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DONOR RENIN ACTIVITY AND FUNCTION OF CADAVERIC RENAL ALLOGRAFTS
75
DONOR RENIN ACTIVITY AND FUNCTION OF CADAVERIC RENAL ALLOGRAFTS P. G. YUILE
J. M. HAYES
S. M. TAIT
Garvan Institute of Medical Research and Renal St. Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia
Unit,
retrospective study of renin activity (R.A.) in the donor’s peripheral venous blood and renal allograft function (as measured by serum-creatinine) in the recipient revealed no direct correlation between donor R.A. and allograft function. However, early transplant function was poor in 15 out of 19 allografts in which the donor R.A. A
R.A. was determined by radioimmunoassay of antiotensin by the method of Haber et aU The mean standard deviation (S.D.) of replicates in seven standard curves was 5.1 % i
and of five assays of unknowns was 1’4%. The S.D. of replicates in one of the two assays used to measure R.A. in this study was 2-8%. Allograft function was assessed by the recipient’s serumcreatinine on the fifth postoperative day. This time was chosen to avoid the overt manifestation of allograft rejection which generally occurs after this time.s
Summary
was more
than ten times the normal
It is
mean.
suggested that a high donor R.A. indicates prognosis for early allograft function.
a
poor
INTRODUCTION
POOR renal allograft function has been shown to happen in those organs with a high intrarenal vascular resistance. This increased resistance may manifest in poor perfusion of the organ after removal.1 The renin-angiotensin system probably plays a role in the regulation of afferent arteriolar tone, and hence in intrarenal vascular resistance.22 Certain states in which there is poor cortical perfusion have been shown to correlate with high renin activity (R.A.) and the risk of acute renal failure.3 Conversely, in established acute renal failure high R.A.4 and raised angiotensin levels have been found 5; these fall towards normal during recovery.6 It seemed likely that in cadaveric renal transplantation those allografts with poorest function may come from donors with the highest R.A. levels. METHODS
potential donors were collected by the tissue typing laboratory of the Red Cross Blood Transfusion Service, Sydney. In 32 out of 40 donors serum was collected on the day of death or the day preceding death. In the Sera from
remainder the interval between the collection and death varied from 2 to 10 days. The sera were stored frozen until assayed.
RESULTS
wide scatter of R.A. in the donors, the from <1 to 192 ng. per ml. per hour ranging (of generated angiotensin I). 14 donors had R.A. levels more than ten times the normal mean (3-4 ±2-0 ng. per ml. per hour in erect subjects having an unrestricted sodium intake). 58 of the 69 recipients had serum-creatinine levels on the fifth postoperative day that were either<2 mg. per 100 ml. or > 5 mg. per 100 ml. ("good" and " poor " early function, respectively). 11 recipients had intermediate function. Dialysis of the recipient in the early postoperative period did not lead to allograft function being classified as good when in fact it was
There
was a
values
poor.
The relation between donor R.A. and the recipient’s serum-creatinine is shown in the figure. 15 of the 19 allografts from donors with a very high R.A. had poor early function, whereas the 39 allografts from donors with a normal or less high R.A. were evenly divided between those with good and those with poor early function. The difference was significant at the 5% level (x2=476). There was no direct correlation between donor R.A. and allograft function
(r=0-14, n=68, p>0’05). Serum-creatinine and/or blood-urea-nitrogen levels were available for 26 of the 40 donors, and only 1 was considered unequivocally abnormal. Where both organs were transplanted in 30 of the 40 donors there was a similar outcome for 23 of the pairs-i.e., each of the pair functioned well (12) or poorly (11). In the remainder, the outcome was dissimilar. These findings are significantly different from those expected if chance determined the outcome
(X2=7’5, p
In this retrospective study many variables controlled. Amongst these were:
(1) (2)
were not
The interval between collection of the donor sera and the time of death. The interval between collection and freezing of the
separated sera. (3) Donor hypotension, hypoxia, and hypovolasmia. (4) Medication given to the donor before death (intravenous fluids, blood-transfusions, potent diuretics, mannitol infusions, pressor amines, and corticosteroids). (5) Warm and cold ischaemic times.
Patients with results in the hatched function in association with
area
a
had poor early allograft high donor R.A.
very
Despite these variables, we did find a relation between very high donor R.A. levels and poor allograft function, though for the whole series there was no correlation between donor R.A. and serumcreatinine.
76
A higher plasma-renin level has been found in those cirrhotics with reduced glomerular filtration and renal plasma flow than in those with normal cortical perfusion.3 Similarly, raised renin4 or angiotensinlevels have been demonstrated in patients with acute renal failure. These situations have a similar pathophysiology to the one under consideration.9 In most forms of acute renal failure, of the acute tubular necrosis type, the major abnormality is almost certainly poor cortical perfusion.9 It is uncertain if the raised renin or angiotensin level is the cause or the result of the diminished cortical blood-flow, and the paucity of certain clinical data and the complexity of the situation make it difficult to identify the factor(s) important in the increased R.A. in the donors whose allografts functioned poorly. This increase exceeded that due to the stimulus of potent diuretic therapy. A prospective study is needed to confirm the possible importance of donor R.A. in cadaveric renal transplantation. It is unlikely, because of the delay in determining R.A., that the test could be a practical
Hypothesis LACTOSE NUTRITION AND NATURAL SELECTION GEBHARD FLATZ Institut für Genetik, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
HANS WERNER ROTTHAUWE Universitäts-Kinderklinik Bonn, Bonn, Federal Republic of Germany
Contrary to the current hypothesis of unspecific nutritional advantage of milk as cause of the high prevalence of adult lactose tolerance in some human populations, it is proposed that the singularly high proportion of this trait in European populations is due to a specific selective advantage of the lactose-tolerant adult lactase producer caused by a lactose-induced enhancement of calcium absorption in an environment with low ultraviolet irradiation and low dietary supply of vitamin D. Summary an
REVIEWING the distribution of lactose tolerance in human populations, McCracken1 stated that " in those environments where lactose constitutes a significant portion of the adult diet, the lactase deficient individual is at a selective disadvantage in comparison to the lactase producing individual. In such environments, over long periods of time, adult lactase producers will tend to be established at the expense of the lactase deficient". Others have expressed similar views 2e This hypothesis implies that adult lactase deficiency and production are genetically determined, an assumption supported by the results of family studies.4,5 Since adult mammals, except man, have very low levels of intestinal lactase activity,3 it is likely
predictive one, but, if our findings were confirmed, suppression of donor R.A. might lead to a greater percentage of allografts with good early function. We thank the physicians and surgeons of the transplant groups of the Universities of Sydney and New South Wales and the staff of the Tissue Typing Laboratory of the Red Cross Blood Transfusion Service for their generous cooperation.
Requests for reprints should be addressed
to
J. M. H.
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8.
9.
Belzer, F. O., Reed, T. W., Pyror, J. F., Kountz, S. L., Dunphy, J. E. Surgery Gynec. Obstet. 1970, 130, 467. Thurau, K. Am. J. Med. 1964, 36, 698. Schroeder, E. T., Eich, R. H., Smulyan, H., Gould, A. B., Gabuzda, G. J. ibid. 1970, 49, 186. Tu, W. H. Circulation, 1965, 31, 686. Massini, Z. M., Finkielman, S., Worcel, M., Agrest, A., Paladini, A. C. Clin. Sci. 1966, 30, 473. Kokot, F., Kuska, J. Nephron, 1969, 6, 115. Haber, E., Koerner, T., Page, L. B., Kliman, B., Purnode, A. J. clin. Endocr. Metab. 1969, 29, 1349. Hume, D. M., Lee, H. M., Williams, G. M., White, H. J. O., Ferre’, J., Wolf, J. S., Prout, G. R., Slapak, M., O’Brien, J., Kilpatrick, S. J., Kauffman, H. M., Cleveland, R. J. Ann. Surg. 1966, 164, 352. Hollenburg, N. K., Epstein, M., Rosen, S. M., Basch, R. I., Oken, D. E., Merrill, J. P. Medicine, Baltimore, 1968, 47, 455.
man entered the era of domestication of animals with adult lactase deficiency as the normal state and that the gene or genes permitting adult lactase production arose by mutation. To explain the high prevalence of lactose tolerance in human populations it is, therefore, appropriate to assume a selective advantage of the lactase producer in a milking environment, rather than to think in terms of a disadvantage of the lactase deficient. The current hypothesis seems to imply an undefined general nutritional advantage of milk consumption. Since carbohydrates are usually not scarce in human societies, even at a primitive level of development, the general nutritional advantage of milk is most likely due to an increased supply of protein and fat. In our opinion, the distribution of adult lactose tolerance in human populations does not support the assumption of an unspecific beneficial effect of milk as the selective factor. We propose an alternative hypothesis which seems better suited to explain the limitation of high proportions of adult lactose tolerance to the populations of northern Europe and their descendants in other parts of the world. We question the validity of the concept of an unspecific nutritional advantage for lactose-tolerant individuals for several reasons:
that
(1) Contrary to the current interpretation there is no parallelism between milk production and milk consumption on the one side and the prevalence of lactose tolerance on the other. The only large population with a high prevalence of lactose tolerance (>80°o) and a correspondingly high frequency of the presumed " adult lactase production (A.L.P.) gene (>0-6, the figure cited in the annex to McCracken’s paper 1) is that of northern Europe (Europe exclusive of the Mediterranean countries) and their descendants.J,6 All other people, except for a few tribal groups in Africa,7 have rates of adult lactose intolerance in excess of 70% and correspondingly low frequencies of the A.L.P. gene This includes Afghans,S Arabs,9,10 Indians,ll and Israelis,l2 people who inhabit areas where the milking habit is present. Historical evidence suggests "
(<0-2).
DONOR RENIN ACTIVITY AND FUNCTION OF CADAVERIC RENAL ALLOGRAFTS P. G. YUILE
J. M. HAYES
S. M. TAIT
Garvan Institute of Medical Research and Renal St. Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia
Unit,
retrospective study of renin activity (R.A.) in the donor’s peripheral venous blood and renal allograft function (as measured by serum-creatinine) in the recipient revealed no direct correlation between donor R.A. and allograft function. However, early transplant function was poor in 15 out of 19 allografts in which the donor R.A. A
R.A. was determined by radioimmunoassay of antiotensin by the method of Haber et aU The mean standard deviation (S.D.) of replicates in seven standard curves was 5.1 % i
and of five assays of unknowns was 1’4%. The S.D. of replicates in one of the two assays used to measure R.A. in this study was 2-8%. Allograft function was assessed by the recipient’s serumcreatinine on the fifth postoperative day. This time was chosen to avoid the overt manifestation of allograft rejection which generally occurs after this time.s
Summary
was more
than ten times the normal
It is
mean.
suggested that a high donor R.A. indicates prognosis for early allograft function.
a
poor
INTRODUCTION
POOR renal allograft function has been shown to happen in those organs with a high intrarenal vascular resistance. This increased resistance may manifest in poor perfusion of the organ after removal.1 The renin-angiotensin system probably plays a role in the regulation of afferent arteriolar tone, and hence in intrarenal vascular resistance.22 Certain states in which there is poor cortical perfusion have been shown to correlate with high renin activity (R.A.) and the risk of acute renal failure.3 Conversely, in established acute renal failure high R.A.4 and raised angiotensin levels have been found 5; these fall towards normal during recovery.6 It seemed likely that in cadaveric renal transplantation those allografts with poorest function may come from donors with the highest R.A. levels. METHODS
potential donors were collected by the tissue typing laboratory of the Red Cross Blood Transfusion Service, Sydney. In 32 out of 40 donors serum was collected on the day of death or the day preceding death. In the Sera from
remainder the interval between the collection and death varied from 2 to 10 days. The sera were stored frozen until assayed.
RESULTS
wide scatter of R.A. in the donors, the from <1 to 192 ng. per ml. per hour ranging (of generated angiotensin I). 14 donors had R.A. levels more than ten times the normal mean (3-4 ±2-0 ng. per ml. per hour in erect subjects having an unrestricted sodium intake). 58 of the 69 recipients had serum-creatinine levels on the fifth postoperative day that were either<2 mg. per 100 ml. or > 5 mg. per 100 ml. ("good" and " poor " early function, respectively). 11 recipients had intermediate function. Dialysis of the recipient in the early postoperative period did not lead to allograft function being classified as good when in fact it was
There
was a
values
poor.
The relation between donor R.A. and the recipient’s serum-creatinine is shown in the figure. 15 of the 19 allografts from donors with a very high R.A. had poor early function, whereas the 39 allografts from donors with a normal or less high R.A. were evenly divided between those with good and those with poor early function. The difference was significant at the 5% level (x2=476). There was no direct correlation between donor R.A. and allograft function
(r=0-14, n=68, p>0’05). Serum-creatinine and/or blood-urea-nitrogen levels were available for 26 of the 40 donors, and only 1 was considered unequivocally abnormal. Where both organs were transplanted in 30 of the 40 donors there was a similar outcome for 23 of the pairs-i.e., each of the pair functioned well (12) or poorly (11). In the remainder, the outcome was dissimilar. These findings are significantly different from those expected if chance determined the outcome
(X2=7’5, p
In this retrospective study many variables controlled. Amongst these were:
(1) (2)
were not
The interval between collection of the donor sera and the time of death. The interval between collection and freezing of the
separated sera. (3) Donor hypotension, hypoxia, and hypovolasmia. (4) Medication given to the donor before death (intravenous fluids, blood-transfusions, potent diuretics, mannitol infusions, pressor amines, and corticosteroids). (5) Warm and cold ischaemic times.
Patients with results in the hatched function in association with
area
a
had poor early allograft high donor R.A.
very
Despite these variables, we did find a relation between very high donor R.A. levels and poor allograft function, though for the whole series there was no correlation between donor R.A. and serumcreatinine.
76
A higher plasma-renin level has been found in those cirrhotics with reduced glomerular filtration and renal plasma flow than in those with normal cortical perfusion.3 Similarly, raised renin4 or angiotensinlevels have been demonstrated in patients with acute renal failure. These situations have a similar pathophysiology to the one under consideration.9 In most forms of acute renal failure, of the acute tubular necrosis type, the major abnormality is almost certainly poor cortical perfusion.9 It is uncertain if the raised renin or angiotensin level is the cause or the result of the diminished cortical blood-flow, and the paucity of certain clinical data and the complexity of the situation make it difficult to identify the factor(s) important in the increased R.A. in the donors whose allografts functioned poorly. This increase exceeded that due to the stimulus of potent diuretic therapy. A prospective study is needed to confirm the possible importance of donor R.A. in cadaveric renal transplantation. It is unlikely, because of the delay in determining R.A., that the test could be a practical
Hypothesis LACTOSE NUTRITION AND NATURAL SELECTION GEBHARD FLATZ Institut für Genetik, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
HANS WERNER ROTTHAUWE Universitäts-Kinderklinik Bonn, Bonn, Federal Republic of Germany
Contrary to the current hypothesis of unspecific nutritional advantage of milk as cause of the high prevalence of adult lactose tolerance in some human populations, it is proposed that the singularly high proportion of this trait in European populations is due to a specific selective advantage of the lactose-tolerant adult lactase producer caused by a lactose-induced enhancement of calcium absorption in an environment with low ultraviolet irradiation and low dietary supply of vitamin D. Summary an
REVIEWING the distribution of lactose tolerance in human populations, McCracken1 stated that " in those environments where lactose constitutes a significant portion of the adult diet, the lactase deficient individual is at a selective disadvantage in comparison to the lactase producing individual. In such environments, over long periods of time, adult lactase producers will tend to be established at the expense of the lactase deficient". Others have expressed similar views 2e This hypothesis implies that adult lactase deficiency and production are genetically determined, an assumption supported by the results of family studies.4,5 Since adult mammals, except man, have very low levels of intestinal lactase activity,3 it is likely
predictive one, but, if our findings were confirmed, suppression of donor R.A. might lead to a greater percentage of allografts with good early function. We thank the physicians and surgeons of the transplant groups of the Universities of Sydney and New South Wales and the staff of the Tissue Typing Laboratory of the Red Cross Blood Transfusion Service for their generous cooperation.
Requests for reprints should be addressed
to
J. M. H.
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8.
9.
Belzer, F. O., Reed, T. W., Pyror, J. F., Kountz, S. L., Dunphy, J. E. Surgery Gynec. Obstet. 1970, 130, 467. Thurau, K. Am. J. Med. 1964, 36, 698. Schroeder, E. T., Eich, R. H., Smulyan, H., Gould, A. B., Gabuzda, G. J. ibid. 1970, 49, 186. Tu, W. H. Circulation, 1965, 31, 686. Massini, Z. M., Finkielman, S., Worcel, M., Agrest, A., Paladini, A. C. Clin. Sci. 1966, 30, 473. Kokot, F., Kuska, J. Nephron, 1969, 6, 115. Haber, E., Koerner, T., Page, L. B., Kliman, B., Purnode, A. J. clin. Endocr. Metab. 1969, 29, 1349. Hume, D. M., Lee, H. M., Williams, G. M., White, H. J. O., Ferre’, J., Wolf, J. S., Prout, G. R., Slapak, M., O’Brien, J., Kilpatrick, S. J., Kauffman, H. M., Cleveland, R. J. Ann. Surg. 1966, 164, 352. Hollenburg, N. K., Epstein, M., Rosen, S. M., Basch, R. I., Oken, D. E., Merrill, J. P. Medicine, Baltimore, 1968, 47, 455.
man entered the era of domestication of animals with adult lactase deficiency as the normal state and that the gene or genes permitting adult lactase production arose by mutation. To explain the high prevalence of lactose tolerance in human populations it is, therefore, appropriate to assume a selective advantage of the lactase producer in a milking environment, rather than to think in terms of a disadvantage of the lactase deficient. The current hypothesis seems to imply an undefined general nutritional advantage of milk consumption. Since carbohydrates are usually not scarce in human societies, even at a primitive level of development, the general nutritional advantage of milk is most likely due to an increased supply of protein and fat. In our opinion, the distribution of adult lactose tolerance in human populations does not support the assumption of an unspecific beneficial effect of milk as the selective factor. We propose an alternative hypothesis which seems better suited to explain the limitation of high proportions of adult lactose tolerance to the populations of northern Europe and their descendants in other parts of the world. We question the validity of the concept of an unspecific nutritional advantage for lactose-tolerant individuals for several reasons:
that
(1) Contrary to the current interpretation there is no parallelism between milk production and milk consumption on the one side and the prevalence of lactose tolerance on the other. The only large population with a high prevalence of lactose tolerance (>80°o) and a correspondingly high frequency of the presumed " adult lactase production (A.L.P.) gene (>0-6, the figure cited in the annex to McCracken’s paper 1) is that of northern Europe (Europe exclusive of the Mediterranean countries) and their descendants.J,6 All other people, except for a few tribal groups in Africa,7 have rates of adult lactose intolerance in excess of 70% and correspondingly low frequencies of the A.L.P. gene This includes Afghans,S Arabs,9,10 Indians,ll and Israelis,l2 people who inhabit areas where the milking habit is present. Historical evidence suggests "
(<0-2).