therapeutics to start the diet?24 These questions have been poorly controls and non-randomised, crossover, or prospec-

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1 2 Kaplan EL, Meier P. Nonparametric estimation from incomplete obsersa- 29 Simmonds P, Lainson FA, Cuthbert R, Steel CM, Peutherer JF, Ludlam CA. tions.journaloftheamertcan StatisticalAssociataon 1958;53:5-81. HIV antigen and antibody detection: variable responses to infection in the 25 Cox DR. Regression models and life-tables.j R Stat Soc[B] 192;3: Edinburgh haemophiliac cohort. BM3r 1988;29: Thomas DG, Breslow N, Gart JJ. Trend and homogeneity analyses of 30 Pizzo PA. Pediatric AIDS: problems within problems.j Infect Dis 1990;11: proportions and life table data. Comput Biomed Res 19;10: Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis atnd other 31 Cuthbert RJG, Ludlam CA, rucker J, Steel CM, Beatson D, Rebus S, et al. multivariate methods. Boston: PWS-Kent Publishing Company, Five year prospective study of HIV infection in the Edinburgh haemophiliac 28 Medley GF, Billard L, Cox DR, Anderson RIMI. The distribution of the cohort. BMJ 1990;301:95-1. incubation period for the acquired immunodeficiency syndrome (AIDS). Proc R Soc Lond [B] 1988; 233:3-. (Accepted November 1991) Controlled low protein diets in chronic renal insufficiency: meta-analysis/ D jouque, MNLaville, J Poissel, RiChifflet, M/Labeeuw, P Y/Zech Abstract renal failure to be assessed, taking into consideration Objective-To determine whether low protein the bias due to the various confounding factors (such as diets retard the development of end stage renal regression to the mean) and avoiding the use of disease. intermediate criteria (such as the slope of the time Design-Meta-analysis of trials since 195, course for the reciprocal values of serum creatinine from which six randomised controlled trials were concentration and the rate of decay of creatinine selected. clearance). Setting-Five trials in Europe and one in Australia between 1982 and Subjects-890 patients with mild to severe chronic Methods renal failure who were followed up for at least one The principle of meta-analysis entails the adjusted year. 50 patients received a low protein diet and 0 analysis of results in a collection of studies, with a a control diet. unique criterion for all studies. Meta-analysis is parti- Intervention-Difference in protein intake cularly suitable for studies of rare events in, for between control and treated groups of at least 0*2 g example, ponderous or longlasting trials that do not protein/kg/day. include many patients.9 The quality and impact of a Main outcome measure-number of renal deaths meta-analysis depends on the selection process for the (the necessity to start dialysis or death of patient criterion, which must be well defined at the beginning during study). of the meta-analysis, and easily collected by non- Results- 15 renal deaths were recorded, 1 in the specialist observers. low protein diet group and 95 in the control group, Definition ofa common event-we defined renal death leading to an odds ratio of low protein to control of as either the necessity to begin dialysis or the death of 0-5 with a 95% confidence interval of 0 3 to 0 9. patients during the study. Patients receiving grafts Conclusions-This result, obtained on a large before starting dialysis were counted as having had population of patients suffering from chronic renal renal death. Patients who were lost to follow up or who insufficiency, strongly supports the effectiveness of stopped taking the diet were not counted as having had low protein diets in delaying the onset of end stage renal death. These criteria were applied independently renal disease. of the randomised treatment by the authors on the basis of published data or complementary data kindly provided by the investigators. Introduction Collection of data and study selection-to avoid During the past 10 years a lot of experimental data omission of results from less well known studies we have suggested that dietary protein restriction may scanned research reports with a computer search of retard or even halt the development of non-specific Medline files and abstract books from the International glomerular lesions and hence the progression of end Society of Nephrology and the American Society of stage renal disease. Despite the many studies on dietary Nephrology. We also asked many investigators for Service de Nphrologie, interventions that were performed a few decades ago, complete or incomplete, published or unpublished JJpital Edouard Herriot, some questions have re-emerged'-what kind of randomised studies. We restricted the review to 9x Lyon)Cedex 03 proteins? What degree of restriction? Is a supplement randomised trials because without randomisation lack D Pouque,kID, head ofclinic with essential amino acids or keto-analogues of amino of bias cannot be guaranteed. Trials that used other M Laville, MD, professor of acids required? When is the most appropriate moment methods of allocating treatments (such as retrospective therapeutics to start the diet?2 These questions have been poorly controls and non-randomised, crossover, or prospec- MLabeeuw,MD,professorof answered by numerous studies showing that low tive uncontrolled protocols) were therefore not in- P Zech MD professor of protein diets reduce the time related increase in plasma cluded. Trials studying only diabetic nephropathy Pech, M creatinine concentration. However, the validity of were not selected, because the equilibrium of diabetes nephrology - plasma creatinine concentration as an estimate of renal is of major importance in the progression of renal Laboratoire de function,5 especially during reduced protein intake, failure and cannot be adequately measured between Pharmacologie Clinique, has not really been investigated in terms of extrarenal control and treated groups. Table I summarises 12 Avenue_Lacassagne, creatinine metabolism and the tubular secretion of studies on protein restriction and its effects on the 92 Lyon creatinine, which is dependent on protein intake. The progression of chronic renal insufficiency. Individual J P Boissel, MD, professor of physician's main goal is to maintain clinical improve- data and extra details if not mentioned in the original clinical pharmacology ment in patients who wish to delay starting dialysis for papers, were collected from investigators who kindly R Chifflet, PHD, statistician as long as possible, and so we have reanalysed research agreed to send us their raw data. data to determine the number of patients reaching end Statistical methods-intention to treat analysis was Correspondence to: Dr Fouque. stage renal disease during follow up. This meta- made on the selected populations, randomly assigned analysis, should enable the strength of the association to control or treated groups (a restricted protein diet). BMJ 1992;30:21-20 between low protein diet and reduction in end stage Standard statistical methods were used (percentage 21 BMJ VOLUME JANUARY 1992

2 TABLE I-Summant of different trials studying the impact of protein restriction on renal Jinction since 195 and reasons for exclusion Jrom analysis First author and No of reference No Year Reason for exclusion patients Walser" 195 Prospective non-controlled Burns" 198 Prospective non-controlled Alvestrand" 1980 Retrospective 8 Frohling" 1980 Prospective controlled 2 Hecking' 1980 Prospective, dotuble blind 15 crossover, six week study Kampf' 1980 Prospective non-controlled 20 Barsotti' 1981 Retrospective 5 Maschilo 1982 Prospective controlled 5 Alvestrand' 1983 Retrospective 1 Attman-i 1983 Prospective non-controlled 21 Barsotti' 1983 Same patients as Barsotti' Bennett Retrospective 9 Frohling' 1983 Prospective non-controlled Gretz" 1983 Prospective controlled 11 Barsotti" 198 Prospective controlled 55 El Nahas" 198 Prospective non-controlled 3 Mitch' 198 Prospective non-controlled 2 Rosman" 198 -t 228 Gretz2' 1985 Same patients as Gretz Oldrizzi"' 1985 Prospective controlled 100 Rosman" 1985 Same patients as Rosman"' Williams3' 1985 Same patients as Bennett' Zakar" 1985 Prospective controlled 0 Attman3 198 Retrospective 119 Chauveau" 198 Same patienits as Jungers" Di Landro" 198 Prospective controlled 8 Gentile 198 Same patients as Locatelli Gretz" 198 Same patients as Gretz21 Lucas" 198 Prospective non-controlled 12 Rosman' 198 Same patients as Rosman" Schmicker" 198 Prospective controlled 119 Gretz 198 Same patients as Gretz! Jungers" 198 -t 19 Meisinger 198 Prospective controlled 38 Schmicker 198 Same patients as Schmicker Walser 198 Prospective non-controlled 12 Williams 198 -t 5 Barsotti" 1988 Prospective non-controlled 8 Gentile" 1988 Same patients as Locatelli" Bagros* t 50 Frohling' 1989 Prospective controlled 81 Gretz" 1989 Same patients as Gretz' Ihle' t 2 Levine" 1989 Prospective non-controlled Locatelli" t 5 Zeller" 1991 Diabetic patients only 35 *Unpublished. tselected for meta-analvsis. TABLE Ii -Summary ofdata from six randomised controlled studies selected for meta-analysis Mean age No of Study Place, Year of No of (years) Follow up No with No of No of renal No reference No publication patients (range) (months) dialysis deaths grafts deaths 1 Groningen, Rosman" (15-3) Paris, Jungers" (32-9) Northern Italy, Locatelli' ) Tours, Bagros Unpublished (15-5) Victoria, IhIe' Liverpool, Williams` (15-0) All TABLE iii-details of populations and renal deaths in control and treated groups ofeach tnral and summaty of results No of patients with: Study No of Sex ratio Glomerulo- Polycystic Interstitial Other Renal No Diet patients (Ml/F) nephritis disease nephritis nephropathies death JControl 110 2/ I LFreated 118 2/ JControl 9 2/ ltreated 10 5/ Control 22 12/ Treated / IControl 25 15/10 Treated 25 1/ Control itreated i1 2/ Treated Control /11 20/ All Control 0 251/ ttreated 50 25/ differences; logarithm of odds ratio; Cochran; Mantel- Haenszel; Peto). As they all gave similar p values for the difference between control and treated groups, only the results from the analysis of the logarithm of odds ratio are given. These results represent the ratios of the number of events in the treated group times the number of non-events in the control group to the number of events in the control group times the number of non-events in the treated group. For simplification it is useful to consider the odds ratio and its 95% confidence interval. An odds ratio of 0 0 corresponds to a reduction of 0% in the odds of experiencing an event. Heterogeneity between trialsthat is, the interaction between trials and the effect of treatment-was tested by the appropriate X test.'0 However, such tests of heterogeneity between many different trials have a limited value, partly because they are dominated by unstable contributions from the smaller studies that could obscure any real heterogeneity between the larger studies and, partly because of a low power. Results STUDY POPULATION From trials between 195 and 1991 (table I), only six reports of randomised controlled trials were selected. Four were reported as full length articles (studies 1, 2, 3, and 5), one was presented as an oral communication and is not yet published (study, Bagros et al, personal communication), and the sixth was published as an abstract (study ). Randomisation was from one centre in all six studies and by allocating an envelope after stratification by age, sex, and renal function in study 1, by allocating an envelope in studies 2, 5, and, by random number table and a telephone call in study 3, and by random number table in study. DESCRIPTION OF PATIENTS STUDIED The data on the patients studied are summarised in tables II and III. Patients varied between trials in age, sex ratio, and population size. The length of follow up was homogeneous, between 12 and 2 months. In study 1 not all the randomised patients were followed up for 18 months, but we considered the initial randomised population for intention to treat analysis. In study 5 we considered the initial 2 randomised patients and not the final patients in the published results. In study we considered two of the three randomised groups (control, low protein diet, and low phosphorus diet), rejecting the low phosphorus group because lowering phosphorus intake alone was not suitable for our analysis. The level of renal insufficiency was heterogeneous (table IV), from mild (study 3) to severe (study 2). The follow up criteria for renal function were also heterogeneous, with the use of serum creatinine concentration in studies 1, 2, and ; renal survival (end point defined as the need for dialysis or the doubling of the plasma creatinine concentration) in study 3; estimation of glomerular filtration rate ((creatinine clearance+ urea clearance)/2) according to Lubowitz et a15 in study ; and the clearance of ethylenediaminetetra-acetic acid labelled with chromium-51 in study 5. The incidence of renal death in control groups was variable (0-1 in study I to 0 8 in study 2), which may be a result of renal insufficiency at inclusion. However, the heterogeneity test for the control groups was not significant. TREATMENTS A large heterogeneity was observed for the reduced protein intakes. It should be noted that the intake of protein in the control group in study 2 was about the BMJ VOLUME JANUARY

3 TABLE IV- Follow up, renalffunction at inclusion, and diets in six studies selectedfor meta-analysis Diet Study Follow up criterion of No renal function Renal function at inclusion Treated group Control group I Reciprocal of serum creatinine Creatinine clearance B 0- g Protein/kg body weight/day Free diet (Al, A2) (all groups) (A2, C- 30 and >10 ml/min C 0- g Protein/kg body weight/day Al, B-0 and >30 ml/min) 2 Increase in serum creatinine Serum creatinine between g Protein/kg body weight/day 0- g Protein/kg body weight/day and 900 fimol/l with ketoacids supplementation Ketosteril 1 tablet/ kg/dax 3 Renal survival curve (doubling Serum creatinine between g Protein/kg body weight/day 1 g Protein/kg body weight/day of serumn creatinine at inclusion and 20,umol/l or need for dialysis) EstimAted glomerular filtration Serum creatinine between g Protein/kg body weight/day 0-5 g Protein/kg body weight/day ((creatinine clearance+ urea and 900 fimoul with ketoacids supplementation clearance)/2) (Ketosteril 1 tablet/ kg/day) 5 Plasma clearance of "Cr-EDTA Serum creatinine between g Protein/kg body weight/day Free diet >05 g protein/kg body and 1000 fimol/l weight/day Reciprocal of serum creatinine Serum creatinine between g Protein/kg body weight/day >08 g Protein/kg body weight/day and 00 fmol/l 'Cr-EDTA=ethylenediaminetetra-acetic acid labelled with chromium-51. TABLE v-odds ofrenal death in six prospective randomised studies of protein restriction in chronic renal insufficiency Odds ratio 95% (treatment/ Confidence Study control) interval tol to to to to to3-02 All to 0 9 x2=o05, df=5, p=05 for test of heterogeneity between odds ratios. 218 same as the degree of protein restriction in the treated group in study 3 (table IV). However, the mean difference in protein intake between control and treated groups was at least 0 35 g/kg/day in all studies except studies 2 and, when it was 0 2 g/kg/day. Interestingly, the treated groups in studies 2 and, which had the strictest restrictions received a ketoacid supplement. HOMOGENEITY OF STUDIES There was no qualitative interaction between effect and treatment. The X2 heterogeneity test between odds ratios was 05, with five degrees of freedom (p=0 5). Thus, the hypothesis that the effect of treatment in the different trials is heterogeneous is rejected. EFFECTS OF DIETARY INTERVENTION ON INCIDENCE OF RENAL DEATH Renal deaths are noted in tables II and III and the statistical results are shown in table V. In the six studies the number of renal deaths observed in treated and control groups were respectively 8 and 15 in study 1, 5 and in study 2, 21 and 32 in study 3, 11 and 1 in study, and 13 in study 5, and 12 and 11 in study. Five trials showed a reduction in renal death in treated groups and one a slight increase in renal death in the treated group (study ). Only the results for study 5 were significant as the confidence interval of the odds ratio did not include 1. After summarising the data 15 renal deaths were recorded, 1 for the treated groups (50 patients) and 95 for the control groups (0 patients). This represents a highly significant reduction in renal death (odds ratio 0 5, 95% confidence interval 0-3 to 0-9; p<0o002) for subjects allocated to low protein diets. Discussion One of the problems in measuring the progression of renal insufficiency is the identification of aetiological or therapeutic factors that may improve renal function.5 Inadequate markers or protocols or confounding factors may mask the effects of low protein diets.5 Of the trials analysed, only three used reference methods to measure glomerular filtration rate-that is 119 out of 22 patients (5-2%).5255 To avoid problems raised by surrogate criteria we chose a clearly defined clinical end point, renal death. This end point was easily observed for all patients retrospectivelythat is, the date of the first dialysis session. These data were obtained accurately from each paper or by direct contact with the investigators. In this review low protein diets were shown to reduce renal deaths significantly in the treated groups. The reduction of renal deaths occurred in five of the six trials (table V). In practical terms this reduction represents a longer period before the start of dialysis, but it should not be taken to represent a reduction in the progression of renal disease. This review has four potential limitations. Firstly, although the populations studied are clinically heterogeneous in age, sex ratio, level of renal insufficiency, and protein restriction, as seen in tables II, III, and IV, the effects of treatment are not statistically different. This heterogeneity of patients and degree of renal function is due, in part, to the small number of subjects. Interestingly, as observed for patients entering dialysis,58 more male subjects were present in these trials (sex ratio (m/f) 1-2) and were identically distributed in both control and treated groups (table III). The different kinds of nephropathies were also equally distributed to avoid clustering of glomerulonephritides which are more sensitive to low protein diets.' The limited number of patients presenting with stabilised renal insufficiency associated with the difficulty of dietary follow up may explain the individual trial sizes and the low significance of results. However, this heterogeneity may be viewed as an advantage for metaanalysis, because if it gives positive results it thus indicates a broader applicability of the treatment. Secondly, as the decision to begin dialysis varies locally, the definition of our criterion depends on physicians' opinions, the dialysis unit, and sometimes financial restrictions. The five countries involved (the Netherlands, France, Italy, Australia, and England) do not have dialysis restrictions and may start at similar degrees of renal insufficiency. Nevertheless, dialysis should be started at the same time for each trial in both treated and control groups according to clinical symptoms. Thirdly, although the protein intake in the treatment and control diets varies, the fact that a common effect is found indicates that the gradient in protein content is the therapeutic factor. In fact, the widely observed drift during low protein diets is due to a regular increase in the protein intake with time for treated groups59 and an underestimation of protein intake by the dietary reports.' These two facts tend to minimise the real gradient of protein intake between control and treated groups. Despite this, our metaanalysis is significant, and any factor that would minimise the difference in protein intake between control and treated groups-poor observance of protein restriction in the treated group or spontaneous restriction in the control group-would in fact enhance the significance of the meta-analysis. Thus, one reason why the individual studies gave weakly significant results could be that there was a too small protein gradient between treated and control groups at the start or during the trial (studies 2 and ). The only significant study (study 5) showed a mean difference in protein intake of 13 g/day at six months (estimated by BMJ VOLUME JANUARY 1992

4 urea nitrogen excretion; Maroni, et al's correction is insufficienc n ptet treated with low-protein diets. Kidng Int Suppl 1983;1:28-2. not usefl inesimatinga gradiet of prtein inake) in not uefulin etimatng agradent f proein ntak) in 20 Attman PO, Bucht H, Larsson 0, Uddebom G. Protein-reduced diet in 50 patients.' For a mean estimated weight of 0 kg diabetic renal failure. Cli'n Nephrol 1983;19: (two thirds male patients, one third female) this 21 Barsotti G, Miorelli E, Giannoni A, Guiducci A, Lupetti Restricted phosphorus and 5, Giovannetti nitrogen intake to slow the progression S. of represents a difference of 0-25 g/kg/day of protein. The chronic renal failure: a controlled trial. Kidney IntSuppl 1983;1:28-8. significance of this meta-analysis could decrease if the 22 Bennett SE, Russell GI, Walls J. Low protein diets in uraemia. 1983;28: BMJ treated groups ate less protein than prescribed and the 23 Frohling PT, Kokot F, Smicker R, Kaschube I, Lindenau K, Vetter K. control groups more. This would probably improve Influence of ketoacids on serum parathyroid hormone levels in patients with chronic the effecs oftrueprotein rstrictionon renal renal failure. Cli'n unction. Nephrol 1983;20: the efectso restictionon real funtion. 2 Gretz N, Korb E, Strauch Mi. Low-protein diet supplemented by keto acids in Fourthly, in the control groups (less or unrestricted chronic renal failure, a prospective controlled study. Kidney Int Suppl protein intake) increased urea production may decrease ;1: Barsotti G, Giannoni A, Morelli E, Lazzeri M, Vlamis I, Baldi R, et al. The clinical tolerance and hasten the decision to start decline tof renal function slowed by very low phosphorus intake in chronic dialysis, compared with the treated groups. This 2E renal patients following a low nitrogen diet. Clin Nephrol 198;21:5-9. potential limitation has not been resolved, so clinical intolerance of urea is only one of many reasons for BMJ 198;289: starting dialysis. 2ElNahas AM, Masters-Thomas A, Brady SA, Farrington K, Wilkinson V, HilsonAJ,et al. Selective effect of low protein diets in chronic renal diseases. 2 Mitch WE, Walser M, Steinman TI, Hill 5, Zeger 5, Tungsanga K. The effect o~~~~~~~~~~~~~~tfa kettt acid-amintt acid supplement to a restricted diet on the progression of chronic renal failure. N EnglJ Med 198;:23-9. CONCLUSION 28 Rosman JB, Tee Wee PM, Meijer 5, Piers-Becht TP, Sluiter WJ, Donker AJ. Prospective randomised trial of early dietary protein restriction in chronic Finally, the heterogeneity does not limit the results renal failure. Lancet 198;ii: from this meta-analysis. From this review low protein 29 Gretz N, Strauch Mt. Delayed progression of chronic renal failure: a prospective controlled trial with a low protein diet supplemented by keto diets have clearly been found to delay end stage renal acids. Contri'b Nephrol 1985;91:8-8. disease. However, no conclusion may be drawn about 30 Oldrizzi L, Rugiu C, Valvo E, Lupo A, Loschiavo C, Gammaro L, et al. its effects on the rate of progression of renal insuf- Progression of renal failure in patients with renal disease of diverse etiology on protein-restricted diet. Kidney Int 1985;2:553-. ficiency or on its nutritional risks or additional benefits 31 Rosman JB, Ter Wee PM, Piers-Becht GP, SluiterWJ, Meijer5, Van der Hem on GK, et al. Early protein restriction in chronic renal failure. In: Davison osteodystrphy, anaemia,and quality o life. Level AM, Guillou Pi, ed. Proceedings of the European Dialysis and Transplant Associaof restriction and need for supplements could also not tion-european Renal Association, 198, Florence, Italy. London: Pitman, be measured. This meta-analysis should not be con : Williams Al, Bennett 'dered sdefintive asrenal dath wasnot theend SE, Russell GI, Walls J. Alteration of the course of sidee sdfntv srnldah wsntteed chronic renal failure by dietary protein restriction. In: Davison AM, Guillou point used in the six studies. A new randomised P1, ed. Proceedings of the European Dialysis and Transplant Associationcontrolled trial should be initiated with a sufficient European Renal Association, 198, Florence, Italv. London: Pitman, 1985:0-. number of patients. From the mean reduction of risk 33 Zakar G. Effects of dietary protein restriction on the course of early renal observed in our meta-analysis, it can be estimated that this trial should include at least 800 patients (control London: Pitman, 198:00-3. risk of event=0-21, odds ratio=0-5, two sided hypo- 3 Attman P0. Long term treatment with low protein diet in uremia. Contrib Nephrol 198;53: thesis, ( =0-05, 13=0.05). Renal death should be closely 35 ChauveauP, Lebkiri B, Ployard F, CiancioniC, Man NK,JungersP. Effetdes failure. In: Davison AM, Guillou Pj, ed. Proceedings ofthe European Dialysis and TransplantAssociation-European RenalAssociation, 198, Florence, Italy. monitored, as well as all other reasons for leaving the ctioanalogues des acides amines essentiels sue la progression de l'insuffisance study. Themodification of diet in renal disease study renale chronique avanctie, diode prospective contrltie. Nephrologzie 198;: suitable for this type of approach."5 3 Di Landro D, Perin N, Bertoli M, Gasparotto ML, Ruffatti A, Naso A, et al. Clinical effects of a low protein diet supplemented with essential am-ino acids and keto analogues in uremic patients. Contrib Nephrol 198;53: Gentile MG, Manna GM, Ferrario L, D'Amico G. Preliminary experience on 1 El Nahas AMi, Coles GA. Dietary treatment of chronic renal failure: ten dietary management of chronic renal failure. Contrib Nephrol 198;53: unanswered questions. Lancet 198;i: Gretz N, Meisinger E, Strauch M. Influence of the underlying renal disease on 2 Druml W, Mitch WE. Protein-restnicted diets and progression of renal failure, the rate of progression. Contri'b Nephrol 198;53: Blood Purif 1988;: Lucas PA, Meadows JH, Roberts DE, Coles GA. The risks and benefits of a 3 Giovannetti S. Answers to ten questions on the dietary treatment of chronic low protein-essential anmino acid-keto acid diet. Kidne Int 198;29: renal failure, on behalf of the Steering Committee of the Eurtopean Study Groups for the Conservative Treatment of Chronic Renal Failure. Lancet 0 Rosman JB, Donker AJ, Meijer 5, Sluiter WJ, Piers-Becht TP, Van Dee Hem 198;ii: GK. Two years' experience with protein restriction in chronic renal failure. Gretz N, Giovannetti 5, Barsotti G, Schmicker R, Rosman J. Influence of Contrib Nephrol 198;53: dietar-v treatment on the rate of progression of chronic renal failure. In: 1 Schmicker R, Frohling PT, Goetz KH, Kaschube I, Rakette I, Vetter K. Giovannetti 5, ed. Nutri'tional treatment of chronic renal failure. Boston, Influence of low protein diet supplemented with amino acids and keto acids Massachusetts: Kluwer, 1989: on the progression of chronic renal failure. Contrib Nephrol 198;53: Walser Mi. Progression of chronic renal failure in man. Kidney Int 1990;3: 2 Gretz N, Meisinger E, Strauch M. Influence of diet and underlying renal disease on the rate of progression of chronic renal failure. Infusionstheraptie Levey A. Nephrologv forum: measuring renal function. Kidne Int 1990;38: und Kli'nischeErnahrung 198;1 (suppl 5): Jungers P, Chauveau P, Ployard F, Lebkiri B, Ciancioni C, Man NK. Boissel JP, Blanchard J, Panak E, Pevreiux JC, Sacks H. Considerations foe Comparison of ketoacids and low protein diet on advanced chronic renal the meta-analysis of random-ized clinical trials, summary of a panel failure progression. Kidney Int 198;22:- 1. discussion. Controlled Clin Trials 1989;l10: Meisinger E, Strauch M. Controlled trial of two ketoacid supplementson renal 8 L'Abbe KA, Detsky AS, O'Rourke E. Meta-analvsis in clinical research. function, nutritional status, and bone metabolism in uremic patients. Kidney Ann Intern Med 198;10: Int 198;22: Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta- 5 Schmicker R, Vetter K, Lindenau K, Frohling PT, Kokot F. Conservative analyses of randomized controlled trials. N Englj Med 198;31:50-5. long-term treatment of chronic renal failure with keto acid and amino acid 10 Hedges LV, Olkmn I. Statistical methods for meta-analvsis. Orlandos, Florida: supplementation. Infusionstherapi'e 198;1:3-8. Academic Press, Walser M, Lafrance N, Ward L, Vanduyn MA. Progression of chronic renal 11I Walser Ml. Ketoacids in the treatment of uremia. Clin Nephrol 195:3:180-. failure in patients given keto acids following am-ino acids. Infusionstherapie 12 Burns J, Cresswell E, ElI 5, Fvnn M, Jackson MA, Lee HA, et al. Comparison und Klinische Ernahrung 198;1(suppl 5): of the effects of ketoacids analogues and essential aminotacids on nitrogen Williams PS, Stevens ME, Fats G, Bone JM. A randomized trial of the effects homeostasis in uremic patients on moderately protein-restricted diets. of protein and phosphate restriction on the progression of chronic renal Amj ClinANutr 198;31: 1-5. failure. Nephrol Dial Transplant 198;: Alvestrand A, Ahlberg Ml, Fuirst P, Bergstrom J. Clinical experience with 8 Barsotti G, Ciardella F, Morelli E, Cupisti A, Mantovanelli A, Giovannetti S. amino acid and keto acid diets. AmJ Clin Nutr 1980;33: Nutritional treatment of renal failure in type 1 diabetic nephropathy. Clin 1 Frohling PTf Schmicker R, Vetter K, Kaschube I, Gotz KH, jacoplan M, Nephrol 1988;29:280-. et al. Conservative treatment with ketsoacid and aminoacid supplemented 9 Gentile MG, Fellin G, Manna GM, D'Amico G. Effects of dietetic manipulalow-protein diets in chronic renal failure. AmJ CnNur98;312. tion on the control of blood pressure and on the progression of chronic renal 15 Hecking E, Andrzejewski LI, Prellnitz W, Opferkuch W, Muller D. Double insufficiency. ScandJ Urol NephrolSuppl 1988;108:13-5. blind cross over study with oral and ketoacids in patients with chronic renal 50 Frohling PT, Lindenau K, Vetter K, Krupki F, Schmicker R. What can be failure. Amj Clin Nutr 1980;33: safely said about predialysis treatment? Blood Punif 1989;:28-32.

5 restricting dietary protein on the progression of renal failurc in patients with 59 Cianctaruso B, Capuano A, D'Amaro E, Ferrera N, Nastasi A, Conte G, et al. insulin-dependent diabetes mellitus. N Englj Med 1991;32:8-8. Dietary compliance to a low protein and phosphate diet in patients with 5 Lubowitz H, Slatopolsky E, Shankel S, Rieselbach RE, Brickcr NS. chronic renal failure. Kidney Int 1989;3 (suppl 2): S13-. Glomerular filtration rate: determination in patients with chronic rcnal 0 Kopple JI), Berg R, Houser H, Steinman TI, Teschan P (MIDRD Study disease.jama 19;199:252-. Group). Nutritional status of patients with different levels of chronic renal 5 Klahr S. The modification of diet in renal disease study. N Engl Med insufficiency. Kidney nt 1989;3 (suppl 2): S ;320:8-. 1 Maroni BJ, Steinrman TI, Mitch WE. A method for estimating nitrogen intake 58 Gretz N, Zeier M, Geberth S, Strauch 1\, Ritz E. Is gender a determinant for of patients with chronic renal failure. Kidney Int 1985;2:58-5. evolution of renal fadlure? A study in autosomal dominant polycystic kidney disease. AmJ Kidney Dis 1989;1: (Accepted November 1991) Mortality and occupational exposure to radiation: first analysis of the National Registry for Radiation Workers G M Kendall, C R Muirhead, B H MacGibbon, J A O'Hagan, A J Conquest, A A Goodill, B K Butland, T P Fell, D A Jackson, M A Webb, R G E Haylock, J M Thomas, T J Silk Abstract States indicated lower risk estimates than the com- Objective-To study cause specific mortality mission recommends, and when the American data of radiation workers with particular reference to are combined with our analysis the overall risks are associations between fatal neoplasms and level of close to those estimated by the commission. This exposure to radiation. first analysis of the National Registry for Radiation Design-Cohort study. Workers does not provide sufficient evidence to Setting-United Kingdom. justify a revision in risk estimates for radiological Subjects radiation workers at major sites protection purposes. of the nuclear industry. Main outcome measure-cause of death. Results-Most standardised mortality ratios were Introduction below 100: 83 unlagged, 85 with a 10 year lag for ali Estimates of the risks of ionising radiation rest causes; 8 unlagged, 8 lagged for all cancers; and 80 mainly on evidence from Japanese atomic bomb for all known other causes, indicating a "healthy survivors and from people exposed for medical reasons. worker effect." The deficit of lung cancer (5 These groups provide information on risks from unlagged, lagged) was significant at the 0-1% exposure to high doses at high dose rates. There is little level. Standardised mortality ratios were signifi- direct evidence of the effects of lower doses and dose cantly raised (21 unlagged, 303 lagged) for thyroid rates typical of occupational exposures. To provide cancer, but there was no evidence for any trend with such direct evidence the National Radiological Protecexternal recorded radiation dose. Dose of external tion Board, after extensive consultation with the radiation and mortality from ali cancers were weakly nuclear industry and other interested groups, set up correlated (p= 010), and multiple myeloma was the National Registry for Radiation Workers in 19 as more strongly correlated (p=0.0); for leukaemia, the national study of radiation workers, following National Radiological excluding chronic lymphatic, the trend was signifi- individuals through different employments.' Protection Board, Chilton, cant (p=0-03; all tests one tailed). The central The first analysis of the registry covers over Didcot OXII ORQ estimates of lifetime risk derived from these data radiation workers whose collective dose from external were 10-0% per Sv (90% confidence interval <0 to radiation is about 3200 man Sv. The essentials of the GM Kendall,PHD, principal 2%) for all cancers and 0-% per Sv (0-0 to 2%) for study are described in this paper; more details can be scientific officer leukaemia (excluding chronic lymphatic leukaemia). found in a separate report.2 C R Muirhead, PHD, These are, respectively, 2-5 times and 1-9 times the principal scientific officer risk estimates recommended by the International B H MacGibbon,FRCPATH, Commission on Radiological Protection, but 90% Methods assistant director confidence intervals are large and the commission's Although the study population for the National higher scaentfic officer risk factors fail well within the range. The positive Registry for Radiation Workers is broadly defined,3 A J Conquest,iBSC, higher trend with dose for all cancers, from which the risk practical considerations have limited the first analysis scientific officer estimate was derived, was not significant. The posi- to certain groups. Radiation workers were divided into A A Goodill, BSC, higher tive association between leukaemia (except chronic four categories: (a) those in radiation work when the scientific officer lymphatic leukaemia) was significant and robust in registry was set up; (b) those in employment at the B K Butland, MSC, higher subsidiary analyses. This study showed no associa- inception of the study but no longer doing radiation scientific officer tion between radiation exposure and prostatic work; (c) those who had left employment before the T P Fell, MSC, senior scientific cancer. inception of the study; and (d) those starting radiation officer Conclusion -There is evidence for an association work after the inception of the study. D A Jackson, BSC, scientific between radiation exposure and mortality from It was recognised that it would be easier to ensure officer M A Webb, MSC, scientific cancer, in particular leukaemia (excluding chronic that data were complete and accurate for those still in officer lymphatic leukaemia) and multiple myeloma, al- radiation work, and at the request of the participating R G E Haylock,MSC, higher though mortality from these diseases in the study organisations those in categories (a) and (d) were scientific officer population overall was below that in the general generally the first to be enrolled. The first analysis of J M Thomas, BSC, scientific population. The central estimates of risk from this the registry includes the following groups of workers: olfcer study lie above the most recent estimates of the from British Nuclear Fuels, category (a) and (d) T J Silk, assistant scientific International Commission on Radiological Protec- workers from 1 January 19, with category (b) and (c) officer tion for leukaemia (excluding chronic lymphatic for Sellafield and Chapelcross; from the Ministry of Corespndeceto: leukaemia) and for all malignancies. However, the Defence Atomic Weapons Establishment, workers in CorKespndence commission's risk estimates are well within the 90% all categories; from the Ministry of Defence, Defence confidence intervals from this study. Analysis of Radiological Protection Service, workers in categories BMJlf 1992;30:220-5 combined cohorts of radiation workers in the United (a) and (d) from 1 January 19; from Nuclear Electric, 220 BMJ VOLUME JANUARY 1992