Divisions of Nephrology, Departments of Medicine and Pediatrics, Stanford University School of Medicine, Stanford, California 94305
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ABSTRACT |
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We evaluated the glomerular filtration rate (GFR) in 34 subjects with membranous nephropathy (MN) of new onset. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (Kf). A morphometric analysis of glomeruli in the diagnostic biopsy permitted computation of the single-nephron ultrafiltration coefficient (SNKf). MN subjects were divided into two groups: moderate or severe, according to whether GFR was depressed by less or more than 50%. SNKf was subnormal but similar in moderate and severe MN. In contrast, two-kidney Kf was significantly more depressed in severe than in moderate MN. We estimated the total number of functioning glomeruli (Ng) by dividing two-kidney Kf by SNKf. Whereas mean Ng was similar in controls and moderate MN (1.5 and 1.4-1.7 × 106, respectively), it was significantly lower in severe MN (0.5 × 106). This degree of glomerulopenia was not reflected in the rate of global sclerosis. We conclude that a combination of depressed SNKf (due to foot process broadening) and profound glomerulopenia accounts for GFR depression of >50% early in the course of MN. The cause of the glomerulopenia remains to be elucidated.
glomerular filtration rate; glomerular hemodynamics; ultrafiltration coefficient; glomerular morphometry; glomerular number
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INTRODUCTION |
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THE ONSET AND EARLY STAGES of membranous nephropathy (MN) are often associated with depression of the glomerular filtration rate (GFR) (11, 25-27). This phenomenon has been shown by micropuncture study of early experimental (Heymann's) MN in the rat to be a consequence of depression of the ultrafiltration coefficient (Kf), a measure of the intrinsic ultrafiltration capacity of glomerular capillary walls (1, 13, 29). The net pressure for ultrafiltration, the remaining determinant of GFR, has invariably been found to be elevated in experimental MN, indicating that Kf depression is the sole factor leading to hypofiltration under these circumstances (1, 13, 29).
Kf is the product of the hydraulic permeability of glomerular capillary walls and the surface area available for filtration (9). We studied these determinants of Kf by using a stereological approach to quantify the structural changes in glomeruli obtained by percutaneous renal biopsy from patients with active MN (11, 27). Such studies reveal the autoimmune injury to glomerular epithelial cells (podocytes) that underlies MN to lead to gross deformation of their foot processes. An ensuing decline in the number of filtration slits, through which filtrate gains access to Bowman's space, impairs the hydraulic permeability of the affected glomerular capillary walls (11). Our morphometric analyses have previously pointed to impaired hydraulic permeability as the only identifiable GFR-lowering factor early in the course of MN (11, 26, 27). In contrast, a recent analysis of serial biopsies revealed that both impaired hydraulic permeability and a loss of filtration surface area contributed to chronic and persistent depression of Kf and GFR after 2-5 yr of MN (26).
GFR depression, presenting as azotemia, at the onset of MN has been identified as an early predictor of eventual progression to end-stage renal failure (6, 20, 22, 30). We thus designed the present study to further elucidate the mechanism of hypofiltration in early MN. We once again used morphometric techniques to examine glomerular structure in the diagnostic biopsies of a large number of patients with MN of new onset. We combined the structural findings with a physiological evaluation of GFR and its hemodynamic determinants. We then used mathematical modeling to estimate ultrafiltration capacity, both at the level of individual glomeruli [single-nephron Kf (SNKf)] and of the aggregate of all functioning glomeruli in the two human kidneys (2-kidney Kf). The subject of this report is the relationship among these two quantities and the extent to which GFR was depressed in two groups of subjects with MN of graded severity.
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METHODS |
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Patient Population
The subjects of our study were 34 adult patients who presented to our clinic with a nephrotic syndrome and a histopathological diagnosis of MN. The patients varied in age from 17 to 71 yr, and 22 were men. All physiological (clearance) studies were performed within a year of the diagnostic biopsy (median interval = 2 mo). Two groups of healthy individuals were studied to provide control values for the glomerular functional and structural parameters. Control group 1 was composed of 130 healthy volunteers. Their ages varied between 18 and 80 yr, and 89 were men. They underwent renal clearance studies comparable to those performed in the patient population. Control group 2 was composed of 19 living kidney transplant donors. Their ages varied between 23 and 48 yr, and 11 were men. Each underwent a renal biopsy at the time of transplantation. All denied a history of renal disease, hypertension, or diabetes mellitus. At the time of evaluation, each was found to be normotensive and normoglycemic, to have a normal serum creatinine level, and to have a urinary protein excretion rate in the normal range.Physiological Evaluation
All patients and volunteers underwent a determination of GFR, renal plasma flow, and preglomerular vascular pressures according to a protocol approved by the Institutional Review Board at the Stanford University School of Medicine. Initially, blood was sampled for determination of plasma oncotic pressure (Sixty minutes after the priming infusion, arterial blood pressure was
determined. Four timed urine collections were then made, each of which
was bracketed by a blood sample drawn from a peripheral vein. The GFR
was expressed as the average value for the four timed inulin
clearances. The rate of renal plasma flow was estimated by dividing the
corresponding clearance of PAH by an estimate of the prevailing renal
arteriovenous extraction ratio for PAH. We showed previously that
reductions of GFR and peritubular capillary protein concentration exert
an additive effect to lower the PAH extraction ratio in patients with
glomerular disease (3). From the relationship observed in
that study between the PAH extraction ratio and GFR, we assigned the
following values to the subjects of the present study: 0.9 for healthy
controls, 0.8 for patients with MN and a normal GFR (>80
ml · min1 · 1.73 m2), and 0.7 for patients with MN and a depressed GFR.
Inulin and PAH were determined with colorimetric methods using a
Technicon Auto Analyzer II (3). Plasma oncotic pressure
was measured directly using a Wescor 4400 membrane osmometer (Wescor,
Logan, UT) and serum creatinine levels by a rate-dependent modification of the Jaffe reaction, employing a Beckman Creatinine Analyzer (model
2, Fullerton, CA).
Morphometric Evaluation
Light micrososcopy.
All glomeruli in a single, 1-µm-thick section stained with periodic
acid-Schiff reagent were analyzed at the light microscopic level. On
average, 14 (range 4-49) glomeruli were examined in each diagnostic
biopsy in the patients with MN. The average number of glomeruli among
the 19 control biopsies was 19 (range 5-58). A dedicated computer
system (Southern Micro Instruments, Atlanta, GA), consisting of a video
camera and monitor, microscope, and digitizing tablet, was used to
perform the measurements. The outline of each glomerular tuft in the
section was traced onto the digitizing tablet and the mean tuft
cross-sectional area was determined using computerized planimetry. The
measured tuft area included any parts with segmental sclerosis. We next
counted the number of patent (Np) and globally
sclerotic (Ns) glomeruli in a single section of
cortical tissue. Serial sections were examined to verify the assignment
of Ns in the single section. The percentage
of globally sclerotic glomeruli (Gl) was calculated by
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(1) |
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(2) |
Electron Microscopy
For transmission electron microscopy, tissue was fixed in 2.5% glutaraldehyde and 2.0% paraformaldehyde in 0.1 M cacodylate buffer and then embedded in Epon. Toluidine blue-stained sections were surveyed to locate blocks with patent glomeruli present entirely within the block. An ultrastructural analysis was performed on two glomerular profiles in each patient. Ultrathin sections (~90 nm) of the selected glomeruli were stained with lead citrate and uranyl acetate. A complete montage of each glomerulus (×2,850 magnification) was prepared and line-intercept counting was used to calculate the fractional surface density of the peripheral capillary wall by standard stereologic methods (28). Six to eight images of peripheral capillary loops in each of the glomerular profiles were then photographed at ×11,280 to evaluate the frequency of epithelial filtration slits and the thickness of the peripheral glomerular basement membrane (GBM). Filtration slit frequency was determined by counting the total number of epithelial filtration slits and dividing that number by the total length of the peripheral capillary wall at the epithelial interface (11). The harmonic mean basement membrane thickness (
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(3) |
Calculations
Glomerular oncotic pressure.
We showed that oncotic pressure in nephrotic humans rises linearly as
plasma flows axially along the glomerular capillaries and water is
removed by ultrafiltration (5). We first calculated efferent (postglomerular) oncotic pressure
(E) as follows:
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(4) |
Two-kidney Kf.
A mathematical model for the glomerular filtration of water (9,
27) was used to calculate the two-kidney
Kf, which is defined in this study as the
product of glomerular hydraulic permeability and the total filtration
surface area of all glomerular capillaries in the two human kidneys.
The input values for the model included the measured values of GFR,
renal plasma flow, and A, as well as an
assumed value for the glomerular transcapillary hydraulic pressure
difference (
P). The latter quantity cannot be directly measured in
humans. However, using an indirect curve-fitting technique, we
estimated that
P approximates 40 mmHg in the healthy human kidney
and assigned this value to both the control and MN groups in the
present study (18, 27). Micropuncture determinations in
Heymann nephritis, a rodent model of MN, indicate that
P is invariably elevated in this form of glomerular injury (1, 13, 29). Moreover, human MN is accompanied by arterial hypertension (see below). Given that a fraction of the increment in arterial pressure is likely transmitted into glomerular capillaries, it is
probable that
P in human MN is also elevated. Thus, an assumption that
P in MN is the same as in healthy controls is a conservative one and should provide an upper bound for the average
Kf in this disorder (27). To allow
for the effect of possible variations in
P on computed membrane
parameters in patients with MN, we performed a sensitivity analysis,
repeating all calculations over a hypothetical
P range (35 to 45 mmHg) that brackets the assumed control value of 40 mmHg.
Single-nephron Kf.
The total filtration surface area in a single glomerular tuft was
calculated from
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(5) |
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(6) |
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(7) |
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(8) |
Number of glomeruli.
We estimated the total number of functioning glomeruli
(Ng) in the two kidneys as the quotient
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(9) |
Statistical Analysis
Initially, Student's t-test was used to assess the difference in the GFR between the control group and all patients with MN. Linear regression analysis was used to elicit possible relationships between the GFR and a number of morphometric measurements in patients with MN. For the remainder of the analysis, we divided the patients with MN into two grades of injury. Values of GFR above or below 50% of the average normal (control) level were used to categorize the MN as either moderate or severe. The degree of nephrosis in the two grades of injury as well as the number of patent glomeruli (Ng) was compared using the Wilcoxon-Mann-Whitney test. Either an analysis of variance combined with the Newman-Keuls test for post hoc comparisons or the Kruskal-Wallis test with the Dunn procedure was used to assess the significance of differences among the groups of patients with moderate MN, severe MN, and controls. Results are reported as means ± SD or the median (range). ![]() |
RESULTS |
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Physiological Assessment
The mean GFR in healthy controls was 101 ± 17 ml · minResults of our physiological assessment of GFR and its determinants are
summarized in Table 1. Whereas GFR in
moderate MN tended to be slightly depressed (83 ± 15 ml/min), the
corresponding rate of renal plasma flow tended to be elevated, 806 ± 188 vs. 566 ± 128 ml/min in controls (P < 0.01). Furthermore, the marked depression of GFR (29 ± 11 ml/min)
according to which subjects were assigned to the severe MN group was
not associated with a significant depression of the rate of renal
plasma flow (504 ± 382 ml/min; Table 1). Thus, a marked
depression of the filtration fraction in each category of MN, 0.11 ± 0.03 in moderate and 0.07 ± 0.03 in severe (vs. 0.18 ± 0.03 in controls), indicates that changes in determinants of GFR other
than renal plasma flow must explain the observed level of
hypofiltration.
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Reflecting the marked hypoproteinemia, afferent oncotic pressure
(A) was markedly depressed in moderate MN,
15.2 ± 3.9 vs. 24.4 ± 2.4 mmHg in the control group
(P < 0.001). The corresponding value for mean oncotic
pressure along the glomerular capillaries (
GC) was proportionately more depressed
compared with the control group, mean 16.2 ± 4.2 vs. 27.1 ± 2.6 mmHg, respectively (P < 0.001).
A (11.2 ± 3.3) and
GC (11.7 ± 3.6 mmHg) were significantly more depressed in the severe MN group (Table 1). The depression in
GC in MN can be inferred to elevate the net
ultrafiltration pressure by ~10 and 14 mmHg in the moderate and
severe groups, respectively. Because
GC is
the force opposing the formation of filtrate, depression of either
P
and/or Kf must be invoked to explain the
observed hypofiltration.
In an effort to estimate the magnitude of the effect attributable to
Kf depression, we first assumed a normal P of
40 mmHg, a value similar to that observed by micropuncture in the
normal euvolemic rat (24). With measured values of
GFR, renal plasma flow, and this value for
P, the ultrafiltration
model of Deen et al. (9) yielded a value for two-kidney
Kf of 11.0 ± 5.7 ml · min
1 · mmHg
1
in healthy controls (Table 1 and Fig. 1).
We next used a sensitivity analysis to estimate the influence of
P
on Kf in each grade of MN. We examined the
effects of a
P that was the same (40 mmHg), higher (45 mmHg), or
lower (35 mmHg) than normal. The computed values indicate that
Kf is depressed in MN regardless of the actual value of
P within this range. There is negligible overlap among controls, moderate and severe MN under any combination of
P values (Fig. 1). Because arterial pressure was elevated in MN (Table 1), we
infer that
P is in fact likely to be elevated. For purposes of the
analysis that follows, however, we made the conservative assumption
that none of the increment in arterial pressure was transmitted into
glomerular capillaries and that
P was equivalent to the control
value (i.e., 40 mmHg). Because
P and Kf are
reciprocally related, this should provide an upper bound for two-kidney
Kf in MN relative to the control. This quantity,
which we will refer to as Kf40, was only 34 and
10% of control Kf40 in moderate and severe MN,
respectively (Table 1).
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Morphological Assessment
Our morphometric analysis is summarized in Table 2. The first finding that is remarkable is that despite the striking differences in GFR and two-kidney filtration capacity (Kf40) between moderate and severe MN, quantitative glomerular morphology was similar in the two grades of injury. The only histopathological finding in the diagnostic biopsy that distinguished severe from moderate injury was a substantial expansion in the former of the interstitial compartment (Table 2). The mean percent global sclerosis was similar in each injury grade (Table 2) as was the prevalence of patients with global sclerosis (8/21 and 5/13 in moderate and severe, respectively; Fig. 2). We determined filtration surface area from the product of glomerular volume and filtration surface density in the patent glomeruli (Table 2). Reflecting a near doubling of glomerular volume (Table 2), filtration surface area was increased in each MN subset (Fig. 3A). Almost all of the resistance to transcapillary water flow is exerted by the glomerular basement membrane and the diaphragms at the bases of the epithelial filtration slits (8, 10, 11). Basement membrane thickness was increased twofold, a phenomenon that is predicted to lower hydraulic permeability (Table 2). Also, broadening of foot processes lowered the frequency of intervening filtration slits to approximately one-third of normal in both injury grades of MN (Table 2), further limiting water flux into Bowman's space.
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We applied the foregoing findings to the mathematical model of viscous
flow of Drumond and Deen (10) to calculate a value for
local hydraulic permeability. It was profoundly impaired in each
category of MN. Surprisingly, however, the impairment of hydraulic
permeability was similar in the two injury grades, 8 ± 3 and
6 ± 3, respectively, in moderate and severe MN vs. 22 ± 3 m · s1 · Pa
1 × 10
10 in controls (Fig. 3B). We next
calculated single-nephron Kf for each individual
from the product of filtration surface and hydraulic permeability. The
determination of single-nephron Kf from
morphometric data is completely independent of the physiological
determination of Kf40. It is thus of interest
that a striking disparity emerged between computed single-nephron
Kf and two-kidney Kf in
the two injury grades. Whereas the value for two-kidney
Kf was severe < moderate MN < controls (Table 1 and Fig. 1), such a graded reduction of
ultrafiltration capacity was not evident at the single-nephron level.
Single-nephron Kf for both moderate and severe
injury (3.1 ± 1.9 and 3.2 ± 2.3 nl · min
1 · mmHg
1,
respectively) was similarly depressed below the control value (7.5 ± 2.6 nl · min
1 · mmHg
1)
(Fig. 3C). In keeping with the group findings, linear
regression analysis revealed no significant relationships across the
two MN groups, between GFR on the one hand and either hydraulic
permeability (R2 = 0.11) filtration surface
area (R2 = 0.11) or single-nephron
Kf (R2 = 0.006) on
the other.
Glomerular Density
Computation of functional glomerular number (Ng) from Eq. 9 suggests that more severe glomerulopenia is the reason for the disproportionately low GFR and two-kidney Kf in severe vs. moderate MN (Table 1). Because the numerator (2-kidney Kf) and denominator (single-nephron Kf) in Eq. 9 were determined in two separate control groups (see METHODS), only a group mean value for Ng in controls could be calculated. This quotient yields a value for Ng of 1.5 × 106 for healthy controls (Table 3), which is close to the value of 1.2 × 106 found by direct morphometric analysis of normal kidneys at autopsy (19). The corresponding value of Ng in moderate MN (i.e., assuming
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DISCUSSION |
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As might be expected, the extent to which GFR declines early in the course of MN is proportional to the magnitude of depression of two-kidney Kf, a measure of the total capacity for ultrafiltration of all functional glomeruli in the two human kidneys. In contrast, no such relationship is apparent between GFR and Kf determined by morphometric analysis of individual glomeruli. The reason for the decline in SNKf, in early MN, is a fall in hydraulic permeability (k). We cannot exclude the possibility that molecular rather than structural alterations in the filtration slit diaphragm lower k more in severe than in moderate MN (15). It seems to us, however, that the most plausible explanation for the disparity is that the disproportionate reduction of two-kidney Kf in severe MN is due to a steep reduction in the number of glomeruli.
Glomerular number has been estimated in the dog kidney. Glomerular density in a kidney biopsy core of known volume was extrapolated to cortical volume, as assessed by MRI. Subsequently, a fractionator method used for validation after nephrectomy demonstrated good agreement (2). However, this technique has not yet been applied to estimate glomerular number in humans. Because there is no technique available that is sufficiently sensitive to directly image human glomeruli in vivo at present, we estimated the number of functional glomeruli in our experimental subjects from the quotient, two-kidney Kf/single-nephron Kf. Our estimate in control subjects is in good agreement with the number of glomeruli estimated by morphometric analyses of kidneys of subjects coming to autopsy with no evidence of renal disease (19). The number was similar in patients with moderate MN. Our estimate in subjects with severe MN, however, is far lower, averaging only 500,000 glomeruli. Although we cannot exclude the possibility that the latter subjects may have been endowed with only a small number of glomeruli at birth, this seems unlikely to us for the following reasons. First, the estimated glomerular number is over two standard deviations below the mean value for normal individuals in the aforementioned autopsy study (mean = 1,234,000; coefficient of variation = 0.25). Second, glomerulopenia of similar magnitude has been demonstrated at autopsy in subjects with severe diabetic nephropathy (4). Finally, marked expansion and collagenization of the interstitial compartment in severe but not moderate MN point to an advanced stage of chronic renal injury in the former. Taken together, these observations suggest that severe MN predisposes to glomerulopenia, perhaps as a result of sclerosis and resorption of heavily damaged glomeruli.
We acknowledge that our estimate of Ng has
limitations as neither of the values needed for the estimate, namely
two-kidney Kf and single-nephron
Kf, is precisely known. The most notable error
in calculating two-kidney Kf is likely to arise
from discrepancies between our assumed P value of 40 mmHg and the
actual value of
P, which cannot be determined in humans. Several
factors could lead to errors in calculation of
SNKf. For example, the use of fixed correction
factors for the glomerular shrinkage associated with paraffin embedding
and immersion fixation could compromise the accuracy of our estimation
of glomerular volume and hence filtration surface area
(17). Similarly, the need to use data from rats could
compromise the accuracy with which we estimated hydraulic permeability
(8).
Whereas we are able to determine the dimensions of major glomerular
structures in humans morphometrically, the characteristics of several
"nanostructures" have to be extrapolated from reported data for the
rat. These latter include the width of the filtration slit
(s) and the fractional area of fenestrae
(
f), both of which we showed to be similar in
the human glomerulus. As stated in METHODS, we find
s in both normal human subjects and those with MN to
average 36 ± 4 nm, a value quite similar to the 41 nm reported for rats (10). Similarly, using scanning electron
microscopy, we showed that
f in humans
averages 0.16 vs. 0.20 in the rat (16). Because of their
large dimensions, the resistance imposed by endothelial fenestrae
accounts for only 1-2% of total resistance to water flow. Thus,
the small aforementioned difference between humans and the rat should
have a negligible influence on computed k (8,
10).
A key example of a nanostructure that has not been validated in humans are the dimensions of the apertures in the filtration slit diaphragms, as determined in the normal rat by Rodewald and Karnovsky (23). Given that MN results primarily from an injury to podocytes, it is possible that changes in their foot processes could alter the dimensions of the apertures. That the latter do not influence model predictions strongly, however, has been shown in minimal change nephropathy, a glomerular injury characterized by essentially identical changes in foot processes to those seen in MN. Drumond and Deen (10) used micropuncture determinations of Kf and a morphometric determination of filtration surface area in rats with adriamycin nephrosis, an analog of minimal change nephropathy, to compute an experimental value of k (kexp) for this disorder (10). They showed that model predictions for k were within the same range as kexp.
We also provided similar evidence to validate the model in humans with minimal change nephropathy (11). We computed kexp from the above-described physiological determination of two-kidney Kf, an assumed value of 1.2 × 106 glomeruli and morphometrically determined filtration surface area. Once again, there was remarkably good agreement between kexp and k predicted by the model (r = 0.71, P < 0.001). Thus, alterations in foot processes do not seem to cause large enough changes in epithelial permeability (kepi) to influence the value of k computed by the model using the normal rodent dimensions of the apertures in the filtration slit diaphragm. It appears that a reduction in fractional area of filtration slits, in turn a function of reduced filtration slit frequency, rather than changes in intrinsic slit diaphragm structure, is responsible for lower kepi and hence k under these circumstances (11). We accordingly submit that our estimate of k should yield a reasonable approximation of SNKf and thus a reasonable estimate of glomerular number. That this is indeed the case is suggested by the relatively good agreement between the mean number of glomeruli estimated in our control subjects from the quotient two-kidney Kf/SNKf and values determined directly in nonnephropathic individuals by using unbiased stereologic techniques at autopsy (19). The rather normal value for estimated Ng in moderate MN is consistent with a relatively low frequency of global glomerulosclerosis. We infer that Eq. 9 should thus be no less successful in estimating Ng in severe MN and that the marked reduction that we calculate in this setting is likely to be real, if not absolutely precise.
Our computation of greater depression of two-kidney
Kf in severe compared with moderate MN is
influenced by the assumption of a value of P of 40-45 mmHg in
each grade of injury. An alternative explanation for the greater
depression of GFR in severe MN is that there was marked reduction in
P in that group. Given known values for GFR,
A, renal
plasma flow, and single-nephron Kf, one can then
use the ultrafiltration model of Deen et al. (8, 9) to
estimate the extent to which
P would have to be depressed to explain
the observed hypofiltration in severe MN, assuming that the premorbid
number of glomeruli in both moderate and severe MN was the same as in
controls, i.e., 1.5 × 106 (21).
This calculation revealed that a reduction of
P to 18 mmHg in severe
MN vs. 34 mmHg in moderate MN would be required to account for the
greater depression of GFR observed in those with severe injury at
baseline. There are two reasons that make this possibility unlikely,
however. As stated previously, micropuncture studies in rat analogs of
MN have invariably revealed afferent arteriolar dilatation with an
ensuing elevation of
P (1, 13, 29). Even if segmental
renovascular resistance in human MN differs from that in the rat, it is
hard to conceive how
P could have been depressed by over 20 mmHg in
our subjects with severe injury. Arterial pressure in these subjects
exceeded normal by 21 mmHg, (Table 1). Transmission of even a minor
fraction of this increment into glomerular capillaries should have
elevated and not reduced
P. By exclusion, this points to a reduction
in glomerular number as the most likely explanation for the
disproportionate depression of GFR in severe MN.
Another potential alteration of glomerular hemodynamics that could
potentially contribute to greater GFR depression in severe than
moderate MN is the significantly lower rate of renal plasma flow in the
former, 504 ± 382 vs. 806 ± 188 ml · min1 · 1.73 m2, respectively (P < 0.01). That this is
unlikely to be the case is suggested by two findings, however. The
first is that renal plasma flow in severe MN is not significantly
different from the normal control value (566 ± 128), despite the
finding that GFR is depressed by ~70% on average in the former
(Table 1). Also, the significantly lower filtration fraction in severe
than in moderate MN, 7 ± 3 vs. 11 ± 3%, respectively
(P < 0.001; Table 1), points to a GFR-lowering effect
by a determinant other than renal plasma flow. Greater
Kf depression owing to glomerulopenia in severe
MN could be such a determinant of the lower GFR than in moderate MN.
Dividing the observed rate of total renal plasma flow by the calculated
number of glomeruli in Table 3 yields a rate of renal plasma flow per
nephron (assuming
P = 40 mmHg). Whereas the latter
quantity is 816 ± 558 nl · min
1 · nephron
1
in moderate MN, it is almost twofold higher in severe MN at 1,679 ± 1,989 nl · min
1 · nephron
1.
Thus, if as we propose, glomerulopenia indeed contributes to the lower
GFR in severe MN, the relative depression of total renal plasma flow in
this circumstance simply represents a loss of capacity by the cortical
microvascular bed and not a reduction in the actual glomerular
perfusion rate.
We conclude that the onset of MN is accompanied by a severe depression in hydraulic permeability of the glomerular capillary wall (Fig. 3B). This is partially offset by enhancement of filtration surface area (Fig. 3A) and by profound depression of glomerular oncotic pressure (Table 1). As a result, GFR initially remains in the normal range or is depressed by <50% in moderate MN. In severe MN, by contrast, we propose that equivalent depression of hydraulic permeability in patent glomeruli is compounded by a marked reduction in functional glomerular number (Ng). Together, these two phenomena lower two-kidney Kf to a level where increases in filtration surface area in remnant glomeruli and depression of oncotic pressure can no longer adequately compensate and the GFR falls by >50%. We showed previously that a progressive reduction of GFR in MN over the medium term is a consequence of declining Kf (26). The latter is attributable, in part, to an increasing prevalence of global glomerulosclerosis, and in part to a progressive loss of filtration surface area in remnant glomeruli, with an ensuing decline in single-nephron Kf. We propose that superimposition of these medium-term changes on a markedly reduced number of glomeruli likely accounts for the subset of patients with MN, who progress rapidly to end-stage renal failure. Advances in imaging that will permit human glomeruli to be counted in vivo will be required to validate our proposal and to confirm that glomerular number is indeed depressed early in the course of severe MN.
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ACKNOWLEDGEMENTS |
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We acknowledge L. Anderson, electron microscopy laboratory supervisor, for assistance with morphometry.
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FOOTNOTES |
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This study was supported by National Institutes of Health Grant 5R01 DK-49372 and General Clinical Research Center Grant M01-RR-00070. M. A. Hladunewich's fellowship was supported by a grant from the Northern California Chapter of the National Kidney Foundation. K. V. Lemley was supported by a Faculty Development Award from the Satellite Dialysis.
Address for reprint requests and other correspondence: B. D. Myers, Division of Nephrology, Rm. M211, Stanford Univ. Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5114 (E-mail: h.takagishi{at}leland.stanford.edu).
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. Section 1734 solely to indicate this fact.
First published January 14, 2003;10.1152/ajprenal.00273.2002
Received 26 July 2002; accepted in final form 31 December 2002.
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