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Temporary Renal Ischemia with Immediate and Delayed Contralateral Nephrectomy
THE JouRKAL OF UROLOGY
Vol. 85, No. 6 June 1961 Copyright © 1961 by The Williams & Wilkins Co. Printed in U.S.A.
TEMPORARY RENAL ISCHEMIA WITH IMMEDIATE A~D DELAYED CONTRALATERAL NEPHRECTOMY JOHN C. CAMPBELL, ERIC C. EDWARDS, JOHN H. GIUNDLAY, FRANK T. MAHER GERSHOM J. THOMPSON
AND
From the Sections of Surgical Research, Clinical Pathology, and Urology, Mayo Clinic, Rochester, Minn
A kidney rendered temporarily ischemic (472 hours' occlusion) receives no stimulus to recovery if the contralateral kidney remains healthy. It was found 1 that the ischemic kidney showed the greatest signs of recovery when the contralateral kidney was removed at the time of the ischemic episode and the life of the clog was prolonged by extracorporeal hemodialysis. The length of time of ischemia was such that spontaneous recovery was ruled out. 2 During the course of the experiments cited above, it was noted that marked deposition of calcium was to be found in the periphery of the infarcted areas. These deposits were particularly noticeable in the dogs that had immediate contralateral nephrectomy following prolonged ipsilateral renal ischemia. Edwarcls 2 conducted a second series of investigations directed specifically to an experimental and clinical inquiry into acute renal calcification. From this he concluded that, before acute calcification occurs in a kidney injured by an ischemic episode, a combination of factors must pertain: 1) there must be appreciable renal damage, 2) there must be adequate re-establishment of circulation and 3) there must be retention of potassium, urea and other waste products such as occurs in uremia. The purpose of this paper is to report a more chronic experiment entailing an ischemic episode of less severity with immediate and delayed contralateral nephrectomy, to note the progress of calcification, and perhaps to relate this to the formation of renal calculi. MA'I'ERIAL AND METHOD
Five clogs were used. In two of these, the left renal artery was occluded for 3 hours and a Accepted for publication December 29, 1960. 1 Edwards, E. C., Maher, F. T., Grindlay, J. H. and Thompson, G. J.: Retention of normal contralateral kidney vs. repeated extracorporeal hemodialysis: Experimental study on recovery of ischemic kidney. Tr. West. S. A., 65: 94-100, 1957. 2 Edwards, E. C.: Acute renal calcification: An experimental and clinicopathologic study. J,
simultaneous right nephrectomy was carried out. In the remaining 3 clogs, the left renal artery was occluded for a like period, but nephrectomy was delayed for 21 days. Each of the dogs made an uneventful recovery from the operative procedures. There followed a series of random ob· servations on the clinical state of these clogs, as assessed by 1) blood pressure, 2) concentration of blood urea, 3) hematocrit reading and 4) body weight. These observations were made over a 16-month period in all but one clog, which died year after the operative procedure. The surviving clogs were killed and the remaining kidney was removed from each for examination. Clinical data are shown in tables 1 and 2. IMMEDIATE CONTRALATERAL NEPHRECTOMY
Dog L2. On macroscopic examination, the kidney was enlarged, but was otherwise normaL The capsule stripped easily from it. There was no surface scarring. Histologically, the glomerular zone showed a decrease in the total number of glomeruli. Some of those still intact showed considerable shrinking. The proximal tubules showed an increase in fibrous stroma. The appear. ance of the remainder of the section was withm normal limits. No areas of calcification were to be seen. Dog L9. This kidney was grossly normal (fig. 1, A), although increased in size. The capsule stripped easily. There was no surface scarring. Histologically, there was again an impression that the total number of glomeruli was reduced. The glomerular tufts appeared healthy (fig. l, There was some round cell infiltration in the outer medulla. No gross structural change was evident here. There was some swelling of the distal tubules along with loss of architectural features, but this may have been clue to a fixation artifact. There were no patches of calcification.
Urol., 80: 161-169, 1958. 875
DELAYED
CONTRALA'I'ERAL NEPHRECTOMY
Dog K782. This kidney was solid and dense to palpation. The capsule was thick and white, and
876
JOHN C. CAMPBELL AND ASSOCIATES
did not strip easily. Indentations of scarring were visible on the surface. Histologically, the thickening of the capsule was confirmed. The immediately subjacent glomerular tufts were shrunken and distorted. Throughout the cortical zone there was diffuse infiltration of round cells. There was very marked fibrosis underlying the pelvic epithelium. No areas of calcification were to be seen. Dog K814. Macroscopically, this kidney was white, scarred and dense (fig. 2, A). Histologically, the capsule was thick. The glomerular zone showed very marked destruction of tissue, with many shrunken distorted tufts. Round cell infiltration was marked, with almost germcenter formation in certain areas. The ,videspread fibrous tissue was mature. Here and there in the outer cortical zone were patches of deeply basophilic calcium deposits (fig. 2, B). Areas of scarring with dense fibrosis and round cell infiltration occurred throughout the remainder of the section.
TABLE
2. Delayed contralateral nephrectomy (21 days) },iean
Date
Dog
Systolic Blood Pressure
Body Weight
Hematocrit Reading
mg./100 ml.
kg.
per cent
39 40 39
Blood Urea
--- ---
111,111,.
12-9-57
Ilg.
K782 K811 K814
145 150 187
74 84 220
13.4 13.6 14.0
12-30-57
K782 K811 K814
95 150 195
140 80 255
13.0 13.6 14.3
1-22-58
K782 K811 K814
-·
_____
· - - - - - - - - - - - - - - - _ _ _ _,
----
75 145 185
_ _ _ _ I_ _ _
12.8 13.8 15.2
77 72 206
52 49 43
--41 47 37
----- - - - ---- - - - ---- ---
2-20-58
K782 K811 K814
75 75 92
86 60 157
14.6 13.9 15.2
29 39 29
----- - - - - - - ---- ---- --TABLE
1. Immediate contralateral nephrectomy Mean Systolic Blood Urea Blood Pressure -----mm. Hg. mg./100 Dog
Date
nil.
12-9-57
L2 L9
127 87
73 61
Hematocrit Reading
Body Weight
kg.
per cent
10.0 10.8
39 41
L2 L9
162 122
-
69 90
10.8 12.0
42 46
i
2-20-58
L2 L9
162 102
56 83
12.2 13.1
46 50
L2 L9
82 112
62 67
13.6 13.0
38 42
------ ---- -
4-16-58
5-30-58
-
--- -------
L2 L9
95 115
59 77
16.6 14.6
39 38
L2 L9
87 145
49 94
17.5 14.6
40 37
-1-;::;--;-
9-17-58
I
63
17.2
42
43 41 45
100 140 120
90 52 71
~-
L2 L9
L9
112
81
15.8
-
41
105
106
72
74 152
182
16.3 14.9 16.7
37 38 36
K782 K811 K814
155 115 112
137 62 130
17.2 14.8 17.6
36 42 32
- - - ---- ---- - - - ---
----1~ 4-9-;--1~- -1;--;-\'-~ -;-;-8-58
5-30-58
7-8-58
-----------
1-22-58
K782 K811 K814
---------- ----------
--
------ ------ --- ---- -
12-30-57
4-16-58
K782 K811 K814
112 107 70
106 74 162
16.8 14.2 17.2
37 45 35
----- --- --- --
9-7-58
K782 K811 K814
125 145 165
80 50 211
4-9-59
K782 K811 K814
125
53
187
1~
41 42 29
I 15.1
44
16.5
30
I
Fibrosis was again marked deep to the pelvic epithelium. COMMENT
Reference has already been made to the apparent "need" 1 for a stimulus to recovery by the ischemic kidney. The gross and microscopic "normal" appearance of the ischemic kidney following immediate contralateral nephrectomy in this current study serves to re-emphasize this point, and contrasts markedly with the fibrotic shrunken appearance of the remaining kidney
TEMPORARY RENAL ISCHEMIA
877
FIG. 1. Kidney of dog L9. A, normal gross appearance. B, normal glomerular architecture (hematoxylin and eosin; X40).
FIG. 2. Kidney of dog K814. A, scarring and marked ischemia of capsule. B, solitary plaque of calcium (hematoxylin and eosin; X325).
following delayed contralateral nephrectomy. It is perhaps permissible therefore to question the wisdom of instituting very early extracorporeal dialysis in the patient whose kidneys have temporarily ceased to function,3 lest this step lead to irreversible structural change in the kidney by removing the stimulus to repair. This experimental finding offers sharp contrast to the clinical desire to institute early hemodialysis, which, most people think, is of value in lowering morbidity and mortality in the metabolic peril of acute renal failure. It may also be pertinent in the poorly understood problem of completeness of renal recovery following dialysis-since there is more than an indication of incomplete restitu3 Maher, F. T. and Broadbent, J. C.: Extracorporeal hemodialysis in the management of acute renal failure. J.A.M.A., 166: 608-615, 1958.
tion of renal reserve following recovery from acute renal failure, with the aid of hemodialysis. This problem is being currently investigated. Paradoxically, it would seem, from this very small experimental series, that despite the fibrotic changes of glomerulosclerosis in a solitary kidney, hypertension is not a necessary sequel. Pathologic calcification differs from normal ossification in that calcium and salts are laid down haphazardly, without arrangement into trabeculae, canals or lacunae. Two forms are recognized: dystrophic, in which calcium is deposited in tissues that have previously been the seat of disease; and metastatic, in which "calcium salts are deposited in tissues hitherto normal, but with a tendency to alkalinity." 4 Deposition 4 Mulligan, R. M.: Metastatic calcification. Arch. Path., 43: 177-230, 1947.
878
JOHN C. CAMPBELL AND ASSOCIA'l'ES
of calcium in ischemic kidneys is a form of dystrophic calcification. The earlier experimental work of Edwards, to which reference has already been made, shows that acute calcification is readily induced in the ischemic kidney. In view of the fact that this deposition can be shown to take place in other locations (for example, in damaged muscle) in the presence of uremia, it may be argued that local and general factors play some part in the deposition, and that its appearance is not simply explained as a "calcareous tombstone to dead tissue." Certainly changes in acid-base balance are of importance systemically as well as locally. A change toward relative alkalinity in the local pH of the damaged tissue, postulated as being due to failure of oxidation in the infarcted region leading to a drop in local production of carbon dioxide, accounts not only for acute calcification but also for the deposition of calcium salts in the "anm.ic" zone of mature fibrosis. Local alkalinity in the kidney may be further induced by the excretion of acid phosphates. Conversely, a retention of negatively charged phosphate ions in damaged tissue may produce a combination with positively charged calcium ions. Maximal deposition occurs peripherally around the infarct, and not, at this stage, at its center, that is, at the junction of viable and nonviable tissue. The source of the calcium may therefore be the systemic circulation, or local tissue that has undergone complete disorganization from the level of molecular, cellular death, to the level of death of one or more complete nephrons, with consequent variation in pH. Edwards 2 noted that the degree of calcification was progressive, as indicated by the increased number and size of the deposits in direct relation-
ship to the length of survival of the dog after temporary occlusion of the renal artery. The background to the present series of experiments was, therefore, to attempt to establish increasing calcification, by a snowballing effect, related to the length of survival of the dog. This has not been established. Such patchy calcification as was evident in only one of the sections was in the outer cortical zone, and was not distributed around the tubules. These patches were in the midst of relatively dense, mature fibrous tissue, and were therefore related to the "calcifiable" potential of fibrous tissue, when, by virtue of its maturity, it approaches a hyaline appearance, and not to any persisting features of the acute deposition of calcium, brought about by chemical upset. It is therefore doubtful that ischemic episodes bear any direct relationship to nephrocalcinosis in the clinical sense, and hence these episodes bear no relationship to the ultimate development of renal calculi. SUMMARY AND CONCLUSIONS
Two dogs with immediate contralateral nephrectomy and two with delayed contralateral nephrectomy (21 days) following ipsilateral renal ischemia for 3 hours were studied over a period of 16 months. There is no evidence in this study to show that calcium deposits found in the peripheral cortical zone of the kidney following an ischemic episode play any part in the production of renal calculi. There is an indication that the institution of very early extracorporeal hemodialysis may be detrimental by leading to the production of irreversible glomerular sclerosis.
Vol. 85, No. 6 June 1961 Copyright © 1961 by The Williams & Wilkins Co. Printed in U.S.A.
TEMPORARY RENAL ISCHEMIA WITH IMMEDIATE A~D DELAYED CONTRALATERAL NEPHRECTOMY JOHN C. CAMPBELL, ERIC C. EDWARDS, JOHN H. GIUNDLAY, FRANK T. MAHER GERSHOM J. THOMPSON
AND
From the Sections of Surgical Research, Clinical Pathology, and Urology, Mayo Clinic, Rochester, Minn
A kidney rendered temporarily ischemic (472 hours' occlusion) receives no stimulus to recovery if the contralateral kidney remains healthy. It was found 1 that the ischemic kidney showed the greatest signs of recovery when the contralateral kidney was removed at the time of the ischemic episode and the life of the clog was prolonged by extracorporeal hemodialysis. The length of time of ischemia was such that spontaneous recovery was ruled out. 2 During the course of the experiments cited above, it was noted that marked deposition of calcium was to be found in the periphery of the infarcted areas. These deposits were particularly noticeable in the dogs that had immediate contralateral nephrectomy following prolonged ipsilateral renal ischemia. Edwarcls 2 conducted a second series of investigations directed specifically to an experimental and clinical inquiry into acute renal calcification. From this he concluded that, before acute calcification occurs in a kidney injured by an ischemic episode, a combination of factors must pertain: 1) there must be appreciable renal damage, 2) there must be adequate re-establishment of circulation and 3) there must be retention of potassium, urea and other waste products such as occurs in uremia. The purpose of this paper is to report a more chronic experiment entailing an ischemic episode of less severity with immediate and delayed contralateral nephrectomy, to note the progress of calcification, and perhaps to relate this to the formation of renal calculi. MA'I'ERIAL AND METHOD
Five clogs were used. In two of these, the left renal artery was occluded for 3 hours and a Accepted for publication December 29, 1960. 1 Edwards, E. C., Maher, F. T., Grindlay, J. H. and Thompson, G. J.: Retention of normal contralateral kidney vs. repeated extracorporeal hemodialysis: Experimental study on recovery of ischemic kidney. Tr. West. S. A., 65: 94-100, 1957. 2 Edwards, E. C.: Acute renal calcification: An experimental and clinicopathologic study. J,
simultaneous right nephrectomy was carried out. In the remaining 3 clogs, the left renal artery was occluded for a like period, but nephrectomy was delayed for 21 days. Each of the dogs made an uneventful recovery from the operative procedures. There followed a series of random ob· servations on the clinical state of these clogs, as assessed by 1) blood pressure, 2) concentration of blood urea, 3) hematocrit reading and 4) body weight. These observations were made over a 16-month period in all but one clog, which died year after the operative procedure. The surviving clogs were killed and the remaining kidney was removed from each for examination. Clinical data are shown in tables 1 and 2. IMMEDIATE CONTRALATERAL NEPHRECTOMY
Dog L2. On macroscopic examination, the kidney was enlarged, but was otherwise normaL The capsule stripped easily from it. There was no surface scarring. Histologically, the glomerular zone showed a decrease in the total number of glomeruli. Some of those still intact showed considerable shrinking. The proximal tubules showed an increase in fibrous stroma. The appear. ance of the remainder of the section was withm normal limits. No areas of calcification were to be seen. Dog L9. This kidney was grossly normal (fig. 1, A), although increased in size. The capsule stripped easily. There was no surface scarring. Histologically, there was again an impression that the total number of glomeruli was reduced. The glomerular tufts appeared healthy (fig. l, There was some round cell infiltration in the outer medulla. No gross structural change was evident here. There was some swelling of the distal tubules along with loss of architectural features, but this may have been clue to a fixation artifact. There were no patches of calcification.
Urol., 80: 161-169, 1958. 875
DELAYED
CONTRALA'I'ERAL NEPHRECTOMY
Dog K782. This kidney was solid and dense to palpation. The capsule was thick and white, and
876
JOHN C. CAMPBELL AND ASSOCIATES
did not strip easily. Indentations of scarring were visible on the surface. Histologically, the thickening of the capsule was confirmed. The immediately subjacent glomerular tufts were shrunken and distorted. Throughout the cortical zone there was diffuse infiltration of round cells. There was very marked fibrosis underlying the pelvic epithelium. No areas of calcification were to be seen. Dog K814. Macroscopically, this kidney was white, scarred and dense (fig. 2, A). Histologically, the capsule was thick. The glomerular zone showed very marked destruction of tissue, with many shrunken distorted tufts. Round cell infiltration was marked, with almost germcenter formation in certain areas. The ,videspread fibrous tissue was mature. Here and there in the outer cortical zone were patches of deeply basophilic calcium deposits (fig. 2, B). Areas of scarring with dense fibrosis and round cell infiltration occurred throughout the remainder of the section.
TABLE
2. Delayed contralateral nephrectomy (21 days) },iean
Date
Dog
Systolic Blood Pressure
Body Weight
Hematocrit Reading
mg./100 ml.
kg.
per cent
39 40 39
Blood Urea
--- ---
111,111,.
12-9-57
Ilg.
K782 K811 K814
145 150 187
74 84 220
13.4 13.6 14.0
12-30-57
K782 K811 K814
95 150 195
140 80 255
13.0 13.6 14.3
1-22-58
K782 K811 K814
-·
_____
· - - - - - - - - - - - - - - - _ _ _ _,
----
75 145 185
_ _ _ _ I_ _ _
12.8 13.8 15.2
77 72 206
52 49 43
--41 47 37
----- - - - ---- - - - ---- ---
2-20-58
K782 K811 K814
75 75 92
86 60 157
14.6 13.9 15.2
29 39 29
----- - - - - - - ---- ---- --TABLE
1. Immediate contralateral nephrectomy Mean Systolic Blood Urea Blood Pressure -----mm. Hg. mg./100 Dog
Date
nil.
12-9-57
L2 L9
127 87
73 61
Hematocrit Reading
Body Weight
kg.
per cent
10.0 10.8
39 41
L2 L9
162 122
-
69 90
10.8 12.0
42 46
i
2-20-58
L2 L9
162 102
56 83
12.2 13.1
46 50
L2 L9
82 112
62 67
13.6 13.0
38 42
------ ---- -
4-16-58
5-30-58
-
--- -------
L2 L9
95 115
59 77
16.6 14.6
39 38
L2 L9
87 145
49 94
17.5 14.6
40 37
-1-;::;--;-
9-17-58
I
63
17.2
42
43 41 45
100 140 120
90 52 71
~-
L2 L9
L9
112
81
15.8
-
41
105
106
72
74 152
182
16.3 14.9 16.7
37 38 36
K782 K811 K814
155 115 112
137 62 130
17.2 14.8 17.6
36 42 32
- - - ---- ---- - - - ---
----1~ 4-9-;--1~- -1;--;-\'-~ -;-;-8-58
5-30-58
7-8-58
-----------
1-22-58
K782 K811 K814
---------- ----------
--
------ ------ --- ---- -
12-30-57
4-16-58
K782 K811 K814
112 107 70
106 74 162
16.8 14.2 17.2
37 45 35
----- --- --- --
9-7-58
K782 K811 K814
125 145 165
80 50 211
4-9-59
K782 K811 K814
125
53
187
1~
41 42 29
I 15.1
44
16.5
30
I
Fibrosis was again marked deep to the pelvic epithelium. COMMENT
Reference has already been made to the apparent "need" 1 for a stimulus to recovery by the ischemic kidney. The gross and microscopic "normal" appearance of the ischemic kidney following immediate contralateral nephrectomy in this current study serves to re-emphasize this point, and contrasts markedly with the fibrotic shrunken appearance of the remaining kidney
TEMPORARY RENAL ISCHEMIA
877
FIG. 1. Kidney of dog L9. A, normal gross appearance. B, normal glomerular architecture (hematoxylin and eosin; X40).
FIG. 2. Kidney of dog K814. A, scarring and marked ischemia of capsule. B, solitary plaque of calcium (hematoxylin and eosin; X325).
following delayed contralateral nephrectomy. It is perhaps permissible therefore to question the wisdom of instituting very early extracorporeal dialysis in the patient whose kidneys have temporarily ceased to function,3 lest this step lead to irreversible structural change in the kidney by removing the stimulus to repair. This experimental finding offers sharp contrast to the clinical desire to institute early hemodialysis, which, most people think, is of value in lowering morbidity and mortality in the metabolic peril of acute renal failure. It may also be pertinent in the poorly understood problem of completeness of renal recovery following dialysis-since there is more than an indication of incomplete restitu3 Maher, F. T. and Broadbent, J. C.: Extracorporeal hemodialysis in the management of acute renal failure. J.A.M.A., 166: 608-615, 1958.
tion of renal reserve following recovery from acute renal failure, with the aid of hemodialysis. This problem is being currently investigated. Paradoxically, it would seem, from this very small experimental series, that despite the fibrotic changes of glomerulosclerosis in a solitary kidney, hypertension is not a necessary sequel. Pathologic calcification differs from normal ossification in that calcium and salts are laid down haphazardly, without arrangement into trabeculae, canals or lacunae. Two forms are recognized: dystrophic, in which calcium is deposited in tissues that have previously been the seat of disease; and metastatic, in which "calcium salts are deposited in tissues hitherto normal, but with a tendency to alkalinity." 4 Deposition 4 Mulligan, R. M.: Metastatic calcification. Arch. Path., 43: 177-230, 1947.
878
JOHN C. CAMPBELL AND ASSOCIA'l'ES
of calcium in ischemic kidneys is a form of dystrophic calcification. The earlier experimental work of Edwards, to which reference has already been made, shows that acute calcification is readily induced in the ischemic kidney. In view of the fact that this deposition can be shown to take place in other locations (for example, in damaged muscle) in the presence of uremia, it may be argued that local and general factors play some part in the deposition, and that its appearance is not simply explained as a "calcareous tombstone to dead tissue." Certainly changes in acid-base balance are of importance systemically as well as locally. A change toward relative alkalinity in the local pH of the damaged tissue, postulated as being due to failure of oxidation in the infarcted region leading to a drop in local production of carbon dioxide, accounts not only for acute calcification but also for the deposition of calcium salts in the "anm.ic" zone of mature fibrosis. Local alkalinity in the kidney may be further induced by the excretion of acid phosphates. Conversely, a retention of negatively charged phosphate ions in damaged tissue may produce a combination with positively charged calcium ions. Maximal deposition occurs peripherally around the infarct, and not, at this stage, at its center, that is, at the junction of viable and nonviable tissue. The source of the calcium may therefore be the systemic circulation, or local tissue that has undergone complete disorganization from the level of molecular, cellular death, to the level of death of one or more complete nephrons, with consequent variation in pH. Edwards 2 noted that the degree of calcification was progressive, as indicated by the increased number and size of the deposits in direct relation-
ship to the length of survival of the dog after temporary occlusion of the renal artery. The background to the present series of experiments was, therefore, to attempt to establish increasing calcification, by a snowballing effect, related to the length of survival of the dog. This has not been established. Such patchy calcification as was evident in only one of the sections was in the outer cortical zone, and was not distributed around the tubules. These patches were in the midst of relatively dense, mature fibrous tissue, and were therefore related to the "calcifiable" potential of fibrous tissue, when, by virtue of its maturity, it approaches a hyaline appearance, and not to any persisting features of the acute deposition of calcium, brought about by chemical upset. It is therefore doubtful that ischemic episodes bear any direct relationship to nephrocalcinosis in the clinical sense, and hence these episodes bear no relationship to the ultimate development of renal calculi. SUMMARY AND CONCLUSIONS
Two dogs with immediate contralateral nephrectomy and two with delayed contralateral nephrectomy (21 days) following ipsilateral renal ischemia for 3 hours were studied over a period of 16 months. There is no evidence in this study to show that calcium deposits found in the peripheral cortical zone of the kidney following an ischemic episode play any part in the production of renal calculi. There is an indication that the institution of very early extracorporeal hemodialysis may be detrimental by leading to the production of irreversible glomerular sclerosis.