Their renal ultrasonogram showed Grade III echoes and altered corticomedullary junction. Hence, renal biopsy was not considered in these patients. The profile of this group is shown in [Table 4].
|Table 4. Baseline characteristics of patients with chronic kidney disease.|
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Most of the patients were in CKD Stage IIIB according to the latest KDIGO-CKD classification. On follow-up, only 11 out of 48 patients showed a significant decrease in eGFR and worsened to the next stage of CKD. The remaining patients remained in the same stage with relatively stable GFR. None of the patients reached Stage V CKD.
| Discussion|| |
Renal involvement in RA can remain asymptomatic as evidenced in 54 of our study patients (60%). The mean age was 46.2 ± 11.3 years. The female: male ratio was 2.3:1, which is slightly lower than the reported ratio of 2.5:1.
Almost all patients had elevated ESR with a mean of 62 mm in 1 h. The mean CRP was 11.2 mg/L. Raised ESR and CRP suggests increased disease activity and greater likelihood of developing renal disease.
The most common symptom was edema legs (30%), followed by oliguria (10%). In our study, 18 patients (20%) presented with nephrotic syndrome, of which six patients also had evidence of renal dysfunction.
Renal biopsy was performed in 42 patients; the most common pathology was mesangial proliferation, which was seen in 10 cases. The proliferation was diffuse in two and focal in eight patients. MN was seen in seven, focal endocapillary proliferation in five, and IgA nephropathy and amyloidosis were observed in four patients each. Minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS) were noted in two patients each.
Nine patients with mesangioproliferative GN had subnephrotic proteinuria and one had nephrotic proteinuria. Honkanen et al reported nephrotic proteinuria in four patients with RA and MN.
There were five cases of focal endocapillary proliferative GN. Ramirez et al  reported three such cases out of 76 patients, and the lesion was considered to be a part of vasculitis. Our patients did not have features of systemic vasculitis and all tested negative for antineutrophil cytoplasmic antibodies. All the patients in this group received a short course of steroids for four weeks, which was then slowly tapered. One patient did not respond and became dialysis dependent.
IgA nephropathy occurred in four patients who presented with subnephrotic proteinuria, and one had renal failure. Nakano et al reported IgA deposits in 50% cases of mesangial GN probably reflecting higher incidence of IgAN in these patients. All four patients with amyloidosis in this study had long duration of the disease, more severe joint involvement with deformities, and nephrotic range proteinuria. Poor prognostic factors include cardiac involvement and serum creatinine level >2.0 mg/dL at presentation. , ,
There were two patients with MCD and both were taking NSAIDS for more than four years. Two patients had FSGS. Friedman et al and Adu et al, each reported a case of FSGS in RA. One patient had acute interstitial nephritis and had a history of consumption of indigenous medicines. Two patients had acute tubular injury. Koseki et al analyzed 235 patients and showed that drug-induced proteinuria and renal dysfunction occurred in 1.5% and 1.7% patients, respectively. One patient had thrombotic microangiopathy (TMA), who tested negative for ANA and anti-phospholipid antibodies. She was treated with plasmapheresis and had partial renal recovery. Only two reports of TMA in RA are available in literature. , Harper et al reported about 10 cases of RA with vasculitis. No case of vasculitis was seen in our study.
Helin et al did a retrospective analysis of renal biopsy in 110 patients with RA. Major cause of the renal disease was mesangial GN (40), followed by amyloidosis.
The most common finding on IF was IgM with C3 deposits. Korpela et al have reported that IgM, IgA, and C3 were the most common IF findings.
Among the 38 patients with glomerular diseases, complete remission was seen in nine patients, partial remission in 15, and persistent proteinuria in 14. Duration of the disease and a high ESR were statistically significant risk factors in contributing to persistent proteinuria. Koseki et al found that high serum CRP, ESR, and age more than 50 years at entry correlated significantly with persistent proteinuria. Patients with MCD and focal endocapillary proliferative GN received oral steroids in the form of prednislone at a dose of 1 mg/kg for six weeks, which was then tapered over another six weeks. Other glomerular diseases were treated with angiotensin- converting enzyme inhibitors and statins.
The total number of patients who presented with CKD at entry in this study was 48. The mean age was 50 ± 10.3 years and female: male ratio was 1:1.7. The mean duration of RA was 11.1 years and the mean serum creatinine and mean eGFR at entry were 2 mg/dL and 36.5 mL/min/1.73 m2, respectively. On follow- up, 11 of the patients showed a significant decrease in eGFR and worsened to the next stage of CKD. The remaining patients remained in the same stage with relatively stable GFR. None of the patients reached Stage V CKD.
In autopsy studies, the proportion of patients with renal failure has ranged from 9% to 27%. Laakso et al followed 500 males and 500 females with RA with age- and sex- matched controls for 10 years. On follow-up, 31 patients died from amyloidosis, and 42 died from renal diseases including chronic renal insufficiency and renal infections. Nakajima et al recently published a follow-up of 7926 RA patients with the observation period being 35443 person-years and reported 289 deaths in the study period. The most common causes of death were malignancy (24.2%) and respiratory involvement (24.2%). Renal failure as a cause of death occurred in only two of the 289 patients (0.6%).
Our study showed a high incidence of heterogeneous renal diseases in patients with RA.
Accurate histopathological diagnosis is needed for therapy and prognostication. Although there was higher incidence of CKD in this study, most of the patients maintained stable GFR at follow-up.
Conflict of interest: None declared.
| References|| |
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:903-11.
Boers M. Renal disorders in rheumatoid arthritis. Semin Arthritis Rheum 1990;20:57-68.
Ramirez G, Lambert R, Bloomer HA. Renal pathology in patients with rheumatoid arthritis. Nephron 1981;28:124-6.
Boers M, Croonen AM, Dijkmans BA, et al. Renal findings in rheumatoid arthritis: clinical aspects of 132 necropsies. Ann Rheum Dis 1987;46:658-63.
Nakano M, Ueno M, Nishi S, et al. Analysis of renal pathology and drug history in 158 Japanese patients with rheumatoid arthritis. Clin Nephrol 1998;50:154-60.
Yoshida A, Morozumi K, Suganuma T, et al. Clinicopathological study of nephropathy in patients with rheumatoid arthritis. Ryumachi 1991;31:14-21.
Saito T, Nishi S, Karasawa R, et al. An ultrastructural study of glomerular basement membrane in rheumatoid arthritis patients with urinary abnormalities. Clin Nephrol 1995;43: 360-7.
Brun C, Olsen TS, Raaschou F, Sorensen AW. Renal biopsy in rheumatoid arthritis. Nephron 1965;2:65-81.
Honkanen E, Törnroth T, Pettersson E, Skrifvars B. Membranous glomerulonephritis in rheumatoid arthritis not related to gold or Dpenicillamine therapy: a report of four cases and review of the literature. Clin Nephrol 1987;27:87-93.
Nakano M, Ueno M, Nishi S, et al. Determination of IgA- and IgM-rheumatoid factors in patients with rheumatoid arthritis with and without nephropathy. Ann Rheum Dis 1996; 55:520-4.
Ahlmen M, Ahlmen J, Svalander C, Bucht H. Cytotoxic drug treatment of reactive amyloidosis in rheumatoid arthritis with special reference to renal insufficiency. Clin Rheumatol 1987;6:27-38.
Tanaka F, Migita K, Honda S, et al. Clinical outcome and survival of secondary (AA) amyloidosis. Clin Exp Rheumatol 2003;21: 343-6.
Elkayam O, Hawkins PN, Lachmann H, Yaron M, Caspi D. Rapid and complete resolution of proteinuria due to renal amyloidosis in a patient with rheumatoid arthritis treated with infliximab. Arthritis Rheum 2002;46:2571-3.
Friedman R, Gallo GR, Buxbaum JN. Renal disease in rheumatoid arthritis. Arthritis Rheum 1980;23:781-3.
Adu D, Berisa F, Howie AJ, et al. Glomerulonephritis in rheumatoid arthritis. Br J Rheumatol 1993;32:1008-11.
Koseki Y, Terai C, Moriguchi M, Uesato M, Kamatani N. A prospective study of renal disease in patients with early rheumatoid arthritis. Ann Rheum Dis 2001;60:327-31.
Nomura M, Okada J, Tateno S, Kobayashi Y, Kondo H. Renal thrombotic microangiopathy in a patient with rheumatoid arthritis and antiphospholipid syndrome: successful treatment with cyclophosphamide pulse therapy and anticoagulant. Intern Med 1994;33:484-7.
Kfoury Baz EM, Mahfouz RA, Masri AF. Thrombotic thrombocytopenic purpura in a patient with rheumatoid arthritis treated by plasmapheresis. Ther Apher 1999;3:314-6.
Harper L, Cockwell P, Howie AJ, et al. Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis. QJM 1997;90:125-32.
Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy findings and clinicopathological correlations in rheumatoid arthritis. Arthritis Rheum 1995;38:242-7.
Korpela M, Mustonen J, Pasternack A, Helin H. Mesangial glomerulopathy in rheumatoid arthritis patients. Clinical follow-up and relation to antirheumatic therapy. Nephron 1991;59:46-50.
Pathan E, Joshi VR. Rheumatoid arthritis and the kidney. J Assoc Physicians India 2004;52: 488-94.
Laakso M, Mutru O, Isomäki H, Koota K. Mortality from amyloidosis and renal diseases in patients with rheumatoid arthritis. Ann Rheum Dis 1986;45:663-7.
Nakajima A, Inoue E, Tanaka E, et al. Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA. Scand J Rheumatol 2010;39:360-7.
Department of Nephrology, Madras Medical College and Rajiv Gandhi government General Hospital, Chennai 600 003, Tamil Nadu
[Table 1], [Table 2], [Table 3], [Table 4]