300 to 400 mg./day, repeated evaluation of renal function. and measurements of urinary and serum urate levels. therapy?

Transcription

1 nn. rheum. Dis. (1966), 25, 681 LLOPURINOL IN PTIENTS WITH IMPIRED RENL FUNCTION BY N. W. LEVIN ND. L. BRHMS Frm the C.S.I.R. Cardi-Pulmnary Unit, Department f Medicine, University f the Witwatersrand, and the Renal Unit, Jhannesburg General Hspital, Republic f Suth frica The:xanthine xidase inhibitr allpurinl wuld excretins were measured. Urine was examined micrscpically. Serum irn and irn-binding capacity appear t be ideally suited fr the treatment f patients with recurrent urinary uric acid stnes r estimatins, SGPT measurements, and full bld cunts gut with impaired renal functin. The latter grup were als carried ut. fter starting allpurinl therapy are ften unrespnsive t uricsuric agents and 3 t 4 mg./day, repeated evaluatin f renal functin and measurements f urinary and serum urate levels befre the advent f allpurinl n suitable therapy were carried ut. Full bld cunts were perfrmed was available. The present study was carried ut in twice mnthly and in the majrity f patients repeated rder t answer the fllwing questins: estimatins f SGPT and SGOT were als dne. (1) Is allpurinl as successful in Patients were seen n an average f every 1 days t 2 decreasing serum uric acid (SU) excretin in patients with renal weeks and a careful histry was taken f attacks f acute disease as it is in individuals with nrmal renal gut and f episdes f urinary calculi. Of the 33 functin patients, all were fllwed fr at least 3 mnths, 21 fr? 6 mnths, 13 fr 9 mnths, and 9 fr 12 mnths. Uric (2) D larger dses have t be used in the treatment acid was measured n sme patients using the utanalyser cyanide methd. Creatinine was measured by f patients with impaired renal functin t btain satisfactry clinical respnse? the alkaline picrate methd, using Llyd's reagent. In sme patients measurements were made f urate and (3) Des allpurinl therapy have any direct r xypurine clearances befre and after allpurinl, and indirect effect n renal functin? in fur patients (tw in renal failure and tw with (4) re the side-effects f allpurinl therapy mderate impairment f f'enal functin) the effect f different in patients with impaired renal alkaliniatin f the urine n xypurine and uric acid functin? clearance was bserved. In these studies plasma and urinary uric acid cncentratins were measured by (5) Is the incidence f urinary calculi decreased in ultravilet spectrphtmetry, using uricase [4 units f patients with impaired renal functin while n Seravac Labratries (Pty) Ltd. uricase] accrding t the allpurinl therapy? methd f Praetrius and Pulsen (1953). Heparinied plasma, separated immediately after cllectin f the (6) Is the increased xypurine clearance nticed in bld, was used in preference t serum, as xypurines nrmal patients n allpurinl therapy als were estimated n the same sample and the breakdwn f bserved in patients with renal functinal adensinetriphsphate (TP) cntained in the bld impairment? leads t frmatin f hypxanthine (Jrgensen and (7) What is the effect f urinary alkaliniatin Pulsen, 1955b). n xypurine excretin in patients n allpurinl Oxypurines were estimated in heparinied plasma and therapy? in urine by the methd f Watts, Watkins, Mathias, and Gibbs (1966). The recvery f xanthine added t plasma and urine using this methd was 9 t 95 per cent. It Material and was Methds fund that the presence f 1 t 4 ug. 4, 6-dihydrxypyralpyrimidine (DHPP, all-xanthine) in the Of 33 patients studied (29 men and 4 wmen, aged frm spectrphtmeter quart curvette did nt inhibit the 8 t 68 years), 22 had endgenus creatinine clearance cnversin f 1,tg. xanthine t uric acid using * 2 ml. f less than and eleven mre than 7 ml./min. Twelve a 1-fld dilutin f xanthine xidase (xanthine xidase, patients had a recent histry f urinary uric acid calculi 4 units, Nutritinal Bichemicals Crpratin). and fur had grss tphaceus gut. Plasma levels f DHPP were estimated as described by fter a cntrl perid f 1 days, when all treatment Rundles, Met, and Silberman (1966b). It was fund that was discntinued, measurements were made f endgenus creatinine clearance, uric acid clearance, urea tins f 4 per cent. r less f the DHPP cncentratin the additin f xanthine r hypxanthine in cncentra- clearance, and urinary prtein excretin. had n effect n the inhibitry prperties f DHPP under In twelve patients standard phenlsulpthalein (PSP) the experimental cnditins, but DHPP cncentratin 681 nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm n 27 pril 218 by guest. Prtected

2 682 NNLS OF THE RHEUMTIC DISESES culd nt be reliably estimated when the cncentratin f xypurines present exceeded 4 per cent. f the cncentratin f DHPP. The slubility f xanthine, hypxanthine, uric acid, and DHPP was measured in bth plasma and urine (the latter atph 5 and 8). The respective media were incubated fr 2 hrs at 37 C. with each f the purines, mixing well at 1-min. intervals. t the end f the incubatin perid, the mixture was filtered and the filtrate tested. Untreated urine and plasma were tested at the same time. Results (1) cute ttacks f Gut.-There was a marked reductin in the number f acute attacks f gut in all the patients wh were subject t this cmplicatin. There did nt seem t be an increased rate f exacerbatin f acute guty arthritis in the early stages f treatment with the dses used. ll patients were given clchicine 1 mg. twice a day fr at least the first 2 mnths because f the reprted high incidence f acute guty arthritis in patients receiving allpurinl. The acute attacks f gut which ccurred seemed f much decreased severity. Many patients cmmented that numerus aches and pains that they had previusly nticed in the muscles f their back, shulders, and arms seem t have disappeared n allpurinl therapy. Limitatin f mbility ften imprved remarkably. Despite these favurable findings, ccasinal acute attacks f gut did ccur in patients with SU levels well belw 5 mg./1 ml. There seemed t be n difference in the favurable respnse f patients with greater impairment f renal functin as cmpared t the thers. (2) Incidence f Calculi.-Of the twelve patients wh had a histry f urinary calculi r gravel, nly tw had any such symptms during the trial (Table I). One was Case 8, wh passed tw uric acid stnes at a TBLE I EFFECTS OF LLOPURINOL ON INCIDENCE OF URINRY CLCULI Previus Therapy llpurinl Case N. Calculi Duratin Calculi Duratin (yrs) (yrs) 1 Cntinuus Many 1-3 gravel 2* 3 8 1* Gravel I -8 8*t * Intermittent 5 Renal 1 5 gravel clic nce 12* *Ccreatinine less than 7 ml./min. turic acid stnes passed while urinary urate excretin 11 mg./day. time when his urinary urate excretin was less than 12 mg./day. It appeared that his urine disslved less xanthine than that f patients with a similar degree f impairment f renal functin (see Table II). The secnd, a man f 55 (Case 11), had ne episde f lin and ureteric pain but n calculus was passed and an intravenus pyelgram carried ut a few days later shwed n abnrmality. Many patients wh had previusly had a persistent histry f passing urinary gravel n mild dehydratin were cmpletely symptm-free n allpurinl therapy. (3) Tphi.-In fur patients with grss tphaceus gut treated fr mre than 9 mnths each, there was sftening and reductin in the sie f tphi leading t cmplete disappearance f sme f them. Renal functin was impaired in these patients (Ccreatinine 48, 63, 96, 82 ml./min.). (4) SU Levels.-The effect f allpurinl n SU levels and the mean dsage used during 3, 6, 9, and 12 mnths f therapy are shwn in Fig. 1 (ppsite). The mean reductin in SU level in TBLE I I SOLUBILITY OF PURINES ND THE PYRIMIDINE DHPP IN PLSM ND URINE Purine r Pyrimidine Uric cid (mg./1 ml.) -1.., (1) (4) (I) Plasma 7 2 Urine ph ph I (1) Nrmal subiect. (2) Patient wh develped uric acid calculi (Table I, Case 8) while n allpurinl (Ccreatinine 12ml./min.). (3) Patient with guty nephrpathy (Ccreatinine 1 ml./min.) (Table I, Case 11). r (4) Measurements reprted by Klinenberg and thers (1965). I nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm n 27 pril 218 by guest. Prtected

3 Cr) J Mnths LLOPURINOL S YMPOSIUM, 1966 * C cr < 7 mi./min. C Cr > 7 ml/min. 1*- S CD S 8 1 I MeOn SU level (mg./lml.) llpurml uduage m%/ uday Fig. I.-Effect f allpurinl therapy n serum uric acid levels. thse with renal impairment des nt differ frm that in thse with nrmal renal functin. There is n significant difference in the dsages used in these tw grups. (5) Urinary Urate Excretin.-The effect f allpurinl during 3, 6, 9, and 12 mnths as cmpared t cntrl levels is shwn in Fig. 2. gain there is n significant difference between patients ll, I!J 75 w > -i w L 5 LhJ W - w w CrCW w a 7- s 6 6- D. a: 5- Liw 4- Vn t MONTHS * s i * n 5 D OMD Cf * ccr <7mnl/min Ccr >7ml./min.. 1 I. i Mean urate excretin (mg./day) Fig. 2.-Effect f allpurinl therapy n urinary urate excretin 683 with renal impairment and thse with nrmal renal functin. lthugh a substantial decrease in urinary urate excretin is demnstrated, the dses used were nt large and it is very likely that with larger dses a greater reductin in excretin wuld have been prduced. The greater decrease in urate excretin after the first 3 mnths can be attributed t the slightly higher dsages used after that time. (6) Renal Functin.-Fig. 3 shws the mean endgenus creatinine clearance at the beginning and end f the study in 29 f the 33 patients. In the ther fur patients clearances were 51, 6, 56, and 64 ml./min. initially and 7, 67, 64, and 63 ml./min. at 5, 5, 12, and 4 mnths later respectively. There are n significant changes in Ccreat:nine. Certainly thse patients with impairment f renal functin shwed n cnsistent deteriratin. -I ' 75'! E- 7s s F 5- i 4p C) 25] I - (I v I I.-. 1 I --I Mnths Fig. 3.-Effect f allpurinl therapy n endgenus creatinine clearance. Fig. 4 (verleaf) shws n significant change in the percentage bld urea level. Thus it can be cncluded that there was n significant change in renal functin as measured by these parameters. There was n significant change in urinary prtein excretin and twelve patients in whm PSP excretin was measured shwed n significant change. Micrscpic examinatin f the urine als shwed n change except fr disappearance f haematuria in sme patients wh had stnes. (The precise reasn fr the impairment f renal functin in the patients in this trial was nt established by renal bipsy. Hwever, frm the clinical findings it wuld seem nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm n 27 pril 218 by guest. Prtected

4 684 > wwf Q< w NNLS OF THE RHEUMTIC DISESES C Cr. < 7OmLfmIn. l CK > 7ffL/ndn. * 4~ Mnths Fig. 4.-Percentage change in bld urea level during allpurinl therapy. that the nly imprtant factr in this grup was the presence f gut. The effects f chrnic infectin fllwing stnes cannt be excluded). (7) Oxypurine/Uric acid Excretin.-The relatinship f Cxypurine t creatinine clearance is shwn Curate in Fig I. 15- ff s ! i6 12 CRETININE CLERNCE ( ml./min.) Fig. 5.-Relatinship f clearance ratis f xypurine and urate t endgenus creatinine clearance. The rati tends t be higher in the patients with better renal functin. Uric acid clearance is much less affected by the state f renal functin. Fig. 6 shws the expected effect f allpurinl therapy n the YP rate excretin rati. Except fr ne..7r a.3.1 -I. O BEFORE TRETMENT Fig. 6.-Effect f allpurinl therapy n xypur excretin rati in urate patients with creatinine clearances less than and greater than 2 ml./min. Clearances 51, 94, 58, 48, and 118 ml./min. * Clearances 11, 8, 6 ml./min., bth reading frm left t right. patient with a creatinine clearance f 8 ml./min., there was a substantial increase in the rati. Hwever, in tw uraemic individuals, the Cxypurine Curate ratis did nt increase (Fig. 7), while patients with less impairment f renal functin shwed an increased rati. The absence f increase in xypurine clearance in patients in renal failure taking all- 4.: *Cr m In. t O Cer.<>2mL/min' L5 L 1.5 O 1..5~~ EFORE TRETMENT Fig. 7.-Effect f allpurinl therapy n C crt< 2 muwn. 2 W./min ypurinc rati. Curate O Clearances 51, 58, 48, 118, and 94 ml./min. * Clearances 6, 8, and 11 ml./min., bth reading frm left t right cr nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm n 27 pril 218 by guest. Prtected

5 purinl was nt due t a decrease in urinary excretin s much as t retentin f plasma xypurines. The previusly reprted disparity between uric acid excretin befre and the sum f uric acid and xypurine excretin after allpurinl therapy was bserved in this study. In seven subjects with renal impairment mean 24-hur urate excretin befre therapy was 688 mg. while ttal purine excretin (uric acid and xypurine) after therapy was 576 mg. (8) Effect LLOPURINOL S YMPOSIUM, 1966 f Urinary lkaliniatin n Oxypurine (1) Side-effects f Therapy.-Tw patients deve- Clearance.--Oxypurine excretin and clearances lped a maculpapular rash which disappeared increased in tw patients with Ccreatinine f 48 and immediately after cessatin f therapy. In ne 12 ml./min. but nt in thse with Ccreatinine f 1 patient this reappeared after therapy was re-institun. (Fig. 8). Increase in urinary ph was ted and became wrse with increasing dsage, and 8 ml./mi while assciated w. ith an increase in urine flw. in the ther patient it did nt recur. Bth patients had impaired renal functin, Ccreatinine being 11 and ml./min. respectively. Gastrintestinal upsets 2( I 1 c ES.j S C cr < 2 mi./twn. Fig. 8.-Effect f urinary alkaliniatin (ph increase) n xypurine cl (9) Plasma Levels f DHPP (Table III).-Sme f the values fund are nt true measures f cncentratins as the plasma xypurine cncentratin was mre than 4 per cent. f the DHPP cncentratin fund. In these cases the levels f DHPP fund are less than the true cncentratin. There was a tendency fr the DHPP cncentratin t be higher in cases f renal failure. 4- C r. > 2ml./nn. 1 / fr persistent nausea in ne patient. nt bvius during allpurinl therapy except The effects f allpurinl n irn absrptin will 4- /be the subject f a separate discussin, but in brief tw techniques were utilied in rder t measure this. - 1One was the methd f Fielding* (1965) fr measuring chelatable irn after the injectin f - <t_ desferrixamine and labelled ferrixamine (Fielding and Brunstrm, 1964). This was carried ut in eight guty patients, fur wh had been n allpuri nl fr at least 6 mnths and fur wh had nt been treated. The secnd technique was the duble c istpe methd fr irn absrptin using labelled ]w t ferric chlride. This was carried ut in a grup f D ten patients. There was n significant difference in D these studies between the patients n allpurinl i 6 therapy and the untreated patients. Further studies ph n the effect f allpurinl n irn metablism are TBLE III PLSM DHPP LEVELS ND CRETININE CLERNCE IN PTIENTS ON LLOPURINOL THERPY Case N. DHPP Ccreatinine (mg./1 ml.) (ml./min.) * * * in preparatin fr publicatin learance during allpurinl therapy. SGPT levels did nt rise appreciably during the Urine FlwJ trial in 22 patients tested: I;21 (ml./min.) 1 C 1-9; 24; 3-6;- 4-7; 4-5 LD 1-; 1-1 SGPT (units) Mean Range Cntrl On allpurinl There were ccasinal increases f SGPT abve the limit f nrmal but these returned t nrmal withut discntinuing allpurinl. (11) Slubility.-The slubility f xanthine, hypxanthine, uric acid, and DHPP was measured in bth serum and urine, the latter at ph 5 and 8 (Table II). *These studies were carried ut by Dr. P. Jacbs and Dr. R. Green under the directin f Dr. T. H. Bthwell. nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm n 27 pril 218 by guest. Prtected

6 686 Discussin Previus studies (Yu and Gutman, 1964; Klinenberg, Gldfinger, and Seegmiller, 1965) have shwn that allpurinl is f cnsiderable value in the management f guty patients, particularly thse with a tendency t stne frmatin. This study cnfirms previus results and extends it als t thse with impaired renal functin. The results d nt indicate that a larger dse f allpurinl is necessary in patients with markedly impaired kidney functin. The incidence f side-effects des nt appear t be any higher in thse wh have decreased glmerular filtratin rates. lthugh xanthine is less sluble in urine than uric acid it is mre sluble in serum. theretical haard f allpurinl therapy is the frmatin f xanthine stnes as has been demnstrated t ccur in cngenital xanthinuria. Hwever, this has nt yet been reprted during allpurinl therapy. The clearance f xypurines is much greater than that f uric acid during allpurinl therapy (Gldfinger, Klinenberg, and Seegmiller, 1965) and it was thught imprtant t ascertain whether in renal failure the renal handling f these substances was similar. The present studies shw an increased rate f xypurine excretin in all patients treated including thse with marked renal impairment. Hwever, xypurine clearance did nt increase t the same extent in the latter grup because f the tendency f these patients t retain xypurines. The highest plasma xypurine level reached was 1 *9 mg./i ml. in a patient with terminal renal failure given 6 ml. allpurinl daily; thus althugh xanthine is sluble in plasma t the extent f 2 mg./1 ml., the chances f xanthine gut ccurring wuld appear t be remte even in renal failure. DHPP plasma levels als tended t be higher in patients with impaired renal functin (Table III), but the level reached was far belw the saturatin level. The likelihd f allpurinl gut is therefre negligible. It is perhaps frtunate that the relative slubilities f xanthine and uric acid are such that retentin f xanthine in renal failure in patients n allpurinl is nt disadvantageus. The patients studied in this series wh were given allpurinl were tld t alkalinie their urine in view f the decreased slubility f uric acid and xanthine in acid urine. The present preliminary studies have shwn that alkaliniatin f the urine is attended by an increased clearance f these substances. It wuld appear that t sme extent the excretin f these substances is influenced by the ph f the urine. Xanthine has pks f -8, 7-44, and NNLS OF THE RHEUMTIC DISESES 11 1, and hypxanthine pks f 1-98, 8 94, and , but the xypurines are nt lipid-sluble and it is therefre unlikely that nn-inic diffusin plays an imprtant part in their handling by the kidney. Increased excretin with urinary alkaliniatin was mre bvius in thse patients with nrmal renal functin, and if the assumptin is made that half the xypurine excretin is xanthine the cncentratin f xanthine in the urine may cnceivably apprach saturatin level under these circumstances. The rate f excretin is als influenced by the rate f urine flw in that a diuresis is accmpanied by an increase in xypurine excretin. The effects f urine flw and ph change have still t be separated and the effect f acetaleamide has yet t be determined. This study and thers have demnstrated that the slubility f the xypurines is influenced by the ttal quantity f purines present in the urine. Thus patients with lw UU cncentratins will tend t have decreased slubility f xypurines as cmpared t thse with a high UU cncentratin. This was well demnstrated by Case 8 (see Table I, abve) wh passed urate stnes, perhaps cincidentally, while excreting very lw quantities f urate [Table 11 (2)]. It was interesting that the slubility f xanthine in his urine was less than that f a patient with equally lw uric acid excretin but n histry f stnes [Table 11 (3)]. In the absence f a suitable cntrl series it is difficult t assess the effects f allpurinl n renal functin. The present trial shws n change in renal functin during the study. lnger fllw-up is necessary t be certain that allpurinl therapy des nt eventually result in an imprvement in renal functin. In Case 8 there had been a gradual reductin in endgenus Ccreatinine until allpurinl therapy was started, and in the last 15 mnths while taking this drug there has been n further change, the endgenus Ccreatinine remaining at ± 11 ml./min. On theretical grunds it wuld be expected that with a reductin in SU and UU cncentratin the pssible deleterius effects f this substance n the kidney might be prevented. Certainly the marked reductin in the number f attacks f renal calculi wuld favurably influence renal functin. Preliminary bservatins n the effects f allpurinl n irn absrptin wuld indicate that there is pssibly sme increased absrptin f irn with the use f this drug. The quantitative aspects f this have yet t be determined but d nt appear significant. It might, hwever, preclude the use f allpurinl in patients with irn verlad f any cause. In regard t the side-effects f allpurinl, nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm n 27 pril 218 by guest. Prtected

7 n cnsistent increase in SGPT have been demnstrated and n ther change in hepatic functin has been bserved. The appearance f a maculpapular rash has been previusly described in the literature and in the tw instances bserved in this trial the rash disappeared immediately after cessatin f therapy. part frm this there were n side-effects at all, and the drug wuld appear t be safe when used under the cnditins f this trial. N change in any f the frmed elements f the bld was bserved n repeated testing thrughut the curse f the trial. Summary (1) llpurinl was used successfully in patients with impaired renal functin t reduce the incidence f urinary calculi and the frequency f acute attacks f gut. (2) The same dsage scheme culd be used in patients with renal impairment as in patients with nrmal renal functin. (3) N change in endgenus Ccreatinine, PSP excretin, r urinary prtein excretin culd be bserved during the trial (33 patients ± 7, patient days). LLOPURINOL SYMPOSIUM, 1966 nn Rheum Dis: first published as /ard.25.Suppl_6.681 n 1 Nvember Dwnladed frm (4) Side-effects cnsisted f a maculpapular rash in tw patients, which recurred in ne n resuming therapy. (5) The increased xypurine excretin nted during allpurinl therapy was bserved in all patients tested including thse with impaired renal functin, but xypurine clearance did nt increase t the same extent in the latter grup because f the increase in plasma xypurines. The xypurine levels bserved did nt apprach saturatin levels in plasma but culd pssibly d s in urine. There appeared t be an increase in xypurine excretin in tw patients with gd renal functin cincident with increased urinary alkaliniatin. Hwever, this was accmpanied by a diuresis and the tw factrs were nt separated. Gratitude is expressed t Dr. B. Wallace and Dr. W. M. Pliter, Bichemistry Department, Suth frican Institute fr Medical Research, t Mrs. S. M. Perld, Department f Chemical Pathlgy, University f the Witwatersrand, and t Dr. B. M. Blmberg, Clinical Labratries, Jhannesburg, fr bichemical assistance, t Prfessr H. B. Stein fr making facilities available in his Department, and t Mrs. N. Hardie and the Phtgraphic Unit, Department f Medicine, University f the Witwatersrand, fr the illustratins. n 27 pril 218 by guest. Prtected