Rheumatoid Arthritis
Neeraja Kambham, MD
Key Facts
Etiology/Pathogenesis
Predominantly therapy related
Tubulointerstitial nephritis and acute renal failure caused by NSAIDs
MGN caused by gold salts, penicillamine, and TNF-α antagonists
ANCA-related disease precipitated by penicillamine and TN-α antagonists
Arteriolar hyalinosis and interstitial fibrosis caused by calcineurin inhibitors
Papillary necrosis in analgesic nephropathy
AA amyloidosis
Chronic inflammation in the setting of RA can result in AA amyloidosis
RA renal diseases unrelated to therapy
Quite rare, but has been documented in absence of drug therapy
Mesangial proliferative GN, some cases of MGN, ANCA-related disease
Clinical Issues
Clinical presentation varies based on type and extent of renal involvement
Withdrawal of offending drug causes resolution of renal manifestations in most cases
Microscopic Pathology
Varied patterns: MGN, amyloidosis, tubulointerstitial nephritis, pauci-immune GN
Diagnostic Checklist
Mesangioproliferative GN, ANCA-related disease, and AA amyloidosis linked to RA
 The GBM is diffusely thickened  , and segmental increase in mesangial matrix and cellularity  is observed in this biopsy specimen with membranous nephropathy. The patient received gold therapy for RA. |
 Amyloid deposits in the mesangium  and capillary walls  are weakly PAS positive. The patient has a longstanding history of RA, and chronic inflammation predisposes to AA amyloidosis. |
TERMINOLOGY
Abbreviations
Rheumatoid arthritis (RA)
Definitions
Renal morphological findings observed in patient with RA, either directly related to RA or due to chronic inflammation and therapy
ETIOLOGY/PATHOGENESIS
Complications of Treatment
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause tubulointerstitial nephritis and acute renal failure
Often occurs after many months of NSAID use
Inhibition of cyclooxygenase and reduced synthesis of vasodilatory prostaglandins cause acute renal failure
Volume depletion, congestive heart failure, and ascites exacerbate the vasoconstrictor effects of NSAIDs
Some patients may also develop minimal change disease due to NSAIDs
Gold salts and penicillamine therapy results in membranous nephropathy (MGN)
No correlation between cumulative dose administered and development of disease
Cyclosporine nephrotoxicity
Related to vasoconstrictor effects or endothelial injury effects of cyclosporine
Analgesic nephropathy due to use of combination drugs with phenacetin
Much less common in modern era, after withdrawal of phenacetin from market
Results in chronic interstitial nephritis, interstitial fibrosis, and papillary necrosis
Penicillamine therapy linked to pauci-immune GN and pulmonary renal syndrome resembling Goodpasture syndrome
Anti-tumor necrosis factor (TNF)-α can precipitate autoantibody formation
Causes proliferative or membranous lupus nephritis, pauci-immune glomerulonephritis (GN), or vasculitis
AA Amyloidosis
Chronic inflammation in setting of RA can result in AA amyloidosis
Duration of RA disease is often > 15 years
Renal Disease Directly Related to RA
Quite rare but has been documented in absence of drug therapy
Includes glomerular involvement by mesangial proliferative GN, MGN, and pauci-immune GN
Vasculitis involving renal artery and its branches has been reported
Thrombotic microangiopathy due to concomitant antiphospholipid antibody syndrome
CLINICAL ISSUES
Epidemiology
Incidence
Renal involvement in RA is predominantly therapy related
MGN secondary to gold and penicillamine therapy occurs in 1-10% of RA patients
Based on autopsy series, prevalence of AA amyloidosis is approximately 15%
Direct kidney involvement as part of RA systemic disease is rare
Presentation
Kidney involvement
Presentation varies based on type and extent of renal involvement
Nephrotic syndrome is presenting feature in MGN, amyloidosis
Rapidly progressive GN is seen with pauci-immune GN and vasculitis
Acute renal failure with NSAID-related interstitial nephritis and acute tubular injury
Isolated hematuria &/or proteinuria in mesangioproliferative GN related directly to RA
Variable decline in renal function and mild proteinuria in most other instances
Systemic manifestations of RA
Arthritis due to autoimmune inflammation of joints
Various extraarticular manifestations include pericarditis, pulmonary nodules, pulmonary interstitial fibrosis, mononeuritis multiplex, and systemic vasculitis
Diagnosis of RA is based on 2010 criteria established by collaborative efforts of American College of Rheumatology and European League Against Rheumatism
Laboratory Tests
p-ANCA test positive in pauci-immune GN secondary to RA and treatment complication
ANA, anti-DNA antibodies, and low serum complement levels in anti-TNF-α therapy-induced autoimmune disease
Treatment
Drugs
Withdrawal of offending drug (NSAIDs; gold, penicillamine) causes resolution of tubulointerstitial nephritis and MGN, respectively, in most cases
If renal dysfunction persists, steroids can help accelerate recovery in NSAID interstitial nephritis
Resolution of disease after withdrawal of gold or penicillamine often takes up to a year
Corticosteroids and cyclophosphamide may be useful in treatment of AA amyloidosis
Immunosuppressive therapy for pauci-immune GN and mesangioproliferative GN
MICROSCOPIC PATHOLOGY
Histologic Features
Tubulointerstitial nephritis
Tubulointerstitial inflammation due to NSAIDs is usually sparse
A few scattered eosinophils may be present
Interstitial edema and inflammation is present in nonatrophic parenchyma
Features of acute tubular injury may be evident with loss of proximal tubular brush borders and sloughed epithelial cells
Membranous glomerulonephritis (MGN)
GBM may be thickened or show basement membrane “spikes,” depending on stage of MGN
Subepithelial deposits can be highlighted by PAS and trichrome stains
Mild mesangial proliferation can be present, especially in therapy-induced membranous lupus nephritis
Cyclosporine toxicity
Normal histology seen in vasoconstriction-induced acute nephrotoxicity
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