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POL J PATHOL 2010; 4: 229–233

PATIENT WITH RHEUMATOID ARTHRITIS AND ACUTE RENAL

FAILURE: A CASE REPORT AND REVIEW OF LITERATURE

ANDRZEJ MARSZAŁEK1,2, NATALIA SKOCZYLAS-MAKOWSKA3, ANNA KARDYMOWICZ4, JACEK MANITIUS4

1Chair and Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń

2Chair and Department of Clinical Pathology, Poznań University of Medical Sciences 3Department of Clinical Pathology, University Hospital No. 1 in Bydgoszcz4Chair and Department of Nephrology, Hypertension and Internal Diseases, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń

Rheumatoid arthritis (RA) is an autoimmune disease also known as an example ofconnective tissue disease. There are no case-controlled studies to determine the fre-quency of renal disease in RA. Most of patients present slow progression of chron-ic kidney disease while acute renal failure is uncommon in rheumatoid arthritis. We report a case of a 40-year-old woman with established medical history of RAwho presented with abrupt onset of severe hypertension with rapidly growingserum creatinine concentration and oliguria. Renal biopsy revealed oedematousintimal thickening of vessels and ischemic changes in glomeruli, and nonspecificlesions in tubules and interstitium. These pathological findings were consistentwith the scleroderma nephropathy. Additionally, we provided a brief literatureoverview on coincidence of hypertension and different types of connective tissuediseases.

Key words: overlap syndrome, “onion skin” lesion, scleroderma renal crisis.

Introduction

Connective tissue diseases also known as autoim-mune diseases usually develop with clinical presenta-tion that in conjunction with laboratory data enablesa direct diagnosis. However, in rare cases an overlapof clinical presentation may occur. The overlapbetween systemic sclerosis (SSc) and rheumatoidarthritis (RA) is rather uncommon. To date thelargest cohort of patients with RA-SSc was reportedby Szucs. In his study 5 of the 22 patients had clini-cal manifestation of renal involvement [1]. Especial-ly at an early stage of disease the differential diagno-sis between RA and SSc may be difficult. Both RAand SSc begins at any age, but it most often starts atthe age of 40 and is more common in women than inmen. Stiffness of joints, which is characteristic of RA,may also appear in SSc patients. Rheumatoid factor isdetected in 70-90% of patients with RA, but it is

also present in about 30% of patients with SSc. Themain clinical problem in RA is chronic joints diseasewith rare emergency states. In early sclerodermathere is a possibility of development of sclerodermarenal crisis (SRC), which is connected with high mor-tality. The most probable renal finding in RApatients is amyloidosis or mesangioproliferativeglomerulonephritis and it correlates with quite slowprogression of chronic kidney disease. Just the oppo-site, the scleroderma more likely develops withabrupt clinical presentation of severe hypertensionand acute renal failure. Scleroderma renal crisis is themost dangerous manifestation of sclerodermanephropathy with the most characteristic pathologi-cal lesion which is intimal thickening of smaller arcu-ate and interlobular arteries and arterioles. The diffi-culty in histological diagnosis may occur in cases ofsevere or malignant hypertension with unclear med-ical history of SSc.

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Case report

A 40-year-old woman was admitted to UniversityHospital No. 1 in Bydgoszcz, the Chair and Depart-ment of Nephrology, Hypertension and InternalDiseases because of acute renal failure with serumcreatinine concentration up to 6.8 mg/dl and severehypertension.

The patient has been treated for rheumatoidarthritis since 2005 with methotrexate administeredorally. After a year the treatment was changed intomonthly intravenous infusions of interleukin 6receptor antagonist (tocilizumab). The serum creati-nine, urine sediment and blood pressure remainedwithin the normal ranges when the patient appearedfor regular check-ups in the out-patient clinic.

In the previous year the systemic sclerosis was sus-pected due to Raynaud’s phenomenon, skin fibrosisaffecting upper extremities and face, as well as char-acteristic megacapillaries in nail fold capillaroscopy,without serological confirmation (ANA and Scl-70antibodies were negative).

The medical history revealed that two weeksbefore the incidence of renal dysfunction the patientwas taking non-steroidal anti-inflammatory agentsbecause of brachialgia. Two months earlier patientreceived amoxicillin with clavulanic acid (Aug-mentin) due to symptoms of the upper airway infec-tion.

The critical moment was the occurrence of rapid-ly growing hypertension with values exceeding 220mmHg and 140 mmHg for systolic and diastolicblood pressure, respectively, and concomitantheadaches, dizziness, nausea and vomiting. Headcomputed tomography, chest X-ray and echocardio-graphy remained normal. Abdominal ultrasoundand duplex-scan examination demonstrated normalkidneys size and structure and excluded renal arter-ies restriction. In ophtalmoscopy, vascular retinopa-

thy grade III according to Keith-Wegener’s classifi-cation was diagnosed. The laboratory tests revealednon-nephrotic proteinuria, erythrocyturia and leuko-cyturia with a high number of eosinophiles in urinesediment. Serological screening was negative includ-ing complement, dsDNA, pANCA, cANCA, ANA,Scl-70, CENP, ACA, U1RNP. Even though the nor-malization of blood pressure was gradually achievedthe patient required renal replacement therapy dueto oliguria and constantly increasing serum creati-nine. Because of acute renal failure of unknown ori-gin and clinical suspicion of acute tubulo-interstitialnephritis the decision for kidney biopsy was made.

The renal tissue samples were taken and sent tothe Chair and Department of Clinical Pathology Col-legium Medicum in Bydgoszcz, Nicolaus CopernicusUniversity in Toruń. The clinical data on the referralincluded: rheumatoid arthritis, acute renal failure,suspicion of acute interstitial renal alterations.Histopathological examination was based on two tis-sue samples taken from the left kidney. One of thecores was fixed in formalin. After a routine proce-dure, a paraffin block was prepared. Haematoxylin-eosin, trichrome Masson, Congo red staining and paSreaction were made on deparaffinized and rehydrat-ed paraffin tissue of 4-μm sections. Another speci-men we have got unfixed for immunofluorescenceexamination. The tissue sample was frozen at –30°C.In 4 μm tissue sections the IgG, IgM, IgA, C3, fib-rinogen were determined with fluorescein-labelledanti-human serum.

The light microscopy examination demonstratedtwenty six glomeruli. Most of them showed ischemicchanges with wrinkled, thickened basement mem-branes and collapsed capillaries (Fig. 1). Slightmesangial proliferation was observed. In part ofglomeruli cuboidal, high podocytes were present.Tubules focally exhibited nonspecific degenerativechanges. Focal interstitial oedema was noted. Lumi-nal narrowing of interlobular and arcuate arteries dueto mucoid intimal thickening with concentricallyarranged cells was the most specific lesion found inthe specimen (Fig. 2). Changes of this type wereobserved within all vessels larger than the diameter ofglomeruli, but also in some smaller ones. A Congored stained section was negative ruling out amyloido-sis. We have seen paS positive thickening of tubulesbasement membranes and paS positive pole aroundBowman’s capsule in half-circulated shape (crescent)(Fig. 3). In immunofluorescence micro scopy, focalpositive staining for fibrin in vessels’ walls of mediumcalibre was present. The pathological diagnosis wasconsistent with morphological lesions characteristic ofsystemic sclerosis. Finally, after dermatological andrheumatologic examination, rheumatoid arthritis –diffuse systemic sclerosis overlap syndrome and scle-roderma renal crisis was diagnosed.

ANDRZEJ MARSZAŁEK, NATALIA SKOCZYLAS-MAKOWSKA, ANNA KARDYMOWICZ, ET AL.

Fig. 1. Ischemic glomeruli with thickened, wrinkledbasement membranes and collapsed capillaries. HE,objective magnification 20×

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Discussion

Systemic sclerosis is a rare multisystem connectivetissue disease mainly affecting women in the third tofifth decade of life. It is characterized by widespreadblood vessels damage and usually by fibrosis of theskin and internal organs. Renal involvement isa common component of systemic sclerosis. The kid-neys affected in the course of systemic sclerosis werereported for the first time in the 1863 [2, 3]. Kid-neys are affected in 60% to 80% of patients with SScas evidenced by autopsy studies [4]. Systemic sclero-sis occurs in two main forms. The first one is diffuseform with symmetric skin involvement of proximaland distal parts of extremities and often the trunkand face. In the limited form of more confined sym-metric involvement of the skin it affects the distalparts of the extremities. Visceral manifestations takemuch longer to become manifest in this form [5]. Itwas thought that the risk of severe organ systeminvolvement in patients with diffuse sclerodermaincreased linearly with disease duration [6]. Howev-er, gradual intensity of organ dysfunction during thecourse of illness does not always take place. Usuallypatients show some evidence of renal dysfunctione.g. mild proteinuria or increased serum creatinine.A quite rare complication is scleroderma renal crisisthat occurs in up to 10% of patients, mainly withdiffuse form of scleroderma. Scleroderma renal crisisis the term used to describe the most severe form ofrenal involvement in systemic sclerosis [5]. It isdefined as the new onset of severe hypertension(although about 10% patients with SRC remain nor-motensive) and/or rapidly progressing renal failurewith oliguria in patients with systemic sclerosis. Theevidence of microangiopathic anaemia or thrombo-

cytopenia may also be present [2, 6, 7, 8]. The labo-ratory findings useful in diagnosis are non-nephroticproteinuria, erythrocyturia, growing creatinine con-centration in blood serum (0.5-1.0 mg/dl/24 hours).SRC episode in 75% occurs in the first four yearsafter the diagnosis of SSc [2]. The long-term out-comes in SRC used to be extremely poor. Althoughthe availability of angiotensin-converting enzymeinhibitors decreased the need of dialysis, the survivalof patients with SRC is 70% at two years [9] and40% after 9 years [5, 6].

Pathologic renal biopsy findings in the course ofsystemic sclerosis in light microscopy include non-specific glomerular changes which may vary consid-erably. In some cases, thickening of basement mem-branes is present. The glomeruli in scleroderma mayshow ischemic collapse, congestion, sclerosis. In renalcrisis they may have fibrillar appearance identical tothe changes seen in haemolytic uremic syndrome.The larger eosinophilic areas in the capillary wallwith fragmented red blood cells in glomeruli reflectthe microangiopathic haemolytic anaemia that maybe present.

The most typical and almost diagnostic lesion,that one should pay attention to, is the mucoid inti-mal thickening. Characteristic SSc changes in arter-ies of interlobular size, smaller arcuate arteries, andarterioles are pathologic hallmarks of progressivesystemic sclerosis. Larger arteries may be normal orreveal nonspecific changes only. The most significantfinding is “onion skin” lesion and it relates tochanges in intimae. The arterial lumen is consider-ably narrowed as a consequence of mucoid intimalthickening with concentrically arranged myointimalcells. The mucinous intimal change mostly consistsof mucopolysaccharides of the hyaluronic acid type.

RHEUMATOID ARTHRITIS AND ACUTE RENAL FAILURE: A CASE REPORT

Fig. 3. paS positive crescent around Bowman’s capsule.paS reaction, objective magnification 4×

Fig. 2. Vascular “onion skin” lesion (the most typical ofSSc nephropathy) with thickened intimae andconcentrically arranged myointimal cells. HE, objectivemagnification 10×. Inset: highlighted the same vessel

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This change is similar to that seen in malignantnephrosclerosis (MN), haemolytic uremic syndrome,thrombotic thrombocytopenic purpura, antiphos-pholipid syndrome and pre-eclampsia [4]. It stainswith Alcian blue and metachromatically with tolui-dine blue. Clear reaction or only a weakly blue stain-ing indicates no or little deposition of mature colla-gen [5]. Another vascular lesion which may also beseen in SSc and malignant nephrosclerosis is fibrinoidnecrosis of the afferent arterioles. However, this casedid not reveal any of such features. The endothelialcells may be swollen. But even endothelial prolifera-tion was described [10]. The media may be thinnedby around the extended intimae. Some authors not-ed slightly adventitial fibrosis [11, 12]. The internalelastic lamina is usually intact, but in chronic injuryarterioles show its reduplication [5, 10]. The changesin tubules and interstitium are nonspecific and sec-ondary to vascular ones. In immunofluorescencemicro scopy, the positive staining for fibrinoid, IgMand C3 in the glomeruli may be seen. The same focalpositive result in the walls of interlobular arteries andarterioles may be present.

Clinical data suggested that in differential diag-nosis we should distinguish between nephropathydue to rheumatoid arthritis and also interstitialnephritis. The clinical diagnosis of systemic sclerosisis based on ACR (American College of Rheumatol-ogy) standards (characteristic skin changes and/orinterstitial pulmonary fibrosis) and might be con-firmed by the presence of specific antibodies (ANA,Scl-70). The unique composition of clinical, serolog-ical and genetic findings in SSc-RA overlap syn-drome patients was reported by Szucs [1]. Contraryto our patient, most of them developed RA afterlong-term SSc and had a limited form of SSc. Therenal involvement occurred in 23% of these patients.Unfortunately, there are no case-controlled studiesto determine the renal disease patients with rheuma-toid arthritis [13]. Clinical manifestation of renalinvolvement in RA in most of the patients is the slowprogression of chronic kidney disease. It correlateswith the most common lesions found in biopsyexaminations, which are mainly amyloidosis andmesangial proliferative glomerulonephritis [5, 13].The acute renal failure may occur in interstitialnephritis due to NSAIDs’ as well as other drugs’intake. We should also take into consideration acuteinterstitial nephritis because of the large amount ofeosinophiles in urine sediment. But among biopsyfindings of our patient, there were diagnostic fea-tures characteristic of neither RA nor interstitialalterations. Malignant nephrosclerosis with fibrinoidnecrosis and “onion skin” lesion in smaller interlobu-lar arteries could also be found, considering severehypertension episode. Nevertheless, degenerativechanges of tubules and interstitial oedema of low

intensity seen in our tissue sample could not reflectsuch symptoms.

Taking into account the pathological picture ofsmall renal vessels, it was necessary to considermalignant nephrosclerosis in the course of malignanthypertension (MH). Although similar intimal thick-ening but rich in collagen is seen in MN and ourknowledge about the composition contents in inti-mal lesion of our patient was unclear (lack of histo-chemical examination with Alcian and toluidineblue), we could quite easily say that this type of inti-mal lesion indicates rather SSc than acceleratedhypertension. Lack of arteriolosclerosis hyperplasticawith concentrically arranged cells in thickenedmedia, fibrinoid necrosis of the vessel wall and fea-tures of acute glomeruli injury, have made us makesuch decision. Considering the fact that in the inti-mal lesion in early phases of MN there is only inti-mal thickening by myxoid connective tissue [14] itwould be interesting to know more about the orderof occurrence the vascular lesions in MN – can onionskin lesion without fibrinoid necrosis exist amongpatients with MN? It is quite difficult to understandthe way of histopathological examination of hyper-tensive patients in Caetano’s study, where themyointimal proliferation defined the diagnosis ofmalignant nephrosclerosis. In this study in a groupof 35 patients with clinically diagnosed malignanthypertension, there was only one with fibrinoidnecrosis of the vessel wall. A similar discrepancybetween clinical and histopathological diagnosis wasshown by Zucchelli and Fogo [15].

After the literature review, differential diagnosisshould also include haemolytic uremic syndrome,thrombotic thrombocytopenic purpura, antiphos-pholipid syndrome and pre-eclampsia. Consideringthe lack of symptoms of the above-mentioned dis-eases in the medical history of our patient, there wasno need to take them into account in pathologicaldifferentiation.

Conclusions

Although the SSc is not the only disease in whichintimal thickening occurs, the mucoid character ofthis lesion confirms the diagnosis. The ACR criteriafor the diagnosis of SSc doesn’t include histopatho-logical examination of neither the skin nor otherorgans. Although the diagnosis of SSc is based onclinical symptoms, there are many early SSc HIV-seropositive patients with Raynaud’s phenomenonand abnormalities in nail fold capillary microscopy.These patients are in a group with the most proba-ble SRC. That is why the renal biopsy may occurespecially important and useful in cases with symp-toms of scleroderma renal crisis with unclear SScmedical history.

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Address for correspondence Andrzej Marszałek MD, PhDDepartment of Clinical Pathomorphology CM UMKul. Skłodowskiej-Curie 985-094 Bydgoszczphone: + 48 52 585 42 00fax: + 48 52 585 40 49e-mail: amars@cm.umk.pl

RHEUMATOID ARTHRITIS AND ACUTE RENAL FAILURE: A CASE REPORT