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Clinical effects of bilateral nephrectomy
Clinical Effects of Bilateral Nephrectomy
KURT H
STENZEL, M.D.
JHOONG S. CHEIGH, M.D JOHN F. SULLIVAN, M.D. LUIS TAPIA, M.D. ROBERT R. RIGGIO, M.D. ALBERT L.. RUBIN, M.D. New York, New York
The effects of removal of all renal tissue on hematopoiesis, osteodystrophy, blood pressure regulation and metabolic functions are reviewed; and, the indications for, and results of, bilateral nephrectomy are discussed. Nephrectomy results in a more severe anemia in dialysis patients which is poorly responsive to androgen therapy. No differences were detected in the severity of osteodystrophy between nephric and anephric patients. However, bilateral nephrectomy can occasionally result in the acute onset of hypocalcemia. Blood pressure regulation must be accomplished in the absence of a functioning renin-angiotensin system. This is largely on the basis of volume, but changes in vascular tone may also be significant. Little is known about the metabolic consequences of nephrectomies. The effect on substances metabolized by the kidney is an area for further investigation. Kidney tissue should be preserved, if at all possible, and nephrectomy performed only for specific indications. As more and more people are being subjected to bilateral nephrectomy, it becomes increasingly important to document and quantitate alterations resulting from loss of kidney tissue. The old view that the kidneys’ function is to make urine is certainly no longer tenable. The kidneys are the main source of renin production, of erythroid-stimulating factor, of activation, production and hydroxylation of 25hydroxycholecalcifero1, and probably subserve many other, less obvious, metabolic functions. We review the clinical consequences of bilateral nephrectomy in patients with chronic renal disease, especially in terms of erythropoiesis, osteodystrophy, control of blood pressure and metabolic consequences, and consider the indications for, and results of, bilateral nephrectomy. HEMATOPOIESIS
From the Rogosin Kidney Center, The New York Hospital-Cornell Medical Center, New York, New York. This work was supported in part by the New York State Kidney Disease Institute and the Kidney Foundation of New York. Requests for reprints should be addressed to Dr. K. H. Stenzel. 525 East 68th Street, Room D-208, New York, New York 10021.
IN ANEPHRIC PATIENTS
Erslev [l] demonstrated a factor in plasma that could stimulate erythropoiesis, and the kidney was soon found to be the site of production of erythropoietic-stimulating factor (ESF) [ 21. The kidney is the major site of ESF production, and other sites appear to vary from species to species [3]. The importance of extrarenal sites in man is currently unknown, although some investigators have found significant levels of ESF in anephric patients [4]. Nevertheless, several reports have documented the fact that anephric dialysis patients have a more severe anemia and require more transfusions than do nephric patients [5,6]. It has also been observed that patients with adult polycystic kidney disease tend to have higher hematocrit values than patients with other chronic renal diseases, characterized by small, shrunken, scarred “end-stage” kidneys. This is quite probably due to retention of more parenchymal ESFproducing tissue in patients with adult polycystic kidney disease.
January 1975
The American Journal of Medicine
Volume 58
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CLINICAL EFFECTS OF BILATERAL
TABLE
I
Average Anephric
NEPWECTOMY-STENZEL
Hematocrit Patients
Male
Values
in Nephric
ET AL
and
Female
Average Average Average Average Age Hematocrit Age Hematocrit (yr) No. (%) (vr) (%) ~~~~.___. 31 43 29 23 38 25 12 35 15 2 36 15
Total Patient No. No. Nephric Anephric
54 14
Certainly, presence or absence of ESF is not the sole stimulus to red cell production. Nathan et al. [7] noted that in anephric patients acute hypoxia resulted in an increased red cell production and that even without this stimulus there was some erythropoietic activity. Nevertheless, anemia in anephric patients remains a problem. Fourteen of 68 patients in our outpatient dialysis center, who have been on maintenance hemodialysis for more than 6 months, are anephric. Table I indicates the makeup of the nephric and anephric groups and clearly indicates the lower average hematocrit values found in anephric patients. These patients also required more transfusions than did the nephric group. All patients in our series underwent dialysis three times a week for 15 to 18 hours on coiltype dialyzers. Both the nephric and anephric patients received similar diet, antacid and vitamin theraPY. Androgenic hormones have been reported to be useful in diminishing the anemia found in patients on maintenance dialysis [8-lo]. The effect of these hormones in anephric patients is, however, not clear. Some of our male patients received testosterone enanthate, 200 mg/week, intramuscularly, and some of the female patients received nandrolone decanoate (Decadurabolin”) 100 mg/week, intramuscularly. We studied the effect of this therapy on the average hematocrit values of the patients before and after initiating dialysis, before and after treatment with androgens, and, in a small group of nephric patients, after discontinuing androgen therapy. Dialysis itself seems to cause a slight improvement in the hematocrit values (Figure 1). Determinations were made after a minimum of 6 months of dialysis. Uremic toxins have been reported as important in this anemia, and the dialysis effect on hematocrit values may well be due to removal of these materials. Androgens have a marked effect in nephric patients, and result in a greater increase in hematocrit values in male than in female patients (Figure 2). These determinations were all made after a minimum of 3 months of androgen therapy. The difference in response of female patients could well be due to the different dosages and preparations that they received in hopes of pre-
70
January 1975
The American Journal of Medicine
venting
the masculinizing
effects
of these
hormones.
In eight nephric male patients, androgen therapy was discontinued because the patients had a good response and moderate acne had developed. Figure 3 illustrates the prompt fall in hematocrit values after androgen therapy was discontinued. Nephrectomy resulted in a decrease in hematocrit values, and this anemia was completely unresponsive to androgen therapy (Figure 2) at the dosages we consider safe and appropriate. The anemia of anephric patients is thus severe and unresponsive to anabolic steroid therapy, and, as already stated, these patients often require frequent transfusions. Figure 4 shows the course of a patient who illustrates the importance of kidney tissue, with or with-. out excretory function, in maintaining hematocrit levels. This 62 year old gentleman had a congenital absence of one kidney, and hypernephroma developed in the remaining kidney. After radical nephrectomy, he was immediately placed on hemodialysis, as often as four to five times a week, in hopes of preventing anemia, osteodystrophy and neuropathy. His hematocrit level, nevertheless, dropped. A functioning kidney transplant rapidly corrected the anemia but, when this had to be removed, the hematocrit value fell again.
After
transplant
of a second
kidney
that
-
n-17
T
-
-
d
I
I
Pre-hemodialysis Post-hemodialysis Figure 1. Change in hemotocrit values following institution of hemodialysis therapy. Bars = SEM.
Volume 58
CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
never functioned, hematocrit values again improved and stabilized, but fell again after the nonfunctioning graft was removed. This patient now has SH antigenpositive hepatitis, and the hematocrit level has risen slightly and stabilized. The finding of improved red cell mass after recovery from hepatitis has been noted in the past [ 111. The mechanism of this phenomenon remains unknown. Decreased red blood cell destruction, decreased ESF destruction or elaboration of ESF, or a similar material, have all been suggested. This hepatitis stimulus would appear to be effective even in the absence of kidneys. OSTEODYSTROPHY
IN ANEPHRIC
FEMALE h= 9)
I
I
Pre-anabolic steroids
45 n=8
I
40 -
PATIENTS
1,25-dihydrocholecalciferol (1,25 DHCC) is produced in the kidney from a precursor, and is secreted and transported to target organs where it acts in the nucleus in a manner similar to that of steroid hormones. 1,25 DHCC thus should be classified as a kidney hormone [ ‘121. It is the most active form of vitamin D3 in promoting intestinal calcium absorption [ 13,141 and skeletal calcium mobilization [ 151. Osteodystrophy has, of course, long been recognized as a complication of chronic renal failure. The genesis of this osteodystrophy is complex and characterized clinically by a variety of abnormalities. There is a defect in in-
1
ET AL.
ANEPHRIC h=141
I
Post-anabolic steroids
Figure 2. Change in hematocrit values of male and female dialysis patients following treatment with anabolic steroids. Bars = SEM.
January
20 -
15 rI
I
Pre-anabolic steroids
I
I
On Anabolic
Off steroids
Change in hematocrit values in eight male diFigure 3. alysis patients before, during and after discontinuing anabolic steroids. Bar = SEM.
testinal absorption of calcium and a resistance to vitamin D [ 161. Secondary hyperparathyroidism is an almost constant feature of chronic renal failure, with very high levels of circulating parathyroid hormone (PTH) [ 171. This aspect of renal osteodystrophy is probably secondary to chronic hypocalcemia. The initial stimulus may occur early in the course of renal failure when phosphate retention leads to transient hypocalcemia, and then to increased parathyroid activity to again normalize the divalent ions, but at the expense of increased PTH secretion [ 781. This abnormality is theoretically correctable b!y the administration of phosphate binding gels. As renal failure advances, loss of kidney tissue undoubtedly leads to a progressive defect in metabolism of vitamin D [ 191. In most patients with chronic renal disease, therefore, there may be gradual loss in most of the ability to hydroxylate 25 DHCC at the 1 position. In reviewing the data on our patients, we found no differences in calcium, phosphorous or alkaline phosphatase levels. or in symptomatic osteodystrophy, between nephric and anephric dialysis patients. We did, however, note that severe hypocalcemia developed in a patient with adult polycystic kidney disease after bilateral nephrectomy [ 201. This patient’s serum calcium level dropped precipitously from 10 to 4 mg/lOO ml, accompanied by an in-
1975
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CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
Procedures
Transfusion (units/wk)
Angioplasty 1
l
4
ET AL.
r Suprapubic cystostomy
I
I
o SONDJFMAMJJASON 1972 1973
I IDJFMAM 11974
crease in alkaline phosphatase from 150 to 200 to over 400 mU/ml. Calcium and dihydrotachysterol therapy, and increased dialysate calcium were required to control the hypocalcemia. Sudden loss of 1,25DHCC by nephrectomy in a chronically uremic patient may result in severe hypocalcemia, despite increased PTH secretion, because of the combination of poor skeletal calcium content, presence of uremic “toxins” affecting vitamin D activity and loss of the most potent vitamin D metabolite. In our patient, who had a single, normally functioning kidney removed for hypernephroma, this severe hypocalcemia did not develop, possibly because these other problems of uremia had not yet arisen. REGULATION OF BLOOD PRESSURE IN ANEPHRIC PATIENTS Hypertension is a common feature of chronic renal disease. In most cases, it can be controlled by antihypertensive drug therapy and diuretics, and, when the kidneys become end-stage, by dialysis. In rare cases, however, severe, malignant hypertension occurs that can only be controlled by bilateral nephrectomy. This complication is usually accompanied by very high plasma renin levels, and bilateral nephrectomy results in improvement [21-231. Patients who have had bilateral nephrectomies seldom require antihypertensive agents. If the blood pressure does increase, it can be readily controlled by fluid removal during hemodialysis. Rao et al. [24] found the incidence of hypotension during hemodialysis much higher in nephrectomized patients than in nephric patients. The nephrectom-
72
January
1975
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of Medicine
Volume
Figure 4. Clinical course of a 62 year old man with a congenital solitary kidney, in whom hypernephroma developed and who was treated with radical nephrectomy. Nx = nephrectomy, TX(C) = cadaveric transplant, TxNx = transplant nephrectomy.
ized patients often required infusions of saline solution and, occasionally, even vasopressor drugs. Hemodialysis-induced hypotension is a rather common complication and may have multiple etiologies. Hypovolemia certainly plays an important part in many patients. Kersh et al. [ 151, in a study of eight patients who had severe hypotension during hemodialysis, found that only two of them had normal responses to the Valsalva maneuver or to amyl nitrite inhalation. In the remaining six, total systemic resistance fell during hemodialysis-related hypotension, and tachycardia did not develop. Volume therapy was relatively ineffective in this group of patients. An autonomic insufficiency was postulated to account for these abnormalities. Control of arterial blood pressure is accomplished in the absence of a functioning renin-angiotensin system in anephric patients. This control appears to be very sensitive to volume changes. Coleman et al. [26], in a study of three anephric patients, found that chronic volume expansion resulted in increased arterial blood pressure, which was a function of changes in cardiac output and peripheral resistance. Initially, there was an increase in cardiac output, with no change in peripheral resistance. After maintenance of an increased pressure and cardiac output for several days, peripheral resistance rose, and even remained elevated as weight, cardiac output and blood pressure were being reduced by hemodialysis. No information is given pertaining to acute changes during hemodialysis-induced hypotension or to any concomitant changes in peripheral vascular resistance. The relatively slow changes observed in peripheral resis-
58
CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
tance may be due to resetting of baroreceptors, a process known to be slow, i.e., requiring several days to adapt [27]. Regulation of blood pressure from day to day may be controlled, as Coleman suggests, by changes in intravascular volume, which then affect cardiac output and blood pressure, and, after a lag, peripheral resistance. The propensity of anephric patients to become hypotensive during acute loss of intravascular volume, as occasioned by hemodialysis, could be due to the relative insensitivity of remaining autonomic mechanisms in controlling minute to minute changes in pressure. Khairallah [28] and others suggest that an important role of angiotensin is to increase the number of norepinephrine molecules able to reach specific receptor sites in smooth muscle. This could be an important factor in controlling vascular tone. Thus, a relatively normal autonomic response to dialysis-induced hypotension in anephric patients may be blunted by the loss of the renin-angiotensin system. Schwartz et al. [29] recently reported that the decrease in blood pressure after nephrectomy was always accompanied by a decrease in peripheral vascular resistance. Many studies have appeared recently on the regulation of plasma aldosterone in anephric patients [30,31]. The clinical significance of aldosterone in the absence of kidneys is unknown but probably has little to do with controlling blood pressure. Walker and Cooke [32] reported marked fluctuations in plasma potassium ion associated with postural changes and ambulation in anephric patients. Aldosterone may regulate potassium ion flux in cells of these patients and thus could serve a potentially important physiologic function. METABOLIC CONSEQUENCES ANEPHRIC STATE
OF THE
Clearly, the kidney is of great importance in regulating erythropoietin, activating vitamin D and controlling blood pressure. Kidney tissue is also important in metabolizing a variety of biologic products and drugs. Clements et al. [33] postulated that raised levels of plasma myoinositol might be responsible for uremic polyneuropathy. Whether or not this turns out to be the case, they present an interesting example of the role of kidney tissue in metabolizing, as opposed to excreting, a potentially toxic metabolite. Myoinositol, a cyclic hexitol with a molecular weight of 180, is oxidized to D-glucuronate in the kidney, then further metabolized to D-xylulose&phosphate and incorporated into the pentose-phosphate pathway to finally appear as glucose and carbon dioxide. Patients with chronic renal failure have elevated levels of this substance. Clements found that in rats fed large amounts of
January
myoinositol creased.
motor
nerve
conduction
velocities
ET AL.
de-
As chronic renal failure develops and progresses, there is a gradual loss of kidney tissue. Quite possibly, many of the metabolic functions of the kidney decrease in the same manner as the decrease in excretory functions. This would result in a gradual loss of the ability to handle such metabolites as myoinositol. On the other hand, it would appear that significant amounts of renin, ESF and possibly also 1,25 DHCC can be produced even in the presence of end-stage kidney disease. It is conceivable, therefore, that loss of kidney tissue, even in patients on chronic dialysis, could lead to loss of important metabolic pathways. Fortunately, most of the metabolites would be expected to be of low molecular weight, and therefore diffusible through the artificial kidney membranes. The importance of the variety and amounts of enzymes within the kidney, including d-amino oxidases, would seem to be a fruitful area for future research. CLINICAL INDICATIONS AND BILATERAL NEPHRECTOMY
RESULTS
OF
From the information now available, it appears that every effort should be made to preserve kidney tissue. Control of hypertension is probably one of the most frequent indications for bilateral nephrectomy. With the introduction of propranolol hydrochloride, however, and its effect in reducing plasma renin levels, many patients can be adequately treated without nephrectomy. Only in malignant hypertension, that does not respond to medical therapy, should nephrectomy be considered. Preparation for transplantation is another popular indication for nephrectomy. Again, one of the reasons for this is to prevent hypertension in the posttransplant period and possible damage to the transplanted kidney. Our experience indicates that it is better to postpone nephrectomy until the patient has a functioning homograft. If hypertension persists after transplantation, nephrectomy can be performed with minimal morbidity and short hospitalizations. We found a 37 per cent incidence of complications following nephrectomies in chronic dialysis patients compared to only 8 per cent in patients with functioning homografts [34]. Hospitalization averaged 24 days in the dialysis group and only 11 days in the transplant group. Control of blood pressure by nephrectomy was excellent in both groups. The average preoperative diastolic pressure was 100 mm Hg, and this fell to 82 to 90 mm Hg after surgery. Renal function was not affected by surgery in the transplant group, nor was red cell mass, as measured by hematocrit (Table II). In addition to hypertension, there are several other indications for nephrectomy in preparation for trans-
1975
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58
73
CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL ET AL.
TABLE
II
Nephrectomies in Patients Kidney Transplants*
with
Functioning .._____ ~__
Blood Pressure
Systolic
Serum Creatinine Drastolic (mg/lOO ml)
163+4
106*2
(mm H8) _____~ Before surgery After surgery
132 i
2
86xt2
Creatinine Clearance (ml/min)
Hematocrit (%)
1.810.1
61.1+5.9
35
1.610.1
66.0zt33.8
38
* Based on a study of 18 patients who received their transplants between April 1969 and February 1972 and who subsequently underwent bilateral nephrectomies.
plantation. Certainly, with the availability of chronic dialysis and transplantation, malignancies involving both kidneys can be treated with bilateral nephrectomy. The results in the small series reported have been quite good, and the immunosuppression required for transplantation does not appear to be a significant risk [35]. Chronic renal infections, especially those associated with lower urinary tract disease, are indications for nephrectomy in preparation for transplantation. Most of these patients have either bilateral ureteral reflux with hydroureter and hydronephrosis, or cutaneous ureterostomies or nephrostomies. Even in instances in which the bladder is irretrievably damaged, patients can be treated by nephrectomy and creation of an ileal conduit [36]. These conduits have been quite satisfactory for use in future transplants. Occasionally adult polycystic kidneys are so large that the surgeons do not have enough room in which to place a transplanted kidney. This is unusual, however, and in most instances a transplant can be accomplished with the kidneys in place. Finally, immunologic disease may be an indication for nephrectomy prior to transplantation. dence is rather slim, however, because ficulties in adequately controlling clinical
The eviof the diftransplant
series. Most transplant physicians agree that patients with circulating antiglomerular basement membrane (anti-GBM) antibody, or with kidney disease associated with the typical immunofluorescent staining suggestive of anti-GBM disease, should undergo nephrectomy, and antibody titers should be decreased prior to transplantation. Dialysis staff often characterize patients on hemodialysis as either “successful” or “unsuccessful” on the basis of a variety of factors that have seldom been quantitated. We rated our patients in a scoring system developed by Kennedy [37] that attempts to quantitate a variety of medical and psychosocial parameters. Twenty-five per cent of our patients with the lowest scores were rated as successful, and 25 per cent with the highest scores were considered unsuccessful. A variety of parameters were then studied to see if they differed between the high and low score groups. These included type of kidney disease, previous transplant, nephrectomies, daily urine output, time on dialysis, age, sex and several other social parameters. The most striking finding was that only 2 of 15 patients with the lowest (best) scores had had nephrectomies, whereas 8 of the 15 with the highest (worst) scores had lost their kidneys. There was, as might be expected, a similar correlation with 24 hour urine volume. In none of the other parameters was such a significant relationship found
[381. The kidneys are thus emerging as physiologically important organs, even if they do not make urine, and they certainly should be retained if at all possible. If they must be removed, the opportunity should be seized to further explore the metabolic consequences of physical loss of this highly active tissue. ACKNOWLEDGMENT
We wish to express our deep appreciation to the nurses, fellows and house staff, who have diligently cared for these patients, nephric and anephric, over the years.
REFERENCES 1. 2. 3. 4. 5.
6.
74
Erslev AJ: Humoral regulation of red cell production. Blood a: 349. 1953. Jacobson LO, Goldwasser E, Fried W, Plazak L: Role of the kidney in erythropoiesis. Nature (Lond) 179: 633, 1957. Fischer J, Friederici L: Erthropoiesis in bilateral nephrectomized rabbits. Experientia 17: 318, 1961. Murphy GP, Mirand EA, Kenny GM: Renal and extrarenal erythropoietin in man. NY State J Med 69: 2007, 1969. Van Ypersele de Strihon C, Stragier A: Effect of bilateral nephrectomy on transfusion requirements of patients undergoing chronic dialysis. Lancet 2: 7623, 1969. Kominami N, Lowrie EG, lanberg LE. Skaren A, Hampers CL, Merrill JP, Lange RD: The effect of total nephrectomy on hematopoiesis in patients undergoing chronic hemodialysis. J Lab Clin Med 78: 524, 1971.
January 1975
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11.
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Nathan DG, Schupak E, Stohlman V Jr, Merrill JP: Erythropoiesis in anephric man. J Clin Invest 43: 2188. 1964. Fried W, Jonasson 0, Lang G, Schwartz F: The hematologic effect of androgens in uremic patients. Ann Intern Med 79: 823, 1973. Richardson JR, Weinstein MB: Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 73: 403, 1970. Eschbach JW, Adamson JW: Improvement in the anemia of chronic renal failure with fluoxymesterone. Ann Intern Med 78: 527. 1973. Kolk-Vegter AJ, Bosch E, Van Leeuwen AM: Influence of serum hepatitis on hemoglobin level- in patients on regular hemodialysis. Lancet 1: 526, 197 1.
CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
12. 13.
14.
15.
16.
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18.
19.
20.
21.
22.
23.
24.
25.
Kodicek E: The story of vitamin D: from vitamin D to hormone. Lancet 2: 7853, 1974. Omdahl J, Holick M, Suda T, Tanaka Y, DeLuca HF: Biological activity of 1-25-dihydroxycholecalciferol. Biochemistry IO: 2935, 1971. Boyle IT, Miravet L, Gray RW, Holick MF: The response of intestinal calcium transport to 25hydroxy and 1.25-dihydroxy vitamin D in nephrectomized rats. Endocrinology 90: 605, 1972. Tanaka Y, DeLuca HF: Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D. Arch Biochem Biophys 146: 574, 1972. Stanberg SW, Lumb GA: Metabolic studies of renal osteodystrophy. I. Calcium, phosphorous and nitrogen metabolism in rickets, osteomalacia. and hyperparathyroidism complicating chronic uremia. Medicine 41: 1, 1962. Berson SA, Yalow RS: Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia, and bronchogenic carcinoma. Science 154: 907, 1966. Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Ress E, Bricker NS: On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50: 492, 197 1. Avioli LV, Slatopolsky E: The absorption and metabolism of vitamin D in chronic renal failure. J Clin Invest 46: 1032, 1967. Cheigh JS, Rubin AL, Stenzel KH, Whitsell JC: Hypocalcemia following bilateral nephrectomy. Urology 2: 121, 1973. Unesti G. Swartz C, Ramirez 0, Brest AN: Bilateral nephrectomy for control of hypertension in uremia. Trans Am Sot Artif Intern Organs 14: 361, 1968. Lazarus JM, Hampers CL, Bennett AH, Vandam LD, Merrill JP: Urgent bilateral nephrectomy for severe hypertension. Ann Intern Med 76: 733, 1972. Mahony JF, Gibson GR, Sheil AG, Storey BG, Stokes GS, Stewart JH: Bilateral nephrectomy for malignant hypertension. Lancet 1: 1036, 1972. Rao TKS, Manis T, Delano BG, Friedman EA: Continuing high morbidity during maintenance hemodialysis consequent to bilateral nephrectomy. Trans Am Sot Artif Intern Organs 19: 340, 1973. Kersh ES, Kronfield SJ, Unger A, Popper RW, Cantor S. Cohn K: Autonomic insufficiency in uremia as a cause of
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26.
27. 28.
29.
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31.
32. 33.
34.
35.
36.
37.
38.
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hemodialysis-induced hypotension. N Engl J Med 290: 650, 1974. Coleman TG, Bower JD, Langford HG, Guyton AC: Regulation of arterial pressure in the anephric state. Circulation 42: 509, 1970. Krieger EM: Time course of baroreceptor resetting in acute hypertension. Am J Physiol 218: 486, 1970. Khairallah PA: Pharmacology of angiotension. Kidney Hormones (Fisher J, ed), New York and London, Academic Press, 1971, p 129. Schwartz C, Kim KE, Onesti G: The hemodynamics of hypertension in uremia. Adequacy of Dialysis Conference, Bethesda, Department of Health, Education & Welfare, 1974, p 60. Williams GH, Bailey GL, Hampers CL, Lauler DP, Merrill JP. Underwood RH, Blair-West JR, Coghlan JP, Denton DA, Scoggins BA, Wright RD: Studies on the metabolism of aldosterone in chronic renal failure and anephric man. Kidney Int 4: 280, 1973. Weidman P, Horton R, Maxwell MH, Franklin SS, Fichman M: Dynamic studies of aldosterone in anephric man. Kidney Int 4: 289, 1973. Walker WG, Cooke CR: Plasma aldosterone regulation in anephric man. Kidney Int 3: 1, 1973. Clements RS Jr, De Jesus PV, Winegrad Al: Raised plasma myoinositol levels in uremia and experimental neuropathy. Lancet 1: 1137, 1973. Aronian JM, Stubenbord WT, Stenzel KH, Whitsell JC, Rubin AL: Bilateral nephrectomy in chronic dialysis and renal transplant patients. Am J Surg 126: 635, 1973. Belzer FO, Schweizer RT, Kountz SL, de Lorimier AA: Malignancy and immunosuppression. Transplantation 13: 164, 1972. Stenzel KH, Stubenbord WT. Whitsell .JC, Lewy JE, Riggio RR, Cheigh JS, Marshall VF, Rubin AL: Kidney transplantation: use of intestinal conduits. JAMA 229: 534,1974. Kennedy AC, Lindsay RM, Murphy AV, Allison MEM, McLeod 0: A scoring system for assessing patients on regular dialysis. Lancet 1: 701, 1969. Leonard M, Sullivan MT, Green B, Davenport U, Hickerson M, Sullivan J: A study of factors related to long-term success of patients on a chronic hemodialysis program. Trans Am Sot Dial Nurs Tech (in press).
The American
Journal of Medicine
Volume 58
75
KURT H
STENZEL, M.D.
JHOONG S. CHEIGH, M.D JOHN F. SULLIVAN, M.D. LUIS TAPIA, M.D. ROBERT R. RIGGIO, M.D. ALBERT L.. RUBIN, M.D. New York, New York
The effects of removal of all renal tissue on hematopoiesis, osteodystrophy, blood pressure regulation and metabolic functions are reviewed; and, the indications for, and results of, bilateral nephrectomy are discussed. Nephrectomy results in a more severe anemia in dialysis patients which is poorly responsive to androgen therapy. No differences were detected in the severity of osteodystrophy between nephric and anephric patients. However, bilateral nephrectomy can occasionally result in the acute onset of hypocalcemia. Blood pressure regulation must be accomplished in the absence of a functioning renin-angiotensin system. This is largely on the basis of volume, but changes in vascular tone may also be significant. Little is known about the metabolic consequences of nephrectomies. The effect on substances metabolized by the kidney is an area for further investigation. Kidney tissue should be preserved, if at all possible, and nephrectomy performed only for specific indications. As more and more people are being subjected to bilateral nephrectomy, it becomes increasingly important to document and quantitate alterations resulting from loss of kidney tissue. The old view that the kidneys’ function is to make urine is certainly no longer tenable. The kidneys are the main source of renin production, of erythroid-stimulating factor, of activation, production and hydroxylation of 25hydroxycholecalcifero1, and probably subserve many other, less obvious, metabolic functions. We review the clinical consequences of bilateral nephrectomy in patients with chronic renal disease, especially in terms of erythropoiesis, osteodystrophy, control of blood pressure and metabolic consequences, and consider the indications for, and results of, bilateral nephrectomy. HEMATOPOIESIS
From the Rogosin Kidney Center, The New York Hospital-Cornell Medical Center, New York, New York. This work was supported in part by the New York State Kidney Disease Institute and the Kidney Foundation of New York. Requests for reprints should be addressed to Dr. K. H. Stenzel. 525 East 68th Street, Room D-208, New York, New York 10021.
IN ANEPHRIC PATIENTS
Erslev [l] demonstrated a factor in plasma that could stimulate erythropoiesis, and the kidney was soon found to be the site of production of erythropoietic-stimulating factor (ESF) [ 21. The kidney is the major site of ESF production, and other sites appear to vary from species to species [3]. The importance of extrarenal sites in man is currently unknown, although some investigators have found significant levels of ESF in anephric patients [4]. Nevertheless, several reports have documented the fact that anephric dialysis patients have a more severe anemia and require more transfusions than do nephric patients [5,6]. It has also been observed that patients with adult polycystic kidney disease tend to have higher hematocrit values than patients with other chronic renal diseases, characterized by small, shrunken, scarred “end-stage” kidneys. This is quite probably due to retention of more parenchymal ESFproducing tissue in patients with adult polycystic kidney disease.
January 1975
The American Journal of Medicine
Volume 58
69
CLINICAL EFFECTS OF BILATERAL
TABLE
I
Average Anephric
NEPWECTOMY-STENZEL
Hematocrit Patients
Male
Values
in Nephric
ET AL
and
Female
Average Average Average Average Age Hematocrit Age Hematocrit (yr) No. (%) (vr) (%) ~~~~.___. 31 43 29 23 38 25 12 35 15 2 36 15
Total Patient No. No. Nephric Anephric
54 14
Certainly, presence or absence of ESF is not the sole stimulus to red cell production. Nathan et al. [7] noted that in anephric patients acute hypoxia resulted in an increased red cell production and that even without this stimulus there was some erythropoietic activity. Nevertheless, anemia in anephric patients remains a problem. Fourteen of 68 patients in our outpatient dialysis center, who have been on maintenance hemodialysis for more than 6 months, are anephric. Table I indicates the makeup of the nephric and anephric groups and clearly indicates the lower average hematocrit values found in anephric patients. These patients also required more transfusions than did the nephric group. All patients in our series underwent dialysis three times a week for 15 to 18 hours on coiltype dialyzers. Both the nephric and anephric patients received similar diet, antacid and vitamin theraPY. Androgenic hormones have been reported to be useful in diminishing the anemia found in patients on maintenance dialysis [8-lo]. The effect of these hormones in anephric patients is, however, not clear. Some of our male patients received testosterone enanthate, 200 mg/week, intramuscularly, and some of the female patients received nandrolone decanoate (Decadurabolin”) 100 mg/week, intramuscularly. We studied the effect of this therapy on the average hematocrit values of the patients before and after initiating dialysis, before and after treatment with androgens, and, in a small group of nephric patients, after discontinuing androgen therapy. Dialysis itself seems to cause a slight improvement in the hematocrit values (Figure 1). Determinations were made after a minimum of 6 months of dialysis. Uremic toxins have been reported as important in this anemia, and the dialysis effect on hematocrit values may well be due to removal of these materials. Androgens have a marked effect in nephric patients, and result in a greater increase in hematocrit values in male than in female patients (Figure 2). These determinations were all made after a minimum of 3 months of androgen therapy. The difference in response of female patients could well be due to the different dosages and preparations that they received in hopes of pre-
70
January 1975
The American Journal of Medicine
venting
the masculinizing
effects
of these
hormones.
In eight nephric male patients, androgen therapy was discontinued because the patients had a good response and moderate acne had developed. Figure 3 illustrates the prompt fall in hematocrit values after androgen therapy was discontinued. Nephrectomy resulted in a decrease in hematocrit values, and this anemia was completely unresponsive to androgen therapy (Figure 2) at the dosages we consider safe and appropriate. The anemia of anephric patients is thus severe and unresponsive to anabolic steroid therapy, and, as already stated, these patients often require frequent transfusions. Figure 4 shows the course of a patient who illustrates the importance of kidney tissue, with or with-. out excretory function, in maintaining hematocrit levels. This 62 year old gentleman had a congenital absence of one kidney, and hypernephroma developed in the remaining kidney. After radical nephrectomy, he was immediately placed on hemodialysis, as often as four to five times a week, in hopes of preventing anemia, osteodystrophy and neuropathy. His hematocrit level, nevertheless, dropped. A functioning kidney transplant rapidly corrected the anemia but, when this had to be removed, the hematocrit value fell again.
After
transplant
of a second
kidney
that
-
n-17
T
-
-
d
I
I
Pre-hemodialysis Post-hemodialysis Figure 1. Change in hemotocrit values following institution of hemodialysis therapy. Bars = SEM.
Volume 58
CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
never functioned, hematocrit values again improved and stabilized, but fell again after the nonfunctioning graft was removed. This patient now has SH antigenpositive hepatitis, and the hematocrit level has risen slightly and stabilized. The finding of improved red cell mass after recovery from hepatitis has been noted in the past [ 111. The mechanism of this phenomenon remains unknown. Decreased red blood cell destruction, decreased ESF destruction or elaboration of ESF, or a similar material, have all been suggested. This hepatitis stimulus would appear to be effective even in the absence of kidneys. OSTEODYSTROPHY
IN ANEPHRIC
FEMALE h= 9)
I
I
Pre-anabolic steroids
45 n=8
I
40 -
PATIENTS
1,25-dihydrocholecalciferol (1,25 DHCC) is produced in the kidney from a precursor, and is secreted and transported to target organs where it acts in the nucleus in a manner similar to that of steroid hormones. 1,25 DHCC thus should be classified as a kidney hormone [ ‘121. It is the most active form of vitamin D3 in promoting intestinal calcium absorption [ 13,141 and skeletal calcium mobilization [ 151. Osteodystrophy has, of course, long been recognized as a complication of chronic renal failure. The genesis of this osteodystrophy is complex and characterized clinically by a variety of abnormalities. There is a defect in in-
1
ET AL.
ANEPHRIC h=141
I
Post-anabolic steroids
Figure 2. Change in hematocrit values of male and female dialysis patients following treatment with anabolic steroids. Bars = SEM.
January
20 -
15 rI
I
Pre-anabolic steroids
I
I
On Anabolic
Off steroids
Change in hematocrit values in eight male diFigure 3. alysis patients before, during and after discontinuing anabolic steroids. Bar = SEM.
testinal absorption of calcium and a resistance to vitamin D [ 161. Secondary hyperparathyroidism is an almost constant feature of chronic renal failure, with very high levels of circulating parathyroid hormone (PTH) [ 171. This aspect of renal osteodystrophy is probably secondary to chronic hypocalcemia. The initial stimulus may occur early in the course of renal failure when phosphate retention leads to transient hypocalcemia, and then to increased parathyroid activity to again normalize the divalent ions, but at the expense of increased PTH secretion [ 781. This abnormality is theoretically correctable b!y the administration of phosphate binding gels. As renal failure advances, loss of kidney tissue undoubtedly leads to a progressive defect in metabolism of vitamin D [ 191. In most patients with chronic renal disease, therefore, there may be gradual loss in most of the ability to hydroxylate 25 DHCC at the 1 position. In reviewing the data on our patients, we found no differences in calcium, phosphorous or alkaline phosphatase levels. or in symptomatic osteodystrophy, between nephric and anephric dialysis patients. We did, however, note that severe hypocalcemia developed in a patient with adult polycystic kidney disease after bilateral nephrectomy [ 201. This patient’s serum calcium level dropped precipitously from 10 to 4 mg/lOO ml, accompanied by an in-
1975
The American
Journal
of Medicine
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58
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CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
Procedures
Transfusion (units/wk)
Angioplasty 1
l
4
ET AL.
r Suprapubic cystostomy
I
I
o SONDJFMAMJJASON 1972 1973
I IDJFMAM 11974
crease in alkaline phosphatase from 150 to 200 to over 400 mU/ml. Calcium and dihydrotachysterol therapy, and increased dialysate calcium were required to control the hypocalcemia. Sudden loss of 1,25DHCC by nephrectomy in a chronically uremic patient may result in severe hypocalcemia, despite increased PTH secretion, because of the combination of poor skeletal calcium content, presence of uremic “toxins” affecting vitamin D activity and loss of the most potent vitamin D metabolite. In our patient, who had a single, normally functioning kidney removed for hypernephroma, this severe hypocalcemia did not develop, possibly because these other problems of uremia had not yet arisen. REGULATION OF BLOOD PRESSURE IN ANEPHRIC PATIENTS Hypertension is a common feature of chronic renal disease. In most cases, it can be controlled by antihypertensive drug therapy and diuretics, and, when the kidneys become end-stage, by dialysis. In rare cases, however, severe, malignant hypertension occurs that can only be controlled by bilateral nephrectomy. This complication is usually accompanied by very high plasma renin levels, and bilateral nephrectomy results in improvement [21-231. Patients who have had bilateral nephrectomies seldom require antihypertensive agents. If the blood pressure does increase, it can be readily controlled by fluid removal during hemodialysis. Rao et al. [24] found the incidence of hypotension during hemodialysis much higher in nephrectomized patients than in nephric patients. The nephrectom-
72
January
1975
The American
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of Medicine
Volume
Figure 4. Clinical course of a 62 year old man with a congenital solitary kidney, in whom hypernephroma developed and who was treated with radical nephrectomy. Nx = nephrectomy, TX(C) = cadaveric transplant, TxNx = transplant nephrectomy.
ized patients often required infusions of saline solution and, occasionally, even vasopressor drugs. Hemodialysis-induced hypotension is a rather common complication and may have multiple etiologies. Hypovolemia certainly plays an important part in many patients. Kersh et al. [ 151, in a study of eight patients who had severe hypotension during hemodialysis, found that only two of them had normal responses to the Valsalva maneuver or to amyl nitrite inhalation. In the remaining six, total systemic resistance fell during hemodialysis-related hypotension, and tachycardia did not develop. Volume therapy was relatively ineffective in this group of patients. An autonomic insufficiency was postulated to account for these abnormalities. Control of arterial blood pressure is accomplished in the absence of a functioning renin-angiotensin system in anephric patients. This control appears to be very sensitive to volume changes. Coleman et al. [26], in a study of three anephric patients, found that chronic volume expansion resulted in increased arterial blood pressure, which was a function of changes in cardiac output and peripheral resistance. Initially, there was an increase in cardiac output, with no change in peripheral resistance. After maintenance of an increased pressure and cardiac output for several days, peripheral resistance rose, and even remained elevated as weight, cardiac output and blood pressure were being reduced by hemodialysis. No information is given pertaining to acute changes during hemodialysis-induced hypotension or to any concomitant changes in peripheral vascular resistance. The relatively slow changes observed in peripheral resis-
58
CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL
tance may be due to resetting of baroreceptors, a process known to be slow, i.e., requiring several days to adapt [27]. Regulation of blood pressure from day to day may be controlled, as Coleman suggests, by changes in intravascular volume, which then affect cardiac output and blood pressure, and, after a lag, peripheral resistance. The propensity of anephric patients to become hypotensive during acute loss of intravascular volume, as occasioned by hemodialysis, could be due to the relative insensitivity of remaining autonomic mechanisms in controlling minute to minute changes in pressure. Khairallah [28] and others suggest that an important role of angiotensin is to increase the number of norepinephrine molecules able to reach specific receptor sites in smooth muscle. This could be an important factor in controlling vascular tone. Thus, a relatively normal autonomic response to dialysis-induced hypotension in anephric patients may be blunted by the loss of the renin-angiotensin system. Schwartz et al. [29] recently reported that the decrease in blood pressure after nephrectomy was always accompanied by a decrease in peripheral vascular resistance. Many studies have appeared recently on the regulation of plasma aldosterone in anephric patients [30,31]. The clinical significance of aldosterone in the absence of kidneys is unknown but probably has little to do with controlling blood pressure. Walker and Cooke [32] reported marked fluctuations in plasma potassium ion associated with postural changes and ambulation in anephric patients. Aldosterone may regulate potassium ion flux in cells of these patients and thus could serve a potentially important physiologic function. METABOLIC CONSEQUENCES ANEPHRIC STATE
OF THE
Clearly, the kidney is of great importance in regulating erythropoietin, activating vitamin D and controlling blood pressure. Kidney tissue is also important in metabolizing a variety of biologic products and drugs. Clements et al. [33] postulated that raised levels of plasma myoinositol might be responsible for uremic polyneuropathy. Whether or not this turns out to be the case, they present an interesting example of the role of kidney tissue in metabolizing, as opposed to excreting, a potentially toxic metabolite. Myoinositol, a cyclic hexitol with a molecular weight of 180, is oxidized to D-glucuronate in the kidney, then further metabolized to D-xylulose&phosphate and incorporated into the pentose-phosphate pathway to finally appear as glucose and carbon dioxide. Patients with chronic renal failure have elevated levels of this substance. Clements found that in rats fed large amounts of
January
myoinositol creased.
motor
nerve
conduction
velocities
ET AL.
de-
As chronic renal failure develops and progresses, there is a gradual loss of kidney tissue. Quite possibly, many of the metabolic functions of the kidney decrease in the same manner as the decrease in excretory functions. This would result in a gradual loss of the ability to handle such metabolites as myoinositol. On the other hand, it would appear that significant amounts of renin, ESF and possibly also 1,25 DHCC can be produced even in the presence of end-stage kidney disease. It is conceivable, therefore, that loss of kidney tissue, even in patients on chronic dialysis, could lead to loss of important metabolic pathways. Fortunately, most of the metabolites would be expected to be of low molecular weight, and therefore diffusible through the artificial kidney membranes. The importance of the variety and amounts of enzymes within the kidney, including d-amino oxidases, would seem to be a fruitful area for future research. CLINICAL INDICATIONS AND BILATERAL NEPHRECTOMY
RESULTS
OF
From the information now available, it appears that every effort should be made to preserve kidney tissue. Control of hypertension is probably one of the most frequent indications for bilateral nephrectomy. With the introduction of propranolol hydrochloride, however, and its effect in reducing plasma renin levels, many patients can be adequately treated without nephrectomy. Only in malignant hypertension, that does not respond to medical therapy, should nephrectomy be considered. Preparation for transplantation is another popular indication for nephrectomy. Again, one of the reasons for this is to prevent hypertension in the posttransplant period and possible damage to the transplanted kidney. Our experience indicates that it is better to postpone nephrectomy until the patient has a functioning homograft. If hypertension persists after transplantation, nephrectomy can be performed with minimal morbidity and short hospitalizations. We found a 37 per cent incidence of complications following nephrectomies in chronic dialysis patients compared to only 8 per cent in patients with functioning homografts [34]. Hospitalization averaged 24 days in the dialysis group and only 11 days in the transplant group. Control of blood pressure by nephrectomy was excellent in both groups. The average preoperative diastolic pressure was 100 mm Hg, and this fell to 82 to 90 mm Hg after surgery. Renal function was not affected by surgery in the transplant group, nor was red cell mass, as measured by hematocrit (Table II). In addition to hypertension, there are several other indications for nephrectomy in preparation for trans-
1975
The American
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58
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CLINICAL EFFECTS OF BILATERAL NEPHRECTOMY-STENZEL ET AL.
TABLE
II
Nephrectomies in Patients Kidney Transplants*
with
Functioning .._____ ~__
Blood Pressure
Systolic
Serum Creatinine Drastolic (mg/lOO ml)
163+4
106*2
(mm H8) _____~ Before surgery After surgery
132 i
2
86xt2
Creatinine Clearance (ml/min)
Hematocrit (%)
1.810.1
61.1+5.9
35
1.610.1
66.0zt33.8
38
* Based on a study of 18 patients who received their transplants between April 1969 and February 1972 and who subsequently underwent bilateral nephrectomies.
plantation. Certainly, with the availability of chronic dialysis and transplantation, malignancies involving both kidneys can be treated with bilateral nephrectomy. The results in the small series reported have been quite good, and the immunosuppression required for transplantation does not appear to be a significant risk [35]. Chronic renal infections, especially those associated with lower urinary tract disease, are indications for nephrectomy in preparation for transplantation. Most of these patients have either bilateral ureteral reflux with hydroureter and hydronephrosis, or cutaneous ureterostomies or nephrostomies. Even in instances in which the bladder is irretrievably damaged, patients can be treated by nephrectomy and creation of an ileal conduit [36]. These conduits have been quite satisfactory for use in future transplants. Occasionally adult polycystic kidneys are so large that the surgeons do not have enough room in which to place a transplanted kidney. This is unusual, however, and in most instances a transplant can be accomplished with the kidneys in place. Finally, immunologic disease may be an indication for nephrectomy prior to transplantation. dence is rather slim, however, because ficulties in adequately controlling clinical
The eviof the diftransplant
series. Most transplant physicians agree that patients with circulating antiglomerular basement membrane (anti-GBM) antibody, or with kidney disease associated with the typical immunofluorescent staining suggestive of anti-GBM disease, should undergo nephrectomy, and antibody titers should be decreased prior to transplantation. Dialysis staff often characterize patients on hemodialysis as either “successful” or “unsuccessful” on the basis of a variety of factors that have seldom been quantitated. We rated our patients in a scoring system developed by Kennedy [37] that attempts to quantitate a variety of medical and psychosocial parameters. Twenty-five per cent of our patients with the lowest scores were rated as successful, and 25 per cent with the highest scores were considered unsuccessful. A variety of parameters were then studied to see if they differed between the high and low score groups. These included type of kidney disease, previous transplant, nephrectomies, daily urine output, time on dialysis, age, sex and several other social parameters. The most striking finding was that only 2 of 15 patients with the lowest (best) scores had had nephrectomies, whereas 8 of the 15 with the highest (worst) scores had lost their kidneys. There was, as might be expected, a similar correlation with 24 hour urine volume. In none of the other parameters was such a significant relationship found
[381. The kidneys are thus emerging as physiologically important organs, even if they do not make urine, and they certainly should be retained if at all possible. If they must be removed, the opportunity should be seized to further explore the metabolic consequences of physical loss of this highly active tissue. ACKNOWLEDGMENT
We wish to express our deep appreciation to the nurses, fellows and house staff, who have diligently cared for these patients, nephric and anephric, over the years.
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6.
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Erslev AJ: Humoral regulation of red cell production. Blood a: 349. 1953. Jacobson LO, Goldwasser E, Fried W, Plazak L: Role of the kidney in erythropoiesis. Nature (Lond) 179: 633, 1957. Fischer J, Friederici L: Erthropoiesis in bilateral nephrectomized rabbits. Experientia 17: 318, 1961. Murphy GP, Mirand EA, Kenny GM: Renal and extrarenal erythropoietin in man. NY State J Med 69: 2007, 1969. Van Ypersele de Strihon C, Stragier A: Effect of bilateral nephrectomy on transfusion requirements of patients undergoing chronic dialysis. Lancet 2: 7623, 1969. Kominami N, Lowrie EG, lanberg LE. Skaren A, Hampers CL, Merrill JP, Lange RD: The effect of total nephrectomy on hematopoiesis in patients undergoing chronic hemodialysis. J Lab Clin Med 78: 524, 1971.
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Nathan DG, Schupak E, Stohlman V Jr, Merrill JP: Erythropoiesis in anephric man. J Clin Invest 43: 2188. 1964. Fried W, Jonasson 0, Lang G, Schwartz F: The hematologic effect of androgens in uremic patients. Ann Intern Med 79: 823, 1973. Richardson JR, Weinstein MB: Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 73: 403, 1970. Eschbach JW, Adamson JW: Improvement in the anemia of chronic renal failure with fluoxymesterone. Ann Intern Med 78: 527. 1973. Kolk-Vegter AJ, Bosch E, Van Leeuwen AM: Influence of serum hepatitis on hemoglobin level- in patients on regular hemodialysis. Lancet 1: 526, 197 1.
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12. 13.
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Kodicek E: The story of vitamin D: from vitamin D to hormone. Lancet 2: 7853, 1974. Omdahl J, Holick M, Suda T, Tanaka Y, DeLuca HF: Biological activity of 1-25-dihydroxycholecalciferol. Biochemistry IO: 2935, 1971. Boyle IT, Miravet L, Gray RW, Holick MF: The response of intestinal calcium transport to 25hydroxy and 1.25-dihydroxy vitamin D in nephrectomized rats. Endocrinology 90: 605, 1972. Tanaka Y, DeLuca HF: Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D. Arch Biochem Biophys 146: 574, 1972. Stanberg SW, Lumb GA: Metabolic studies of renal osteodystrophy. I. Calcium, phosphorous and nitrogen metabolism in rickets, osteomalacia. and hyperparathyroidism complicating chronic uremia. Medicine 41: 1, 1962. Berson SA, Yalow RS: Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia, and bronchogenic carcinoma. Science 154: 907, 1966. Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Ress E, Bricker NS: On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50: 492, 197 1. Avioli LV, Slatopolsky E: The absorption and metabolism of vitamin D in chronic renal failure. J Clin Invest 46: 1032, 1967. Cheigh JS, Rubin AL, Stenzel KH, Whitsell JC: Hypocalcemia following bilateral nephrectomy. Urology 2: 121, 1973. Unesti G. Swartz C, Ramirez 0, Brest AN: Bilateral nephrectomy for control of hypertension in uremia. Trans Am Sot Artif Intern Organs 14: 361, 1968. Lazarus JM, Hampers CL, Bennett AH, Vandam LD, Merrill JP: Urgent bilateral nephrectomy for severe hypertension. Ann Intern Med 76: 733, 1972. Mahony JF, Gibson GR, Sheil AG, Storey BG, Stokes GS, Stewart JH: Bilateral nephrectomy for malignant hypertension. Lancet 1: 1036, 1972. Rao TKS, Manis T, Delano BG, Friedman EA: Continuing high morbidity during maintenance hemodialysis consequent to bilateral nephrectomy. Trans Am Sot Artif Intern Organs 19: 340, 1973. Kersh ES, Kronfield SJ, Unger A, Popper RW, Cantor S. Cohn K: Autonomic insufficiency in uremia as a cause of
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hemodialysis-induced hypotension. N Engl J Med 290: 650, 1974. Coleman TG, Bower JD, Langford HG, Guyton AC: Regulation of arterial pressure in the anephric state. Circulation 42: 509, 1970. Krieger EM: Time course of baroreceptor resetting in acute hypertension. Am J Physiol 218: 486, 1970. Khairallah PA: Pharmacology of angiotension. Kidney Hormones (Fisher J, ed), New York and London, Academic Press, 1971, p 129. Schwartz C, Kim KE, Onesti G: The hemodynamics of hypertension in uremia. Adequacy of Dialysis Conference, Bethesda, Department of Health, Education & Welfare, 1974, p 60. Williams GH, Bailey GL, Hampers CL, Lauler DP, Merrill JP. Underwood RH, Blair-West JR, Coghlan JP, Denton DA, Scoggins BA, Wright RD: Studies on the metabolism of aldosterone in chronic renal failure and anephric man. Kidney Int 4: 280, 1973. Weidman P, Horton R, Maxwell MH, Franklin SS, Fichman M: Dynamic studies of aldosterone in anephric man. Kidney Int 4: 289, 1973. Walker WG, Cooke CR: Plasma aldosterone regulation in anephric man. Kidney Int 3: 1, 1973. Clements RS Jr, De Jesus PV, Winegrad Al: Raised plasma myoinositol levels in uremia and experimental neuropathy. Lancet 1: 1137, 1973. Aronian JM, Stubenbord WT, Stenzel KH, Whitsell JC, Rubin AL: Bilateral nephrectomy in chronic dialysis and renal transplant patients. Am J Surg 126: 635, 1973. Belzer FO, Schweizer RT, Kountz SL, de Lorimier AA: Malignancy and immunosuppression. Transplantation 13: 164, 1972. Stenzel KH, Stubenbord WT. Whitsell .JC, Lewy JE, Riggio RR, Cheigh JS, Marshall VF, Rubin AL: Kidney transplantation: use of intestinal conduits. JAMA 229: 534,1974. Kennedy AC, Lindsay RM, Murphy AV, Allison MEM, McLeod 0: A scoring system for assessing patients on regular dialysis. Lancet 1: 701, 1969. Leonard M, Sullivan MT, Green B, Davenport U, Hickerson M, Sullivan J: A study of factors related to long-term success of patients on a chronic hemodialysis program. Trans Am Sot Dial Nurs Tech (in press).
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