Lupus nephritis: clinicopathological study of 162 cases in Thailand

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1 J Clin Pthol 1986;39: Lupus nephritis: clinicopthologicl study of 162 cses in Thilnd P PARICHATIKANOND, ND FRANCIS,* P MALASIT, T LAOHAPAND, S NIMMANNIT, L SINGCHOOVONG, S NILWARANGKUR, P CHRIRAWONG, S VANICHAKARN From the Deprtment of Pthology nd Renl Unit, Deprtment of Medicine, Sirirj Hospitl, Bngkok, Thilnd, nd the *Deprtment ofexperimentl Pthology, St Mry's Hospitl Medicl School, London SUMMARY One hundred nd sixty two cses of lupus nephritis biopsied over three yers in Thilnd were studied. A pttern of clinicl nd histologicl renl disese very similr to tht seen in the United Sttes or Europe emerged. The predominnt histologicl type ws World Helth Orgnistion clss IV (diffuse prolifertive; 58-6%). Ptients with renl insufficiency (cretinine > 2 mg/100 ml) or hypertension t the time of biopsy hd considerbly worse three yer survivl. Certin fetures such s sclerotic glomeruli, tubulr trophy, nd n interstitil mononucler cell infiltrte were significntly ssocited with worse outcome (0 05 > p > 0-01), nd ptients who died with poor renl function hd significntly higher chronicity scores thn those in other groups (p < 0-05). These findings emphsise the importnce of chronic renl dmge in the morbidity nd mortlity of ptients with lupus nephritis. The number of ptients with systemic lupus erythmtosus registered ech yer is , representing 3-3% of the totl medicl inptients t the Sirirj Hospitl. The renl unit dmits such ptients nnully, nd during the period covered by this study 162 ptients out of 230 hd clinicl evidence of renl disese. In the bsence of ny studies of this condition from Thilnd it seemed initilly tht the degree of concomitnt renl disese, both cliniclly nd histologiclly, ws more severe thn we hd thought. We therefore crried out detiled investigtions to estblish ny clinicopthologicl or prognostic differences tht might be seen when our study ws compred with other series' -10 from res of much lower prevlence. We report 162 ptients with lupus nephritis who ttended the renl unit, Sirirj Hospitl, Bngkok, who underwent renl biopsy between Jnury 1981 nd December 1983, nd who were nlysed ccording to the World Helth Orgnistion clssifiction (Tble 1). " (These ptients hve now become prt of long term follow up study. Accepted for publiction 14 October 1985 Ptients nd methods Of 1119 renl biopsies performed between Jnury 1981 nd December 1983, 180 were from 173 ptients fulfilling four or more of the preliminry'2 or revised, 3 or both, Americn Rheumtism Assocition criteri for the dignosis of systemic lupus erythmtosus. Eleven biopsies were indequte resulting in 169 from 162 ptients (154 new cses nd eight repet biopsies). The femle:mle rtio ws 154:8 (19:1) nd men ge ws 26-6 ((SD) 9-8 yers) (rnge 6-66 yers) t the time of biopsy. In ech cse serologicl evidence of systemic lupus erythmtosus (LE preprtion, ANF, nti-ds DNA) ws sought s one of the criteri nd ws obtined in ll but one cse, in which six other criteri were fulfilled. There ws no obvious geogrphicl bis mong the popultion studied: Sirirj Hospitl (750 beds) is one of six teching hospitls in Bngkok (popultion 4-5 million) serving lrge prt of Bngkok s well s provincil cities ll over Thilnd. CLINICAL EVALUATION Renl function ws clssified by serum cretinine, nd concentrtion of > 2 mg/dl ws ctegorised s renl insufficiency. Ptients were divided into those with 160

2 Lupus nephritis: clinicopthologicl study of 162 cses in Thilnd Tble 1 Histologicl ptterns, ge, sex, ndpthologicl scores in renl biopsiesfrom 162 ptients with systemic lupus erythmtosus WHO clss11 Ptients Age t biopsy Sex Pthologicl scores (men (SD)) (yers) men (SD) No Totl % FM Activity Chronicity Totl Norml glomeruli: No immune deposits : Mesngil: Mild cellulrity (11-4) 28:1 19 (1-0) 1-1 (1-4) 3-0 (2.2) Moderte cellulrity Focl prolifertive: "Active" lesion 12 Sclerosing lesion (8-6) 15:1 4-2 (1-8) 1-9 (1.5) 6-1 (2.5) "Active" nd sclerosing lesion Diffuse prolifertive: Pure prolifertion 9 "Active" lesion (9-8) 90:5 8-0 (2-4) 3-1 (1-9) 11-3 (2-9) "Active" nd sclerosing lesion 6 Membrnous: Pure I 11 WithfetureofclssIII* feture (8-6) 20:1 5-7(2-1) 2-1(1-8) 7-8(3-5) With feture ofclss IV* 6 Totl :8 *My be clssified s clss III nd IV. In this study if numerous or lrge subendothelil deposits, or both, or prolifertion ws severe, the biopsy ws clssified s clss IV. nd without renl insufficiency t the time of biopsy. For evlution of outcome chnge of more thn one third of the serum cretinine ws considered to be cliniclly importnt nd on this bsis ptients were llocted into five groups t the end of the study: A better; B no chnge; C worse, or deth from renl filure, or from nother cuse, but with record of deteriorting renl function; D deth without record of deteriorting renl function; E lost to follow up. Ptients in group B were rellocted if there hd been chnge in hemturi, (+ to - or - to +) or by chnge in proteinuri of more thn 2 +. Clinicl definitions used in this study were: cliniclly importnt hemturi, > 5 red blood cells/high power field; cliniclly importnt proteinuri, > 1 g/24 hours; hypertension, distolic blood pressure > 95 mm Hg on two seprte occsions, or record of nti-hypertensive tretment. Tissue ws divided into three portions for light microscopy with immunoperoxidse stining (n estblished method),'4 immunofluorescence, nd high resolution light microscopy (1 gm). EVALUATION OF BIOPSIES All cses hd t lest five glomeruli in sections embedded in prffin nd epoxy resin. Ech biopsy ws ssessed independently by two observers (PP nd NDF) nd clssified into one of the WHO clsses.1' Cses with repet biopsies were clssified by the first one except in the eight cses coming to biopsy before 1981 for which no immunopthologicl studies were vilble. A pthologicl scoring system4 ws used, resulting in ctivity, chronicity, nd totl scores for ech biopsy. Ech feture ws grded 0 to 3 + (O = bsent, 1+ = < 25%, 2 + = 25-75%, 3 + = > 75%). There ws rrely difference of greter thn 1 + for ny feture mong the observers. This supports the findings of others.6 15 SEROLOGY ANF nd nti ds-dna were tested using stndrd methods."6 17 Differences between ech WHO clss were compred using the Mnn-Whitney test. Individul pthologicl fetures relted to outcome were tested by the x2 test nd contingency tble methods. Survivl dt were nlysed by the life tble method'8 nd clculted from the time of biopsy. Results 161 CLINICAL Aprt from renl disese, the most common presenting signs were skin rsh, nemi, nd joint symptoms. Tble 2 shows the clinicl mnifesttions throughout the course of follow up. All ptients hd clinicl renl disese, nd the most common fetures were those relted to skin nd joints. Hypertension nd nemi were common complictions, mostly from clss IV ptients. Disese of the centrl nervous

3 162 Prichtiknond, Frncis, Mlsit, Lohpnd, Nimmnnit, Singchoovong, Nilwrngkur, Chrirwong, Vnichkrn Tble 2 Clinicl mnifesttions throughout follow up period of 162 ptients with systemic lupus erythmtosus WHO clss Totl I II III IV V Cse % No of ptients Skin rsh Joint symptoms Hypertension Anemi Infection Orl ulcer Vsculitis CNS symptoms Serositis Rynud's phenomenon Oculr signs I Avsculr necrosis of femur system ws not predominnt feture in ny WHO clss. Infections were common nd often multiple. There ws no cler ge difference between ptients from WHO clsses. Evidence of renl disese, obtined from referrl informtion, histories, nd recorded dt t presenttion, comprised oedem (72-3%), proteinuri (28-4%), nd gross hemturi (14-2%). PATHOLOGY Tble I shows the distribution of ge, sex, nd pthologicl scores within ech group. Tble 3 shows some specific fetures t the time of biopsy, the most striking of which ws the high proportion of ptients with hemturi nd those in clsses IV nd V with proteinuri in the nephrotic rnge. Men ctivity scores between ech clss, chronicity scores between clsses II nd V, nd totl pthologicl scores between ech clss except III nd V were ll significntly different (p < 0-01). The reminder were mrginlly significnt (0-05 > p > 0-01). Clss IV ptients hd the highest men scores. Adequte mteril ws vilble for immunofluorescence or immunoperoxidse studies, or both, in 134 cses. Most were positive for IgG (130), IgA (129), IgM (128), nd C3 (131). Sixty eight of 130 ptients were positive for fibrinogen nd 49 of 60 of those tested were positive for C4. IgG ws the predominnt immunoglobulin in 97 cses. Tble 3 Renlfindings t time ofbiopsy WHO clss SEROLOGY LE cell preprtion, ANF nd nti ds-dna were positive in 55-4%, 91-9%, nd 62-1%, respectively, of the ptients tested. In ll but one of the ptients whose test for ANF ws negtive or not recorded, the LE cell preprtion nd nti ds-dna were positive. FOLLOW UP (TABLE 4) Fourteen ptients were lost to follow up. The remining 148 were followed up for two to 44 months (men 14-9 (10-0)) fter biopsy. Thirty six (24%) showed no chnge, 69 (47%) improved, nd 19 (13%) deteriorted. Follow up intervls vried widely within ech clss, nd no sttisticl nlysis ws ttempted. Twenty four (16%) ptients died, 17 of whom were in clss IV. Infection ws the cuse of deth in nerly hlf of them. Renl filure ws n importnt cuse of deth nd occurred only in clss IV ptients. Survivl curves from the time of biopsy seen in Fig. 1 show tht clss IV ptients hd the worst three yer survivl. REPEAT BIOPSIES Thirteen cses hd more thn one dequte biopsy, resulting in 30 biopsies for nlysis. Six cses showed no chnge in WHO clss. Three cses chnged from clss IV to II, two from III to IV, one from II to IV, nd one from IV to V. Totl I II 111 IV V No % No of ptients Hypertension Hemturi (> 5 rbcs hpf) Proteinuri 1-3 g/24 hours > 3 g/24 hours hour protein (g) (men (SD)) 0-7 (1-4) 1-7 (1-4) 5-28 (3-2) 5-4 (4-3) Cretinine mg/100 ml (men (SD)) (0-4) 1-4 (0-7) 2-1 (2-0) 1-3 (0-8)

4 Tble 4 Lupus nephritis: clinicopthologicl study of 162 cses in Thilnd IV 40J I * *I I I I Fig. 1 Survivl ofptients in WHO biopsy clss II, III, IV, nd V. ANALYSIS Chronicity scores of the eight ptients who died s result of renl filure (5) or who hd renl filure t the time of deth from nother cuse (3) were significntly higher thn those of the other outcome groups (p < 0-05, Tble 4). Division of ptients into those with totl pthologicl score of < 8 nd those with > 8 showed only slightly worse (insignificnt) three yer survivl of the second group (89-6% v 951%). Within ech WHO clss there ws no significnt difference between the pthologicl scores of the different outcome groups. The presence of more thn 25% of the following fetures ws ssocited with worse outcome: sclerotic glomeruli (p = 0-014), tubulr trophy (p = 0 036), nd interstitil mononucler cell infiltrtion (p = ). Ptients who hd "renl insufficiency" (33 Follow up dt cses) or hypertension (63 cses) t the time of biopsy hd significntly poorer three yer survivl (45 4% v 835%,p < 0-001;655% v884%,0001 < p < 0-01, respectively) (Figs. 2 nd b). Despite creful serching only two cses with definite cpillry fibrin thrombi nd one cse with vsculitis were found. Hemtoxyphil bodies were noted in only six cses (3 6%); four in clss IV nd two in clss III, ll in res of necrosis. Discussion Our study shows tht systemic lupus erythmtosus is unusully common nd tht lrge proportion of the ptients seen t this hospitl present with renl disese. The preselection of ptients for renl biopsy, however, nd the fct tht this is referrl centre mens conclusions drwn bout this group do not necessrily pply to ll cses of systemic lupus erythmtosus in Thilnd. The unusully high femle to mle rtio (19:1) is, in prt, fortuitous. A previous report from Thilnd'9 showed rtio close to tht reported in the United Sttes nd United Kingdom of 10:1, but the combined figures from show rtio of 14:1 (397:28). The reson for this higher prepondernce mong women is uncler. Frnk20 drew ttention to the higher incidence of systemic lupus erythmtosus mong the Chinese in Mlysi, nd two other studies indicted high prevlence of the disese mong Chinese in Hwii2" nd higher mortlity mong Chinese with systemic lupus erythmtosus in the United Sttes.22 It is extremely difficult to nlyse the ethnic origin of our ptients, but intermrrige between Thi nd Chinese is common. The min conclusion of our study is tht the pttern of renl disese nd clinicl presenttion is WHO clss Totl Pthologicl score I II III IV V Totl Activity Chronicity Totl No of ptients: Intervl (biopsy to end of study inmonths) (men (SD)) (17-3) 15-1 (10-6) 16-3(13-5) 11-5(7-5) Outcome: Improvement (3 3) 2-4 (1-8) 8-6 (4-3) No chnge (3 5) 2-1 (1-6) 8-0 (4.6) Deteriortion (3-1) 2-5 (2-1) 7-6 (4-4) Deth from: i Renlfilure 5 5 ii Hert filure I (1)* 1 (1)* iii Infection (2)* 2 11 (2)* iv CNS I 1 vunknown Deths due to nd ssocited with renl filure (2-1) 5 (3-2) 12-4 (3-6) *Numbers in prentheses indicte No of ptients who hd renl filure t the time of deth but whose deth ws not cused by renl filure. 163

5 164 Prichtiknond, Frncis, Mlsit, Lohpnd, Nimmnnit, Singchoovong, Nilwrngkur, Chrirwong, Vnichkrn () 100 (ii) 80 b _ 80] b 60 \60-I I ~ I I I L.~~~~~~ (A I L (iii) I I I I b - l - 1-! 60*._: (iv) Fig. 2 Survivl ofptients: i) with () nd without (b) renl insufficiency; ii) with () nd without (b) hypertension; iii) with crescents ofmore () nd less (b) thn 25% of the glomeruli; nd iv) with () nd without (b) hyline thrombi. very similr to tht seen in the United Sttes or United Kingdom. We found 10% higher proportion of ptients in WHO clss IV nd 9% lower proportion of ptients in clss II nd III combined, when compred with combined dt presented by Hill;23 these differences re not significnt, which is of importnce in the light of recent report24 in which 27 Koren ptients were found to hve significntly higher percentge of clss IV (77T8%) nd fewer clss VII cses. This pprent discrepncy could be due to the reltively smll number of Koren ptients, or it could reflect difference in the pttern of renl disese in Thilnd nd Kore. Compred with other series our cses show similr ge distribution, clinicl mnifesttions of systemic lupus erythmtosus, renl presenttion, nd prevlence of hypertension. Our follow up period ws short, but cuses of deth re similr to those discussed in previous reports,5 7 with infections being the commonest nd renl filure the second commonest cuse. Our three yer survivl rtes were close to those of Appel et l' in ll clsses; clss IV ptients showed the worst survivl, which supports the view tht histologicl clss is prognosticlly importnt. Using the scoring system, we found clss IV 40 b

6 Lupus nephritis: clinicopthologicl study of 162 cses in Thilnd ptients hd significntly higher men pthologicl scores (ctivity, chronicity, nd totl) s did Blow et l4 nd Austin et l,s but the overlp of scores between clsses ment tht the score lone ws not good predictor of clss or survivl. Our findings, lthough not directly comprble, do not support Kslow's22 findings of higher mortlity in orientl ptients with systemic lupus erythmtosus. Our follow up period ws short, however, nd we only looked t ptients with lupus nephropthy, while Kslow's dt were tken from deth certificte records. Assessing indictors of outcome, we found tht renl insufficiency nd hypertension t the time of biopsy were ssocited with worse three yer survivl, nd cliniclly importnt presence of sclerotic glomeruli: tubulr trophy, nd n interstitil mononucler cell infiltrte were ssocited with worse outcome. In ddition, ptients who died with deteriorting renl function hd considerbly higher chronicity score thn other outcome groups. These findings emphsise the importnce of chronic renl dmge in lupus nephritis. The totl pthologicl score ws not ssocited with deteriorting renl function or development of renl filure, unlike Blow's study,4 nd importnt differences between scores of ech outcome group within ech clss were not found. In view of previous uthors weighting their scoring systems8 25 for cellulr crescents we were surprised to find no ssocition between crescents nd worse outcome nd no importnt difference in the three yer survivl between these ptients. It will be interesting to see if longer term follow up shows ny such ssocition, s ptients my hve n initilly good response to ggressive tretment, which my dely the decline in renl function for s much s three or four yers. A recent pper by Austin et 126 reported tht fter four yers of follow up cellulr crescents predicted decline in renl function: further report27 identified crescentic glomerulonephritis s the most common underlying pthology of cute deteriortion in renl function. We re indebted to the Wellcome Trust for their support of this project by providing generous grnt to Dr N Frncis s reserch fellow nd for their continuing support of Drs Mlsit nd Lohpnd. We re indebted to Miss P Chiynon, S Mingkum, K Srisuk, nd S Khunsuwn for their expert technicl help nd Mr V Supttee for the illustrtions. We thnk Mrs P Dodi nd Miss P Ip-Un for secretril help. We lso sincerely thnk Professor KA Porter for his help, encourgement, nd support of this study. References 165 ' Appel GB, Silv FG, Pirni CL, Meltzer JI, Estes D. Renl involvement in systemic lupus erythemtosus (SLE): study of 56 ptients emphsising histologicl clssifiction. Medicine 1 978;57: Bldwin DS, Lowenstein J, Rothfield NF, Gllo G, McCluskey RT. 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Oxford: Blckwell Scientific Publictions, 1981: Arden LA, Grott ER, Feltkmp TEW. Immunology of DNA. III. Crithidi lucilie, simple substrte for the determintion of nti-ds-dna with the immunofluorescent technique. Ann NY Acd Sci 1975;254: Rimm AA, Hrtz AT, Klbfleisch JH, Anderson JA, Hoffmn RG. Bsic biosttistics in medicine nd epidemiology. New York: Appleton-Century-Croft, 1980: Chirwong P, Nimmnnit S, Vnichkrn S, Singchoovong L, Nilwrngkur S. Lupus nephritis: n nlysis of tretments in 163 cses. Sirirj Hospitl Gzette 1981;33: Frnk AO. Apprent predisposition to systemic lupus erythemtosus in Chinese ptients in west Mlysi. Ann Rheum Dis 1980;39: Serdul MK, Rhods GC. Frequency of systemic lupus erythemtosus in different ethnic groups in Hwii. Arthritis Rheum 1979;22: Kslow RA. High rte of deths cused by systemic lupus erythemtosus mong US residents of Asin descent. Arthritis Rheum 1982;25: Hill GS. Systemic lupus erythemtosus nd mixed connective tissue diseses. In: Heptinstll RH, ed. 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7 166 Prichtiknond, Frncis, Mlsit, Lohpnd, Nimmnnit, Singchoovong, Nilwrngkur, Chrirwong, Vnichkrn 1984;25: Yeung CK, Ng WL, Wong WS, Wong KL, Chn MK. Acute deteriortion in renl function in systemic lupus erythemtosus. Q J Med 1985;219: Boston: Little Brown nd Co, 1983: Lee HS, Sprgo BH. A renl biopsy study of lupus nephropthy in the United Sttes nd Kore. Am J Kidney Dis 1985;5: Austin HA, Muenz LR, Joyce KM, et l. Prognostic fctors in lupus nephritis: contribution of renl histologicl dt. Am J Med 1983;75: Austin HA, Muenz LR, Joyce KM, Antonovych TA, Blow JE. Diffuse prolifertive lupus nephritis: identifiction of specific pthologicl fetures ffecting outcome. Kidney Int Requests for reprints to: Dr P Prichtiknond, Deprtment of Pthology, Sirirj Hospitl, Bngkok 10700, Thilnd. J Clin Pthol: first published s /jcp on 1 Februry Downloded from on 7 July 2018 by guest. Protected by copyright.