- Email: [email protected]
POLYCYSTIC KIDNEYS AND ABDOMINAL AORTIC ANEURYSMS
646 ABNORMAL LIVER
*Not
an
F.D.A.
approved
use.
FUNCTIONJAUNDICE ASSOCIATED WITH DANAZOL IN FIVE
tLaboratory
data
(in units) with,
in
parentheses,
PATIENTS
either baseline values for
(A-E)
patients
A and B
or
normal values
(patient E). chemical evidence of hepatic injury and one of jaundice in patients taking danazol (’Danocrine’) (table). The amount of drug which had been taken ranged from 400 mg/day for 28 days to 500 mg/day for 5 months. Patients ranged in age from 13to 34 years. There were no concurrent medications or concurrent disorders in the four patients (A, B, C, and E) for whom that information was available. Patients C and D recovered when the drug was withdrawn; in patient A the effect of drug withdrawal was not reported; and patient E is still under treatment. The data on these cases are limited by the nature of the reporting. Nevertheless, they are sufficient to support the view that danazol may have the adverse effects on the liver that would be expected from its chemical structure. Presumably they are mainly cholestatic.
He-
was
established
1979, when he
was
home hacmodialysis until December, given a cadaver renal transplant, which is on
functioning. Routine post-transplantation 99mTc-DTPA imaging revealed an abnormal abdominal aorta (figure, a) compared with the image of another polycystic patient with a renal transplant (c). 99mTc-Iabelled red blood cell pool studies were also used to demonstrate the aneurysm (b, d.) Ultrasonography measured the diameter of the aneurysm to be 6 cm. Case 2.--7-year-old man. Following the diagnosis of his polycystic kidneys he had a bilateral Rovsing’s operation at the now
These patients were reported to the Division of Drug Experience of the Bureau of Drugs, F.D.A. which collects and evaluates reports of reactions obtained through our spontaneous reporting system. H.J.Z.’s laboratory houses the registry for drug-induced hepatic injury for the D.C. metropolitan area. Division of Drug Experience, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland 20857, U.S.A.
KAY PEARSON
Liver Disease Laboratory, V.A. Medical Center,
George Washington University School of Medicine,
Washington, D.C. 20422, U.S.A.
HYMAN J. ZIMMERMAN
POLYCYSTIC KIDNEYS AND ABDOMINAL AORTIC ANEURYSMS
SIR,-Following the incidental finding, by 99mTc-DTPA imaging, of an abdominal aortic aneurysm in a patient with polycystic kidneys, we decided to review’our experience of this combination of lesions. We have had 3 patients with abdominal aortic aneurysms and polycystic renal failure, out of a total of 31 patients with adult polycystic disease who have been on our dialysis and transplantation programme at some time. This contrasts with no known aneurysms in patients with other renal diseases on the programme. Aortic aneurysms have not previously been described in association with polycystic kidneys, though berry aneurysms are well known. In studies of aortic aneurysms, polycystic kidneys have not been noted.’>2 Case I.-54-year-old man. Ankle swelling, resistant to diuretic therapy, precipitated the diagnosis of his polycystic renal failure at the age of 52. He was hypertensive (160/110 mm Hg) with a grade I retinopathy. His blood pressure was well controlled with diuretics and prazosin. 1 year later he was started on peritoneal dialysis and, subsequently, hxmodialysis. .
99mTc-DTPA images and red blood cell pool studies.
(a) 0-30 aorta
Murtaugh JF, et Med Assoc
2.
al. The ultimate audit: Case
presentations. J Indiana State
1977; 70: 915-17.
Johnson JG, et al. Review of 207 abdominal aortic aneurysms: 1964-74. Irish Med J 1977; 70: 164-67, 184.
99mTc-DTPA
(b) 99mTc-labelled
aneurysm of case 1. (c) 0-30
1.
s
image showing renal transplant and dilated
of case 1.
s
red blood cell
99mTc-DTPA
pool study confirming
the aortic
image showing renal transplant and normal
another polycystic patient. (d) 99m-labelled red blood cell pool study showing normal aorta and compressed abdominal vasculature in another transplanted polycysnc aorta in
patient.
647 age of 37. Over the next 10 years his renal function declined and his blood pressure was poorly controlled, with values between and 180/110 mm Hg. Hsemodialysis was started when he was 47. 6 months later a bilateral nephrec-
GEOGRAPHICAL DISTRIBUTION OF SUPPLEMENTED AND CONTROL
MOTHERS
240/130
tomy was performed in preparation for renal transplantation. At this operation a clinically undetected aortic aneurysm was discovered. He recovered from the operation but died from rupture of the aneurysm while on haemodialysis awaiting surgical repair. Case 3.-Renal stones and polycystic kidneys were diagnosed at the age of 34 after an X-ray taken for a minor back injury. He had intermittent gout from the age of 40 y and intermittent claudication in both legs from 51 years. He was hypertensive, controlled with propranolol and hydralazine (200/105-150/80 mm Hg). Angiography demonstrated a fusiform aneurysm at the aortic bifurcation (which was not palpable) and severe iliac vessel disease. Social circumstances ruled out long term hxmodialysis. Renal transplantation was attempted at the same time as resection of the aortic aneurysm and right nephrectomy. Postoperatively, infarction of the colon developed and, despite resection and ileostomy, the patient died. Polycycstic kidneys may grow very large and prevent palpation of abdominal aortic aneurysms-as occurred in our three cases. Aortic aneurysms may show on the intravenous urogram if the walls are calcified, or they may be detected incidentally when ultrasonography is done on the kidneys. After transplantation the 99mTc-DTPA image may show the aortic dilatation between the kidneys. Ultrasonography, 99"’TC-labelled red blood cell pool studies, or angiography may be needed to demonstrate the aneurysm. There are obvious implications of finding an aortic aneurysm in a patient being assessed for a chronic dialysis or transplant programmes. Peritoneal dialysis is relatively contraindicated in polycystic disease: the possibility of rupturing an unsuspected aortic aneurysm must make it absolutely contraindicated, except when insertion of the catheter is under direct vision. The presence of an aneurysm will alter the pattern and timing of operations in preparation for renal transplantation or long term dialysis. The frequency of abdominal aortic aneurysms in our adult polycystic patients on chronic haemodialysis or with renal transplants is thus at least 10% (3 out of 31). We believe that the possibility of an aneurysm should be considered in all cases of adult polycystic disease. Clinical examination will be unreliable, so the aorta should be examined by ultrasound. We are now investigating our patients with polycystic kidneys to determine whether the apparent association we have found can be confirmed in a larger series. Renal Unit and Department of Nuclear Medicine,
Guy’s Hospital, London SE1 9RT
J. R. CHAPMAN A. J. W. HILSON
POSSIBLE PREVENTION OF NEURAL-TUBE DEFECTS BY PERICONCEPTIONAL VITAMIN SUPPLEMENTATION
SIR,-Professor Smithells and others (Feb. 16, p. 339) believe they have observed a preventive effect of periconceptional vitamin supplementation on the recurrence of neuraltube defect (NTD). Their conclusions are based on the observation that the incidence of NTD in 185 fully supplemented women was significantly lower than that in 264 unsupplemented or control women. Such an interpretation of the data rests upon the assumption that both the supplemented and the control women were, initially, at equal risk of conceiving a further affected fetus. A geographical analysis of the total sample shows that this was probably not so. In the accompanying table the study subjects
as falling into one of two groups-a "relagroup, residing in Northern Ireland, Lancashire, and Cheshire; and a "relatively low risk" group, residing in south-east England and Yorkshire. (The varying geographical risk of NTD is well established.l,2 It is clear that the supplemented sample is as heavily biased towards "relatively low risk" areas as the control sample is towards "relatively high risk" areas. The higher incidence of recurrent NTD in the control group is therefore hardly surprising. Why, I wonder, did Professor Smithells and his co-workers not evaluate their interesting hypothesis by means of a randomised controlled trial, which would have been eminently practicable, would have minimised selection bias, and would have been more likely to convince the sceptics? are
characterised
tively high risk"
of Glasgow Social Pædiatric Psediatric and Obstetric Research Unit, 64 Oakfield Avenue, Glasgow G12 8LS
University
DAVID H. STONE
SIR,-With the wisdom of hindsight, we should have stated in our preliminary communication that our original intention had been a double-blind controlled study for which placebo tablets had already been prepared, but that the protocol was rejected by three separate hospital research ethics committees, and we had to resort to a less satisfactory design. The number of fully supplemented (S) and "control" mothers (C) was almost identical in all centres except Northern Ireland which had an excess of controls (Northern Ireland S 37, C 122; S-E England S 70, C 70; Yorkshire S 38, C 35; Lancashire S 31, C 27; Cheshire S 9, C10). The recurrence rate of NTDs in the controls was in keeping with earlier reports. The excess of controls in Northern Ireland does not alter the fact that there was only 1 recurrence among the progeny of 185 fully supplemented mothers. The geographical variation in the incidence of NTD is well recognised. What is relevant to our study is geographical variation in recurrence rate, about which little is known. Dr Stone makes reference to what we "believe", to our "conclusions", and to "an interpretation". In our paper we subscribe to no belief, reach no conclusions, and offer four possible interpretations, of which the first covers the point Dr Stone raises. We are not trying "to convince the sceptics", amongst whom we count ourselves. We present some observations (which will be fully detailed in a later paper) and would welcome further studies to assist in their interpretation. Department of Pædiatrics and Child Health
University if Leeds, Leeds LS1 3ET
R. W. SMITHELLS S. SHEPPARD
1. Fedrick J. Anencephalus: variation with maternal age, parity, social class and region in England, Scotland and Wales. Ann Hum Genet 1970; 34: 31-37. 2. Stocks P. Incidence of congenital malformations in the regions of England
and Wales. Br J Prev Soc Med 1970; 24: 67-77.
*Not
an
F.D.A.
approved
use.
FUNCTIONJAUNDICE ASSOCIATED WITH DANAZOL IN FIVE
tLaboratory
data
(in units) with,
in
parentheses,
PATIENTS
either baseline values for
(A-E)
patients
A and B
or
normal values
(patient E). chemical evidence of hepatic injury and one of jaundice in patients taking danazol (’Danocrine’) (table). The amount of drug which had been taken ranged from 400 mg/day for 28 days to 500 mg/day for 5 months. Patients ranged in age from 13to 34 years. There were no concurrent medications or concurrent disorders in the four patients (A, B, C, and E) for whom that information was available. Patients C and D recovered when the drug was withdrawn; in patient A the effect of drug withdrawal was not reported; and patient E is still under treatment. The data on these cases are limited by the nature of the reporting. Nevertheless, they are sufficient to support the view that danazol may have the adverse effects on the liver that would be expected from its chemical structure. Presumably they are mainly cholestatic.
He-
was
established
1979, when he
was
home hacmodialysis until December, given a cadaver renal transplant, which is on
functioning. Routine post-transplantation 99mTc-DTPA imaging revealed an abnormal abdominal aorta (figure, a) compared with the image of another polycystic patient with a renal transplant (c). 99mTc-Iabelled red blood cell pool studies were also used to demonstrate the aneurysm (b, d.) Ultrasonography measured the diameter of the aneurysm to be 6 cm. Case 2.--7-year-old man. Following the diagnosis of his polycystic kidneys he had a bilateral Rovsing’s operation at the now
These patients were reported to the Division of Drug Experience of the Bureau of Drugs, F.D.A. which collects and evaluates reports of reactions obtained through our spontaneous reporting system. H.J.Z.’s laboratory houses the registry for drug-induced hepatic injury for the D.C. metropolitan area. Division of Drug Experience, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland 20857, U.S.A.
KAY PEARSON
Liver Disease Laboratory, V.A. Medical Center,
George Washington University School of Medicine,
Washington, D.C. 20422, U.S.A.
HYMAN J. ZIMMERMAN
POLYCYSTIC KIDNEYS AND ABDOMINAL AORTIC ANEURYSMS
SIR,-Following the incidental finding, by 99mTc-DTPA imaging, of an abdominal aortic aneurysm in a patient with polycystic kidneys, we decided to review’our experience of this combination of lesions. We have had 3 patients with abdominal aortic aneurysms and polycystic renal failure, out of a total of 31 patients with adult polycystic disease who have been on our dialysis and transplantation programme at some time. This contrasts with no known aneurysms in patients with other renal diseases on the programme. Aortic aneurysms have not previously been described in association with polycystic kidneys, though berry aneurysms are well known. In studies of aortic aneurysms, polycystic kidneys have not been noted.’>2 Case I.-54-year-old man. Ankle swelling, resistant to diuretic therapy, precipitated the diagnosis of his polycystic renal failure at the age of 52. He was hypertensive (160/110 mm Hg) with a grade I retinopathy. His blood pressure was well controlled with diuretics and prazosin. 1 year later he was started on peritoneal dialysis and, subsequently, hxmodialysis. .
99mTc-DTPA images and red blood cell pool studies.
(a) 0-30 aorta
Murtaugh JF, et Med Assoc
2.
al. The ultimate audit: Case
presentations. J Indiana State
1977; 70: 915-17.
Johnson JG, et al. Review of 207 abdominal aortic aneurysms: 1964-74. Irish Med J 1977; 70: 164-67, 184.
99mTc-DTPA
(b) 99mTc-labelled
aneurysm of case 1. (c) 0-30
1.
s
image showing renal transplant and dilated
of case 1.
s
red blood cell
99mTc-DTPA
pool study confirming
the aortic
image showing renal transplant and normal
another polycystic patient. (d) 99m-labelled red blood cell pool study showing normal aorta and compressed abdominal vasculature in another transplanted polycysnc aorta in
patient.
647 age of 37. Over the next 10 years his renal function declined and his blood pressure was poorly controlled, with values between and 180/110 mm Hg. Hsemodialysis was started when he was 47. 6 months later a bilateral nephrec-
GEOGRAPHICAL DISTRIBUTION OF SUPPLEMENTED AND CONTROL
MOTHERS
240/130
tomy was performed in preparation for renal transplantation. At this operation a clinically undetected aortic aneurysm was discovered. He recovered from the operation but died from rupture of the aneurysm while on haemodialysis awaiting surgical repair. Case 3.-Renal stones and polycystic kidneys were diagnosed at the age of 34 after an X-ray taken for a minor back injury. He had intermittent gout from the age of 40 y and intermittent claudication in both legs from 51 years. He was hypertensive, controlled with propranolol and hydralazine (200/105-150/80 mm Hg). Angiography demonstrated a fusiform aneurysm at the aortic bifurcation (which was not palpable) and severe iliac vessel disease. Social circumstances ruled out long term hxmodialysis. Renal transplantation was attempted at the same time as resection of the aortic aneurysm and right nephrectomy. Postoperatively, infarction of the colon developed and, despite resection and ileostomy, the patient died. Polycycstic kidneys may grow very large and prevent palpation of abdominal aortic aneurysms-as occurred in our three cases. Aortic aneurysms may show on the intravenous urogram if the walls are calcified, or they may be detected incidentally when ultrasonography is done on the kidneys. After transplantation the 99mTc-DTPA image may show the aortic dilatation between the kidneys. Ultrasonography, 99"’TC-labelled red blood cell pool studies, or angiography may be needed to demonstrate the aneurysm. There are obvious implications of finding an aortic aneurysm in a patient being assessed for a chronic dialysis or transplant programmes. Peritoneal dialysis is relatively contraindicated in polycystic disease: the possibility of rupturing an unsuspected aortic aneurysm must make it absolutely contraindicated, except when insertion of the catheter is under direct vision. The presence of an aneurysm will alter the pattern and timing of operations in preparation for renal transplantation or long term dialysis. The frequency of abdominal aortic aneurysms in our adult polycystic patients on chronic haemodialysis or with renal transplants is thus at least 10% (3 out of 31). We believe that the possibility of an aneurysm should be considered in all cases of adult polycystic disease. Clinical examination will be unreliable, so the aorta should be examined by ultrasound. We are now investigating our patients with polycystic kidneys to determine whether the apparent association we have found can be confirmed in a larger series. Renal Unit and Department of Nuclear Medicine,
Guy’s Hospital, London SE1 9RT
J. R. CHAPMAN A. J. W. HILSON
POSSIBLE PREVENTION OF NEURAL-TUBE DEFECTS BY PERICONCEPTIONAL VITAMIN SUPPLEMENTATION
SIR,-Professor Smithells and others (Feb. 16, p. 339) believe they have observed a preventive effect of periconceptional vitamin supplementation on the recurrence of neuraltube defect (NTD). Their conclusions are based on the observation that the incidence of NTD in 185 fully supplemented women was significantly lower than that in 264 unsupplemented or control women. Such an interpretation of the data rests upon the assumption that both the supplemented and the control women were, initially, at equal risk of conceiving a further affected fetus. A geographical analysis of the total sample shows that this was probably not so. In the accompanying table the study subjects
as falling into one of two groups-a "relagroup, residing in Northern Ireland, Lancashire, and Cheshire; and a "relatively low risk" group, residing in south-east England and Yorkshire. (The varying geographical risk of NTD is well established.l,2 It is clear that the supplemented sample is as heavily biased towards "relatively low risk" areas as the control sample is towards "relatively high risk" areas. The higher incidence of recurrent NTD in the control group is therefore hardly surprising. Why, I wonder, did Professor Smithells and his co-workers not evaluate their interesting hypothesis by means of a randomised controlled trial, which would have been eminently practicable, would have minimised selection bias, and would have been more likely to convince the sceptics? are
characterised
tively high risk"
of Glasgow Social Pædiatric Psediatric and Obstetric Research Unit, 64 Oakfield Avenue, Glasgow G12 8LS
University
DAVID H. STONE
SIR,-With the wisdom of hindsight, we should have stated in our preliminary communication that our original intention had been a double-blind controlled study for which placebo tablets had already been prepared, but that the protocol was rejected by three separate hospital research ethics committees, and we had to resort to a less satisfactory design. The number of fully supplemented (S) and "control" mothers (C) was almost identical in all centres except Northern Ireland which had an excess of controls (Northern Ireland S 37, C 122; S-E England S 70, C 70; Yorkshire S 38, C 35; Lancashire S 31, C 27; Cheshire S 9, C10). The recurrence rate of NTDs in the controls was in keeping with earlier reports. The excess of controls in Northern Ireland does not alter the fact that there was only 1 recurrence among the progeny of 185 fully supplemented mothers. The geographical variation in the incidence of NTD is well recognised. What is relevant to our study is geographical variation in recurrence rate, about which little is known. Dr Stone makes reference to what we "believe", to our "conclusions", and to "an interpretation". In our paper we subscribe to no belief, reach no conclusions, and offer four possible interpretations, of which the first covers the point Dr Stone raises. We are not trying "to convince the sceptics", amongst whom we count ourselves. We present some observations (which will be fully detailed in a later paper) and would welcome further studies to assist in their interpretation. Department of Pædiatrics and Child Health
University if Leeds, Leeds LS1 3ET
R. W. SMITHELLS S. SHEPPARD
1. Fedrick J. Anencephalus: variation with maternal age, parity, social class and region in England, Scotland and Wales. Ann Hum Genet 1970; 34: 31-37. 2. Stocks P. Incidence of congenital malformations in the regions of England
and Wales. Br J Prev Soc Med 1970; 24: 67-77.