Renal function in newly diagnosed multiple myeloma - A demographic study of 1353 patients

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1 Eur J Hueniurol IYY4: 53: Priiirrd 111 Brlyiuiii - rill riyhrs reserved Cop,vrighr 0 Munksguurd I994 EUROPEAN JOURNAL OF HAEMATOLOGY ISSN Renal function in newly diagnosed multiple myeloma - A demographic study of 1353 patients Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J. Renal function in newly diagnosed multiple myeloma - A demographic study of 1353 patients. Eur J Haematol 1994: 53: Munksgaard Abstract: This study describes the occurrence of renal failure among 1353 newly diagnosed cases of multiple myeloma. Renal function was evaluated by serum creatinine concentration in 1353 cases, 3 1 of whom had renal failure at the time of diagnosis. In 1206 cases an estimation of creatinine clearance was made. When renal failure was defined by using creatinine clearance estimation, 49% had renal failure at the time of diagnosis. Renal failure was present in 24% of patients with an M component of IgG-, 31 ;; of IgA- and 100% of IgD-type. 52% of patients with light chain disease had renal failure. The frequency of renal failure was similar in lambdaand kappa-light chain disease. Patients with a high excretion of Bence Jones protein in the urine (> 10 g/24 h) had renal failure significantly more often than patients with lower excretion. Renal failure was related to advanced disease; 41 :(, of patients with stage 111 (Durie-Salmon) disease had renal failure. Renal failure was found in 45 /, of patients with hypercalcaemia. When estimated creatinine clearance was used as a predictor of renal function, the same trends were found as mentioned above. In addition, the proportion of patients with renal failure was found to increase with advancing age. Lene Meldgaard Knudsen, Erik Hippe, Martin Hjorth, Erik Holmberg3 and Jan Westin4 for the Nordic Myeloma Study Group Department of Internal Medicine and Haematology, Herlev Hospital Copenhagen, Denmark, Department of Medicine, Lidkoping Hospital, Lidkoping, Sweden, Oncology Centre, Sahlgrenska Hospital, Goteborg, Sweden, Department of Internal Medicine and Haematology, University Hospital, Lund, Sweden Key words: multiple myeloma - myelomatosis - renal failure Correspondence: Lene Meldgaard Knudsen M.D., Department of Internal Medicine and Haematology L, Herlev Hospital, DK Herlev, Denmark Accepted for publication 27 April 1994 Introduction Renal failure is a common presenting feature in multiple myeloma, and represents one of the major complications of the disease (1). Renal impairment is observed in about 50% of the patients during the course of their disease (1). The causes of renal failure in myelomatosis are multiple and renal impairment is often reversible. Renal failure has been associated with a poor prognosis (1, 2). Prognosis, however, also depends on tumour mass load and response to treatment. In a recent study, the presence or degree of renal failure at the time of diagnosis did not affect prognosis adversely. In fact, myeloma control, i.e. response to treatment, was found to be the major factor in predicting the ultimate outcome of the patients (3). In previous studies the frequency of renal failure at the time of diagnosis varied considerably, from 16 to 82% (2, 4, 5). This is, in part, due to the fact that some of the studies described highly selected materials, whereas others describe unselected groups of myeloma patients. Further- more, the definition of renal failure varies between the different studies. Finally, most of the studies comprise only a small number of patients. Since 1984 prospective studies have been carried out in the Nordic countries with the purpose of comparing traditional oral melphalan-prednisolone therapy with combination chemotherapy ( ) and with melphalan-prednisolone-interferon ( ) in multiple myeloma. The notification of all newly diagnosed cases of myeloma from the participating centres has provided an opportunity to study patient characteristics in large unselected groups of untreated myeloma patients. The purpose of the present study was to analyse the frequency of renal failure and the characteristics of myeloma patients with renal failure at the time of diagnosis. Material and methods Patients The material consists of two cohorts of patients. The first cohort has been described earlier (6) and com- 207

2 Knudsen et al. prises 300 cases of myeloma diagnosed in Western Sweden from Jan 1, 1984 until Dec 31, This cohort represents the total population of newly diagnosed myeloma patients within the defined geographical area. The second cohort comprises 1078 cases of myeloma who were reported to the secretariat of the 4th trial of the Nordic Myeloma Study Group from June 1, 1990 until Nov 4, In this trial, which is still in progress, 126 Nordic centres cooperate, covering an area of 12 million inhabitants. The participating centres were requested to report all newly diagnosed cases of multiple myeloma. The 1078 cases represent about 70% of the expected new cases of myeloma within the defined area in the period registered. The two cohorts are similar regarding age, sex, stage of disease and type of myeloma. In the following they are put together and evaluated as one group. Out of the total material (n= 1378) 1353 cases were evaluable with regard to renal function at the time of diagnosis. For the remaining 25 cases insufficient data were available. Diagnostic criteria The following criteria for the diagnosis of multiple myeloma were used: (A) serum M component concentration > 30 g/1 (IgG) or > 20 g/1 (IgA) or serum M-component of type IgD or IgE, irrespective of concentration, and/or Bence Jones proteinuria > 1 g/ 24 h, (B) serum M component concentration or Bence Jones proteinuria less than stated above, (C) bone marrow plasma cells > lo%, (D) osteolytic bone lesions. A diagnosis of multiple myeloma was accepted if criteria A + C or A + D or B + C + D were fulfilled. Evaluation Renal function was estimated by serum creatinine concentration at the time of diagnosis. Renal impairment was defined as serum creatinine concentration pmol/l. Three subgroups were defined with respect to serum creatinine concentration: (1) no renal impairment = serum creatinine < 130 pmol/l, (2) moderate renal impairment = serum creatinine = pmol/l, (3) severe renal impairment = serum creatinine > 200 pmol/l. In addition, creatinine clearance (Ccr) was estimated, using following equations given by Cockcroft and Gault (7): Males: 1.23 x (140 - age in years) x (weight in kg) Ccr = serum creatinine in pmol/l Females: 1.04 x (140 - age in years) x (weight in kg) Ccr = serum creatinine in pmol/l Four subgroups of renal function were defined from a nomogram (8), using sex, age and the estimated creatinine clearance value: (A) normal renal function, (B) mildly impaired renal function, (C) moderately impaired renal function and (D) severe renal impairment. Data regarding age, sex, clinical stage (Durie- Salmon) (9), serum M-component type, Bence Jones proteinuria (light chain type and concentration) and serum calcium concentration were evaluated in the three subgroups defined by serum creatinine concentration, and in the four subgroups defined by estimated creatinine clearance. Statistical methods Differences between groups were determined by using the Chi-square test. Results A serum creatinine concentration pmol/l was present in 416 of the 1353 patients (3 1 yo). The renal impairment was moderate in 15% and severe in 16%. In 1206 of the 1353 cases enough data were available to make a creatinine clearance estimation. The 1206 cases were distributed as follows: 620 (51%) had normal renal function, 296 (25:/,) had mild, 175 (15 /,)moderate and 115 (9 /,) severerenal impairment. Sex and age was known for 1336 of the 1353 cases. There were 726 male and 610 female patients. Their median age was 68 yr (range 32-94). The age distribution was similar in the 1206 cases in whom Ccr could be estimated, and in the 1336 cases with a known serum creatinine concentration. A difference in the frequency of renal failure in different age groups was, however, found if serum creatinine concentration and Ccr were used as a predictor of renal function (Fig. 1). Renal failure was found in 24% of women and in 38% of men. When estimated Ccr was used as a predictor of renal function, 47 % of men and 53 % of women had renal failure. Serum M component type was known for 1306 of the 1353 cases, and was distributed as follows: IgG = 793, IgA = 288, IgD = 8, light chain = 217. The presence of renal failure in patients with different serum M component types is presented in Fig. 2. All 8 patients with a serum M component of IgD type had renal impairment. In the group with light chain disease a higher proportion of patients had renal failure (52%) than in the groups with M component 208

3 % 8o msaeatinine W Estimated Ccr Renal function in newly diagnosed multiple myeloma - A demographic study of 1353 patients n :....::::: g.;.:...: i:i$$ iiii:i iij! :::::: Fig. I. Proportion of patients with renal failure in multiple myeloma at the time of diagnosis in different age groups, using serum creatinine concentration (1336 patients) and estimated creatinine clearance (Ccr) (1206 patients) as a parameter of renal function. Years % Stage I Stage l Stage III Fig. 3. Proportion of patients with renal failure in multiple myeloma at the time of diagnosis in different stages according to Durie-Salmon, using serum creatinine concentration (1336 patients) and estimated creatinine clearance (Ccr) (1206 patients) as a parameter of renal function. % IgG IgA Light chain IgD Fig. 2. Proportion of patients with renal failure in multiple myeloma at the time of diagnosis in different M component groups, using a serum creatinine concentration (1306 patients) and estimated creatinine clearance (Ccr) (1206 patients) as a parameter of renal function. used to define renal function the same trend appeared (Fig. 3). A corrected serum calcium concentration ( = serum calcium concentration + l.l(o.700-serum albumin concentration)) or an ionised serum calcium concentration was available in 1322 of the 1353 cases. Hypercalcaemia (defined as corrected serum calcium concentration mmol/l or ionised serum calcium mmol/l) was present in 39% of all patients. The relationship of serum calcium concentration and serum creatinine concentration is presented in Table 1. Patients with hypercalcaemia more often had renal impairment (45 %) than patients without hypercalcaemia (2 l %). The difference was statistically significant (p = ). The same trend was found in the groups defined by estimated Ccr (38% of the normocalcaemic and 65% of the hypercalcaemic group had renal failure). of IgG- (24%) or IgA-type (31%). The difference was statistically significant (p = ). The same trend was found when estimated Ccr was used; a higher frequency of renal impairment of IgD myeloma (looo/o) and in light chain disease (65%), than in other myeloma types (IgG = 43 % and IgA = 48 %) (Fig. 2). In 1336 of the 1353 cases the clinical stage according to Durie-Salmon was registered with 205 patients in stage I, 412 in stage I1 and 719 in stage % of all patients had stage 111 disease, whereas 72% of the patients with renal failure had stage 111 disease. In stage 111 patients there were a higher proportion of patients with renal impairment (41 %) than in stage I and I1 patients (15% and 20% respectively) (Fig. 3). The difference was statistically significant (p = ). When estimated Ccr was Table 1. Serum calcium concentration, light chain type, Bence Jones proteinuria and serum creatinine concentration at the time of diagnosis in multiple myeloma Serum calcium concentration: S-Ca < 2.6 mmol/l S-Ca22.6 mmol/l tight chain type: Kappa Lambda Kappa/lambda ratio Bence Jones Proteinuria: < 1 g/24h l-log/24h > 10 g/24h N= N= N= No. of patients with serum creatinine concentration (pmoiii) < > (21%) 236 (45%) 210(39%) 1 17 (40%) (25%) %) 46 (70%) 209

4 Knudsen et al. Bence Jones proteinuria was detected in 8 11 of the 1353 patients. 40% of the patients with Bence Jones proteinuria had renal impairment. No difference in incidence of renal failure was found between patients excreting kappa (39%) or lambda (40%) light chains in the urine (Table 1). Patients who excreted Bence Jones protein > 1 g/24 h had higher incidence of renal impairment (49% of patients excreting 1-10 g/24 h and 70% of patients excreting > 10 g/24 h) than patients with lower excretion of Bence Jones protein (25%). The difference was statistically significant (p = ) (Table 1). The same trend was found in the Ccr-defined groups. In the 217 patients with light chain disease, the kappa/lambda ratio of 1.6 was similar to that of the total patient population, where the kappa/lambda ratio was 1.9. The incidence of renal failure was similar in patients with kappa light chain disease (56%) and lambda light chain disease (45%). Patients with light chain disease and high excretion of Bence Jones protein more often had renal failure than patients with low excretion of Bence Jones protein, which was also found in the groups defined by Ccr. Discussion In our study 31 % of the patients had renal impairment at the time of the diagnosis of multiple myeloma. In the fourth MRC myelomatosis trial (10) 42% had renal failure at the time of diagnosis, using the same definition of renal impairment as in our study: serum creatinine concentration ymol/ 1. In the literature over the past decade the incidence of renal failure at the time of diagnosis varies considerably. This is, in part, due to the fact that study materials are very different. Some studies are performed at nephrology centres in patients with severe renal damage undergoing dialysis (3, while other studies include all newly diagnosed myeloma patients (1, 3, l l). Furthermore the definition of renal failure varies considerably. Serum creatinine concentration is an unsatisfactory parameter for the estimation of renal function as it is not directly related to glomerular filtration rate. Creatinine production is largely determined by muscle mass, which in turn is related to age, sex and bodyweight and will vary considerably from patient to patient (12). In fact the serum creatinine concentration is related to glomerular filtration rate in a reciprocal fashion; when renal function is normal or only mildly impaired, small changes in serum creatinine concentration correspond to large changes in glomerular filtration rate (12). Serum creatinine concentration will be in the range of normal until the glomerular filtration rate is reduced as much as 50% of the total glomerular filtration rate (13). The incidence of renal failure found in our study and in all other studies where serum creatinine concentration is used as a parameter for renal function is therefore probably underestimated. When we used the estimated creatinine clearance as a parameter for renal function we found a higher frequency of renal failure (49%). Formula estimates of creatinine clearance correlate well with measured values of glomerular filtration rate (GFR) or creatinine clearance (7). There was a striking difference between frequency of renal failure defined by serum creatinine concentration and estimated creatinine clearance with more advanced age. This reflects the fact that serum creatinine concentration in an elderly patient is a poorer indicator of renal function than in younger patients. The difference in incidence of renal failure in men and women is due to the fact that the normal range of serum creatinine concentration is different in the sexes. If renal failure in women was defined as serum creatinine concentration pmol/l (the upper normal limit for serum creatinine concentration for women used in our laboratory), there was no difference in incidence of renal failure in men and women. In addition, the difference in incidence between men and women was abolished when estimated Ccr was used as a parameter of renal function. The etiology of renal failure in multiple myeloma is multifactorial. Excretion of light chains in the urine seems to be an essential factor, although some patients can excrete large amount of Bence Jones protein for years without developing renal failure (14). The pathogenetic mechanisms by which urinary light chains produce renal impairment is not fully understood. The most constant association with light chain proteinuria is tubular dysfunction, including impaired reabsorption of water and low molecular weight glycosylated proteins (15). In a large study of 522 patients, Cooper et al. (1 1) found tubular dysfunction in almost all (98 %) patients with light chain proteinuria > 1 g/24 h. Light chain proteinuria may lead to cast formation, tubular obstruction and distal tubular dysfunction (16). Our study confirms the association between free urinary light chains and renal failure. 17% of the total myeloma population had light chain disease, whereas in the group with renal failure 28 % had light chain disease. This confirms the findings of others (3, 11). There was no difference in the incidence of renal impairment with respect to the type of light chain in our study. In previous studies lambda light chains seemed to be more nephrotoxic than kappa light chains (17), but Cooper et a]. (1 1) did not find any difference regarding light chain type and renal failure. There was in our study a positive correlation between the amount of Bence Jones protein excreted and renal failure, which is also stressed by others (3, 11). Patients excreting more than 109 light chain per 24 h 210

5 Renal function in newly diagnosed multiple myeloma - A demographic study of 1353 patients in the urine have a very high risk of developing renal failure. All 6 IgD myeloma patients in our study had renal failure. It is well known that IgD myeloma is associated with a high incidence of renal failure. Rergesio et al. (18) described 9 patients with IgD myeloma, of whom 8 had renal failure as the most important presenting symptom of the disease. Hypercalcaemia is well known to impair renal function by a number of mechanisms, including reduction of glomerular filtration rate, altered renal blood flow and precipitation of calcium in the tubules and renal interstitium (19). In all previous reports hypercalcaemia has been an essential factor in renal failure in multiple myeloma (1, 2, 3, 4, 5). This was also the finding in this study, where 45% of the patients with hypercalcaemia had renal failure. The incidence of renal failure increased with more advanced disease, expressed as a high incidence of renal failure in stage I11 disease. This association is also recognised by others (3, 4, 5). Other factors such as infections (2, 5), dehydration (lo), hyperuricaemia (4, 5), use of nephrotoxic drugs (5) and hyperviscosity (2) can contribute to development of acute renal failure in patients with multiple myeloma. These factors, however, were not available for evaluation in this study. Factors such as diabetes, hypertension, chronic pyelonephritis and other disorders not related to multiple myeloma can also contribute to renal failure in this group of mostly elderly patients. In summary, at least 3 1 % of the myeloma patients had renal failure (defined by serum creatinine concentration) at the time of diagnosis. Using creatinine clearance estimates 49% had renal failure. Renal failure was related to advanced disease, hypercalcaemia, IgD myelomatosis, light chain disease and high excretion of light chain in the urine. The same trend was found when estimated creatinine clearance was used as a parameter of renal function and, in addition, the proportion of patients with renal failure was found to increase with advancing age. Acknowledgements We wish to express our gratitude to Maj-Lis Polgary and Susanne Amsler-Nordin for secretarial assistance and the meinbers of the Nordic Myeloma Study Group for rewarding collaboration. References 1. KYLE RA. Multiple myeloma. Review of 869 cases. Mayo Clin Proc 1975: 50: DE FRONZO RA. HUMPHREY RL, WRIGHT JR. Acute renal failure in multiple myeloma. Medicine 1975: 54: ALEXANIAN R, BARLOGIE B, DIXON D. Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990: 150: CAVO M, BACCARANI M, GALIENI P, GOBBI M, TURA S. Renal failure in multiple myeloma. A study of presenting findings, response to treatment and prognosis in 26 patients. Nouv Rev Fr Hematol 1986: 28: ROTA S, MOUGENOT B. BAUDOIN B, et al. Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients. Medicine 1987: 66: HJORTH M, HOLMBERG E, R0DJER s, WESTIN J for the Myeloma Group of Western Sweden. Impact of active and passive exclusions on the results of a clinical trial in multiple myeloma. Br J Haematol 1992: 80: COCKROFT DW, GAULT MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976: 16: BR0CHNER-MORTENSEN J, JENSEN s, R0DBRO P. Delimitation of plasma creatinine concentration values for assessment of relative renal function in adult patients. Scand J Urol Nephrol 1977: 11: DURIE BGM, SALMON SE. A clinical staging system for multiple myeloma. Cancer 1975: 36: MRC Working Party on Leukemia in Adults. Analysis and management of renal failure in the fourth MRC myelomatosis trial. Br Med J 1984: 288: COOPER EH, FORBES MA, CROCKSON RA, MACLENNAN ICM. Proximal renal tubular function in myelomatosis: observations in the fourth Medical Research Council trial. J Clin Path : 37: DAUGAARD G, ABILDGAARD U. Evaluation of nephrotoxicity secondary to cytostatic agents. Crit Rev Oncol-Hematol 1992: 13: SHEMESH 0, GOLBETZ H, KRISS JP, MYERS BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985: 28: KYLE RA, GREIPP PR. Idiopathic Bence Jones proteinuria: Long-term follow-up in seven patients. N Engl J Med 1982: 306: MACLENNAN ICM, COOPER EH, CHAPMAN CE, KELLY KA, CROCKSON RA. Renal failure in myelomatosis. Eur J Haematol 1989: 43 (Suppl 51): FANG LS. Light-chain nephropathy. Kidney Int 1985: 27: BERNSTEIN SP, HUMES HD. Reversible renal insufficiency in multiple myeloma. Arch Intern Med 1982: 142: BERGESIO F, SALVADORI M, LOMBARDI M, et al. Renal involvement in IgD myeloma. Scand J Urol Nephrol 1988: 22: MUNDY GR. Calcium homeostasis: hypercalcemia and hypocalcemia. London: Martin Dunitz Ltd, 1989: pp The following members and centres of the Nordic Myeloma Study Group collaborated in this study: Steering Committee: Jan Westin, Lund (Chairman), Martin Hjorth, Lidkoping, Eva Lofvenberg, Ume$ Stig Rodjer, Goteborg, Ingemar Turesson, Malmo and Goran Zador, Schering-Plough AB, Stockholm, Sweden; Finn Wisloff, Oslo, Ingebrigt Talstad, Bergen, Jon Lamvik, Trondhjem and Inger Marie S Dahl, Troms~r, Norway; Erik Hippe and Peter Gimsing, K~rbenhavn, Johan Lanng Nielsen, Aarhus, Denmark; Ilmari Palvari, Tampere, Finland; Sigmundur Magnusson, Reykjavik, Iceland. Secretariat and data management. Martin Hjorth, Erik Holmberg and Stig Rodjer, Goteborg, Sweden. Statistics: Anders Odkn, Kungalv, Sweden. 21 1

6 Knudsen et al. Safety committee: Arne Wallgren and Lars Wilhelmsen, Goteborg, Sweden. Local collaborators and centres: SWEDEN: Louise Hellqvist, Halmstad; Sverker Hasselblom, Varberg: Jan Carneskog, Sahlgrenska Hospital and Stig Rodjer, Ostra Hospital, Goteborg; Sigvard Olsson, Molndal; Olof Lindqvist, Uddevalla; Peter Hoffman, Lysekil; Kurt Olsson, Stromstad; Anders Tholtn, AllingsAs; Carl-Magnus Stolt, BorAs; Arne Rinder, Skene, Rolf Svensson, Falkbping; Martin Hjorth, Lidkoping, Jan Vaart, Skovde; Soren Hansen, Eksjo; Leif Engqvist, Varnamo; Owe Lannemyr, Saffle, Ingemar Turesson, Malmo; Per-Gunnar Nilsson, Lund; Inger Linne, Trelleborg; Goran Lilja, Angelholm; Gustav Tallroth, Ystad; John Hallgren, Simrishamn; Birgitta Andersson, Hassleholm; Rolf Billstriim, Helsingborg; Sigvard Persson, Kristianstad; Torgny Samuelsson, Vaxjo; Hfikan Odeberg, Karlskrona; Magnus Adriansson, Kalmar; Hans Tove, Oskarshamn; Nils Stobeus, Motala; Jan Habberstad, Vastervik; Tiina End, Norkoping; Magnus Dahltn, Visby; Eva Lofvenberg and Mikael Eriksson, UmeA; Nils Anagrius, Falun; Dic Aronson, Mora; Lubor Nezadal, Hudiksvall; Karin Eriksson, Ostersund; Michael Hedenus, Sundsvall; Jan Ryden, Hairnosand; Lennart Westin, SollefteA; Lars-Olof Andersson, Ornskbldsvik; Anita Bjurman, Lycksele; Karin Forsberg, SkellefteA; Dan Fors, PiteA; Staffan Wikstrom, LuleA; Bernt Thult, Kalix; Ulf Bolsery, Gallivare; Klas Lennermo, Kiruna; Tomas Strand, S andviken. FINLAND: Ilmari Palva, Tampare; Anders Almqvist, Vasa; Bo Isomaa, Jakobstad; Kalevi Oksanen, Hameenlinna. NOR WA Y: Finn Wislerff, UllevAl Hospital, Clas Eika, Diakonhjemmet Hospital and Bernt Ly, Aker Hospital, Oslo; Eystein Brandt, Lillehammer; Christian Fossum, Gjervik; Kfire LnvAsen, Kongsvinger; Eva Marie Jacobsen, Elverum; Sverre Nyhus, Larvik; Johannes Kahrs, Fredrikstad; Tore Steen and Hege Gravdahl, Akershus; Lars Borge, Drammen; Kjell A. Grerttnum, Kristiansand; 0ystein Flerttererd, Porsgrunn; Bjarne Riis Strerm, Hernefoss; Hfivar Knutsen, Gjettum; Audun Drivenes, Moss; Jerrn Paulsen, Rjukan; Svein Riis, Sarpsborg; Ingebrigt Talstad, Bergen; Peter Coll, Voss; Knut HAkon Hole, Odda; Trygve Saeter, Stord; Terje Sindre, Florer; Harald Nes, Haugesund; Ove Hagen, Nordfjordeid; Geirfinn Vagstad, Fmde; Reino Heikkela, Stavanger; Jon Lamvik, Trondheim; Bottolf Lerdemel, Volda; Odd R. Skogen, Alesund; Yngve Serrum, Molde; Vidar Kvambe, Kristiansund; Otto Bull, Levanger; Inger Marie S Dahl, Tromser; Steinar Jerger, Boder; Per Gunnar Ingvaldsen, Hammerfest; Kjell Pedersen, Harstad; Berit Dahl, Kirkenes; Arne Fossli, Narvik; Gjermund Liljedal, Gravdal; Leif Tormod Hansen, Stokmarknes; Martha Onkiehong, Mo i Rana; Tor Hauge, Mosjeren; Dag Stefansen, Sandnessjeren. DENMARK: Erik Hippe, KAS-Herlev, Peter Gimsing and Ole Gadeberg, Rigshospitalet, Kerbenhavn; Johan Lanng Nielsen, Aarhus, Henning Jans, Holstebro; Torben Mourits-Andersen, Esbjerg; Bent Neubauer, Vejle; Nielsaage Terffner Clausen, H aderslev. ICELAND: Sigmundur Magnusson, Landspitalinn and Gudmundur Eyjdfsson, Borgarspitalinn, Reykjavik; Sigurdur Bjornsson, Tungotu. 212