249

IINNTTRROODDUUCCTTIIOONN

Systemic lupus erythematosus (SLE), anautoimmune disorder of unknown etiology,demonstrates a chronic inflammatory characterand can occur at almost any age. It may affect theskin, joints, lungs, heart, serous membranes,nervous system, and other organs. Renalinvolvement is common and can influence thepatient's prognosis. SLE is predominantly adisease of women, with a female: male ratio ofabout 9:1 [1]. Overt clinical prevalence of renaldisease varies from 35% to 75% of patients withwell-documented SLE [2]. Results of renalbiopsies have shown that SLE involves the kidneyin almost all cases even in the absence ofproteinuria or abnormal urinary sediment [3].

Hyperuricaemia is associated with renaldisease. Approximately 20% to 60% of patientswith gout have mild or moderate renalinsufficiency [4]. There is strong evidence that inthe overwhelming majority of middle-aged,predominantly male patients with gout,hyperuricaemia results from an inheriteddecreased fractional clearance of urate in thekidney.

Although some patients with SLE may havehyperuricaemia due to renal insufficiency, theyseldom develop gout. We recently diagnosed uricacid nephropathy in a young man with lupusnephritis. This case prompted us to examine thefrequency of gout and hyperuricaemia in SLEpatients and to explain the factors which maypredispose individuals to its development.

CCAASSEE RREEPPOORRTT

A 29-year-old man, without a familialhistory of lupus, gout or nephritis, was diagnosed

Hyperuricaemia and gout are predominant diseases of middle-aged men and postmenopausal

women. Systemic lupus erythematosus is primarily a disease of young women, with a female:

male ratio of about 9:1. Uric acid nephropathy and lupus nephritis are often the cause of renal

failure. The incidence and prevalence of these two diseases are low in young men. We report a 29-

year-old man who presented with anasarca, gross hematuria, proteinuria, mild anaemia,

hyperuricaemia and acute renal failure. He had developed a rash on his face and right hand, and

pain in both knee joints six months prior to presentation. Gouty arthritis was diagnosed because

of coexistent hyperuricaemia. He was admitted to hospital because of exacerbated anasarca

which had been progressing slowly for over half a year. Severe proteinuria and hematuria were

also noted and a renal biopsy revealed uric acid nephropathy superimposed on lupus nephritis.

Long term medication with immunosuppressants and a uric acid-lowering agent were prescribed

after the pathohistologic diagnosis. The patient's serum creatinine level had improved after six

months of therapy. ( Mid Taiwan J Med 2004;9:249-54 )

KKeeyy wwoorrddss

lupus nephritis, renal failure, uric acid nephropathy

Received : 7 November 2003. Revised : 4 September 2004.Accepted : 15 October 2004.Address reprint requests to : Min-Tsung Kao, Division ofNephrology, Department of Internal Medicine, China MedicalUniversity Hospital, 2 Yuh-Der Road, Taichung 404, Taiwan,R.O.C.

Uric Acid Nephropathy Superimposed on Lupus Nephritis

Po-Wen Lin, Yuan-Chuan Kuo, Jiung-Hsiun Liu, Tze-Yi Lin1

, Min-Tsung Kao

Division of Nephrology, 1Department of Pathology, China Medical University Hospital, Taichung, Taiwan, R.O.C.

CASE REPORT

250 Uric Acid Nephropathy Superimposed on Lupus Nephritis

as having primary hypertension at age 20. Hisblood pressure was poorly controlled between140-160/70-90 mmHg by atenolol 100 mg daily.About six months prior to this admission, hepresented with moderately painful erythema in hisright hand and para-oral area, followed byarthralgias in both knee joints. Gouty arthritis wasdiagnosed because of coexistent hyperuricaemiaand treated with allopurinol and benzbromarone.Urinalysis revealed microscopic hematuria andproteinuria. However, three months prior to thisadmission, he had developed eyelid puffiness,gross hematuria, stiffness in both ankle joints andoccasional bilateral flank pain. Anasarca had alsobeen developing for over half a year. Uponadmission, the white blood cell count was 6.74 109/L (6.74 103/µL), hemoglobin 6.88 mmol/L

(11.1 g/dL), platelet 76 109/L (76 103/µL),blood urea nitrogen 42.8 mmol/L (120 mg/dL),creatinine level 469 µmol/L (5.3 mg/dL), albumin22 g/L (2.2 g/dL), uric acid 964 µmol/L (16.2mg/dL), 24 h urinary protein 10.64 g, creatinineclearance 29.9 ml/min, 24 h urinary uric acid 280mg. Urinalysis showed proteinuria (3+), pyuria(25-30 white blood cells per high power field)and hematuria (numerous red blood cells per highpower field). Immuological tests were normalexcept for a low C3 complement (0.078 g/L; N:0.85-1.85) (7.82 mg/dL; N: 79-152), a low C4complement (0.112 g/L; N: 0.12-0.54) (11.2mg/dL; N: 16-38) and a positive antinuclearantibody titer at 1:80 with a speckled pattern.

A renal biopsy specimen showed diffuseproliferative glomerulonephritis, manifested by a

Fig. 1. Marked intraglomerular cellular proliferation, lobularaccentuation and mild to focally moderate karyorrhexis. (H & E stain, 400 )

Fig. 2. Subendothelial deposits in a wire loop pattern andfibrinoid necrosis were present in the intraglomerular area.(H & E stain, 400 )

Fig. 3. Alternating degenerative and regenerative changes ofthe lining epithelium. (H & E stain, 400 )

Fig. 4. Mild to moderate interstitial infiltration composedprimarily of mononuclear cells. (H & E stain, 400 )

251Wen-Pin Liu, et al.

marked intraglomerular cellular proliferation,lobular accentuation and mild to focally moderatekaryorrhexis (Fig. 1). Subendothelial deposits in awire loop pattern and fibrinoid necrosis were alsonoted (Fig. 2). The tubulointerstitial compartmentshowed patchy tubular epithelial cell injury withsimplification and alternating degenerative andregenerative changes of the epithelial lining (Fig.3). Mild to moderate interstitial inflammatoryinfiltration in the interstitial area was also noted(Fig. 4). Discernible needle to rectangular sodiumurate crystals could be seen in the injuried tubulesunder a polarized microscope (Fig. 5). Theimmune fluorescent study demonstrated a stronggranular "full-house" deposition of IgG, IgM,IgA, C3, C1q and C4 in the subendothelial andmesangial regions. Based on the histopathologicaland immunofluorescent features, lupus nephritisclass IVc (modified World Health Organizationclassification) and tubulointerstitial injuriescaused by acute uric acid nephropathy weresuspected. The patient's serum creatinine haddecreased to around 265.2 µmol/L after six-months of treatment with immunosuppressantsand a uric acid-lowering agent (prednisolone 10mg daily, cyclosporine 50 mg bid, and allopurinol100 mg daily).

DDIISSCCUUSSSSIIOONN

Systemic lupus erythematosus (SLE) is achronic inflammatory disorder characterized byoverproduction of autoantibodies and other

distinct immunological abnormalities. It may bemultisystemic or may involve only one organsystem with additional manifestations occurringlater. Lupus nephritis usually develops within 3years after diagnosis of SLE [3] and only one-quarter of patients with renal lupus presents withrenal disease as the first manifestation. Arthritisand facial rash usually precede nephritis [5].

Our patient, who fulfilled the AmericanRheumatism Association criteria for SLE,clinically presented with acute renal failure,severe proteinuria, hematuria and hyperuricemiaon admission. He had sudden onset of arthralgiaattacks in both knees and gouty arthritis wasdiagnosed without arthrocentesis six months prior to presentation. Patients with SLE arepredominantly young and female. Coexistent SLE and gout, as in our case, is uncommon. Thecommon clinical features of this group includenephritis manifested by proteinuria. Diuretic andcorticosteroid therapy is the most commontreatment. Patients with coexistent SLE and gouttend to be older and more frequently male thanthe general population of SLE patients [6]. It hasbeen reported that most patients develop goutafter the onset of SLE and many of them havehypertension and serious cardiovascular diseases.In one study, serum uric acid and 24-h urine uricacid indicated that all of the patients werehyperuricaemic and underexcretors of uric acid[7]. Most of the above clinical features were alsoseen in our case.

Hyperuricaemic SLE patients often presentwith the same clinical features associated withgout. One study reported that hyperuricaemia wasfound in 29% of patients and that it was closelyassociated with renal involvement and diuretictherapy. Particularly striking was the very highprevalence of proteinuria in these patients,although most of them had normal serumcreatinine levels [6]. Thus the major factorscontributing to hyperuricaemia in our patientappeared to be decreased clearance of uric acid,including decreased glomerular filtration rate andimpaired tubular secretion, and enhanced tubular reabsorption due to intravascular volume contraction. The uricosuric effect of

Fig. 5. Discernible needle to rectangular sodium uratecrystals in the injuried tubules under a polarized microscope.(H & E stain, 400 )

252 Uric Acid Nephropathy Superimposed on Lupus Nephritis

benzbromarone, NSAIDs and corticosteroid could also have been a factor. Recent studies have reported that hyperuricaemia induceshypertension, intrarenal vascular disease andrenal injury. Despite the association betweenhyperuricaemia and renal disease, controversyexists as to whether uric acid plays an etiologicrole [8-10]. In this study, the rectangular sodiumurate crystals within the tubular lumen seen underpolarized microscopy were mainly uric acidcrystals. Tubular blockage and tubular ingestionof crystals, which induce tubular injury, tubularinflammation and minimal interstitial cellularinfiltraton, lead to acute uric acid nephropathyand may exacerbate acute renal failure. About60% to 70% of patients with lupus nephritis showsome degree of interstitial inflammation, tubulardamage, and interstitial fibrosis. Together withinflammatory lesions, some 30% to 50% of casesshow immune deposits (mostly IgG and C3)along tubular basement membranes, in theinterstitium, and along the peritubular capillaryand arteriolar walls. Usually the degree ofinterstitial lesions correlates with the severity ofglomerular changes. The presence of immunedeposits in these structures has suggested thattubulointerstitial damage may be immunecomplex-mediated [11]. Therefore, acute uric acidnephropathy seen in our patient is different fromtypical lupus interstitial nephritis.

Gout with renal failure in young patients is possibly due to hereditary nephritis, ahypoxanthine guanine phosphoribosyltransferase(HGPRTase) defect leading to purine over-production, or an inherited defect in the tubularhandling of urates which reduces urate excretion [12,13]. Although our patient was an underexcretor, calculation of fractional urate excretion (FEur) and red cell HGPRTasedeficiency testing would have provided additionalinformation to help rule out hereditary nephritis.

The severity of proteinuria, ranging fromthe minimal to nephrotic usually correlates withthe histologic type of lesion in lupus nephritis.The main cause of overt proteinuria in our patient was attributed to class IVc lupus nephritis.Neither acute uric acid nephropathy nor chronic

urate nephropathy would have been able to induce nephrotic proteinuria. Acute nephriticsyndrome, which is characterized by the abruptonset of hematuria, proteinuria temporallyassociated with acute renal failure resulting in the development of oligouria, salt and water retention, and hypertension as seen in ourcase, is most commonly due to proliferativeglomerulonephritis and less commonly due toacute interstitial nephritis. We believe that activeimmunosuppressive therapy for his class IVclupus nephritis led to improved renal function,decreasing the the serum creatinine level from469 µmol/L (5.3 mg/dL) to 265 µmol/L (3.0mg/dL). This implies that acute uric acidnephropathy was simply superimposed on lupusnephritis and not the main cause of his acute renalfailure.

Renal biopsies of lesions in SLE patientswith gout and hyperuricacemia offen revealmembranous nephritis [6,7], membrano-proliferative nephritis and diffuse proliferativenephritis [6]. Acute uric acid nephropathysuperimposed on diffuse proliferative nephritishas never been reported. Based on theepidemiology of uric acid nephropathy and lupusnephritis, young males have a relatively lowincidence of developing those two diseases. Renalbiopsy plays a crucial role in identifying theselesions and may have prognostic and therapeuticimplications.

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