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The starved kidney: A defect in renal concentrating ability
Metabolism Clinical and Experimental VOL. XXIV,
PRELIMINARY
NO. 4
APRIL
1975
REPORT
The Starved Kidney: A Defect in Renal Concentrating Ability Charnel Macaron,
George
Schneider,
The renal tubular responsiveness to antidiuretic hormone was assessed in seven obese patients during starvation and feeding by an overnight dehydration test followed by exogenous vasopressin. All seven subjects showed a mean reduction
and Norman
H. Ertel
of one-third in their maximum urinary osmolality on day 4 of starvation. These datashow that the renal tubule is partially insensitive to antidiuretic hormone at a time when it is also insensitive to mineralocorticoids.
I
T HAS BEEN NOTED for some time that the initiation of total starvation leads to a greater loss of weight than can be attributed to caloric deprivation. During this initial phase of starvation, there is a profound natriuresis,’ a rise in immunoreactive pancreatic glucagon,*” and renal tubular resistance to exogenous and endogenous mineralocorticoids. ’ Because of the refractoriness of the renal tubule to mineralocorticoids, the present study was designed to see if there may also be renal tubular refractoriness to antidiuretic hormone during the initial phase of fasting. MATERIALS
AND
METHODS
Seven obese patients were studied in the Special Diagnostic and Treatment Unit (SDTU) of the VA Hospital, East Orange, N.J. Their average age was 48.6 yr (range, 41-57 yr), and their average weight was 177.9 kg (range, 13tS200 kg). Three of the seven patients had diabetic glucose tolerance tests, but none exhibited glycosuria. No patient had renal, hepatic, or endocrine disease. The study consisted of a IO-day period of feeding, followed by starvation. During the feeding period, the
From the Department of Medicine, Division of Endocrinology. Veterans Administration Hospital, East Orange. N. J. and Department of Medicine, New Jersey Medical School, Newark, N. J. Received for publication November 8. 1974. Reprint requests should be addressed to George Schneider, M.D.. Medical Service. VA Hospital, East Orange, N. J. 07019. o 1975 by Grune di Stratton, Inc.
Metabolism, Vol. 24, No. 4 (April), 1975
457
MACARON,
458
Table 1. Response to Dehydration Maximum Study Patient
Period
Dehydration
lest During Feeding (F) and Starvation
Osmolality
on
(milliosmols/kg)
AND ERTEL
(5)
Change in
Urinary
Urinary
Osmolality
SCHNEIDER,
After
Vasoprersin (milliosmols/kg)
Urinary Osmololity (milliormolr/kg)
W)
GG
F
902
900
-2
GG
s
617
605
-12
DD
F
907
895
-12
DD
S
527
644
+117
+22.2 +0.8
-0.3 - 2.0 - 1.4
JS
F
956
964
+8
JS
S
712
670
-42
MS
F
852
860
+8
MS
S
639
641
+2
+0.3
AN
F
770
762
-8
- 1 .o
AN
S
490
500
+10
H8
F
736
765
+29
+3.9
HB
S
451
475
+24
+5.3
- 5.9 +0.9
+2.0
JD
F
1071
1102
+31
+2.9
JD
S
704
693
-11
- 1.6
Mean
F
884.9
892.6
SD
113.2
117.9
17.0
2.0
SE
42.8
44.6
6.4
0.8
Mean
+7.7
+0.8
+2.9
591.4
604.0
SD
103.5
84.4
50.5
9.2
SE
39.1
31.9
19.1
3.5
S
+12.6
subjects
received a 1500-calorie liquid diet composed of 40% carbohydrate, 40% fat, and 20% protein divided into six equal portions. During both periods, the subjects received a constant daily intake of 50 meq sodium, 85 meq potassium, and 2000 ml of fluid. The patients underwent an overnight dehydration test, done by the method of Miller et al.’ both during the feeding phase and on day 4 of starvation. This procedure is designed to identify patients with partial antidiuretic hormone defects. RESULTS
(TABLE
1)
During the feeding period, the subjects all showed a normal response to dehydration with little change in urinary osmolality following exogenous aqueous vasopressin. However, these same subjects, when starved, showed a mean reduction of one-third in their maximum urinary osmolality following overnight dehydration. Six of the seven subjects showed negligible changes in urinary osmolality following exogenous vasopressin during this period. Although the seventh subject showed a 22.2% increase in urinary osmolality following aqueous vasopressin, he was not able to concentrate his urine, even with vasopressin, to the extent that he did while feeding. None of the subjects complained of significant polyuria during the fasting period. All patients remained normokalemic and normocalcemic during the starvation period. DISCUSSION
These results indicate that, at a time in starvation when there is resistance to mineralocorticoids, there is also tubular resistance to vasopressin, as demonstrated by a mean reduction of one-third in maximum urinary osmolality after overnight dehydration and after exogenous aqueous vasopressin. There was no evidence of partial deficiency of antidiuretic hormone in at least six of these
STARVED
459
KIDNEY
patients by the criteria of Miller et a1.5 The exact mechanism of this partial unresponsiveness of the renal tubule to vasopressin is unclear at present. The response of the collecting tubule to antidiuretic hormone is dependent on the hypertonicity of the renal medulla. If the hypertonicity of the renal medulla is reduced by either a solute diuresis or osmotic diuresis, the volume of isosmotic tubular fluid reaching the collecting tubule increases and the maximum concentration of urine decreases.‘j The subjects all underwent a natriuresis with a net loss of 44-180 meq of sodium prior to the dehydration test during fasting. It is therefore conceivable that this natriuresis, leading to a reduced sodium content of the medullary interstitial tissue, was responsible for the decreased urinary osmolality. Increases in renal medullary blood flow will also cause a decrease in urinary osmolality.6 Both sodium restriction and a natriuresis will lead to decreased renal cortical blood flow and increased medullary flow.’ Therefore, it is also possible that the natriuresis observed early in fasting led to an increase in renal medullary blood flow in these patients and hence to a decrease in maximal urinary osmolality. An additional factor which might decrease maximum urinary-concentrating ability is restriction of dietary protein.6 Glucagon rises early during fasting and has been implicated as an etiologic agent for the natriuresis seen during fasting* and for the unresponsiveness of the renal tubule to mineralocorticoids.9 Whether glucagon plays a direct role in the partial unresponsiveness of the renal tubule to antidiuretic hormone remains to be determined. Further studies are in progress to define the exact mechanisms behind this observed partial insensitivity to antidiuretic hormone, and to delineate other renal tubular abnormalities that may occur early in fasting. REFERENCES I. Boulter PR, Hoffman RS, Arky RA: Pattern of sodium excretion accompanying starvation. Metabolism 22:675, 1973 2. Aguilar-Parada E, Eisentraut AM, Unger RH: Effects of starvation on plasma pancreatic glucagon in normal man. Diabetes 18:761, 1969 3. Marliss EB, Aoki TT, Unger RH, Soeldner JS, Cahill GF: Glucagon levels and metabolic effects in fasting man. J Clin Invest 49: 2256, 1970 4. Boulter PR, Spark RF, Arky RA: Dissociation of the renin-aldosterone system and refractoriness to the sodium-retaining action of mineralocorticoid during starvation in man. J Clin Endocrinol Metab 38:248, 1974 5. Miller M, Dalkos T, Moses AM, Fellerman H, Streeten DHP: Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 73:721, 1970
6. Kleeman CR, Vorherr H: Water metabolism and the neurohypophyseal hormones, in Bondy PK, Rosenberg LE (eds): Duncan’s Diseases of Metabolism, vol. 2. Philadelphia, Saunders, 1974, p 1459 7. Hollenberg NH, Epstein M, Guttman RD, Conroy M, Bosch RI, Merrill JP: Effect of sodium balance on intrarenal distribution of blood flow in normal man. J Appl Physiol 28312, 1970 8. Saudek CD, Boulter PR, Arky RA: The natriuretic effect of glucagon and its role in starvation. J Clin Endocrinol Metab 36:761. 1973 9. O’Brian JT, Saudek CD, Spark RF, Arky RA: Glucagon induced refractoriness to exogenous mineralocorticoid. J Clin Endocrinol Metab 38: 1147, 1974
PRELIMINARY
NO. 4
APRIL
1975
REPORT
The Starved Kidney: A Defect in Renal Concentrating Ability Charnel Macaron,
George
Schneider,
The renal tubular responsiveness to antidiuretic hormone was assessed in seven obese patients during starvation and feeding by an overnight dehydration test followed by exogenous vasopressin. All seven subjects showed a mean reduction
and Norman
H. Ertel
of one-third in their maximum urinary osmolality on day 4 of starvation. These datashow that the renal tubule is partially insensitive to antidiuretic hormone at a time when it is also insensitive to mineralocorticoids.
I
T HAS BEEN NOTED for some time that the initiation of total starvation leads to a greater loss of weight than can be attributed to caloric deprivation. During this initial phase of starvation, there is a profound natriuresis,’ a rise in immunoreactive pancreatic glucagon,*” and renal tubular resistance to exogenous and endogenous mineralocorticoids. ’ Because of the refractoriness of the renal tubule to mineralocorticoids, the present study was designed to see if there may also be renal tubular refractoriness to antidiuretic hormone during the initial phase of fasting. MATERIALS
AND
METHODS
Seven obese patients were studied in the Special Diagnostic and Treatment Unit (SDTU) of the VA Hospital, East Orange, N.J. Their average age was 48.6 yr (range, 41-57 yr), and their average weight was 177.9 kg (range, 13tS200 kg). Three of the seven patients had diabetic glucose tolerance tests, but none exhibited glycosuria. No patient had renal, hepatic, or endocrine disease. The study consisted of a IO-day period of feeding, followed by starvation. During the feeding period, the
From the Department of Medicine, Division of Endocrinology. Veterans Administration Hospital, East Orange. N. J. and Department of Medicine, New Jersey Medical School, Newark, N. J. Received for publication November 8. 1974. Reprint requests should be addressed to George Schneider, M.D.. Medical Service. VA Hospital, East Orange, N. J. 07019. o 1975 by Grune di Stratton, Inc.
Metabolism, Vol. 24, No. 4 (April), 1975
457
MACARON,
458
Table 1. Response to Dehydration Maximum Study Patient
Period
Dehydration
lest During Feeding (F) and Starvation
Osmolality
on
(milliosmols/kg)
AND ERTEL
(5)
Change in
Urinary
Urinary
Osmolality
SCHNEIDER,
After
Vasoprersin (milliosmols/kg)
Urinary Osmololity (milliormolr/kg)
W)
GG
F
902
900
-2
GG
s
617
605
-12
DD
F
907
895
-12
DD
S
527
644
+117
+22.2 +0.8
-0.3 - 2.0 - 1.4
JS
F
956
964
+8
JS
S
712
670
-42
MS
F
852
860
+8
MS
S
639
641
+2
+0.3
AN
F
770
762
-8
- 1 .o
AN
S
490
500
+10
H8
F
736
765
+29
+3.9
HB
S
451
475
+24
+5.3
- 5.9 +0.9
+2.0
JD
F
1071
1102
+31
+2.9
JD
S
704
693
-11
- 1.6
Mean
F
884.9
892.6
SD
113.2
117.9
17.0
2.0
SE
42.8
44.6
6.4
0.8
Mean
+7.7
+0.8
+2.9
591.4
604.0
SD
103.5
84.4
50.5
9.2
SE
39.1
31.9
19.1
3.5
S
+12.6
subjects
received a 1500-calorie liquid diet composed of 40% carbohydrate, 40% fat, and 20% protein divided into six equal portions. During both periods, the subjects received a constant daily intake of 50 meq sodium, 85 meq potassium, and 2000 ml of fluid. The patients underwent an overnight dehydration test, done by the method of Miller et al.’ both during the feeding phase and on day 4 of starvation. This procedure is designed to identify patients with partial antidiuretic hormone defects. RESULTS
(TABLE
1)
During the feeding period, the subjects all showed a normal response to dehydration with little change in urinary osmolality following exogenous aqueous vasopressin. However, these same subjects, when starved, showed a mean reduction of one-third in their maximum urinary osmolality following overnight dehydration. Six of the seven subjects showed negligible changes in urinary osmolality following exogenous vasopressin during this period. Although the seventh subject showed a 22.2% increase in urinary osmolality following aqueous vasopressin, he was not able to concentrate his urine, even with vasopressin, to the extent that he did while feeding. None of the subjects complained of significant polyuria during the fasting period. All patients remained normokalemic and normocalcemic during the starvation period. DISCUSSION
These results indicate that, at a time in starvation when there is resistance to mineralocorticoids, there is also tubular resistance to vasopressin, as demonstrated by a mean reduction of one-third in maximum urinary osmolality after overnight dehydration and after exogenous aqueous vasopressin. There was no evidence of partial deficiency of antidiuretic hormone in at least six of these
STARVED
459
KIDNEY
patients by the criteria of Miller et a1.5 The exact mechanism of this partial unresponsiveness of the renal tubule to vasopressin is unclear at present. The response of the collecting tubule to antidiuretic hormone is dependent on the hypertonicity of the renal medulla. If the hypertonicity of the renal medulla is reduced by either a solute diuresis or osmotic diuresis, the volume of isosmotic tubular fluid reaching the collecting tubule increases and the maximum concentration of urine decreases.‘j The subjects all underwent a natriuresis with a net loss of 44-180 meq of sodium prior to the dehydration test during fasting. It is therefore conceivable that this natriuresis, leading to a reduced sodium content of the medullary interstitial tissue, was responsible for the decreased urinary osmolality. Increases in renal medullary blood flow will also cause a decrease in urinary osmolality.6 Both sodium restriction and a natriuresis will lead to decreased renal cortical blood flow and increased medullary flow.’ Therefore, it is also possible that the natriuresis observed early in fasting led to an increase in renal medullary blood flow in these patients and hence to a decrease in maximal urinary osmolality. An additional factor which might decrease maximum urinary-concentrating ability is restriction of dietary protein.6 Glucagon rises early during fasting and has been implicated as an etiologic agent for the natriuresis seen during fasting* and for the unresponsiveness of the renal tubule to mineralocorticoids.9 Whether glucagon plays a direct role in the partial unresponsiveness of the renal tubule to antidiuretic hormone remains to be determined. Further studies are in progress to define the exact mechanisms behind this observed partial insensitivity to antidiuretic hormone, and to delineate other renal tubular abnormalities that may occur early in fasting. REFERENCES I. Boulter PR, Hoffman RS, Arky RA: Pattern of sodium excretion accompanying starvation. Metabolism 22:675, 1973 2. Aguilar-Parada E, Eisentraut AM, Unger RH: Effects of starvation on plasma pancreatic glucagon in normal man. Diabetes 18:761, 1969 3. Marliss EB, Aoki TT, Unger RH, Soeldner JS, Cahill GF: Glucagon levels and metabolic effects in fasting man. J Clin Invest 49: 2256, 1970 4. Boulter PR, Spark RF, Arky RA: Dissociation of the renin-aldosterone system and refractoriness to the sodium-retaining action of mineralocorticoid during starvation in man. J Clin Endocrinol Metab 38:248, 1974 5. Miller M, Dalkos T, Moses AM, Fellerman H, Streeten DHP: Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 73:721, 1970
6. Kleeman CR, Vorherr H: Water metabolism and the neurohypophyseal hormones, in Bondy PK, Rosenberg LE (eds): Duncan’s Diseases of Metabolism, vol. 2. Philadelphia, Saunders, 1974, p 1459 7. Hollenberg NH, Epstein M, Guttman RD, Conroy M, Bosch RI, Merrill JP: Effect of sodium balance on intrarenal distribution of blood flow in normal man. J Appl Physiol 28312, 1970 8. Saudek CD, Boulter PR, Arky RA: The natriuretic effect of glucagon and its role in starvation. J Clin Endocrinol Metab 36:761. 1973 9. O’Brian JT, Saudek CD, Spark RF, Arky RA: Glucagon induced refractoriness to exogenous mineralocorticoid. J Clin Endocrinol Metab 38: 1147, 1974