1 Department of Medicine, We determined the effect of postischemic injury to
the human renal allograft on
p-aminohippurate (PAH) extraction
(EPAH) and renal
blood flow. We evaluated renal function in 44 allograft recipients on
two occasions: 1-3 h after reperfusion (day
0) and again on postoperative day
7. On day 0 subsets
underwent intraoperative determination of renal blood flow
(n = 35) by Doppler flow meter and
EPAH
(n = 25) by renal venous assay. Blood
flow was also determined in another subset of 16 recipients on
postoperative day 7 by phase contrast-cine-magnetic resonance imaging, and
EPAH was computed from the
simultaneous PAH clearance. Glomerular filtration rate (GFR) on
day 7 was used to divide subjects into
recovering (n = 23) and sustained
(n = 21) acute renal failure (ARF)
groups, respectively. Despite profound depression of GFR in the
sustained ARF group, renal plasma flow was only slightly depressed,
averaging 296 ± 162 ml · min
p-aminohippurate extraction; organic anion transport; renal plasma flow; phase
contrast-cine-magnetic resonance imaging
SIXTY YEARS HAVE ELAPSED since Homer Smith first
proposed that the urinary clearance of
p-aminohippuric acid (PAH) would prove to be an ideal method for determining the rate of renal plasma flow in
intact humans (30). The necessary attribute identified by Smith was
almost complete extraction of PAH from the renal circulation,
with subsequent delivery into final urine (29). Smith's proposal has
since been validated in subjects with healthy kidneys in whom the
extraction ratio of PAH (EPAH)
has repeatedly been shown to approximate 0.9 (4, 5, 32). Smith's
postulate does not appear to be valid in the presence of
postischemic acute renal failure (ARF), however. Under the
latter circumstances, EPAH has
been shown to be severely impaired, with the result that the PAH
clearance markedly underestimates renal plasma flow (7, 10, 11, 21,
27).
Although glomerular filtration of PAH contributes, the predominant
mechanism whereby PAH is transferred from the renal circulation to
urine is one of active secretion into tubule fluid by cells of the
proximal tubule (25). This is achieved by an organic anion transporter
that is located on the basolateral membrane and transports PAH from
peritubular capillary plasma into proximal tubule cells against its
electrochemical gradient. With the development of
postischemic ARF, however, proximal tubule cells sustain
severe cytoskeletal injury (12). An ensuing derangement in the
composition of the cell membrane has been shown to result in loss of
cell polarity (20). As a result, vectorial transport of a variety of
solutes, including PAH, is likely to become impaired.
In an attempt to elucidate the pathophysiology of ARF in the human
kidney, we have studied the postischemic injury that
follows transplantation of a cadaveric renal allograft (2). We have shown that ~50% of cases exhibit a transient renal excretory failure that has most of the functional and histopathological hallmarks of
postischemic ARF. One such hallmark is disruption of both
the apical and basolateral cell membranes of proximal tubule cells, with an ensuing loss of proximal tubule cell polarity (1, 18, 19). To
determine the extent to which such injury is associated with impairment
of organic anion transport across the proximal tubule, we have measured
the EPAH intraoperatively, some 60 min after reperfusion, in recipients of cadaveric renal allografts. In
an effort to determine the duration of impairment of the PAH transporter, we then used an indirect approach to reassess
EPAH on the seventh day after
transplantation. Our findings, and their implications for the
determination of renal plasma flow in postischemic ARF, are
the subject of this report.
Patient Population
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
1 · 1.73 m
2 on day
0 and 202 ± 72 ml · min
1 · 1.73 m
2 on day
7, respectively. These values did not differ from
corresponding values in the recovering ARF group: 252 ± 133 and 280 ± 109 ml · min
1 · 1.73 m
2, respectively.
EPAH was profoundly depressed on
day 0, averaging 18 ± 14 and 10 ± 7% in recovering and sustained ARF groups, respectively, vs. 86 ± 6% in normal controls (P < 0.001). Corresponding values on day 7 remained significantly depressed at 65 ± 20 and 11 ± 22%,
respectively. We conclude that postischemic injury to the renal allograft results in profound impairment of
EPAH that persists for at least 7 days, even after the onset of recovery. An ensuing reduction in urinary
PAH clearance results in a gross underestimate of renal plasma flow,
which is close to the normal range in the initiation, maintenance, and
recovery stages of this injury.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
20 ml/min. Group
2 was composed of the remaining 21 subjects, who were
classified as exhibiting sustained ARF because of persistent depression
of inulin clearance (<20 ml/min). The latter value was selected
because it represented depression of GFR by >75% below the average
value in a group of control subjects, who provided an optimal range of
values for the renal allograft. These control subjects were 18 recipients of long-standing renal allografts that were donated by a
living sibling or parent and had never undergone a known episode of
rejection. A second control group composed of 13 cardiac transplant
recipients never exposed to cyclosporine provided a value for
EPAH in healthy controls. All had
a normal GFR as measured by inulin clearance.
EPAH in these controls was
determined by sampling renal venous plasma during the course of routine
right cardiac catheterization, as described in detail elsewhere (5).
Transplantation Procedures
The surgical management of donors and recipients at our institution has been described in detail recently (2, 19). Each cadaveric donor in this series died from a severe brain injury. All recipients received immunosuppressive therapy with prednisone and either mycophenolate mofetil or azathioprine during the first posttransplant week. These agents are not known to impair renal blood flow. In addition, subjects received a third immunosuppressive agent during the first posttransplant week. This was either cyclosporine (n = 38 subjects) or tacrolimus (n = 6). The latter two agents are renal vasoconstrictors. They were used in modest dosages so as to achieve whole blood trough levels of 300-400 ng/ml for cyclosporine and 10-15 ng/ml for tacrolimus. Other drugs routinely used in the first transplant week to treat or prevent infections included trimethoprim-sulfa, acyclovir, and cephazolin, the latter being administered for the first three postoperative days only. In addition, each subject also received a single dose of gentamycin (100 mg) on the day of surgery.Serial clearances were performed in each of the 44 recipients of a cadaveric renal allograft. The initial clearance studies were performed on the day of transplantation (day 0). The repeat clearances were performed a week later, on posttransplant day 7. Most subjects (n = 35) also underwent a PAH-independent determination of renal blood flow on day 0. This was combined with a determination of EPAH in 25 instances. In a subset of seven of the former subjects and in nine additional subjects, a PAH-independent determination of renal blood flow was again performed on day 7, permitting the EPAH to be calculated.
Evaluation of early allograft function.
As soon as the renal allograft was removed from cold storage in
preparation for transplantation, each recipient was given 0.03-0.04 ml/kg of 20% sodium PAH (Merck, West Point, PA) by
intravenous injection. PAH was allowed to equilibrate between intra-
and extravascular compartments during implantation of the kidney, which
took an average of 45 ± 14 min (mean ± SD), followed by a
subsequent period of allograft reperfusion lasting 40-60 min.
Samples of blood (10 ml) were then drawn simultaneously from the renal
allograft vein and the iliac artery. Samples were centrifuged, and the
supernatant plasma was removed and stored at 70°C until the
day of assay. The EPAH was
calculated as the arteriovenous PAH concentration difference
([A]PAH
[V]PAH) divided by
the arterial PAH concentration ([A]PAH)
![]() |
(1) |
Evaluation of postoperative allograft function. Standard urinary clearances of inulin and PAH were determined on posttransplant day 7, as described previously (19). In a subset of 16 subjects, the rate of blood flow to the renal allograft was determined by phase contrast-cine-magnetic resonance imaging (MRI) on the same day as the clearance study. Renal plasma flow (RPF) was computed from renal blood flow (RBF) with the use of Eq. 2
![]() |
(2) |
![]() |
(3) |
Laboratory determinations. Concentrations of inulin in urine and plasma were determined by the AutoAnalyzer method of Fjeldbo and Stamey (13) with the use of resorcinol as the colorimetric reagent. PAH concentrations in urine and plasma were assayed simultaneously, employing a modification of the colorimetric assay of Bratton and Marshall (6). The concentration of creatinine in urine and plasma was determined by an automated rate-dependent picrate method with the use of a creatinine analyzer (Creatinine Analyzer 2; Beckman Instruments, Fullerton, CA). This method minimizes the influence of slow-reacting, noncreatinine chromagens and thus provides an estimate of the true creatinine concentration. Concentrations of sodium were determined by ion-selective electrode (NOVA 11; NOVA Biomedical, Waltham, MA), and osmolality was determined by a vapor pressure osmometer (model no. 5500; Wescor, Logan, UT).
MRI measurement of renal blood flow. The phase contrast-cine-MRI method used to determine blood flow in the renal allograft has been validated and described by Myers et al. (22) in detail. It depends on the use of magnetic field gradients to acquire velocity information from phase data. As the precessing protons move in the presence of a magnetic field gradient, they acquire a phase shift that is proportional to velocity. Images encoding the phase information are called phase contrast-MRI. Cine-MRI is a technique that acquires data throughout the cardiac cycle and uses a simultaneously monitored electrocardiogram to produce images at selected intervals. When the cine-MRI technique is combined with phase contrast to produce images that portray the spatial distribution of velocities during the cardiac cycle, the technique is known as phase contrast-cine-MRI. If the phase contrast acquisition is encoded for motion through the imaging plane, the product of the average velocity in a region encompassing a blood vessel and the vessel area yields the flow rate.
When phase contrast-cine-MRI data are used the flow rate at each point in the cardiac cycle can be computed. These time-dependent measurements are then averaged and scaled to yield the average flow rate through the vessel (ml/min). The plane of acquisition for the phase contrast-cine-MRI was defined with the use of gradient-recalled images of the allograft vein, with the acquisition plane set as perpendicular as possible to the vessel, near the anastomosis with the external iliac vein. The following conditions were employed: electrocardiogram gating, respiratory compensation, pulse repetition time of 25 ms, echo time of 12 ms, slice thickness of 4 mm, and a maximum flow encoding velocity of 50 cm/s. After acquisition of data, an analysis of renal blood flow was performed off-line. Dedicated software was used to compute and integrate renal blood flow from the product of velocity and renal venous cross-sectional area through 16 equal phases of the cardiac cycle.Statistical Analysis
Analysis of the data described above involved 30 separate but related comparisons among 18 variables. For six variables there were three groups (controls and recovering and sustained ARF); in all others there were two groups. Evaluation with the Shapiro-Wilk test revealed the distribution of data to be approximately Gaussian. However, the separate groups had different variance and in some instances different sample sizes, thereby rendering ordinary pooled t-tests inappropriate. Instead, we tested the significance of differences among the groups and paired differences between days 0 and 7 within the ARF groups by using the Behrens-Fisher-Welch t-test, which respects differences in population variances. Our implementation was with the Minitab package (28). All results are expressed as means ± SD. ![]() |
RESULTS |
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Early Allograft Function (1-3 h Postreperfusion)
The duration of cold ischemia averaged 1,100 ± 421 min in the group with recovering ARF and 1,356 ± 503 min in the group with sustained ARF [P = not significant (NS)]. The corresponding durations of subsequent rewarming times during performance of the vascular anastomosis were also similar: 35 ± 12 vs. 42 ± 21 min, respectively (P = NS, Table 1). Classification of subjects into recovering and sustained ARF groups according to inulin clearance on posttransplant day 7 also separated the two groups by creatinine clearance on day 0. The latter measure of effective GFR immediately after surgery was significantly lower in those destined to exhibit sustained ARF than in those destined to manifest recovering ARF: 5 ± 5 vs. 16 ± 10 ml · min
|
Renovascular pressures and flows, determined intraoperatively after 1 h
of reperfusion, also failed to distinguish the recovering and sustained
ARF groups. Mean arterial pressure averaged 94 ± 24 in recovering
ARF vs. 85 ± 23 mmHg in sustained ARF subjects (P = NS). Corresponding central venous
pressures averaged 12 ± 5 and 17 ± 16 mmHg, respectively
(P = NS). Despite the low GFR observed
in each group, the renal blood flow rate was close to the expected
value for a normal single kidney in both the recovering and sustained
ARF groups: 340 ± 190 vs. 427 ± 221 ml/min
(P = NS). The same was true
for corresponding renal plasma flow rates, which averaged 252 ± 133 and 296 ± 162 ml · min1 · 1.73 m
2, respectively
(P = NS). As a result, the filtration
fraction was depressed to only 0.07 ± 0.05 in those
destined to exhibit recovering ARF and even more profoundly to 0.02 ± 0.02 in those destined to exhibit sustained ARF
(P < 0.001 vs. recovering ARF). Thus
GFR depression in this postischemic injury cannot be
attributed to impairment of renal plasma flow.
In keeping with a severe tubule injury, suggested by the presence of
isosthenuria and marked elevation of the fractional sodium excretion
(Table 1), EPAH was severely
depressed in each group (Fig. 1). Arterial
PAH concentration exceeded 3 mg/dl in three members of the recovering
ARF group and two members of the sustained ARF group. Because the PAH
transporter begins to become saturated at concentrations of this
magnitude, these five individuals were excluded from the assessment of
EPAH. In the remaining subjects, the arterial PAH concentrations averaged 1.5 ± 0.4 and 1.9 ± 0.5 mg/dl in recovering (n = 10) and sustained (n = 10)
ARF groups, respectively. The corresponding values for the
EPAH (×100) were profoundly
depressed, averaging only 18 ± 14 and 10 ± 7%, respectively. These group ratios did not differ from each other but were profoundly and significantly lower than the control value for our laboratory of 87 ± 10% (P < 0.0001, Fig. 1).
Mean EPAH in subjects who received furosemide before renal venous blood sampling did not differ from that
in subjects who did not receive furosemide. Among the subjects who
received furosemide, the EPAH
averaged 14 ± 12%. The corresponding value among those patients
who did not receive furosemide was 13 ± 12%
(P = NS).
|
Late Allograft Function (Day 7)
Judged by inulin clearance, the effective GFR remained depressed below the normal allograft "control" level even in those subjects assigned to the recovering ARF group: 37 ± 21 vs. 77 ± 15 ml · min
|
Arterial pressure was similar in each ARF group and controls (Table 2).
In contrast, the clearance of PAH was lower in those with recovering
ARF than in our long-standing allograft controls: 200 ± 126 vs. 340 ± 66 ml · min1 · 1.73 m
2, respectively
(P < 0.001). PAH clearance was even
more depressed in the sustained ARF group, averaging only 50 ± 48 ml · min
1 · 1.73 m
2
(P < 0.001 vs. controls and
recovering ARF). That the low PAH clearance does not result from
depression of the renal plasma flow rate is suggested by determination
of the latter quantity by phase contrast-cine-MRI in the control group
and subsets of the two ARF groups. True renal plasma flow was similar
to the control value in those with recovering ARF: 347 ± 67 vs. 280 ± 109 ml · min
1 · 1.73 m
2, respectively. Although
true renal plasma flow was significantly depressed below the control
value in sustained ARF (P < 0.05), the depression was far more modest than suggested by PAH clearance, averaging 202 ± 72 ml · min
1 · 1.73 m
2 (Table 2).
The disparity between PAH clearance and true renal plasma flow was used
to compute a value for the EPAH in
those subjects studied by both clearance and MRI techniques. The
EPAH for the allograft control
group (n = 13) averaged 87 ± 10%. As shown in Fig. 2, the true
renal plasma flow exceeded the PAH clearance in all but one of the 16 subjects with postischemic allograft injury who underwent
the MRI determinations of renal plasma flow. From the disparity between
the two, we estimate that the EPAH averaged 66% (range: 42-100%) in subjects with recovering ARF (Fig. 3). Of the five subjects with
sustained ARF studied by MRI on day 7,
three were anuric, with the result that the
EPAH is computed to be zero. In
the remaining two subjects with sustained ARF, the computed
EPAH values were 7 and 50%,
despite a high urinary flow rate (Fig. 3). Persistently profound
depression of extraction in the sustained ARF group indicates that PAH
transport remains severely depressed in recipients whose ARF fails to
enter the recovery stage in the first postoperative week.
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DISCUSSION |
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We have demonstrated that postischemic injury to the cadaveric renal allograft is associated with profound impairment of EPAH. This abnormality is particularly marked in the immediate wake of reperfusion, independent of whether the transplanted kidney is destined to have a protracted episode of or recover rapidly from postischemic ARF (Fig. 1). We have also provided indirect evidence that impairment of EPAH persists for at least 7 days and remains evident even after the injury has entered the recovery stage (Figs. 2 and 3). Our findings confirm earlier reports of impaired PAH transport during postischemic injury, both in experimental animal ARF (10, 11, 14, 24) and in humans with ARF (7, 21).
The mechanism whereby PAH transport in the reperfused renal allograft becomes depressed is likely related to the fact that such transport is an active process. One possible mechanism is the presence in high concentrations within the circulation of organic anions that compete with PAH for the proximal tubule transporter. Such inhibitors could be endogenous solutes that are retained because of renal failure. An important role for endogenous inhibitors seems unlikely in the present study, however. This is because, in keeping with our routine practice, 42 of the 44 recipients were hemodialyzed immediately before transplantation surgery. As a result, our finding of a uniform and marked depression of EPAH during surgery on day 0 appears to coincide precisely with what might be expected to be the postdialysis nadir levels of any retained solutes that serve as endogenous inhibitors of PAH transport.
Several drugs that are organic anions have been shown to serve as exogenous inhibitors of PAH transport. However, no member of this class of drugs can be clearly identified among the immunosuppressive and antimicrobial agents that were administered on the seventh postoperative day in the present study (see METHODS). It has been suggested that active secretion by the organic anion transporter of mycophenolic acid glucuronide, the stable metabolic product in which form mycophenolate mofetil is eliminated, accounts for its urinary excretion (8). In this event, it could compete with PAH for transport and contribute to the impaired EPAH observed on day 7 (but not during the day 0 study, which preceded therapy). Two factors suggest that such a contribution is unlikely to be quantitatively important, however. First, EPAH on day 7 was far more impaired in subjects with sustained than recovering ARF, although members of both groups were being treated with mycophenolate at this time. Second, the renal clearance of mycophenolic acid glucuronide has been estimated in healthy volunteers, patients with autoimmune disorders, and renal transplant recipients to average <50% of the corresponding creatinine clearance (8). Mycophenolic acid glucuronide seems likely therefore to be eliminated either exclusively by glomerular filtration or by a combination of glomerular filtration and minor tubular secretion. Given the low clearance, the rate of tubular secretion would appear to be too low to lead to a measurable reduction of PAH transport by competitive inhibition of the organic anion transporter.
As stated in the introduction, PAH transport is vectorial, from peritubular capillaries to tubule lumen, and occurs along the entire length of the proximal tubule; the highest rate of transport per millimeter of tubule length is normally found in the proximal straight segment (31). We have shown that the proximal tubule in general and the straight segment in particular bear the brunt of postischemic injury in the reperfused renal allograft (1, 18, 19). Using lithium as a surrogate, we have also shown that proximal sodium reabsorption is markedly diminished under these circumstances (18). Structural disruption of the cell membranes of the proximal tubule is also evident during postischemic allograft ARF. This is manifest by redistribution of Na+-K+-ATPase and various adhesion molecules from the basolateral to either the apical membrane or to the cytosol in the interior of the cell (1, 18, 19). The ensuing loss of cell polarity and dislocation of Na+-K+-ATPase from the basolateral cell membrane could play a major role in limiting the extent of proximal sodium reabsorption (20).
It seems likely that a loss of cell polarity could also impair the
active proximal secretion of PAH by the organic anion transporter. Such
impairment could result from disruption of the cell membrane proteins
that constitute the basolateral PAH transport system. The recent
cloning of a human organic anion transporter (17) should allow this
hypothesis to be tested. It is noteworthy, however, that the
aforementioned redistribution of
Na+-K+-ATPase
could limit PAH transport, even in the event that the organic anion
transporter should prove to be normally retained in the basolateral
membranes of proximal tubule cells in postischemic ARF. The
third step in the tertiary active process of transport by which PAH is
secreted is one in which PAH enters the cell in exchange for a
dicarboxylate ion (-ketoglutarate) moving out of the cell down an
electrochemical gradient. The outward dicarboxylate gradient is
maintained, in part, by
Na+-coupled transport that depends
on energy derived from ATP through the activity of the basolateral
Na+-K+-ATPase
(25). In the absence of such activity, PAH entry into the cell and
subsequent active transport across the apical membrane into the tubular
lumen would not eventuate. We submit that altered composition of cell
membranes with an ensuing loss of proximal tubule cell polarity is
likely the predominant cause of the impaired PAH transport observed in
the present study.
In contrast to the striking impairment of PAH transport, our study has demonstrated that there is little or no reduction in renal plasma flow in either the initiation, maintenance, or recovery stages of postischemic ARF in the cadaveric renal allograft (Tables 1 and 2). A disproportionately profound depression of GFR with preservation of relatively normal or only modestly depressed rates of renal plasma flow in the freshly transplanted kidney has also been reported by others (3, 15). The same is true for postischemic ARF of the native human kidney, during both initiation (21) and maintenance stages of the injury (16, 26). In each of the aforementioned studies, invasive techniques were required to demonstrate that renal plasma flow is not an important determinant of GFR depression in this setting. Such invasive techniques involved either direct application of an electromagnetic flow meter to the renal artery (3, 21) or cannulation of the latter vessel to measure flow by the washout of radioactive xenon (15, 16, 26). Whereas PAH clearance is a relatively noninvasive technique, it is clearly an invalid measure of renal plasma flow in this circumstance, and its use would give the artifactual impression that renal plasma flow is profoundly depressed in this disorder (Table 2, Fig. 2).
In this respect it is important to emphasize that in routine clinical practice, isotopic renal scanning is frequently used in the differential diagnosis of prolonged depression of renal allograft function in the days and weeks after transplantation (9, 23, 33). Commonly used radiopharmaceuticals are [131I]orthoiodohippurate and 99Tc-labeled mercaptoacetyltriglycerine (known as MAG-3), both of which share the same transport system as PAH. Minimal uptake of these isotopes during postischemic ARF is frequently misinterpreted as representing renal underperfusion. In fact, our findings suggest that it is impaired transtubular transport (and an ensuing absence of concentration of the isotope in the tubule fluid) that is responsible for diminished isotope uptake by the kidney. We submit that the current diagnostic use of isotope renography either to distinguish postischemic ARF from acute rejection and cyclosporine toxicity or to estimate effective renal plasma flow is likely to be of limited use. Certainly, the malfunction of the organic anion transporter that we have demonstrated during postischemic allograft injury should be taken into account in the attempt to interpret isotope renographic findings.
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ACKNOWLEDGEMENTS |
---|
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-50712 and DK-48051 and by General Clinical Research Center Grant MO1-PR-00070-DK. The fellowship to G. Corrigan was supported by a grant from Chiron.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: B. D. Myers, Division of Nephrology, Rm. S201, Stanford Univ. Hospital, 300 Pasteur Drive, Stanford, CA 94305.
Received 1 September 1998; accepted in final form 10 May 1999.
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