- Email: [email protected]
The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation
The Pathogenesis of Hyperchloremic Metabolic Acidosis Associated with Kidney Transplantation
DANIEL C. BATLLE, M.D. MARTIN F. MOZES, M.D. JOSE MANALIGOD, M.D. JOSE A. L. ARRLJDA, M.D. NEIL A. KURTZMAN,
M.D.
Chicago, Illinois
From the Section of Nephrology,. and Departments of Pathology and Transplant Surgery, University of Illinois Hospital and the Veterans Administration West Side Hospital, Chicago, Illinois. Parts of this work were presented at the National Meeting of the Amdrican Society of Nephrology, Boston, November 1979. This research waspnpported in part by VA Central Of: fice Grant 7083, VA Basic Institutional Support Grant 3324, Chicago Heart Association Grants A79-28 and A79-30. and National Institutes of Health Grant AM 20170. Requests for reprints should be addressed to Dr. Daniel C. Batlle, Section of Nephrology. University of Illinois Hospital, 840 South Wood Street, Chicago, Ill. 60612. Manuscript accepted August 13.1980.
786
April 1981
The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was irivestigated in six patients. In five patients in whom acidosis failed to loweir the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pC02) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pC0~ normally with the administration of phosphate, demonstrating that this patient’s distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone defidiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion in response to stimulation with SOdium sulfate or acetaiolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement ((23)along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection. Hyperchloremic metabolic acidosis due to the development of renal tubular acidosis after kidney transplantation was first well documented in 1967 in a patient studied by Massry et al. [l]. Subsequently, the occurrence of renal tubular acidosis after kidney transplantation was confirmed in several studies [Z-11]. Most of the patients described presented with mild hyperchloremic metabolic acidosis, and their urine pH was inappropriately high. In some of them, however, the urine pH was inappropriately high with ammonium chloride-induced acidosis, but they were not spontaneously acidotic [4,9]. Thus, they appear to have an incomplete form of distal renal tubular acidosis. Proximal renal tubular acidosis with generalized proximal tubular dysfunction has also been described [6-lo]. In these early studies, the defect in urinary acidification was usually observed in the first few months after transplantation; in some cases it appeared to be reversible [3,5,9]. It was suggested that the defective urinary acidification was related to acute rejection episodes or caused by ischemic tubular damage [Z-5,9]. Bicarbonate wastage due to secondary hyperparathyroidism was also implicated [9]. More recently, Wilson and Siddiqui [9] confirmed previous observations that defective urinary acidification commonly develops in the early post-transplant period but also demonstrated that in some cases it was persistent over a one to three year period. Furthermore, these investigators noticed
The American Journal of Medicine
Volume 70
HYPERCHLOREMIC
ACIDOSIS
AFTER
KIDNEY
TRANSPLANTATION--BATLLE
ET AL.
that persistence of a defect in lowering the urine pH normally was often accompanied by the development of clinical features of chronic rejection, and they suggested that distal renal tubular acidosis in long-standing renal allografts could be the result of the immunologic injury that causes chronic rejection. In recent years, it has become clear that hyperchloremit metabolic acidosis can also develop in association with isolated aldosterone deficiency [12-171 and that in this syndrome, unlike in distal renal tubular acidosis, the ability to lower the urine pH during acidosis is preserved [x4-171. Furthermore, our studies in animals and in human subjects have shown that an acquired distal acidification defect can result from a secretory or a nonsecretory defect in hydrogen ion transport [17-231. Both defects can be distinguished by the acidification response to sodium sulfate or neutral phosphate administration. In patients with a secretory defect for hydrogen ion secretion, urine pH after the administration of sodium sulfate is not lowered normally, and the urine-blood (U-B) pCO2 gradient during the infusion of neutral phosphate at a urine pH close to 6.8is subnormal [17]. Contrarily, patients with a nonsecretory defect respond normally to both maneuvers [w]. In the present study we used these maneuvers to investigate the pathogenesis of persistent hyperchloremic metabolic acidosis associated with renal transplantation. It is of interest that in all of our patients, with the exception of one who lost his transplant due to early accelerated rejection, histologic changes of chronic rejection ultimately developed. A possible relationship between immunologic kidney damage and a tubular defect for distal hydrogen ion secretion is postulated in order to correlate our morphologic and functional findings. PATIENTS
AND METHODS
Ten patients who had received kidney transplants were studied. Persistent hyperchloremic metabolic acidosis was recognized in six of them; five received a kidney transplant from cadaveric donors, and one patient received a kidney from a living related donor. The remaining four patients received grafts from three cadaveric and one living related donor. In these patients hyperchloremic acidosis was not present, and they served as a control group. All patients were treated with a similar immunosuppressive protocol consisting of azathioprine and prednisone. Acute rejection episodes were treated with local radiation to the graft and by increasing the dose of prednisone to z mg/kg body weight daily for seven days and then gradually decreasing the dose to the previous level over a period of 30 days. Other medications which could interfere with urinary acidification and renal potassium handling, such as diuretics and alkalinizing agents, were not administered for at least three days prior to study. The patients were allowed to continue their regular diets at the time of all the studies. The diagnosis of the original renal disease and other clinical features are listed in Table 1. In all but one patient (Case 4). renal transplant biopsies were performed during the first
April 1981
The American
Journal of Medicine
Volume
70
HYPERCHLOREMIC
TABLE II
CaSe No. 1
2
3
4
5
6
ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
ET AL.
Clinical Course in Six R&al Transplant Reclplents wlth Hyperchloremlc Metabolic Acldosls (HMA)
time after Tranapiantation
HMA
Hwtansioil
Plasma Creatinina >1.5 ma/l00 ml
Proteinuria >0.5 g/24 hr
Renal Biopsy
Outcome:>l yr Afterthe Transplant
2mo
+
-
+
+
Mild AR
. .
6mo
+
-
+
+
CR
8mo 2nio
+ +
+ +
+ -
+ +
8mo
+
+
+
2 Yr 1 mo
+ +
+ +
+
6mo
+
+
:
Severe CR AR Early CR Severe CR Mild AR Early CR
Transplant Nephrectomy
25 mo 1 mo 6mo
+ + + + + + + + + +
+ + + + + + +
3 yr 6 yr 1 mo 6mo 1 yr 1 mo 3mo
+
+
+ + -
+ + + + + +
+ +
CR NP NP CR CR Mild AR CR CR Mild AR Accelerated AR
... &table CR
... &bie
CR
... . . &bie
CR
... Stable CR Transplant Nephrectomy
NOTE: AR = acute rejection: CR = chronic rejection; NP = not performed.
month after transplantation. They were repeated approximately six months and more than one year after transplantation, except in one patient (Case 6) who required early transplant nephrectomy. Table II summarizes the time sequence of development of common clinical features of rejection as well as the corresponding histologic findings. Two patients (Cases 3 and 5) received two cadaveric kidney transplants. Only data from the course of the second transplant are presented. In both patients hyperchloremic metabolic acidosis was recogniied during each post-transplantation period. Studies of renal function were carried out at least two months after renal transplantation when the patients were clinically stable. They were performed on an outpatient basis or during hospitalization for biopsy of the renal transplant. All studies were performed in the morning. After obtaining blood axid urine samples for baseline determination of electrblytes, the patients were instructed to empty their bladders completely; timed urine collections were then begun. The urine was collectecj in mineral oil for measurement of urine pH and carbon dioxide tension. Tap ice water was given ad libitum to guarantee an adequate urinary output. Venous blood was obtained from a heparinized indwelling catheter at the midpoint of each collection. The urine collections were of approximately 30 to 60 minutes duration.,The glomerular filtration rate (GFR) was measured either by the clearance of endogenous creatinine or by the administration of iothalamate P5 in a dose of 10 &i with 0.1 ml of epinephrine administered subcutaneously 1 hour before starting the clearance collections. Four basic protocols were followed. Clearance Study During Spontaneous
Metabolic Acidosis.
Two to three collections were obtained for determination of GFR, electrolytes and acid excretion. Sodium Sulfate Infusion. In this protocol, the patients and the controls (two normal subjects and one of the control patients with.cadaveric kidney transplantation] were given 1 mg
788
April lS81
The American Journal of Medicine
fludrocortisone orally the night before the study to guarantee the presence of sufficient levels of mineralocorticoid. thus ensuring a state of sodium avidity in all cases. Two control clearance collections of approximately 30 minutes each were obtained and followed by the intravenous administration of a 500 ml solution of 4 percent sodium sulfate, which was infused over a period of 45 to 60 minutes. Four clearance collections were completed at.approximately 60,120,180 and 240 minutes after the beginning of the sodium sulfate infusion. Neutral Phosphate Infusion. This study was performed on a separate day. After completion of two control clearance collections of 30 minutes each, a solution of 0.2 M neutral phosphate was infused tit a rate of 1 to 1.5 ml/min for 120 to 180 minutes. Three to four clearance collections were completed at 120,180 and 240 minuies after the beginning of the neutral phosphate infusion. Two normal subjects and one patient with a cadaveric kidney transplant served as control group for this protocol. In the subjects in whom the urinary pH was not close to the pk of the phosphate system (6.81,a solution of 0.9 M sodium bicarbonate was infused prior to the infusion of phosphate in order to achieve a urine pH as close to 6.8 as possible. Measurement of Renal Potassium Excretion. Renal potassium excretion was measured in the patients with hyperchloremit metabolic acidosis before and after the infusion of sodium sulfate as described. In the four normokalemic patients with a renal transplant, without hyperchloremic metabolic acidosis who served as a control group, the baseline value for potassium excretion was obtained during two clearance collections of approximately 30 minutes each. This was followed by the administration of sodium sulfate in one of them. The remaining three patients were given an intravenous bolus dose of 500 mg acetazolamide; subsequently three clearance collections of approximately 60 minutes duration each were obtained. Acetazolamide administration is known to stimulate
Volume 70
HYPERCHLOREMIC
renal potassium excretion. In patients with chronic renal insufficiency and in normal subjects, we found similar increments in fractional potassium excretion after the infusion of sodium sulfate or acetazolamide [23]. Plasma and urine electrolytes were measured as previously described [24]. Titratable acidity was measured as the amount of 0.1 N sodium hydroxide required to titrate 1 ml of urine sample from the urine pH up to the blood pH. Ammonia was measured by the formalin titrimetric method of Cunnarro and Weiner [25]. Plasma cortisol (at 9 A.M.) and plasma aldosterone levels were determined using a standard radioimmunoassay kit (Diagnostic Products Corporation, Los Angeles]. Plasma renin activity was measured by radioimmunoassay (E. R. Squibb and Sons, Inc., Princeton]. Volume contraction was induced by the oral administration of three doses of 40 mg of furosemide the day before the determinations (at 6 P.M., 12 midnight and 6 A.M.). Blood samples were obtained at 9 A.M. The normal values obtained in our laboratory with this protocol are 3.6 f 1.2 ng/ml/hour for plasma renin activity, and 26.5 i 4.76 ng/dl for plasma aldosterone. Fractional excretion of bicarbonate, sodium and potassium was calculated by the formulas: clearance of bicarbonate/GFR X 100. clearance of sodium/GFR X 100,and clearance of potassium/GFR X 100, respectively. Renal tissue biopsy specimens were analyzed by light mi-
croscopy and immunofluorescence according to standard techniques [26]. No adverse side effects occurred during the course of the studies. Statistical analyses were made using the t test for paired or unpaired data when appropriate. RESULTS General
Data. The nature of the original diseases that lead to chronic renal failure and subsequent kidney transplantation are given in Table I. None of the patients had hyperchloremic acidosis prior to transplantation. Urine acidification studies were not performed before transplantation. Only one of the patients (Case Z] had a condition known to have the potential to impair distal acidification. A distal acidification defect due to recurrence of sickle cell nephropathy in the transplanted kidney cannot be totally excluded in this patient. One of the control patients, however, also had sickle cell’(SS] disease, and he exhibited normal urine acidification during a similar follow-up period of two years posttransplant. In all patients a satisfactory level of over-all graft function had been obtained by the end of the third week post-transplantation as judged by a decrease in serum creatinine below 1.6 mg/lOO ml. Hyperchloremic metabolic acidosis was recognized during the first month after transplantation in four patients and during the second month in the remaining two (Cases 1 and 2). In all cases it persisted thereafter during a follow-up period ranging from three months to nine years (Table II]. Acute and reversible rejection episodes were recognized clinically and histologically in all but one patient (Case 4); they occurred in the first or second month after the transplant (Table II). By the sixth month after the
ACIDOSIS
AFTER
KIDNEY
TRANSPLANTATION-BATLLE
ET AL
kidney transplantation, all but two patients showed unequivocal histologic changes of chronic rejection. In one of these two patients (Case 5), chronic rejection was demonstrated by a transplant biopsy in the third year post-transplantation. The other patient (Case 6) lost his graft in the third month post-transplantation due to an episode of accelerated rejection. Other clinical features of chronic rejection are summarized in Table II in the sequential manner in which they developed. Plasma creatinine was increased above 1.6 mg/dl in all but one case [Case 4) by the end of the first month or during the second month post-transplantation ranging from 1.6 to 2.1 mg/dl. It increased steadily in all but one case (Case 41, ranging from 1.7 to 2.8 mg/dl by the sixth month after renal transplantation. The four control patients had the following plasma creatinine levels by the sixth month after transplantation: 1.0,1.8, 1.1 and 3.2 mg/dl. Long-term hemodialysis was required in two patients (Cases 1 and 6) by the third and eighth month aftei: transplantation, respectively. In addition, two other patients [Cases 2 and 5) had received a second transplant after undergoing nephrectomy of their first transplant due to chronic rejection associated with hyperchloremic metabolic acidosis. Thus, of a total of eight transplanted kidneys, three were lost to chronic rejection before the end of one year post-transplantation, and one was lost to accelerated rejection during the third month after transplantation. In the remaining four transplanted kidneys, function is sufficient to sustain the lives of the recipients at the present follow-up period of at least two years post-transplantation. One of these kidneys was obtained from a living related donor. The recipient (Case 4) has stable chronic rejection with hyperchloremit metabolic acidosis and a GFR of 35 ml/min nine years after transplantation. Proteinuria of more than 0.5 g/24 hours and hypertension were present during the sixth month after transplantation in only one patient (Case 2) and two patients [Cases 2 and 3). respectively. With further deterioration of,graft function, hypertension developed in all patients and proteinuria in three of the five. In only one of the four control patients did evidence of chronic rejection develop during a follow-up period of approximately 18 months. In this patient hyperchloremic metabolic acidosis has not developed. Plasma potassium levels were elevated in two patients [Cases 2 and 5) and normal in the remaining four (Table I). Of the two hyperkalemic patients, one (Case 21 had persistently elevated plasma potassium levels ranging from 5.6 to 6.8 meq/liter throughout the observation period of two years. The other one (Case 5) exhibited intermittent hyperkalemia (plasma potassium ranging from 4.6 to 6.0 meq/liter) during a similar period of observation. Plasma renin activity and plasma aldosterone were measured in all patients during acute volume contraction induced
by furosemide.
This maneuver
April 1981 The American lournal of Medicine
Volume
resulted
70
in
789
HYPERCHLOREMIC
799
April 1981
ACIDOSIS
AFTER KIDNEY TRANSPLANTATION-BATLLE
*
*
I
*
The American Journal of Medicine
ET AL.
increased values of plasma renin activity and normal plasma aldosterone concentrations in the four normokalemic patients (mean plasma renin activity 6.8 f 3.0 ng/ml/hour, mean plasma aldosterone 28.3 f 9.0 ng/dl). These values were not significantly different than those of the four control subjects (mean plasma renin activity 7.1 f 3.2 ng/ml/hour, mean aldosterone 39.0 f 11 ng/lOO ml). The two hyperkalemic patients (Cases z and 5) had very low levels of plasma aldosterone (1.5 and 0.01 pg/liter, respectively] despite their elevated plasma potassium levels. Plasma renin activity was low in Case 2 (0.7 ng/ml/hour) and in the normal range in Case 5 (2.7 ng/ml/hour). Plasma cortisol levels at 9 A.M. were normal in all patients, ranging from 15 to 19 /*g/dl. Urinary Acidification During SIjontaneous Metabolic Acidosis (Table I). Despite the presence of persistent hyperchloremic metabolic acidosis, in five of the six patients urine pH was repeatedly above 5.5. This inability to lower the urine pH was found to antedate the appearance of overt rejection in all but one (Case 6) of these patients, who was not studied until eight years after transplantation. Table I summarizes the blood acid-base and urine pH data during spontaneous systemic acidosis in the six patients. All of them had a mild nonanion gap metabolic acidosis (blood pH 7.31 f 0.01, plasma bicarbonate 17 f 1.2 meq/liter, venous pCOZ 35 f 2.0 mm Hg, plasma chloride 111.2 f 1.3 meq/liter and anion gap 16.5 f 1.2 meq/liter). One of the patients (Case 5) had a urine pH below 5.5 (5.19) during spontaneous metabolic acidosis. In the four control patients with a renal transplant the urine pH was below 5.5 (5.17 f 0.2) in the absence of acidosis, and thus they were not tested with acid loading. Fractional bicarbonate excretion calculated at plasma bicarbonate concentrations ranging between 18 and 22 meq/liter was less than 4 percent in all patients (mean 1.2 f 0.5 percent]. These findings are inconsistent with a diagnosis of proximal renal tubular acidosis [27,28]. Net acid excretion corrected per 100 milliliters of GFR was not significantly different between the patients and the controls (55.2 f 7.6 and 58.2 f 9.3 peq/lOO ml of GFR, respectively). This lack of difference. was likely due to the fact that the controls were not acidotic. Thus, the values of acid excretion observed in the patients were probably inappropriately low for their degree of acidosis. The findings of inability to lower the urine pH below 5.5 with systemic acidosis in five patients indicate that their hyperchloremic metabolic acidosis was due to impaired distal acidification. In order to further investigate the mechanism(s) of defective urinary acidification, studies with neutral phosphate and sodium sulfate infusions were undertaken. Measurement of U-B pCOz Gradient During Neutral Phosphate Infusion (Table III and Figure 1). The administration of neutral phosphate resulted in a signifi-
Volume 70
HYPERCHLOREMIC
r
NEUTRAL
IO
ACIDOSIS
AFTER
PHOSPHATE INFUSION
20
30
40
KIDNEY
TRANSPLANTATION-BATLLE
ET AL.
AT URINE pH OF 6.5 TO 7.1
50
60
URINE PHOSPHATE (mM)
igure 1. Shows urine-blood (U-B) carbon djoxide ten&on gradient plotted against urine phosphate concentration. The shaded area corresponds to values observed in control subjects. Observe that the points of all patients, except from those of a patient with selective aldosterone deficiency (Case 5); fail below the normal range.
cant increase
in plasma phosphate and urinary phosphate concentrations in all patients studied. As urine phosphate concentration increases above 15 mM, and providing that urine pH is close to 6.8, normal subjects display a progressive increase in U-B pCOs as depicted in Figure 1. The five patients in whom urine pH was abnormally high during acidosis also had a subnormal U-B pCOZ (5.8 f 2.9 mmHg) during phosphate infusion. In the patient (Case 5) with a normally low urine pH during acidosis, the U-B pCOs increased from 12 to 25 mm Hg during phosphate infusion. This response was similar to that of control subjects in whom the U-B pCOZ increased from 5.6 f 8.9 to 31 f 4.1 mm Hg. Urinary Acidification with Sodium Sulfate Infusion to all the (Table IV). Sodium sulfate was administered patients in whom the urine pH was abnormally high during acidosis except one [Case 4). This maneuver resulted in a marked increase in fractional sodium excretion in all cases. The GFR and plasma bicarbonate concentration remained essentially unchanged. In none of the patients could the urine pH be lowered below 5.5 with sodium sulfate (6.03 f O.Z]. Sodium sulfate had no effect on acid excretion in these patients. In contrast, in control subjects the urine pH was consistently lowered below 5.5 (4.74 f 6.24) and acid excretion increased. Renal Potassium Handling (Table V and Figure 2). Under baseline conditions, fractional potassium excretion in the four normokalemic patients was higher
April
than that of the two hyperkalemic patients, suggesting the presence of impaired renal potassium excretion in the latter. Stimulation of potassium excretion with sodium sulfate resulted in a significant increase in fractional potassium excretion from 37 f 4.8 percent to 81 f 12 percent, p <0.05, in the four normokalemic patients. These values are similar to those of subjects with similarly low GFR levels (Figure 2). One of the hyperkalemic patients [Case 2) had only a modest increase in fractional potassium excretion from 11 percent to 38 percent in response to sodium sulfate infusion despite her elevated plasma potassium level (6.3 meq/liter). The remaining patient (Case 5) was not hyperkalemic at the time of sodium sulfate administration. Fractional potassium excretion in this patient did not increase in response to acetazolamide administration (24 percent versus 28 percent). The two patients with low fractional potassium excretion were the only ones who had diminished plasma aldosterone levels. In the four control patients with a renal transplant, fractional potassium excretion increased from 20 f 7.1 percent to 54 f 3.8 percent, p
19LIi
The American lournal of Medicine
Volume
70
791
HYPERCHLOREMIC
ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
ET AL.
Urinary Acidification in Response to Soditim Sulfate lnfbsion
TABLE IV
Titratable Acidity (wq/mW B SO4
Net Acid Excretion (gsq/min)
PlasmaHCOs(msq/liter) B BOa
Fractional Sodium Excretion (%) B SO.
31 42 58 24
25 17 15 22
17 18 17 27
3.0 0.8 3.7 1.5
4.1 3.0 8.2 10
6.69 5.80 5.93 6.50
6.16 5.55 5.82 8.62
6.9 0.46 1.5 2.3
2.8 0.43 1.1 18
4.9 21 14 3.5
5.5 20 18 12
24 10.5 16 7.3
22 15 15.5 20.5
22 31 29 8
25 35 33 14
Mean (n = 4) 4f6.O
39 f7.4
20 f2.4
21 f2.8
2.2 f0.8
5.8 f1.5
6.23 f0.2
8.03 f0.2
2.8 f1.4
5.5 f4.1
10.8 f4.1
11.4 f3.1
14 f3.5
18 f1.8
22.5 f5.1
26.6 f4.6
p value
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
124 f4.8
26 f0.5
22 f3.0
0.36 ho.16
2.9 kO.13
6.07 f0.4
4.74 f0.24
2.3
l 1.2
0.10 f0.3
16 f9.2
35 f14
14 f3.5
23 f3.2
27 f13
58 f17
GFR (ml/mm) B SOA
Case No. 1 2 3 8
38 82 43 34
Controls 134 (n = 3) f12
B
Urlne pH SO.
HCOs- Excretion (peq/mln) B SOa
NH., Excretion (peq/miri) B SO4
934
NOTE: 6 = baseline; SO4 = sodium sulfate infusion: NH4 = ammonium: HCOs- = bicarbonate.
months after the transplant. In four patients, biopsy specimens taken six months after the transplant revealed interstitial fibrosis and inononuclear cell infiltration as well as intimal proliferation in small arteries. These changes are consistent with chronic rejection [29,30]. There were no comparable biopsy specimens
TABLE V
in the remaining two patients. In one of them (Case 6) accelerated acute rejection developed with prominent vascular changes, and early transplant nephrectomy was required. The other patient (Case 9) received a kidney from a living related donor and, although there were no early detectable problems with rejection, bi-
Renal Handling of Potassium in Patients with Hyperchloremic Acidosis
CW No.
GFR (mllmln)
Plasma Potassium (msqllile~)
Fractional SodiumExcretion (%)
(%)
1
B NazS04
38 31
3.4 3.4
3.0 4.1
40 85
2
B Nasos
42 48
4.0 3.9
3.7 5.5
32 44
8
8 Na&Od
34 24
3.5 3.4
1.5 10
28 100
4
B A2
27 35
4.9 4.2
0.9 5.2
50 94
B
35 zk3.1
3.9 f0.3
2.2 f0.6
37 f4.8
p
NS
NS
0.05
Na2S04
34 f5.0
3.7 f0.2
6.2 f1.3
81 f12
3
B Na$SO,
62 42
6.0 6.3
0.80 3.0
11 38
5
B AZ
47 48
4.4 4.3
1.2 0.8
24 28
B
72 f20.5
4.1 fO.13
1.1 zto.4
20 f7.1
P
NS
NS
0.01
70 f22.5
3.9 f0.19
2.9 f0.7
54 f3.8
. Mean n=4
Controls n=4 AZ or Na2S04
NOTE: .GFR = glomerular filtration rate; B = baseline; Na2S0, = sodium sulfate; AZ = acetazolamide.
792
Fractional Potassium Excretion
April 1981
The American Journal of Medicine
Volume 70
ACIDOSIS
HYPERCHLOREMIC
AFTER
KIDNEY
TRANSPLANTATION-BATLLE
ET AL.
P< 0.05
cl Base1 ine
q Stimulated
1
TRANSPLANT
TRANSPLANT
CONTIIOLS
I
REJECTION
RJZJECTION
CR1 CONTROLS
GFR=72ml/mh
GFR=35ml/min.
GFR=44ml/min.
GFR=Jlml/min.
TRANSPLANT
ALDO+STERONE
D&A
DEFICIENCY
gure 2. Depicts fractional potassium excretion in patients and controls with a renal transplant as compare to subjects with chronic renal insufficiency (CM). At comparable GFR, fractional potassium excretion was similar among the various groups except for the patients with aldosterone deficiency.
opsy specimens taken three and nine years after transplantation revealed chronic rejection. In all four patients with demonstrable arterial changes at six months, persistence and progression of chronic rejection were noted in biopsy specimens taken six months to one and a half years later (Figure 3). In three of them, immunofluorescent microscopy of biopsy specimens taken at six months revealed homogeneous deposition of C3 along thickened basement membranes of many tubules [Figure 4) and also along the walls of arterioles. COMMENTS This study documents the presence of impaired distal acidification as the mechanism responsible for the hyperchloremic metabolic acidosis seen in our patients after kidney transplantation, Distal renal tubular acidosis is characterized by an inability to lower the urine pH normally (i.e., below 5.5) regardless of the degree of systemic acidosis present [27]. The proximal form of renal tubular acidosis is associated with impaired bicarbonate reabsorption at normal or even low plasma bicarbonate concentrations [28]. In patients with proximal renal tubular acidosis urine pH may be below 5.5 when the plasma bicarbonate level falls to a critical
level when tubular bicarbonate reabsorption becomes complete [29]. The occurrence of hyperchloremic metabolic acidosis after kidney transplantation has been reported in several studies [2-111. Proximal renal tubular acidosis [6-lo] and more often distal renal tubular acidosis have been demonstrated [2,4,9,11]. In these previous studies urinary acidification was assessed by measuring acid excretion in response to acid loading only. In recent years, however, it has become clear that hyperchloremic acidosis can also be associated with aldosterone deficiency and that this kind of acidosis is associated with a preserved capacity to lower the urine pH below 5.5 during acidosis [la-171. In the present study, one of our six patients (Case 5) exhibited the features commonly seen in the hyperchloremic acidosis associated with selective aldosterone deficiency; he was intermittently hyperkalemic, his GFR was moderately reduced, and he had barely detectable levels of plasma aldosterone. His ammonium excretion was low during spontaneous systemic acidosis despite the fact that his urine pH was below 5.5. We do not know whether mineralocorticoid replacement would have restored acid excretion to normal in this patient. In the remaining five patients of our study, the urine
April 1981 The American Journal of Medicine
Volume 70
793
HYPERCHLOREMIC
ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
ET AL.
by virtue of its buffer properties minimizes the pH gradient against which hydrogen ions are secreted. Therefore, if the secretory mechanism for hydrogen ion is impaired (proton pump failure), either one of these two maneuvers should not result in normal urinary acidification [l7]. In contradistinction, if distal renal tubular acidosis originates from mechanism(s) other than proton pump secretory failure, one might see a normal acidification in response to these agents. Both the secretory and the nonsecretory types of distal renal tubular acidosis, however, are characterized by the inability to lower the urine pH normally with acidosis
Figure 3. Case 1. Chronic rejection, arterial type. Severe fibrosis and intimal thickening with occlusion of lumen.
pH was high during chronic systemic acidosis; thus they had distal renal tubular acidosis. One of the five (Case 2) was also aldosterone deficient. All of them responded to sodium sulfate and neutral phosphate administration in a homogeneous fashion; they exhibited a urine pH above 5.5 with the former, and a subnormal U-B pCOs gradient with the latter. As previously shown in experimental models of distal acidification defects [18-221 and other forms of human distal renal tubular acidosis [17], an abnormal response to these maneuvers is best interpreted as indicative of a true defect for hydrogen ion secretion [secretory distal renal tubular acidosis). These two maneuvers complement each other as they assess the component of distal hydrogen ion secretion that is dependent on a favorable electrical gradient (increased luminal negativity as a result of enhanced distal delivery of sodium with a poorly reabsorbable anion, i.e., sodium sulfate administration) and the component dependent on the chemical hydrogen ion gradient since phosphate
Flgure 4. Case 3. lmmunofluorescence microscopy. The thickened basement membrane of some tubules shows homogeneous deposit of Cs. The same deposit was also noted along the walls of arterioles.
794
April 1981
The American Journal of Medicine
1171. Our two hyperkalemic patients had very low levels of plasma aldosterone after acute volume contraction. This hormone is essential for efficient potassium excretion by the kidney. That renal potassium excretion was defective in these two hyperkalemic patients is demonstrated by the findings of low baseline fractional potassium excretion in the face of hyperkalemia and failure to increase fractional potassium excretion in response to sodium sulfate infusion [in Case 2) or acetazolamide (in Case 5). Impaired potassium excretion was likely the result of isolated aldosterone deficiency in Case 5 in which the patient had the typical pattern of’ impaired acid and potassium excretion of selective aldosterone deficiency [13-171. We cannot be certain, however, that his defective potassium excretion was solely the result of aldosterone deficiency since mineralocorticoid was not administered to this patient. The impaired capacity for potassium secretion in the other hyperkalemic patient (Case 2) could also be due to aldosterone deficiency. This patient, however, had a tubular defect for hydrogen ion secretion as demonstrated by her failure to acidify the urine normally during acidosis and sodium sulfate or neutral phosphate administration. It is likely that she also had a tubular defect for potassium secretion since her fractional potassium excretion failed to increase normally in response to sodium sulfate and fludrocortisone administration. We have recently observed a group of patients with obstructive uropathy who had a similar impairment for potassium and hydrogen ion secretion: they also were not responsive to sodium sulfate and mineralocorticoid administration [23]. The occurrence of hyperkalemia after kidney transplantation has been previously reported [3,31]. DeFronzo et al. [3l] studied four patients who had hyperkalemia despite normal aldosterone levels and in whom potassium excretion could not be increased normally after mineralocorticoid and acetazolamide administration. The tubular defect observed in these patients was not associated with systemic acidosis, suggesting that distal acidification was intact. Our two hyperkalemic patients differ from those of DeFronzo et al. [3l] in that they were both aldosterone deficient. Our findings of normal renal handling of potassium in the remaining four patients suggest that chronic rejection in
Volume 70
HYPERCHLOREMIC
the absence of aldosterone deficiency may not compromise potassium excretion. The findings of characteristic histologic changes of chronic rejection in association with impaired distal acidification deserve some comment. Impaired acidification is the result of tubular dysfunction. Our findings of homogeneous deposition of C3 along the tubular basement membrane in association with distal renal tubular acidosis in three patients suggest that hyperchloremic metabolic acidosis may be the functional expression of immunologically mediated allograft rejection. Unfortunately, immunofluorescence studies were not performed in all cases. The characteristic findings of interstitial mononuclear cell infiltration, interstitial fibrosis and intimal proliferation in small arteries were present in the five patients with chronic rejection. Mononuclear cell infiltration of the kidney interstitium is also found in other forms of distal renal tubular acidosis associated with autoimmune diseases such as Sjijgren’s syndrome and systemic lupus erythematosus [32-341. Therefore, it appears reasonable to hypothesize that impaired distal acidification in our patients was the result of immunologically mediated
ACIDOSIS
AFTER
KIDNEY
TRANSPLANTATION-BATLLE
ET AL.
kidney damage. We were unable to find any significant differences in histologic appearance between proximal and distal tubules. The reasons why only distal damage is functionally evident are not clear. Controlled longitudinal studies are needed to definitively establish a cause and effect relationship between immunologic tubular damage and distal renal tubular acidosis. Lastly, it should be emphasized that in our study as well as in other studies [1,2,9], hyperchloremic metabolic acidosis was recognized in the first two months after transplantation. The serial acidification studies of Wilson and Siddiqui [9] and the present study suggest that impaired distal acidification after kidney transplantation, when persistent, signals the development of chronic rejection. Long-term prospective studies of urine acidification are needed to clarify the prevalence and significance of renal tubular acidosis after kidney transplantation. The findings of distal renal tubular acidosis as the cause of hyperchloremic metabolic acidosis in patients with a renal transplant may indicate permanent tubular damage and should be regarded as an adverse sign of graft function and survival.
REFERENCES 1. 2. 3.
4. 5.
6.
7. 8.
9. IO. Il. 12.
Massry SG, Preuss HG. Maher JF, Schreiner GE: Renal tubular acidosis after cadaver kidney homotransplantation. Am J Med 1967: 42: 284-292. Mookerjee B, Gault MH, Dossetor JB: Hyperchloremic acidosis in early diagnosis of renal allograft rejection. Ann Intern Med 1969; 71: 47-57. Gyory AZ, Stewart JH, George CRP, et al.: Renal tubular acidosis, acidosis due to hyperkalemia, hypercalcemia, disordered citrate metabolism and other tubular dysfunctions followine human renal transolantation. 0._,1Med 1969; 38: 231-254. ” Better OS. Chaimowitz C. Naveh Y. et al.: Svndrome of incompleie renal tubular acidosis after cadaver kidney transplantation. Ann Intern Med 1969; 71: 39-46. Better OS, Chaimowitz C, Ahoy GG. et al.: Spontaneous remission of the defect in urinary acidification after cadaver kidney homotransplantation. Lancet 1970; 1: 110-112. Henderson LW, Nolph KD, Puschett JB, Goldburg M: Proximal tubular malfunction as a mechanism for diuresis after renal homotransplantation. N Engl J Med 1968; 278: 467-473. Liebau G. Miiller R, Schad H, Edel HH: Proximale tubulare Acidose bei nierentransulantierten Patienten. Klin Wochenschr 1970; 48: 624-6i9. Briggs WA, Kominami N, Wilson RE, Merrill JP: Kidney transplantation and Fanconi syndrome. N Engl J Med 1972; 286: 25. Wilson DR, Siddiqui AA: Renal tubular acidosis after kidney transplantation. Natural history and significance. Ann Intern Med 1973; 79: 352-361. _ Vertuno LL. Preuss HG. Argy WP, Schreiner GE: Fanconi syndrome following homotransplantation. Arch Intern Med 1974: 133: 302-305. Vaziri ND, ‘Nellands RE, Brueggmann RM. Barton CH, Martin DC: Renal tubular dysfunction in transplanted kidneys. Southern Med J 1979; 72: 530-534. Schambelan M, Stockigt J, Biglier E: Isolated hypoaldosteronism in adults. A renin-deficiency syndrome. N Engl J Med 1972: 287: 573-578.
13. Perez G, Siegel L. Schreiner GE: Selective hypoaldosteronism with hyperkalemia. Ann Intern Med 1972; 76: 757-763. 14. Schambelan M, Sebastian A: Hyporeninemic hypoaldosteronism. Adv Intern Med 1978; 24: 385-405. 15. Hulter HN. Ilnocki LP. HarlottIe JA. Sebastian A: Impaired renal H+ secretion and NHs production in mineralocorticoid-deficient glucocorticoid-teplete dogs. Am J Physiol 1977; 232: Fl36-F146. 16. DiTella P, Sodhi B, McCreary J. Arruda JAL, Kurtzman NA: The mechanism of the metabolic acidosis of selective mineralocorticoid deficiencv. Kidnev Int 1978: 14: 466-477. 17. Batlle DC, Sehy JT, Roseman MK, Arruda JAL, Kurtzman NA: The clinical and pathophysiological spectrum of acquired distal renal tubular acidosis. Kidnev Int 1981 (in press). 18. Thirakomen K, Kozolov N, Arruda JAL, Kurtzman NA: Renal hvdronen ion secretion followinr! the release of unilateral u;eter& obstruction. Am J Phy&ll976; 231: 1233-1239. 19. Arruda JAL, Nascimento L, Kumar SK, Kurtzman NA: Factors influencing the formation of urinary carbon dioxide tension. Kidney Int 1977; 11: 307-317. 20. Arruda JAL, Nascimento L, Mehta PK. et al.: The critical importance of urinary concentrating ability in the generation of urinary carbon dioxide tension. J Clin Invest 1977; 60: 922-935. 21. Kurtzman NA, Arruda JAL: Physiologic significance of urinary carbon dioxide tension. Min Elect Metab 1978; 1: 241-246. 22. Arruda JAL, Kurtzman NA: Metabolic acidosis and alkalosis. Chin Neph 1977: 7: 201-215. 23. Batlle DC, Arruda IAL. Kurtzman NA: Hvnerkalemia and distal renal tubuiar acidosis associated”&th obstructive uropathy. N Engl J Med 1981; 304: 373-380. 24. Kurtzman NA: Regulation of renal bicarbonate reabsorption by extracellular volume. J Clin Invest 1970; 49: 586-595. 25. Cunnarro JA, Weiner MW: A comparison of methods for measuring urinary ammonium. Kidney Int 1974; 5: 303305.
April 1981
The American Journal of Medicine
Volume
70
795
HYPERCHLOREMIC ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
26. 27.
28. 29.
30.
796
Pirani CL, Salinas-Madrigal L: Evaluation of percutaneous renal biopsy. In: Sommers SC, ed. Pathology annual. New York: Appleton Century Crofts, 1978; 249-296. Sebastian A. McSherrv E. Morris RC Ir.: Metabolic acidosis with special reference to the renal acidosis. In: Brenner BM, Rector FC Jr., eds. The kidney. Philadelphia: WB Saunders, 1976; 615-660. Sorianno JR, Edelmann CM, Jr: Renal tubular acidosis. Ann Rev Med 1969: 20: 363-382. Olsen S: Pathology of the renal allograft rejection. In: Churg V. Snargo B, Mostofi FK. Abel1 M. eds. Kidnev disease: present-status. Baltimore: Williams & Wilkins. 1979; 327-355. Rowlands DT, Hill GS, Zmijewski CM: The pathology of
April 1961 The American Journal of Medicine
ET AL.
renal hemograft rejection. A review. Am J Path01 1976: 85:744-804. 31. DeFronzo RA, Goldberg M, Cooke CR, Barker C, Grossman RA. Aaus ZS: Investigations into the mechanisms of hvperkalgmia following renal transplantation. Kidney btt 1977;ll: 357-365. 32. Shioji R, Furuyama T, Onodera S, et al.: Sjogren’s syndrome and renal tubular acidosis. Am J Med 1970; 48:456-463. 33. Tu WH, Shearn MA: Systemic lupus erythematosus and latent renal tubular dysfunction. Ann Intern Med 1967; 67: 100-109. 34. Andres GA, McCluskey RT: Tubular and interstitial renal disease due to immunologic mechanisms. Kidney Int 1975; 7: 271-289.
Volume 70
DANIEL C. BATLLE, M.D. MARTIN F. MOZES, M.D. JOSE MANALIGOD, M.D. JOSE A. L. ARRLJDA, M.D. NEIL A. KURTZMAN,
M.D.
Chicago, Illinois
From the Section of Nephrology,. and Departments of Pathology and Transplant Surgery, University of Illinois Hospital and the Veterans Administration West Side Hospital, Chicago, Illinois. Parts of this work were presented at the National Meeting of the Amdrican Society of Nephrology, Boston, November 1979. This research waspnpported in part by VA Central Of: fice Grant 7083, VA Basic Institutional Support Grant 3324, Chicago Heart Association Grants A79-28 and A79-30. and National Institutes of Health Grant AM 20170. Requests for reprints should be addressed to Dr. Daniel C. Batlle, Section of Nephrology. University of Illinois Hospital, 840 South Wood Street, Chicago, Ill. 60612. Manuscript accepted August 13.1980.
786
April 1981
The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was irivestigated in six patients. In five patients in whom acidosis failed to loweir the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pC02) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pC0~ normally with the administration of phosphate, demonstrating that this patient’s distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone defidiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion in response to stimulation with SOdium sulfate or acetaiolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement ((23)along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection. Hyperchloremic metabolic acidosis due to the development of renal tubular acidosis after kidney transplantation was first well documented in 1967 in a patient studied by Massry et al. [l]. Subsequently, the occurrence of renal tubular acidosis after kidney transplantation was confirmed in several studies [Z-11]. Most of the patients described presented with mild hyperchloremic metabolic acidosis, and their urine pH was inappropriately high. In some of them, however, the urine pH was inappropriately high with ammonium chloride-induced acidosis, but they were not spontaneously acidotic [4,9]. Thus, they appear to have an incomplete form of distal renal tubular acidosis. Proximal renal tubular acidosis with generalized proximal tubular dysfunction has also been described [6-lo]. In these early studies, the defect in urinary acidification was usually observed in the first few months after transplantation; in some cases it appeared to be reversible [3,5,9]. It was suggested that the defective urinary acidification was related to acute rejection episodes or caused by ischemic tubular damage [Z-5,9]. Bicarbonate wastage due to secondary hyperparathyroidism was also implicated [9]. More recently, Wilson and Siddiqui [9] confirmed previous observations that defective urinary acidification commonly develops in the early post-transplant period but also demonstrated that in some cases it was persistent over a one to three year period. Furthermore, these investigators noticed
The American Journal of Medicine
Volume 70
HYPERCHLOREMIC
ACIDOSIS
AFTER
KIDNEY
TRANSPLANTATION--BATLLE
ET AL.
that persistence of a defect in lowering the urine pH normally was often accompanied by the development of clinical features of chronic rejection, and they suggested that distal renal tubular acidosis in long-standing renal allografts could be the result of the immunologic injury that causes chronic rejection. In recent years, it has become clear that hyperchloremit metabolic acidosis can also develop in association with isolated aldosterone deficiency [12-171 and that in this syndrome, unlike in distal renal tubular acidosis, the ability to lower the urine pH during acidosis is preserved [x4-171. Furthermore, our studies in animals and in human subjects have shown that an acquired distal acidification defect can result from a secretory or a nonsecretory defect in hydrogen ion transport [17-231. Both defects can be distinguished by the acidification response to sodium sulfate or neutral phosphate administration. In patients with a secretory defect for hydrogen ion secretion, urine pH after the administration of sodium sulfate is not lowered normally, and the urine-blood (U-B) pCO2 gradient during the infusion of neutral phosphate at a urine pH close to 6.8is subnormal [17]. Contrarily, patients with a nonsecretory defect respond normally to both maneuvers [w]. In the present study we used these maneuvers to investigate the pathogenesis of persistent hyperchloremic metabolic acidosis associated with renal transplantation. It is of interest that in all of our patients, with the exception of one who lost his transplant due to early accelerated rejection, histologic changes of chronic rejection ultimately developed. A possible relationship between immunologic kidney damage and a tubular defect for distal hydrogen ion secretion is postulated in order to correlate our morphologic and functional findings. PATIENTS
AND METHODS
Ten patients who had received kidney transplants were studied. Persistent hyperchloremic metabolic acidosis was recognized in six of them; five received a kidney transplant from cadaveric donors, and one patient received a kidney from a living related donor. The remaining four patients received grafts from three cadaveric and one living related donor. In these patients hyperchloremic acidosis was not present, and they served as a control group. All patients were treated with a similar immunosuppressive protocol consisting of azathioprine and prednisone. Acute rejection episodes were treated with local radiation to the graft and by increasing the dose of prednisone to z mg/kg body weight daily for seven days and then gradually decreasing the dose to the previous level over a period of 30 days. Other medications which could interfere with urinary acidification and renal potassium handling, such as diuretics and alkalinizing agents, were not administered for at least three days prior to study. The patients were allowed to continue their regular diets at the time of all the studies. The diagnosis of the original renal disease and other clinical features are listed in Table 1. In all but one patient (Case 4). renal transplant biopsies were performed during the first
April 1981
The American
Journal of Medicine
Volume
70
HYPERCHLOREMIC
TABLE II
CaSe No. 1
2
3
4
5
6
ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
ET AL.
Clinical Course in Six R&al Transplant Reclplents wlth Hyperchloremlc Metabolic Acldosls (HMA)
time after Tranapiantation
HMA
Hwtansioil
Plasma Creatinina >1.5 ma/l00 ml
Proteinuria >0.5 g/24 hr
Renal Biopsy
Outcome:>l yr Afterthe Transplant
2mo
+
-
+
+
Mild AR
. .
6mo
+
-
+
+
CR
8mo 2nio
+ +
+ +
+ -
+ +
8mo
+
+
+
2 Yr 1 mo
+ +
+ +
+
6mo
+
+
:
Severe CR AR Early CR Severe CR Mild AR Early CR
Transplant Nephrectomy
25 mo 1 mo 6mo
+ + + + + + + + + +
+ + + + + + +
3 yr 6 yr 1 mo 6mo 1 yr 1 mo 3mo
+
+
+ + -
+ + + + + +
+ +
CR NP NP CR CR Mild AR CR CR Mild AR Accelerated AR
... &table CR
... &bie
CR
... . . &bie
CR
... Stable CR Transplant Nephrectomy
NOTE: AR = acute rejection: CR = chronic rejection; NP = not performed.
month after transplantation. They were repeated approximately six months and more than one year after transplantation, except in one patient (Case 6) who required early transplant nephrectomy. Table II summarizes the time sequence of development of common clinical features of rejection as well as the corresponding histologic findings. Two patients (Cases 3 and 5) received two cadaveric kidney transplants. Only data from the course of the second transplant are presented. In both patients hyperchloremic metabolic acidosis was recogniied during each post-transplantation period. Studies of renal function were carried out at least two months after renal transplantation when the patients were clinically stable. They were performed on an outpatient basis or during hospitalization for biopsy of the renal transplant. All studies were performed in the morning. After obtaining blood axid urine samples for baseline determination of electrblytes, the patients were instructed to empty their bladders completely; timed urine collections were then begun. The urine was collectecj in mineral oil for measurement of urine pH and carbon dioxide tension. Tap ice water was given ad libitum to guarantee an adequate urinary output. Venous blood was obtained from a heparinized indwelling catheter at the midpoint of each collection. The urine collections were of approximately 30 to 60 minutes duration.,The glomerular filtration rate (GFR) was measured either by the clearance of endogenous creatinine or by the administration of iothalamate P5 in a dose of 10 &i with 0.1 ml of epinephrine administered subcutaneously 1 hour before starting the clearance collections. Four basic protocols were followed. Clearance Study During Spontaneous
Metabolic Acidosis.
Two to three collections were obtained for determination of GFR, electrolytes and acid excretion. Sodium Sulfate Infusion. In this protocol, the patients and the controls (two normal subjects and one of the control patients with.cadaveric kidney transplantation] were given 1 mg
788
April lS81
The American Journal of Medicine
fludrocortisone orally the night before the study to guarantee the presence of sufficient levels of mineralocorticoid. thus ensuring a state of sodium avidity in all cases. Two control clearance collections of approximately 30 minutes each were obtained and followed by the intravenous administration of a 500 ml solution of 4 percent sodium sulfate, which was infused over a period of 45 to 60 minutes. Four clearance collections were completed at.approximately 60,120,180 and 240 minutes after the beginning of the sodium sulfate infusion. Neutral Phosphate Infusion. This study was performed on a separate day. After completion of two control clearance collections of 30 minutes each, a solution of 0.2 M neutral phosphate was infused tit a rate of 1 to 1.5 ml/min for 120 to 180 minutes. Three to four clearance collections were completed at 120,180 and 240 minuies after the beginning of the neutral phosphate infusion. Two normal subjects and one patient with a cadaveric kidney transplant served as control group for this protocol. In the subjects in whom the urinary pH was not close to the pk of the phosphate system (6.81,a solution of 0.9 M sodium bicarbonate was infused prior to the infusion of phosphate in order to achieve a urine pH as close to 6.8 as possible. Measurement of Renal Potassium Excretion. Renal potassium excretion was measured in the patients with hyperchloremit metabolic acidosis before and after the infusion of sodium sulfate as described. In the four normokalemic patients with a renal transplant, without hyperchloremic metabolic acidosis who served as a control group, the baseline value for potassium excretion was obtained during two clearance collections of approximately 30 minutes each. This was followed by the administration of sodium sulfate in one of them. The remaining three patients were given an intravenous bolus dose of 500 mg acetazolamide; subsequently three clearance collections of approximately 60 minutes duration each were obtained. Acetazolamide administration is known to stimulate
Volume 70
HYPERCHLOREMIC
renal potassium excretion. In patients with chronic renal insufficiency and in normal subjects, we found similar increments in fractional potassium excretion after the infusion of sodium sulfate or acetazolamide [23]. Plasma and urine electrolytes were measured as previously described [24]. Titratable acidity was measured as the amount of 0.1 N sodium hydroxide required to titrate 1 ml of urine sample from the urine pH up to the blood pH. Ammonia was measured by the formalin titrimetric method of Cunnarro and Weiner [25]. Plasma cortisol (at 9 A.M.) and plasma aldosterone levels were determined using a standard radioimmunoassay kit (Diagnostic Products Corporation, Los Angeles]. Plasma renin activity was measured by radioimmunoassay (E. R. Squibb and Sons, Inc., Princeton]. Volume contraction was induced by the oral administration of three doses of 40 mg of furosemide the day before the determinations (at 6 P.M., 12 midnight and 6 A.M.). Blood samples were obtained at 9 A.M. The normal values obtained in our laboratory with this protocol are 3.6 f 1.2 ng/ml/hour for plasma renin activity, and 26.5 i 4.76 ng/dl for plasma aldosterone. Fractional excretion of bicarbonate, sodium and potassium was calculated by the formulas: clearance of bicarbonate/GFR X 100. clearance of sodium/GFR X 100,and clearance of potassium/GFR X 100, respectively. Renal tissue biopsy specimens were analyzed by light mi-
croscopy and immunofluorescence according to standard techniques [26]. No adverse side effects occurred during the course of the studies. Statistical analyses were made using the t test for paired or unpaired data when appropriate. RESULTS General
Data. The nature of the original diseases that lead to chronic renal failure and subsequent kidney transplantation are given in Table I. None of the patients had hyperchloremic acidosis prior to transplantation. Urine acidification studies were not performed before transplantation. Only one of the patients (Case Z] had a condition known to have the potential to impair distal acidification. A distal acidification defect due to recurrence of sickle cell nephropathy in the transplanted kidney cannot be totally excluded in this patient. One of the control patients, however, also had sickle cell’(SS] disease, and he exhibited normal urine acidification during a similar follow-up period of two years posttransplant. In all patients a satisfactory level of over-all graft function had been obtained by the end of the third week post-transplantation as judged by a decrease in serum creatinine below 1.6 mg/lOO ml. Hyperchloremic metabolic acidosis was recognized during the first month after transplantation in four patients and during the second month in the remaining two (Cases 1 and 2). In all cases it persisted thereafter during a follow-up period ranging from three months to nine years (Table II]. Acute and reversible rejection episodes were recognized clinically and histologically in all but one patient (Case 4); they occurred in the first or second month after the transplant (Table II). By the sixth month after the
ACIDOSIS
AFTER
KIDNEY
TRANSPLANTATION-BATLLE
ET AL
kidney transplantation, all but two patients showed unequivocal histologic changes of chronic rejection. In one of these two patients (Case 5), chronic rejection was demonstrated by a transplant biopsy in the third year post-transplantation. The other patient (Case 6) lost his graft in the third month post-transplantation due to an episode of accelerated rejection. Other clinical features of chronic rejection are summarized in Table II in the sequential manner in which they developed. Plasma creatinine was increased above 1.6 mg/dl in all but one case [Case 4) by the end of the first month or during the second month post-transplantation ranging from 1.6 to 2.1 mg/dl. It increased steadily in all but one case (Case 41, ranging from 1.7 to 2.8 mg/dl by the sixth month after renal transplantation. The four control patients had the following plasma creatinine levels by the sixth month after transplantation: 1.0,1.8, 1.1 and 3.2 mg/dl. Long-term hemodialysis was required in two patients (Cases 1 and 6) by the third and eighth month aftei: transplantation, respectively. In addition, two other patients [Cases 2 and 5) had received a second transplant after undergoing nephrectomy of their first transplant due to chronic rejection associated with hyperchloremic metabolic acidosis. Thus, of a total of eight transplanted kidneys, three were lost to chronic rejection before the end of one year post-transplantation, and one was lost to accelerated rejection during the third month after transplantation. In the remaining four transplanted kidneys, function is sufficient to sustain the lives of the recipients at the present follow-up period of at least two years post-transplantation. One of these kidneys was obtained from a living related donor. The recipient (Case 4) has stable chronic rejection with hyperchloremit metabolic acidosis and a GFR of 35 ml/min nine years after transplantation. Proteinuria of more than 0.5 g/24 hours and hypertension were present during the sixth month after transplantation in only one patient (Case 2) and two patients [Cases 2 and 3). respectively. With further deterioration of,graft function, hypertension developed in all patients and proteinuria in three of the five. In only one of the four control patients did evidence of chronic rejection develop during a follow-up period of approximately 18 months. In this patient hyperchloremic metabolic acidosis has not developed. Plasma potassium levels were elevated in two patients [Cases 2 and 5) and normal in the remaining four (Table I). Of the two hyperkalemic patients, one (Case 21 had persistently elevated plasma potassium levels ranging from 5.6 to 6.8 meq/liter throughout the observation period of two years. The other one (Case 5) exhibited intermittent hyperkalemia (plasma potassium ranging from 4.6 to 6.0 meq/liter) during a similar period of observation. Plasma renin activity and plasma aldosterone were measured in all patients during acute volume contraction induced
by furosemide.
This maneuver
April 1981 The American lournal of Medicine
Volume
resulted
70
in
789
HYPERCHLOREMIC
799
April 1981
ACIDOSIS
AFTER KIDNEY TRANSPLANTATION-BATLLE
*
*
I
*
The American Journal of Medicine
ET AL.
increased values of plasma renin activity and normal plasma aldosterone concentrations in the four normokalemic patients (mean plasma renin activity 6.8 f 3.0 ng/ml/hour, mean plasma aldosterone 28.3 f 9.0 ng/dl). These values were not significantly different than those of the four control subjects (mean plasma renin activity 7.1 f 3.2 ng/ml/hour, mean aldosterone 39.0 f 11 ng/lOO ml). The two hyperkalemic patients (Cases z and 5) had very low levels of plasma aldosterone (1.5 and 0.01 pg/liter, respectively] despite their elevated plasma potassium levels. Plasma renin activity was low in Case 2 (0.7 ng/ml/hour) and in the normal range in Case 5 (2.7 ng/ml/hour). Plasma cortisol levels at 9 A.M. were normal in all patients, ranging from 15 to 19 /*g/dl. Urinary Acidification During SIjontaneous Metabolic Acidosis (Table I). Despite the presence of persistent hyperchloremic metabolic acidosis, in five of the six patients urine pH was repeatedly above 5.5. This inability to lower the urine pH was found to antedate the appearance of overt rejection in all but one (Case 6) of these patients, who was not studied until eight years after transplantation. Table I summarizes the blood acid-base and urine pH data during spontaneous systemic acidosis in the six patients. All of them had a mild nonanion gap metabolic acidosis (blood pH 7.31 f 0.01, plasma bicarbonate 17 f 1.2 meq/liter, venous pCOZ 35 f 2.0 mm Hg, plasma chloride 111.2 f 1.3 meq/liter and anion gap 16.5 f 1.2 meq/liter). One of the patients (Case 5) had a urine pH below 5.5 (5.19) during spontaneous metabolic acidosis. In the four control patients with a renal transplant the urine pH was below 5.5 (5.17 f 0.2) in the absence of acidosis, and thus they were not tested with acid loading. Fractional bicarbonate excretion calculated at plasma bicarbonate concentrations ranging between 18 and 22 meq/liter was less than 4 percent in all patients (mean 1.2 f 0.5 percent]. These findings are inconsistent with a diagnosis of proximal renal tubular acidosis [27,28]. Net acid excretion corrected per 100 milliliters of GFR was not significantly different between the patients and the controls (55.2 f 7.6 and 58.2 f 9.3 peq/lOO ml of GFR, respectively). This lack of difference. was likely due to the fact that the controls were not acidotic. Thus, the values of acid excretion observed in the patients were probably inappropriately low for their degree of acidosis. The findings of inability to lower the urine pH below 5.5 with systemic acidosis in five patients indicate that their hyperchloremic metabolic acidosis was due to impaired distal acidification. In order to further investigate the mechanism(s) of defective urinary acidification, studies with neutral phosphate and sodium sulfate infusions were undertaken. Measurement of U-B pCOz Gradient During Neutral Phosphate Infusion (Table III and Figure 1). The administration of neutral phosphate resulted in a signifi-
Volume 70
HYPERCHLOREMIC
r
NEUTRAL
IO
ACIDOSIS
AFTER
PHOSPHATE INFUSION
20
30
40
KIDNEY
TRANSPLANTATION-BATLLE
ET AL.
AT URINE pH OF 6.5 TO 7.1
50
60
URINE PHOSPHATE (mM)
igure 1. Shows urine-blood (U-B) carbon djoxide ten&on gradient plotted against urine phosphate concentration. The shaded area corresponds to values observed in control subjects. Observe that the points of all patients, except from those of a patient with selective aldosterone deficiency (Case 5); fail below the normal range.
cant increase
in plasma phosphate and urinary phosphate concentrations in all patients studied. As urine phosphate concentration increases above 15 mM, and providing that urine pH is close to 6.8, normal subjects display a progressive increase in U-B pCOs as depicted in Figure 1. The five patients in whom urine pH was abnormally high during acidosis also had a subnormal U-B pCOZ (5.8 f 2.9 mmHg) during phosphate infusion. In the patient (Case 5) with a normally low urine pH during acidosis, the U-B pCOs increased from 12 to 25 mm Hg during phosphate infusion. This response was similar to that of control subjects in whom the U-B pCOZ increased from 5.6 f 8.9 to 31 f 4.1 mm Hg. Urinary Acidification with Sodium Sulfate Infusion to all the (Table IV). Sodium sulfate was administered patients in whom the urine pH was abnormally high during acidosis except one [Case 4). This maneuver resulted in a marked increase in fractional sodium excretion in all cases. The GFR and plasma bicarbonate concentration remained essentially unchanged. In none of the patients could the urine pH be lowered below 5.5 with sodium sulfate (6.03 f O.Z]. Sodium sulfate had no effect on acid excretion in these patients. In contrast, in control subjects the urine pH was consistently lowered below 5.5 (4.74 f 6.24) and acid excretion increased. Renal Potassium Handling (Table V and Figure 2). Under baseline conditions, fractional potassium excretion in the four normokalemic patients was higher
April
than that of the two hyperkalemic patients, suggesting the presence of impaired renal potassium excretion in the latter. Stimulation of potassium excretion with sodium sulfate resulted in a significant increase in fractional potassium excretion from 37 f 4.8 percent to 81 f 12 percent, p <0.05, in the four normokalemic patients. These values are similar to those of subjects with similarly low GFR levels (Figure 2). One of the hyperkalemic patients [Case 2) had only a modest increase in fractional potassium excretion from 11 percent to 38 percent in response to sodium sulfate infusion despite her elevated plasma potassium level (6.3 meq/liter). The remaining patient (Case 5) was not hyperkalemic at the time of sodium sulfate administration. Fractional potassium excretion in this patient did not increase in response to acetazolamide administration (24 percent versus 28 percent). The two patients with low fractional potassium excretion were the only ones who had diminished plasma aldosterone levels. In the four control patients with a renal transplant, fractional potassium excretion increased from 20 f 7.1 percent to 54 f 3.8 percent, p
19LIi
The American lournal of Medicine
Volume
70
791
HYPERCHLOREMIC
ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
ET AL.
Urinary Acidification in Response to Soditim Sulfate lnfbsion
TABLE IV
Titratable Acidity (wq/mW B SO4
Net Acid Excretion (gsq/min)
PlasmaHCOs(msq/liter) B BOa
Fractional Sodium Excretion (%) B SO.
31 42 58 24
25 17 15 22
17 18 17 27
3.0 0.8 3.7 1.5
4.1 3.0 8.2 10
6.69 5.80 5.93 6.50
6.16 5.55 5.82 8.62
6.9 0.46 1.5 2.3
2.8 0.43 1.1 18
4.9 21 14 3.5
5.5 20 18 12
24 10.5 16 7.3
22 15 15.5 20.5
22 31 29 8
25 35 33 14
Mean (n = 4) 4f6.O
39 f7.4
20 f2.4
21 f2.8
2.2 f0.8
5.8 f1.5
6.23 f0.2
8.03 f0.2
2.8 f1.4
5.5 f4.1
10.8 f4.1
11.4 f3.1
14 f3.5
18 f1.8
22.5 f5.1
26.6 f4.6
p value
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
124 f4.8
26 f0.5
22 f3.0
0.36 ho.16
2.9 kO.13
6.07 f0.4
4.74 f0.24
2.3
l 1.2
0.10 f0.3
16 f9.2
35 f14
14 f3.5
23 f3.2
27 f13
58 f17
GFR (ml/mm) B SOA
Case No. 1 2 3 8
38 82 43 34
Controls 134 (n = 3) f12
B
Urlne pH SO.
HCOs- Excretion (peq/mln) B SOa
NH., Excretion (peq/miri) B SO4
934
NOTE: 6 = baseline; SO4 = sodium sulfate infusion: NH4 = ammonium: HCOs- = bicarbonate.
months after the transplant. In four patients, biopsy specimens taken six months after the transplant revealed interstitial fibrosis and inononuclear cell infiltration as well as intimal proliferation in small arteries. These changes are consistent with chronic rejection [29,30]. There were no comparable biopsy specimens
TABLE V
in the remaining two patients. In one of them (Case 6) accelerated acute rejection developed with prominent vascular changes, and early transplant nephrectomy was required. The other patient (Case 9) received a kidney from a living related donor and, although there were no early detectable problems with rejection, bi-
Renal Handling of Potassium in Patients with Hyperchloremic Acidosis
CW No.
GFR (mllmln)
Plasma Potassium (msqllile~)
Fractional SodiumExcretion (%)
(%)
1
B NazS04
38 31
3.4 3.4
3.0 4.1
40 85
2
B Nasos
42 48
4.0 3.9
3.7 5.5
32 44
8
8 Na&Od
34 24
3.5 3.4
1.5 10
28 100
4
B A2
27 35
4.9 4.2
0.9 5.2
50 94
B
35 zk3.1
3.9 f0.3
2.2 f0.6
37 f4.8
p
NS
NS
0.05
Na2S04
34 f5.0
3.7 f0.2
6.2 f1.3
81 f12
3
B Na$SO,
62 42
6.0 6.3
0.80 3.0
11 38
5
B AZ
47 48
4.4 4.3
1.2 0.8
24 28
B
72 f20.5
4.1 fO.13
1.1 zto.4
20 f7.1
P
NS
NS
0.01
70 f22.5
3.9 f0.19
2.9 f0.7
54 f3.8
. Mean n=4
Controls n=4 AZ or Na2S04
NOTE: .GFR = glomerular filtration rate; B = baseline; Na2S0, = sodium sulfate; AZ = acetazolamide.
792
Fractional Potassium Excretion
April 1981
The American Journal of Medicine
Volume 70
ACIDOSIS
HYPERCHLOREMIC
AFTER
KIDNEY
TRANSPLANTATION-BATLLE
ET AL.
P< 0.05
cl Base1 ine
q Stimulated
1
TRANSPLANT
TRANSPLANT
CONTIIOLS
I
REJECTION
RJZJECTION
CR1 CONTROLS
GFR=72ml/mh
GFR=35ml/min.
GFR=44ml/min.
GFR=Jlml/min.
TRANSPLANT
ALDO+STERONE
D&A
DEFICIENCY
gure 2. Depicts fractional potassium excretion in patients and controls with a renal transplant as compare to subjects with chronic renal insufficiency (CM). At comparable GFR, fractional potassium excretion was similar among the various groups except for the patients with aldosterone deficiency.
opsy specimens taken three and nine years after transplantation revealed chronic rejection. In all four patients with demonstrable arterial changes at six months, persistence and progression of chronic rejection were noted in biopsy specimens taken six months to one and a half years later (Figure 3). In three of them, immunofluorescent microscopy of biopsy specimens taken at six months revealed homogeneous deposition of C3 along thickened basement membranes of many tubules [Figure 4) and also along the walls of arterioles. COMMENTS This study documents the presence of impaired distal acidification as the mechanism responsible for the hyperchloremic metabolic acidosis seen in our patients after kidney transplantation, Distal renal tubular acidosis is characterized by an inability to lower the urine pH normally (i.e., below 5.5) regardless of the degree of systemic acidosis present [27]. The proximal form of renal tubular acidosis is associated with impaired bicarbonate reabsorption at normal or even low plasma bicarbonate concentrations [28]. In patients with proximal renal tubular acidosis urine pH may be below 5.5 when the plasma bicarbonate level falls to a critical
level when tubular bicarbonate reabsorption becomes complete [29]. The occurrence of hyperchloremic metabolic acidosis after kidney transplantation has been reported in several studies [2-111. Proximal renal tubular acidosis [6-lo] and more often distal renal tubular acidosis have been demonstrated [2,4,9,11]. In these previous studies urinary acidification was assessed by measuring acid excretion in response to acid loading only. In recent years, however, it has become clear that hyperchloremic acidosis can also be associated with aldosterone deficiency and that this kind of acidosis is associated with a preserved capacity to lower the urine pH below 5.5 during acidosis [la-171. In the present study, one of our six patients (Case 5) exhibited the features commonly seen in the hyperchloremic acidosis associated with selective aldosterone deficiency; he was intermittently hyperkalemic, his GFR was moderately reduced, and he had barely detectable levels of plasma aldosterone. His ammonium excretion was low during spontaneous systemic acidosis despite the fact that his urine pH was below 5.5. We do not know whether mineralocorticoid replacement would have restored acid excretion to normal in this patient. In the remaining five patients of our study, the urine
April 1981 The American Journal of Medicine
Volume 70
793
HYPERCHLOREMIC
ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
ET AL.
by virtue of its buffer properties minimizes the pH gradient against which hydrogen ions are secreted. Therefore, if the secretory mechanism for hydrogen ion is impaired (proton pump failure), either one of these two maneuvers should not result in normal urinary acidification [l7]. In contradistinction, if distal renal tubular acidosis originates from mechanism(s) other than proton pump secretory failure, one might see a normal acidification in response to these agents. Both the secretory and the nonsecretory types of distal renal tubular acidosis, however, are characterized by the inability to lower the urine pH normally with acidosis
Figure 3. Case 1. Chronic rejection, arterial type. Severe fibrosis and intimal thickening with occlusion of lumen.
pH was high during chronic systemic acidosis; thus they had distal renal tubular acidosis. One of the five (Case 2) was also aldosterone deficient. All of them responded to sodium sulfate and neutral phosphate administration in a homogeneous fashion; they exhibited a urine pH above 5.5 with the former, and a subnormal U-B pCOs gradient with the latter. As previously shown in experimental models of distal acidification defects [18-221 and other forms of human distal renal tubular acidosis [17], an abnormal response to these maneuvers is best interpreted as indicative of a true defect for hydrogen ion secretion [secretory distal renal tubular acidosis). These two maneuvers complement each other as they assess the component of distal hydrogen ion secretion that is dependent on a favorable electrical gradient (increased luminal negativity as a result of enhanced distal delivery of sodium with a poorly reabsorbable anion, i.e., sodium sulfate administration) and the component dependent on the chemical hydrogen ion gradient since phosphate
Flgure 4. Case 3. lmmunofluorescence microscopy. The thickened basement membrane of some tubules shows homogeneous deposit of Cs. The same deposit was also noted along the walls of arterioles.
794
April 1981
The American Journal of Medicine
1171. Our two hyperkalemic patients had very low levels of plasma aldosterone after acute volume contraction. This hormone is essential for efficient potassium excretion by the kidney. That renal potassium excretion was defective in these two hyperkalemic patients is demonstrated by the findings of low baseline fractional potassium excretion in the face of hyperkalemia and failure to increase fractional potassium excretion in response to sodium sulfate infusion [in Case 2) or acetazolamide (in Case 5). Impaired potassium excretion was likely the result of isolated aldosterone deficiency in Case 5 in which the patient had the typical pattern of’ impaired acid and potassium excretion of selective aldosterone deficiency [13-171. We cannot be certain, however, that his defective potassium excretion was solely the result of aldosterone deficiency since mineralocorticoid was not administered to this patient. The impaired capacity for potassium secretion in the other hyperkalemic patient (Case 2) could also be due to aldosterone deficiency. This patient, however, had a tubular defect for hydrogen ion secretion as demonstrated by her failure to acidify the urine normally during acidosis and sodium sulfate or neutral phosphate administration. It is likely that she also had a tubular defect for potassium secretion since her fractional potassium excretion failed to increase normally in response to sodium sulfate and fludrocortisone administration. We have recently observed a group of patients with obstructive uropathy who had a similar impairment for potassium and hydrogen ion secretion: they also were not responsive to sodium sulfate and mineralocorticoid administration [23]. The occurrence of hyperkalemia after kidney transplantation has been previously reported [3,31]. DeFronzo et al. [3l] studied four patients who had hyperkalemia despite normal aldosterone levels and in whom potassium excretion could not be increased normally after mineralocorticoid and acetazolamide administration. The tubular defect observed in these patients was not associated with systemic acidosis, suggesting that distal acidification was intact. Our two hyperkalemic patients differ from those of DeFronzo et al. [3l] in that they were both aldosterone deficient. Our findings of normal renal handling of potassium in the remaining four patients suggest that chronic rejection in
Volume 70
HYPERCHLOREMIC
the absence of aldosterone deficiency may not compromise potassium excretion. The findings of characteristic histologic changes of chronic rejection in association with impaired distal acidification deserve some comment. Impaired acidification is the result of tubular dysfunction. Our findings of homogeneous deposition of C3 along the tubular basement membrane in association with distal renal tubular acidosis in three patients suggest that hyperchloremic metabolic acidosis may be the functional expression of immunologically mediated allograft rejection. Unfortunately, immunofluorescence studies were not performed in all cases. The characteristic findings of interstitial mononuclear cell infiltration, interstitial fibrosis and intimal proliferation in small arteries were present in the five patients with chronic rejection. Mononuclear cell infiltration of the kidney interstitium is also found in other forms of distal renal tubular acidosis associated with autoimmune diseases such as Sjijgren’s syndrome and systemic lupus erythematosus [32-341. Therefore, it appears reasonable to hypothesize that impaired distal acidification in our patients was the result of immunologically mediated
ACIDOSIS
AFTER
KIDNEY
TRANSPLANTATION-BATLLE
ET AL.
kidney damage. We were unable to find any significant differences in histologic appearance between proximal and distal tubules. The reasons why only distal damage is functionally evident are not clear. Controlled longitudinal studies are needed to definitively establish a cause and effect relationship between immunologic tubular damage and distal renal tubular acidosis. Lastly, it should be emphasized that in our study as well as in other studies [1,2,9], hyperchloremic metabolic acidosis was recognized in the first two months after transplantation. The serial acidification studies of Wilson and Siddiqui [9] and the present study suggest that impaired distal acidification after kidney transplantation, when persistent, signals the development of chronic rejection. Long-term prospective studies of urine acidification are needed to clarify the prevalence and significance of renal tubular acidosis after kidney transplantation. The findings of distal renal tubular acidosis as the cause of hyperchloremic metabolic acidosis in patients with a renal transplant may indicate permanent tubular damage and should be regarded as an adverse sign of graft function and survival.
REFERENCES 1. 2. 3.
4. 5.
6.
7. 8.
9. IO. Il. 12.
Massry SG, Preuss HG. Maher JF, Schreiner GE: Renal tubular acidosis after cadaver kidney homotransplantation. Am J Med 1967: 42: 284-292. Mookerjee B, Gault MH, Dossetor JB: Hyperchloremic acidosis in early diagnosis of renal allograft rejection. Ann Intern Med 1969; 71: 47-57. Gyory AZ, Stewart JH, George CRP, et al.: Renal tubular acidosis, acidosis due to hyperkalemia, hypercalcemia, disordered citrate metabolism and other tubular dysfunctions followine human renal transolantation. 0._,1Med 1969; 38: 231-254. ” Better OS. Chaimowitz C. Naveh Y. et al.: Svndrome of incompleie renal tubular acidosis after cadaver kidney transplantation. Ann Intern Med 1969; 71: 39-46. Better OS, Chaimowitz C, Ahoy GG. et al.: Spontaneous remission of the defect in urinary acidification after cadaver kidney homotransplantation. Lancet 1970; 1: 110-112. Henderson LW, Nolph KD, Puschett JB, Goldburg M: Proximal tubular malfunction as a mechanism for diuresis after renal homotransplantation. N Engl J Med 1968; 278: 467-473. Liebau G. Miiller R, Schad H, Edel HH: Proximale tubulare Acidose bei nierentransulantierten Patienten. Klin Wochenschr 1970; 48: 624-6i9. Briggs WA, Kominami N, Wilson RE, Merrill JP: Kidney transplantation and Fanconi syndrome. N Engl J Med 1972; 286: 25. Wilson DR, Siddiqui AA: Renal tubular acidosis after kidney transplantation. Natural history and significance. Ann Intern Med 1973; 79: 352-361. _ Vertuno LL. Preuss HG. Argy WP, Schreiner GE: Fanconi syndrome following homotransplantation. Arch Intern Med 1974: 133: 302-305. Vaziri ND, ‘Nellands RE, Brueggmann RM. Barton CH, Martin DC: Renal tubular dysfunction in transplanted kidneys. Southern Med J 1979; 72: 530-534. Schambelan M, Stockigt J, Biglier E: Isolated hypoaldosteronism in adults. A renin-deficiency syndrome. N Engl J Med 1972: 287: 573-578.
13. Perez G, Siegel L. Schreiner GE: Selective hypoaldosteronism with hyperkalemia. Ann Intern Med 1972; 76: 757-763. 14. Schambelan M, Sebastian A: Hyporeninemic hypoaldosteronism. Adv Intern Med 1978; 24: 385-405. 15. Hulter HN. Ilnocki LP. HarlottIe JA. Sebastian A: Impaired renal H+ secretion and NHs production in mineralocorticoid-deficient glucocorticoid-teplete dogs. Am J Physiol 1977; 232: Fl36-F146. 16. DiTella P, Sodhi B, McCreary J. Arruda JAL, Kurtzman NA: The mechanism of the metabolic acidosis of selective mineralocorticoid deficiencv. Kidnev Int 1978: 14: 466-477. 17. Batlle DC, Sehy JT, Roseman MK, Arruda JAL, Kurtzman NA: The clinical and pathophysiological spectrum of acquired distal renal tubular acidosis. Kidnev Int 1981 (in press). 18. Thirakomen K, Kozolov N, Arruda JAL, Kurtzman NA: Renal hvdronen ion secretion followinr! the release of unilateral u;eter& obstruction. Am J Phy&ll976; 231: 1233-1239. 19. Arruda JAL, Nascimento L, Kumar SK, Kurtzman NA: Factors influencing the formation of urinary carbon dioxide tension. Kidney Int 1977; 11: 307-317. 20. Arruda JAL, Nascimento L, Mehta PK. et al.: The critical importance of urinary concentrating ability in the generation of urinary carbon dioxide tension. J Clin Invest 1977; 60: 922-935. 21. Kurtzman NA, Arruda JAL: Physiologic significance of urinary carbon dioxide tension. Min Elect Metab 1978; 1: 241-246. 22. Arruda JAL, Kurtzman NA: Metabolic acidosis and alkalosis. Chin Neph 1977: 7: 201-215. 23. Batlle DC, Arruda IAL. Kurtzman NA: Hvnerkalemia and distal renal tubuiar acidosis associated”&th obstructive uropathy. N Engl J Med 1981; 304: 373-380. 24. Kurtzman NA: Regulation of renal bicarbonate reabsorption by extracellular volume. J Clin Invest 1970; 49: 586-595. 25. Cunnarro JA, Weiner MW: A comparison of methods for measuring urinary ammonium. Kidney Int 1974; 5: 303305.
April 1981
The American Journal of Medicine
Volume
70
795
HYPERCHLOREMIC ACIDOSIS AFTER KIDNEY TRANSPLANTATION-BATLLE
26. 27.
28. 29.
30.
796
Pirani CL, Salinas-Madrigal L: Evaluation of percutaneous renal biopsy. In: Sommers SC, ed. Pathology annual. New York: Appleton Century Crofts, 1978; 249-296. Sebastian A. McSherrv E. Morris RC Ir.: Metabolic acidosis with special reference to the renal acidosis. In: Brenner BM, Rector FC Jr., eds. The kidney. Philadelphia: WB Saunders, 1976; 615-660. Sorianno JR, Edelmann CM, Jr: Renal tubular acidosis. Ann Rev Med 1969: 20: 363-382. Olsen S: Pathology of the renal allograft rejection. In: Churg V. Snargo B, Mostofi FK. Abel1 M. eds. Kidnev disease: present-status. Baltimore: Williams & Wilkins. 1979; 327-355. Rowlands DT, Hill GS, Zmijewski CM: The pathology of
April 1961 The American Journal of Medicine
ET AL.
renal hemograft rejection. A review. Am J Path01 1976: 85:744-804. 31. DeFronzo RA, Goldberg M, Cooke CR, Barker C, Grossman RA. Aaus ZS: Investigations into the mechanisms of hvperkalgmia following renal transplantation. Kidney btt 1977;ll: 357-365. 32. Shioji R, Furuyama T, Onodera S, et al.: Sjogren’s syndrome and renal tubular acidosis. Am J Med 1970; 48:456-463. 33. Tu WH, Shearn MA: Systemic lupus erythematosus and latent renal tubular dysfunction. Ann Intern Med 1967; 67: 100-109. 34. Andres GA, McCluskey RT: Tubular and interstitial renal disease due to immunologic mechanisms. Kidney Int 1975; 7: 271-289.
Volume 70