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URINARY RHYTHM AFTER RENAL TRANSPLANTATION
636 URINARY MAGNESIUM AND RENAL STONES SIR,-The paper of Dr. Oreopoulos and his colleagues (Aug. 24, p. 420) raises important problems in attempting to compare data on the composition of the urine in stone-forming patients with that of normal controls. We have chosen to study the total 24-hour urinary calcium and magnesium excretions of subjects taking their normal diets. Although this may be less constant than the composition of a fasting-urine sample, we think that it reflects more closely the conditions under which stones actually form. We consider that the use of ratios between two urinary constituents, without reference to the absolute value of either constituent, is undesirable. The accompanying figure shows the calculated regression line for 24-hour urinary magnesium against 24-hour urinary calcium, together with the individual points, for 83 normal It can be seen that, at a 24-hour urinary calcium men. excretion of 150 mg., the mean " magnesium/calcium ratio " (Mg/Ca x 100) is about 72, whereas at a 24-hour urinary calcium excretion of 400 mg. the mean ratio is about 36. These figures are close to the mean ratios given in the paper of Dr. Oreopoulos and his colleagues for, respectively: (a) normal controls’ and stone-patients’ urines; (b) the 6 hyperparathyroid patients after and before parathyroidectomy; and (c) the good " and " evil " urines described by Mukai and Howard.1 We suggest that the data presented by Dr. Oreopoulos and his colleagues do not provide evidence to incriminate urinary magnesium excretion in the pathogenesis of stones, either idiopathic or in hyperparathyroidism. They are what would be expected when comparing Mg/Ca ratios in groups of subjects known to be strikingly hypercalciuric with groups of normal controls. In order to demonstrate the specific importance of hypomagnesuria it is necessary to compare patients with control groups having a similar calcium excretion, as we did in our study2 published last year, to which Dr. Oreopoulos and his colleagues did not refer. We have recalculated some of our data to determine Mg/Ca ratios (see accompanying table). The ratio of 36 for our stone formers with a daily urinary calcium excretion of less than 300 mg., though it is less than that of the corresponding controls (52), is the same as that of the normal controls with a daily urinary calcium excretion exceeding 300 mg. (36). This further suggests that ratios cannot be used properly to compare groups with different total urinary calcium excretions. It may be, of course, that hypercalciuria itself predisposes to stone formation, because it is usually associated with a low "
Mukai, T., Howard, J. E. Bull. Johns Hopkins Hosp. 1963, 112, 279. Evans, R. A., Forbes, M. A., Sutton, R. A. L., Watson, L. Lancet, 1967, ii, 958.
1. 2.
DAILY URINARY CALCIUM AND MAGNESIUM EXCRETION IN FORMERS AND
83 NORMAL
54 STONE
CONTROLS
urinary Mg/Ca ratio. However, before conditions such as hyperparathyroidism can be claimed to predispose to stone formation as a result of some specific effect on urinary magnesium excretion, it would be necessary to demonstrate a difference between the Mg/Ca ratios of patients and those of normal subjects with a comparable urinary calcium excretion. We are at present engaged in a further study, similar to our previous one, which attempts to distinguish the importance of reduced magnesium excretion from that of hypercalciuria in the pathogenesis of urinary calculi in hyperparathyroidism. For the time being, we feel that the indiscriminate use of ratios should be avoided; each urinary constituent should be considered independently of other variables. In their letter last week (p. 577), Dr. Papadimitriou and Mr. Ram, who agree that ratios are undesirable, state that Modlin3 and wereported no significant differences in urinary magnesium excretion between controls and stone patients. In fact we reported a significant reduction in daily urinary mag"
normocalciuric " renal-stone formers (with a daily urinary calcium excretion below 300 mg.) when compared with normocalciuric controls, similarly defined. Modlin also found a significant reduction of urinary magnesium in White stone formers compared with White controls. Thus we do not agree that urinary calcium " is the only responsible factor for any significantly different ratio involving urinary calcium ".
nesium excretion in
University College Hospital Medical School, University Street, London W.C.1.
ROGER A. L. SUTTON LYAL WATSON.
*** In the last sentence of their letter last week, Dr. Papadimitriou and Mr. Ram referred to " sodium/calcium " ratio (not magnesium/calcium ratio as printed).-ED. L. "
"
URINARY RHYTHM AFTER RENAL TRANSPLANTATION SiR,ŅWe have completed studies on the diurnal rhythm of renal function in 9 patients with renal transplants. Our results indicate inversion of the normal diurnal rhythm similar to that reported by Dr. Berlyne and his colleagues (Aug. 24, p. 435). In contrast to the two patients investigated by them, all our cases received a kidney from a live donor. Inversion of diurnal excretory rhythm was found to be present up to at least 3 months
24-hour urinary calcium and magnesium excretion in 83 normal men.
post-transplantation. The problem of to what extent administration of steroids is responsible for inversion of diurnal rhythm may be elucidated by our finding that one of our patients, who received a kidney from a monozygotic twin and was not treated with steroids or any other drug, also showed this phenomenon. In addition to the parameters studied by Dr. Berlyne and his colleagues, we also examined diurnal variations in the excretion of calcium and phosphate. In all cases phosphate excretion 3.
Modlin, M. Ann.
R. Coll.
Surg. 1967, 40,
155
637 was
higher
excretion
at
was
night, while
no
constant
pattern of calcium
found.
Details of these studies will be published elsewhere. Clinic, KAI ALBERTSEN Municipal Hospital, V. POSBORG PETERSEN. Aarhus, Denmark.
First Medical University
FOLIC-ACID ABSORPTION IN MAN SIR,-We were greatly interested in Dr. Sladen’s letter (Aug. 24, p. 459) referring to the unconventional method of plotting kinetic data used in our paper on the absorption of folic acid (Aug. 10, p. 302). Since the concentrations of folic acid used in our studies were 10, 100, 1000, and 10,000 ng. per ml., the most practical way of plotting the data was logarithmically. We accept that this gives information on the ratio of Km/Vmax rather than precise data on the individual values for these two parameters and that mathematical analysis really adds little to the understanding of the results. The data demonstrate, however, a saturable process of some sort and confirm that, as far as crystalline folic acid is concerned, the absorptive capacity of the small intestine in man is greatly in excess of apparent physiological requirements. G. W. HEPNER C. C. BOOTH J. COWAN Royal Postgraduate Medical School, London W.12.
A. V. HOFFBRAND D. L. MOLLIN.
THE VULNERABLE ŒSOPHAGUS SIR,-Iread with interest your leading article (Aug. 3, p. 267), based upon a comprehensive article by Palmer,’ and I should like to comment on a few statements expressed. My views are based on a prospective study of 628 hiatal-hernia cases seen in the cesophageal clinic, Groote Schuur Hospital, in the past twelve years.2 I have already made an urgent plea for an international nomenclature in oesophagology.3 Since the true incidence of hiatal hernia cannot be assessed, the prevalence in hospitals only should be discussed. The radiological prevalence is also not a true reflection, for many of the hernias displayed may have been iatrogenically produced. Spontaneous hiatal hernias revealed cineradiographically may be valid 23 but even these may be of no clinical significance. What is important is their correlation with the patients’ symptomatology. The gastrooesophageal junction cannot be definitely shown by radiological means. It is only by a combination of manometry, pH studies, potential difference (P.D.), and electromyographic studies that the situation and state of the gastro-oesophageal junction can be truly elucidated. Gastric reflux may indeed occur without hiatal hernia (reflux sans hernia), but in any case is reflux necessarily important ? What has to be considered is the type of fluid refluxed, also the duration of the reflux, the ability of the lower oesophagus to clear this material, and, most important, the sensitivity of the oesophageal mucosa. A sensitive mucosa is the pathogenic explanation for the patient’s symptom of heartburn, the precipitating cause of which is local or diffuse oesophageal spasm. Radiological gastric reflux is of no clinical significance. The patients’ symptomatology may depend on the presence or absence of other intra-abdominal disease (in my series 35% had associated disease), but most importantly, particularly in sliding hiatal hernia, on the presence or absence of an adequate inferior oesophageal sphincter.3 The treatment of the sliding-hiatal-hemia complex should be diligent conservative treatment; only if this fails should surgery be performed, with the proviso that simple herniorrhaphy is inadequate in those without a functioning inferior oesophageal sphincter. Whatever method is used, the postoperative 1. 2. 3.
Palmer, E. D. Am. J. Med. 1968, 44, 566. Silber, W. Unpublished. Silber, W. Rev. Surg. (in the press.)
absence of any anatomical recurrence does not necessarily mean an absence of symptoms. The recurrence-rate of hiatal hernia, postoperative symptoms, or both is very high in longterm follow-up studies. The natural history of these hernias, on the other hand, is of great interest, for many reduce in size and in fact may disappear. The last point which requires further elucidation is the question of strictures. I feel that the virulence of reflux aesophagitis has been over-exaggerated. There are many who develop stenoses in association with hiatal hernia; however, these are not organic fibrous strictures but local spasms which can be treated with excellent effect by antispasmodics. If certain basic criteria are accepted the subject of hiatal hernia should become less controversial. Oesophageal Clinic, University Department of Surgery, Medical School, Observatory, Cape Town.
W. SILBER.
MANAGEMENT OF CERVICAL CARCINOMA-IN-SITU as SIR,-May I, the only British worker cited in the excellent and fair presentation in your leading article last week (p. 548), be allowed to make a few comments ?
Krieger and McCormack1 are satisfied with wide cone biopsy provided certain conditions can be fulfilled. My experience is that they seldom can be, and these workers ignore the fact that cone biopsy may hide a lesion deep in the cervical glands which may not exfoliate again until it has done considerable harm to the patient. Coppleson and Reid2 put misplaced faith in Schiller’s test and colposcopy. Schiller’s test was introduced long before exfoliative cytology and if it had been of any use we should now be holding well-woman Schiller clinics instead of well-woman cytology clinics;and as for the colposcope which magnifies the surface I would merely say that whereas beauty is only skin-deep cancer certainly is not. Your leading article, however, touches on two matters of very great importance. Firstly, you suggest that " It would be helpful if a new term (not containing the word ’cancer ’) could be agreed upon for lesions in which cells with seemingly malignant qualities are seen within the limits of the epithelium ". This in my opinion would be an exceedingly retrogressive step. Certainly these lesions are not " cancer " as the public understands it-namely, as an incurable, painful, disgusting disease associated with severe pain, ostomies of various kinds, emaciation, and inevitable death, and I believe it utterly justifiable to tell a patient with an early lesion that they have not got cancer of this sort; but
to encourage the belief that these lesions are not cancer among the medical profession must be utterly condemned.
These lesions are cancer in its early and easily curable stages and must be recognised as such, for cancer is not something which you have today which you did not have yesterday, but is a long-continuing process in which its preclinical course is much longer than its clinical phase. Indeed Latner, Turner, and I 3 showed that morphologically normal cells in the vicinity of preinvasive carcinoma show typical biochemical characteristics of full-blown malignancy. The second major point that you make is the suggestion that centres be established to study the clinical and laboratory aspects of female genital cancer. In this you undoubtedly show perspicacity; a plea for such centres was made in connection with the increasingly important subject of ovarian carcinoma by Sir John Peel at the Royal Society of Medicine last June. As you suggest these centres could also " provide excellent resources for training selected young gynaecologists in the management of all aspects of pelvic cancer ". This latter aspect is now exercising world gynecological opinion. Last year the International Federation of Obstetrics and Gynaecology set up 1.
2. 3.
Krieger, J. S., McCormack, L. J. Am. J. Obstet. Gynec. 1968, 101, 171. Coppleson, M., Reid, B. Preclinical Carcinoma of the Cervix Uteri; p. 152. London, 1967. Latner, A. L., Turner, D., Way, S. Lancet, 1966, ii, 814.
Mukai, T., Howard, J. E. Bull. Johns Hopkins Hosp. 1963, 112, 279. Evans, R. A., Forbes, M. A., Sutton, R. A. L., Watson, L. Lancet, 1967, ii, 958.
1. 2.
DAILY URINARY CALCIUM AND MAGNESIUM EXCRETION IN FORMERS AND
83 NORMAL
54 STONE
CONTROLS
urinary Mg/Ca ratio. However, before conditions such as hyperparathyroidism can be claimed to predispose to stone formation as a result of some specific effect on urinary magnesium excretion, it would be necessary to demonstrate a difference between the Mg/Ca ratios of patients and those of normal subjects with a comparable urinary calcium excretion. We are at present engaged in a further study, similar to our previous one, which attempts to distinguish the importance of reduced magnesium excretion from that of hypercalciuria in the pathogenesis of urinary calculi in hyperparathyroidism. For the time being, we feel that the indiscriminate use of ratios should be avoided; each urinary constituent should be considered independently of other variables. In their letter last week (p. 577), Dr. Papadimitriou and Mr. Ram, who agree that ratios are undesirable, state that Modlin3 and wereported no significant differences in urinary magnesium excretion between controls and stone patients. In fact we reported a significant reduction in daily urinary mag"
normocalciuric " renal-stone formers (with a daily urinary calcium excretion below 300 mg.) when compared with normocalciuric controls, similarly defined. Modlin also found a significant reduction of urinary magnesium in White stone formers compared with White controls. Thus we do not agree that urinary calcium " is the only responsible factor for any significantly different ratio involving urinary calcium ".
nesium excretion in
University College Hospital Medical School, University Street, London W.C.1.
ROGER A. L. SUTTON LYAL WATSON.
*** In the last sentence of their letter last week, Dr. Papadimitriou and Mr. Ram referred to " sodium/calcium " ratio (not magnesium/calcium ratio as printed).-ED. L. "
"
URINARY RHYTHM AFTER RENAL TRANSPLANTATION SiR,ŅWe have completed studies on the diurnal rhythm of renal function in 9 patients with renal transplants. Our results indicate inversion of the normal diurnal rhythm similar to that reported by Dr. Berlyne and his colleagues (Aug. 24, p. 435). In contrast to the two patients investigated by them, all our cases received a kidney from a live donor. Inversion of diurnal excretory rhythm was found to be present up to at least 3 months
24-hour urinary calcium and magnesium excretion in 83 normal men.
post-transplantation. The problem of to what extent administration of steroids is responsible for inversion of diurnal rhythm may be elucidated by our finding that one of our patients, who received a kidney from a monozygotic twin and was not treated with steroids or any other drug, also showed this phenomenon. In addition to the parameters studied by Dr. Berlyne and his colleagues, we also examined diurnal variations in the excretion of calcium and phosphate. In all cases phosphate excretion 3.
Modlin, M. Ann.
R. Coll.
Surg. 1967, 40,
155
637 was
higher
excretion
at
was
night, while
no
constant
pattern of calcium
found.
Details of these studies will be published elsewhere. Clinic, KAI ALBERTSEN Municipal Hospital, V. POSBORG PETERSEN. Aarhus, Denmark.
First Medical University
FOLIC-ACID ABSORPTION IN MAN SIR,-We were greatly interested in Dr. Sladen’s letter (Aug. 24, p. 459) referring to the unconventional method of plotting kinetic data used in our paper on the absorption of folic acid (Aug. 10, p. 302). Since the concentrations of folic acid used in our studies were 10, 100, 1000, and 10,000 ng. per ml., the most practical way of plotting the data was logarithmically. We accept that this gives information on the ratio of Km/Vmax rather than precise data on the individual values for these two parameters and that mathematical analysis really adds little to the understanding of the results. The data demonstrate, however, a saturable process of some sort and confirm that, as far as crystalline folic acid is concerned, the absorptive capacity of the small intestine in man is greatly in excess of apparent physiological requirements. G. W. HEPNER C. C. BOOTH J. COWAN Royal Postgraduate Medical School, London W.12.
A. V. HOFFBRAND D. L. MOLLIN.
THE VULNERABLE ŒSOPHAGUS SIR,-Iread with interest your leading article (Aug. 3, p. 267), based upon a comprehensive article by Palmer,’ and I should like to comment on a few statements expressed. My views are based on a prospective study of 628 hiatal-hernia cases seen in the cesophageal clinic, Groote Schuur Hospital, in the past twelve years.2 I have already made an urgent plea for an international nomenclature in oesophagology.3 Since the true incidence of hiatal hernia cannot be assessed, the prevalence in hospitals only should be discussed. The radiological prevalence is also not a true reflection, for many of the hernias displayed may have been iatrogenically produced. Spontaneous hiatal hernias revealed cineradiographically may be valid 23 but even these may be of no clinical significance. What is important is their correlation with the patients’ symptomatology. The gastrooesophageal junction cannot be definitely shown by radiological means. It is only by a combination of manometry, pH studies, potential difference (P.D.), and electromyographic studies that the situation and state of the gastro-oesophageal junction can be truly elucidated. Gastric reflux may indeed occur without hiatal hernia (reflux sans hernia), but in any case is reflux necessarily important ? What has to be considered is the type of fluid refluxed, also the duration of the reflux, the ability of the lower oesophagus to clear this material, and, most important, the sensitivity of the oesophageal mucosa. A sensitive mucosa is the pathogenic explanation for the patient’s symptom of heartburn, the precipitating cause of which is local or diffuse oesophageal spasm. Radiological gastric reflux is of no clinical significance. The patients’ symptomatology may depend on the presence or absence of other intra-abdominal disease (in my series 35% had associated disease), but most importantly, particularly in sliding hiatal hernia, on the presence or absence of an adequate inferior oesophageal sphincter.3 The treatment of the sliding-hiatal-hemia complex should be diligent conservative treatment; only if this fails should surgery be performed, with the proviso that simple herniorrhaphy is inadequate in those without a functioning inferior oesophageal sphincter. Whatever method is used, the postoperative 1. 2. 3.
Palmer, E. D. Am. J. Med. 1968, 44, 566. Silber, W. Unpublished. Silber, W. Rev. Surg. (in the press.)
absence of any anatomical recurrence does not necessarily mean an absence of symptoms. The recurrence-rate of hiatal hernia, postoperative symptoms, or both is very high in longterm follow-up studies. The natural history of these hernias, on the other hand, is of great interest, for many reduce in size and in fact may disappear. The last point which requires further elucidation is the question of strictures. I feel that the virulence of reflux aesophagitis has been over-exaggerated. There are many who develop stenoses in association with hiatal hernia; however, these are not organic fibrous strictures but local spasms which can be treated with excellent effect by antispasmodics. If certain basic criteria are accepted the subject of hiatal hernia should become less controversial. Oesophageal Clinic, University Department of Surgery, Medical School, Observatory, Cape Town.
W. SILBER.
MANAGEMENT OF CERVICAL CARCINOMA-IN-SITU as SIR,-May I, the only British worker cited in the excellent and fair presentation in your leading article last week (p. 548), be allowed to make a few comments ?
Krieger and McCormack1 are satisfied with wide cone biopsy provided certain conditions can be fulfilled. My experience is that they seldom can be, and these workers ignore the fact that cone biopsy may hide a lesion deep in the cervical glands which may not exfoliate again until it has done considerable harm to the patient. Coppleson and Reid2 put misplaced faith in Schiller’s test and colposcopy. Schiller’s test was introduced long before exfoliative cytology and if it had been of any use we should now be holding well-woman Schiller clinics instead of well-woman cytology clinics;and as for the colposcope which magnifies the surface I would merely say that whereas beauty is only skin-deep cancer certainly is not. Your leading article, however, touches on two matters of very great importance. Firstly, you suggest that " It would be helpful if a new term (not containing the word ’cancer ’) could be agreed upon for lesions in which cells with seemingly malignant qualities are seen within the limits of the epithelium ". This in my opinion would be an exceedingly retrogressive step. Certainly these lesions are not " cancer " as the public understands it-namely, as an incurable, painful, disgusting disease associated with severe pain, ostomies of various kinds, emaciation, and inevitable death, and I believe it utterly justifiable to tell a patient with an early lesion that they have not got cancer of this sort; but
to encourage the belief that these lesions are not cancer among the medical profession must be utterly condemned.
These lesions are cancer in its early and easily curable stages and must be recognised as such, for cancer is not something which you have today which you did not have yesterday, but is a long-continuing process in which its preclinical course is much longer than its clinical phase. Indeed Latner, Turner, and I 3 showed that morphologically normal cells in the vicinity of preinvasive carcinoma show typical biochemical characteristics of full-blown malignancy. The second major point that you make is the suggestion that centres be established to study the clinical and laboratory aspects of female genital cancer. In this you undoubtedly show perspicacity; a plea for such centres was made in connection with the increasingly important subject of ovarian carcinoma by Sir John Peel at the Royal Society of Medicine last June. As you suggest these centres could also " provide excellent resources for training selected young gynaecologists in the management of all aspects of pelvic cancer ". This latter aspect is now exercising world gynecological opinion. Last year the International Federation of Obstetrics and Gynaecology set up 1.
2. 3.
Krieger, J. S., McCormack, L. J. Am. J. Obstet. Gynec. 1968, 101, 171. Coppleson, M., Reid, B. Preclinical Carcinoma of the Cervix Uteri; p. 152. London, 1967. Latner, A. L., Turner, D., Way, S. Lancet, 1966, ii, 814.