Inactive
Renin Levels in Recurrent By M.A.
Johnston,
R. Carachi,
@A prospective study of four children with nephroblastoma has demonstrated elevation of plasma inactive renin levels at the time of detection of recurrent disease. Three of the four children had been shown to have elevated inactive renin levels at their initial presentation with primary nephroblastoma. These levels returned to normal following operation and chemotherapy. The observation provides further evidence that plasma inactive renin may be a useful tumour marker for nephroblastoma. Copyright o 1991 by WA Saunders Company
G.B.M.
Lindop,
Nephroblastoma and B. Leckie ACTIVE
TOTAL
10,000
1
i lvooo: 2 2
A*
.E
At
5E 100
A A
:A
\
31
INDEX WORDS:
INACTIVE
.
Inactive renin; recurrent nephroblastoma. 10
I
T IS WELL established that a variety of tumours, mainly renal, may secrete renin. Of the 50 patients with these tumours so far described, 40 had nephroblastoma.‘,’ It is now known that the elevation in plasma renin levels is due to a preponderance of the prohormone inactive renin.2*3 This raised the possibility that inactive renin may be of value as a chemical tumour marker for nephroblastoma. We report our experience with plasma renin levels in nephroblastoma patients with recurrent or metastatic disease. MATERIALS
AND
METHODS
At this centre, children with nephroblastoma are managed according to the UK Cancer Children’s Study Group guidelines. At presentation, blood is routinely taken for total plasma renin estimation. This is repeated following initial treatment and again if there is clinical suspicion of recurrent disease. Total plasma renin estimation: 3 mL of blood were place in a lithium heparin tube and kept in ice during transport to the renin laboratory, where the plasma was extracted and stored at -20°C. Twenty microlitres of a 10 mg/mL solution of trypsin was added to 200 uL of ice-cold plasma. This was incubated at 4°C for 3 to 6 minutes. Twenty microlitres of soya bean trypsin inhibitor (20 mg/mL) was added. The renin assay was then carried out, measuring the active and inactive components by microassay as described by Millar et aL4 RESULTS
From 1984 to 1989, a total of 25 children were treated for nephroblastoma. Of these, four children have been identified with recurrent disease (Table 1). One patient had chromosome fragility disease and another presented following a road traffic accident. The mean plasma renin levels for all nephroblastoma patients decreased after tumour excision (Fig l), and subsequently became elevated in the four patients found to have recurrent disease (Table 2, Fig 2). DISCUSSION
The role of the renin-angiotensin system in children with nephroblastoma has been studied prospecJournalof Pediatric Surgery, Vol26,
No 5 (May), 1991: pp 613-614
I
OJ
Pre
Post
Pre
Post
Pre
Post
Fig 1. Mean total, active, and inactive renin levels, preoperation and postoperation for all patients with nephroblastoma. A, Patients with recurrent disease.
tively by several authors.‘U3 High levels of inactive renin were reported, which fell to normal levels after complete removal of the tumour.’ High levels of active renin have been reported in a hypertensive child with a juxtoglomerular secreting tumour.5 Active renin was also found to be elevated in neuroblastoma, in contrast to the inactive renin component.’ The criteria for a tumour marker to be established are that the substance must be readily assayable; it must be sensitive and specific for the tumour type; the levels must return to normal following adequate treatment; and elevation must correlate with clinically detectable recurrent disease. We have followed-up the initial cohort of patients reported by us.* Of the four patients who developed recurrent disease, one had an abdominal recurrence, another had cerebral metastases, and two had recurrent disease in the mediastinum and lungs. In all these patients the plasma renin levels were elevated and,
From the Depattment of Surgical Paediattics, Royal Hospital for Sick Children, the Department of Pathology, University of Glasgow, and the h4RC Blood Pressure Unit. Western Infirmary. Glasgow, Scotland. Presented at the 37th Annual International Congress of the British Association of Paediatric Surgeons, Glasgow, Scotland, July 25-27, 1990. Address reprint requests to R. Carachi, MD, PhD, FRCS, Department of Surgical Paediattics, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8U, Scotland. Copyright o 1991 by W B. Saunders Company 0022-3468/9112605-0027$03.OOfO
613
JOHNSTON
614
ET AL
Table 1. Patients With Recurrent Disease Stage, Histology
Disease Case No.
Age at
Presentation
1
1 vr
2
2 vr
3 4
Operation Nephrectomy (R), partial hepatectomy
Intervalto
Site of Recurrent
Disease
FldapSe
Brain
Outcome
II, favourable
Died, metastases
4 vr
Nephrectomy (R)
II, favourable
4 vr
Lung
Died, metastases
4 vr
Nephrectomy (L)
II, favourable
Mediastinum
Alive, disease-free
5 vr
Emergency nephrectomy (R)
Ill, favourable
2 vr 18mo
Intraabdominal, lung
Died, metastases
Abbreviations: R, right; L, left.
Table 2. Plasma Renin Levels for the Four Patients With Recurrent Disease Renin Levels Total
Active
Inactive
Measurement
(60-200)
(9-50)
(38.180)
Presentation
2,090
Time of Case No.
1
2
3
4
(WlJlmL)
2,205
115
Postoperation
140
58
82
Recurrence
738
186
552
2,980
285
2,695
Postoperation
266
85
181
Recurrence
288
85
195
Presentation
920
170
750
Presentation
Postoperation
118
15
103
Recurrence
353
41
312
No preoperative values obtained
Presentation Postoperation
140
59
81
Recurrence
955
278
677
pU/ml 3000 12695 2000
1 1000
800
600
Fig 2. Plasma inactive renin levels (A) preoperation, (6) postoperation, and (C) at the time of detection of recurrent disease.
therefore, would be of value as a tumour marker. Clinical disease was also present at the time that the elevated inactive renin levels were measured and, therefore, we cannot establish whether this elevation antedated the appearance of clinically detectable disease. The role of inactive renin in recurrent nephroblastoma warrants further investigation because if serial estimations are performed, the outlook for early detection of recurrent disease may improve. We recommend that once a patient with nephroblastoma has completed treatment, plasma inactive renin levels should be estimated as part of their follow-up. REFERENCES 1. Guademar M, Bruneval P, Camilleri JP: Syndromes tumoraux avec secretion inappropriee de renine. Criteres diagnostiques et revue des cas publies. Ann Path01 8:83-90, 1988 2. Carachi R, Lindop GBM, Leckie BJ: Inactive renin: A tumour marker in nephroblastoma. J Pediatr Surg 23:278-280,1987 3. Day RP, Luetscher JA: Big renin: A possible prohormone in kidney and plasma of a patient with Wilm’s tumour. J Clin Endocrinol Metab 38:926-928,1974 4. Millar JA, Leckie BJ, Morton JJ, et al: A microassay for active and total renin concentration in human plasma based on antibody trapping. Clin Chin Acta 1015-15. 1980 5. Khan AB, Carachi R, Lindop GBM, et al: Hypertension associated with increased renin levels in Nephroblastoma. Arch Dis Child (in press) 6. Leckie BJ, Carachi R, Wheldon T, et al: Plasma renin levels in patients with thoracic neuroblastoma. J Pediatr Surg 24:602-603, 1989
Renin Levels in Recurrent By M.A.
Johnston,
R. Carachi,
@A prospective study of four children with nephroblastoma has demonstrated elevation of plasma inactive renin levels at the time of detection of recurrent disease. Three of the four children had been shown to have elevated inactive renin levels at their initial presentation with primary nephroblastoma. These levels returned to normal following operation and chemotherapy. The observation provides further evidence that plasma inactive renin may be a useful tumour marker for nephroblastoma. Copyright o 1991 by WA Saunders Company
G.B.M.
Lindop,
Nephroblastoma and B. Leckie ACTIVE
TOTAL
10,000
1
i lvooo: 2 2
A*
.E
At
5E 100
A A
:A
\
31
INDEX WORDS:
INACTIVE
.
Inactive renin; recurrent nephroblastoma. 10
I
T IS WELL established that a variety of tumours, mainly renal, may secrete renin. Of the 50 patients with these tumours so far described, 40 had nephroblastoma.‘,’ It is now known that the elevation in plasma renin levels is due to a preponderance of the prohormone inactive renin.2*3 This raised the possibility that inactive renin may be of value as a chemical tumour marker for nephroblastoma. We report our experience with plasma renin levels in nephroblastoma patients with recurrent or metastatic disease. MATERIALS
AND
METHODS
At this centre, children with nephroblastoma are managed according to the UK Cancer Children’s Study Group guidelines. At presentation, blood is routinely taken for total plasma renin estimation. This is repeated following initial treatment and again if there is clinical suspicion of recurrent disease. Total plasma renin estimation: 3 mL of blood were place in a lithium heparin tube and kept in ice during transport to the renin laboratory, where the plasma was extracted and stored at -20°C. Twenty microlitres of a 10 mg/mL solution of trypsin was added to 200 uL of ice-cold plasma. This was incubated at 4°C for 3 to 6 minutes. Twenty microlitres of soya bean trypsin inhibitor (20 mg/mL) was added. The renin assay was then carried out, measuring the active and inactive components by microassay as described by Millar et aL4 RESULTS
From 1984 to 1989, a total of 25 children were treated for nephroblastoma. Of these, four children have been identified with recurrent disease (Table 1). One patient had chromosome fragility disease and another presented following a road traffic accident. The mean plasma renin levels for all nephroblastoma patients decreased after tumour excision (Fig l), and subsequently became elevated in the four patients found to have recurrent disease (Table 2, Fig 2). DISCUSSION
The role of the renin-angiotensin system in children with nephroblastoma has been studied prospecJournalof Pediatric Surgery, Vol26,
No 5 (May), 1991: pp 613-614
I
OJ
Pre
Post
Pre
Post
Pre
Post
Fig 1. Mean total, active, and inactive renin levels, preoperation and postoperation for all patients with nephroblastoma. A, Patients with recurrent disease.
tively by several authors.‘U3 High levels of inactive renin were reported, which fell to normal levels after complete removal of the tumour.’ High levels of active renin have been reported in a hypertensive child with a juxtoglomerular secreting tumour.5 Active renin was also found to be elevated in neuroblastoma, in contrast to the inactive renin component.’ The criteria for a tumour marker to be established are that the substance must be readily assayable; it must be sensitive and specific for the tumour type; the levels must return to normal following adequate treatment; and elevation must correlate with clinically detectable recurrent disease. We have followed-up the initial cohort of patients reported by us.* Of the four patients who developed recurrent disease, one had an abdominal recurrence, another had cerebral metastases, and two had recurrent disease in the mediastinum and lungs. In all these patients the plasma renin levels were elevated and,
From the Depattment of Surgical Paediattics, Royal Hospital for Sick Children, the Department of Pathology, University of Glasgow, and the h4RC Blood Pressure Unit. Western Infirmary. Glasgow, Scotland. Presented at the 37th Annual International Congress of the British Association of Paediatric Surgeons, Glasgow, Scotland, July 25-27, 1990. Address reprint requests to R. Carachi, MD, PhD, FRCS, Department of Surgical Paediattics, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8U, Scotland. Copyright o 1991 by W B. Saunders Company 0022-3468/9112605-0027$03.OOfO
613
JOHNSTON
614
ET AL
Table 1. Patients With Recurrent Disease Stage, Histology
Disease Case No.
Age at
Presentation
1
1 vr
2
2 vr
3 4
Operation Nephrectomy (R), partial hepatectomy
Intervalto
Site of Recurrent
Disease
FldapSe
Brain
Outcome
II, favourable
Died, metastases
4 vr
Nephrectomy (R)
II, favourable
4 vr
Lung
Died, metastases
4 vr
Nephrectomy (L)
II, favourable
Mediastinum
Alive, disease-free
5 vr
Emergency nephrectomy (R)
Ill, favourable
2 vr 18mo
Intraabdominal, lung
Died, metastases
Abbreviations: R, right; L, left.
Table 2. Plasma Renin Levels for the Four Patients With Recurrent Disease Renin Levels Total
Active
Inactive
Measurement
(60-200)
(9-50)
(38.180)
Presentation
2,090
Time of Case No.
1
2
3
4
(WlJlmL)
2,205
115
Postoperation
140
58
82
Recurrence
738
186
552
2,980
285
2,695
Postoperation
266
85
181
Recurrence
288
85
195
Presentation
920
170
750
Presentation
Postoperation
118
15
103
Recurrence
353
41
312
No preoperative values obtained
Presentation Postoperation
140
59
81
Recurrence
955
278
677
pU/ml 3000 12695 2000
1 1000
800
600
Fig 2. Plasma inactive renin levels (A) preoperation, (6) postoperation, and (C) at the time of detection of recurrent disease.
therefore, would be of value as a tumour marker. Clinical disease was also present at the time that the elevated inactive renin levels were measured and, therefore, we cannot establish whether this elevation antedated the appearance of clinically detectable disease. The role of inactive renin in recurrent nephroblastoma warrants further investigation because if serial estimations are performed, the outlook for early detection of recurrent disease may improve. We recommend that once a patient with nephroblastoma has completed treatment, plasma inactive renin levels should be estimated as part of their follow-up. REFERENCES 1. Guademar M, Bruneval P, Camilleri JP: Syndromes tumoraux avec secretion inappropriee de renine. Criteres diagnostiques et revue des cas publies. Ann Path01 8:83-90, 1988 2. Carachi R, Lindop GBM, Leckie BJ: Inactive renin: A tumour marker in nephroblastoma. J Pediatr Surg 23:278-280,1987 3. Day RP, Luetscher JA: Big renin: A possible prohormone in kidney and plasma of a patient with Wilm’s tumour. J Clin Endocrinol Metab 38:926-928,1974 4. Millar JA, Leckie BJ, Morton JJ, et al: A microassay for active and total renin concentration in human plasma based on antibody trapping. Clin Chin Acta 1015-15. 1980 5. Khan AB, Carachi R, Lindop GBM, et al: Hypertension associated with increased renin levels in Nephroblastoma. Arch Dis Child (in press) 6. Leckie BJ, Carachi R, Wheldon T, et al: Plasma renin levels in patients with thoracic neuroblastoma. J Pediatr Surg 24:602-603, 1989
