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&p.1:Abstract Glomerular filtration rate (GFR) and effectiverenal plasma flow (ERPF), determined by the clearancesof inulin and para-aminohippuric acid, were evaluated in

119 children with different types of nephrotic syndromeand in different stages: the nephrotic stage (serum albu-min 35 g/l). GFR in the nephrotic stage was significantlylower than in remission and in controls, and was lowestat onset of the disease (846, 1114, and 1192 ml/minper 1.73 m2). ERPF was higher in the nephrotic stagethan in recovery, especially in children with histologicallesions. Thus the filtration fraction (FF) was greatly de-creased in the nephrotic stage. In patients investigatedboth in the nephrotic and the remission phase, GFR andFF increased significantly. There was a direct correlationbetween the serum albumin concentration and FF and aninverse correlation between mean arterial pressure(MAP) and GFR and FF in all patients, a direct correla-tion between the serum albumin concentration and GFRin minimal change nephrotic syndrome patients, and aninverse correlation between ERPF and serum albumin inchildren with histological lesions. In conclusion, GFRand FF were decreased and ERPF increased in the neph-rotic stage, normalizing in remission. The low GFR inthe nephrotic stage was thus not dependent on hypoper-fusion. We suggest that the low GFR is dependent on avery low ultrafiltration coefficient. The direct correlationbetween GFR and serum albumin and the indirect corre-lation between GFR and MAP suggest compensatorymechanisms that increase the ultrafiltration pressure tocounteract the severely reduced ultrafiltration coefficient.

&kwd:Key words Nephrotic syndrome Renal hemodynamics Glomerular filtration rate Renal plasma flow&bdy:

Introduction

In the nephrotic syndrome, a low glomerular filtration

rate (GFR) has been attributed to a low renal plasmaflow due to hypovolemia secondary to the low plasmaoncotic pressure [13]. The low serum albumin concen-tration in the nephrotic syndrome, however, leads to adecrease in plasma oncotic pressure, which increases theultrafiltration pressure which, in turn, would increase theGFR. In a previous study from our unit in a small groupof children with minimal change nephrotic syndrome(MCNS), we found a decreased GFR which was directlycorrelated with the serum albumin concentration [4]. Inthe present study we have investigated further the contri-bution of the serum albumin concentration to renal he-modynamics in a large number of children with the

nephrotic syndrome of various types, such as MCNS,diffuse mesangial proliferation (DMP), focal segmentalglomerulosclerosis (FSGS), mesangiocapillary glomeru-lonephritis type I or II (MCGN), and membranous neph-ropathy (MN).

Patients and methods

Huddinge Hospital is one of the main referral hospitals for chil-dren with kidney diseases in Sweden. All children referred to uswith nephrotic syndrome were investigated by a renal function testand, in most cases, by a renal biopsy. Nephrotic syndrome was de-fined as marked proteinuria (>40 mg/m2 body surface area per

hour), hypoalbuminemia (


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Eight children were not biopsied, but had a clinical history of ste-roid-responsive nephrotic syndrome, probably MCNS (MCNS?).When comparisons were made between different diagnosticgroups these 8 MCNS? children were included in the MCNSgroup. In 4 of the 7 patients with DMP, IgM was found on immu-nofluorescence, but none had IgA. Six patients underwent anotherbiopsy and 5 had an unchanged morphology. One had changedfrom MCNS to DMP.

Renal function tests were performed in connection with the bi-opsy and at various stages of the disease. Renal function was eval-

uated as the GFR and effective renal plasma flow (ERPF) and wasmeasured as clearances of inulin and para-aminohippuric acid(PAH) [4]. Renal function tests were performed either with thesingle-injection technique, mostly in the youngest children, orwith water diuresis, in children above 23 years of age. Since inthis paper we have excluded all investigations performed with asingle injection, the first renal function test performed in several ofthe youngest children has been omitted. The renal function testssubsequently performed with water diuresis have, however, beenincluded in the study.

Water diuresis was induced by an oral water intake of 20 ml/kgduring the 1st h and thereafter 5 ml/kg every 30 min. After a prim-ing dose of inulin (Inutest, 25%, Laevosan-Gesellschaft) and PAH(amino-hippurate sodium 20%, MSD), a continuous infusion wasgiven [4]. After an equilibration time of 1 h, urine was collectedduring four 30-min periods by spontaneous voiding and a blood

sample was taken in the middle of each urine collection period. Theclearance was calculated as the mean of the four clearance periods.The filtration fraction (FF) was calculated as GFR/ERPF.

Inulin was analyzed by the anthrone method [7] and PAH by amodified Smith technique [8]. Thirty-six healthy children, aged3.520.5 years, served as controls for the renal hemodynamic data.Their GFR was 1192 (mean SE) ml/min per 1.73 m2, ERPF62714 ml/min per 1.73 m2, and FF 19.4%0.5%.

The blood pressure was recorded at the time of the first renalfunction test (including both single injection and water diuresis) in117 (2 missing values) children. It was measured in the right armwith an Omron Digital Blood Pressure Monitor (model Hem-700 C, Sjuma AB, Malm, Boehringer Mannheim ScandinaviaAB, Bromma, Sweden) before starting the renal function test.

Medication

At the first renal functional investigation, 64 of the 98 children, inwhom we performed renal function tests during water diuresis,were on daily or alternate-day corticosteroid treatment and 1MCNS child was also treated with chlorambucil. Of the 98 chil-dren, 7 were on antihypertensive medication, all with -blockers,1 of whom was also on a calcium channel blocker and 1 an angio-tensin converting enzyme inhibitor; 8 patients were on diureticsand 2 on spironolactone. None of the patients received any medi-cation on the morning of the function test.

Forty patients were re-investigated at least once. On the last in-vestigation, 12 children were being treated with corticosteroidsand 5 with antihypertensives. All children and their parents gavetheir informed consent. The study was approved by the ethicscommitee at the Karolinska Institute.

Statistical analysis

The results are expressed as the mean SE and/or as the medianand range. Students t-test, analysis of variance with the post testsTukey-Kramer for all pairs and Dunnett for comparisons with acontrol, paired t-test, the Mann-Whitney U non-parametric test,and chi-squared test were used. Linear regression and correlationcoefficients were calculated by the least squares method. P valuesless than 0.05 were considered significant.

Results

The clinical evaluation included 119 patients, while theevaluation of renal function included 98 patients.

Age at onset and time of renal biopsy

Table 1 shows the various types of the nephrotic syn-drome, age at onset of the disease, age when first renalfunction test was performed during water diuresis orwith the single-injection technique, and the time fromonset to the renal biopsy. The age at onset was signifi-cantly higher in the MCGN children than in the MCNS,DMP, and FSGS children (Table 1). The DMP patientswere biopsied significantly earlier after onset than thepatients with MCNS and FSGS.

Renal function in relation to serum albumin

concentrationFigure 1 shows the GFR, ERPF, and FF at the first renalfunctional investigation performed during water diuresisin various stages of the nephrotic syndrome. Patients in-vestigated several times are represented only once. Irre-spective of the underlying diagnoses, GFR and FF in thenephrotic stage were significantly lower than during re-covery, in remission, and in controls. ERPF in the neph-

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Table 1 Age at onset, age atfirst renal function test (single-injection included), and timefrom onset at renal biopsy.

P values are according toMann-Whitney U test &/tbl.c:&tbl.b:

Diagnosis No. of Age at onset in years Age at first renal Time from onset to renalpatients range (median) function test biopsy, years

range (median) range (median)

MCNS 65 0.915.2 (3.9)* 0.915.4 (5.6)* 0.017.8 (0.9)**,***

MCNS? 10 1.810.5 (4.7)* 2.514.2 (6.1)** DMP 9 0.613.1 (3.2)*** 0.613.1 (12.0)** 0.032.1 (0.1)***

FSGS 20 0.611.6 (3.6)* 1.917.3 (5.2)** 0.0311.8 (0.5)MCGN 10 7.117.3 (13.2) 7.819.8 (13.5) 0.12.5 (0.2)MN 5 0.914.0 (8.2) 1.314.1 (8.4) 0.110.37 (0.14)

MCNS, Minimal change nephrotic syndrome, MCNS?, probably MCNS, no biopsy, DMP, diffusemesangial proliferation, FSGS, focal segmental glomerulosclerosis, MCGN, mesangiocapillary glo-merulonephritis type I or II, MN, membranous nephropathy* P


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rotic stage was significantly higher than in recovery. Anearly significant difference (P=0.076) was seen be-tween ERPF in the nephrotic and remission stage. Pa-tients investigated during the nephrotic stage at diseaseonset (within the first 34 months) showed a significant-ly lower GFR (746 ml/min per 1.73 m2) than those in-vestigated later in connection with a recurrence(11512 ml/min per 1.73 m2, P


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Seventeen individual patients were investigated bothin the nephrotic stage and in remission, and the meanGFR and FF were 666 ml/min per 1.73 m2 and10.4%1% in the nephrotic stage, significantly lowerthan in remission, 1186 ml/min per 1.73 m2 and20.1%0.7% (Fig. 4a and b). Nine patients were investi-gated both in the nephrotic and recovery stages, and themean GFR was 877 ml/min per 1.73 m2 in the nephrot-ic stage, significantly lower (paired t-test, P


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Fig. 5a and b), especially in patients with histological le-sions (r=0.666, n=29, P=0.0001).

Discussion

We found a decreased GFR in the nephrotic stage in allof the various diagnostic groups, with a direct correlationbetween GFR and the serum albumin concentration. Thelowest GFR was seen at onset of the disease. The lowGFR may be caused by several factors, such as a de-creased renal plasma flow, a decreased net driving force,which is represented by the balance between the trans-capillary hydraulic pressure gradient and the oncoticpressure difference, and the glomerular ultrafiltration co-efficient, Kf, which is the product of the surface areaavailable for filtration and the effective hydraulic perme-ability of the capillary wall.

When ERPF is measured by PAH clearance, the ex-traction of PAH is reported to be around 90% [10] in

healthy children. In the nephrotic state, however, the ex-traction of PAH was reduced by around 70% [1113]. Ifthe extraction was reduced in the nephrotic stage in ourpatients, the renal plasma flow would be still higher thanin the present study. We found normal to increased ER-PF in our nephrotic patients and a higher ERPF in pa-tients with histological lesions than in those with mini-mal lesions. An increased or normal ERPF has previous-ly been reported in children and adults with MCNS aswell as with histological lesions [4, 1417]. Geers et al.[18] reported that nephrotic patients with histological le-sions have a lower ERPF than those with minimal le-sions. Their patients, however, were adults with more-severe underlying diseases than our patients. The lowerFF we found in patients with histological lesions than inthose with minimal changes was not confirmed by Geerset al. [18], who reported equally reduced FF in the twogroups [18]. The inverse correlation between the serumalbumin concentration and ERPF we found in patientswith histological lesions was also reported by Geers et

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35

P< 0.0001

DMPMCGN

MCNS

FSGS

35

P< 0.0001

10

20

30

Fig. 4 GFR and FF in the nephrotic stage and in remission in 17patients: 12 MCNS, 3 DMP, 1 FSGS, and 1 MCGN. The straightlines indicate the median values and the P value is calculated bythe paired t-test&/fig.c:

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GFR

(ml/m

inper1.7

3m

2)

a

40

60

80

100

120

140

160

120

r = 0.419n = 87P = 0.0001

600

FF(%)

MAP (mm Hg)b120

r = 0.401n = 86P = 0.0001

5

10

15

20

25

30

70 80 90 100 110

70 80 90 100 110

Fig. 5 GFR and FF in relation to mean arterial blood pressure(MAP) in all patients with MCNS


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al. [18] in patients with minimal and histological lesions[18].

In clinical and experimental studies, treatment withglucocorticoids can increase GFR by increasing theglomerular plasma flow without affecting the glomerularmorphology [19, 20]. As we found a decreased GFR thatshowed no correlation with ERPF, it seems unlikely thatthe corticosteroid treatment contributed to the renal he-

modynamic findings.The normal or increased ERPF might favor a normalor increased blood volume. In nephrotic children withminimal and histological lesions, Vande Walle et al. [21]reported normal blood volumes despite a marked reduc-tion in the plasma oncotic pressure. Normal or increasedplasma and blood volumes in the nephrotic syndromehave also been reported by others [22, 23]. This mightexplain the increased ERPF found in our patients withhistological lesions. Increased glomerular volumes inthese patients, reported in a previous paper, might furthersupport hyperperfusion [17].

Another possible explanation for a reduced GFR

could be a decrease in the ultrafiltration pressure. Thelow serum albumin concentration in the nephrotic stageleads to a decreased plasma oncotic pressure in theglomerular capillaries. This has been shown by Guaschet al. [13, 14, 24]. A decrease in plasma oncotic pressureand a simultaneous increase in the oncotic pressure inBowmans space, secondary to the albuminuria, wouldincrease the ultrafiltration pressure and thereby the GFR.To a certain extent, the ultrafiltration pressure might alsobe influenced by the systemic blood pressure, which wefound increased in a high proportion of our nephrotic pa-tients. The high blood pressure in our patients might becaused by the corticosteroid treatment, but Kster et al.

[25] reported an even higher frequency (95%) in neph-rotic children before the institution of corticosteroids.They also reported that the prevalence of hypertensiondecreased to 19% after complete remission. The influ-ence of hypertension on ultrafiltration pressure has beenproposed by others [14], but is hard to evaluate becauseof the autoregulation of GFR and ERPF [26]. Further-more, the influence of albumin in the glomerular filtratewith regard to proximal tubular reabsorption, and there-by the hydrostatic pressure in Bowmans space, is alsohard to evaluate.

Both the low plasma oncotic pressure and the hyper-tension would increase the ultrafiltration pressure andthus increase the GFR. This implies that the low GFRcould not be attributed to changes in ultrafiltration pres-sure. The increase in ultrafiltration pressure could in-stead be seen as a compensatory mechanism to counter-act a greatly decreased ultrafiltration coefficient. The in-verse correlation between MAP and GFR and the directcorrelation between the serum albumin concentrationand GFR found in the present study might further sup-port this hypothesis. A direct relationship between theplasma oncotic pressure and the ultrafiltration coefficienthas been found in micropuncture studies in normal rats[27]. Such a relationship exists in humans, where a par-allel increase in plasma oncotic pressure and computed

ultrafiltration coefficient was found during remission ofproteinuria in adult MCNS patients [14]. According tothe above results, the ultrafiltration pressure could not di-rectly explain the decreased GFR found in the nephroticstage. Instead, this must be due to a decrease in the ultra-filtration coefficient.

The ultrafiltration coefficient is the product of the fil-tration surface area and the hydraulic permeability of the

glomerular capillary walls. Of the patients in the presentstudy, 55 were previously investigated with regard toglomerular volume [17]. In that study, we found that theglomerular volumes were increased in patients withDMP and FSGS compared with those with MCNS. In-creased glomerular volumes in patients with FSGS havealso been reported in children [28] and adults [24], and atendency to larger glomeruli was also observed in pa-tients with MCNS [14, 28], especially in those who laterdeveloped FSGS [28]. Normal or increased glomerularvolumes might imply a normal or an increased filtrationsurface area, indicating that a reduced ultrafiltration co-efficient must be caused by a reduction in hydraulic con-

ductivity.In a previous study in MCNS children, we found aclose inverse correlation between foot process width andGFR, and also between foot process width and serum al-bumin concentration [29]. We also found an inverse corre-lation between foot process width and epithelial slit porelength density [29]. This decrease in slit pore lengthmight lead to a lower ultrafiltration coefficient. Guaschand Myers [14] also observed a significant reduction inthe filtration slit frequency due to epithelial podocytebroadening in patients with MCNS. Using a mathematicalmodel to calculate the ultrafiltration coefficient, theyfound that in patients with MCNS and decreased GFR,

the ultrafiltration coefficient was reduced by about 85%.In fact, they showed that the logarithm of the filtration slitfrequency correlated with the computed ultrafiltration co-efficient. They also noted a correlation between the GFRand the log filtration slit frequency [14], which is inagreement with our previous study [29]. Guasch and My-ers [14] claimed that the two structures that influence thehydraulic permeability are the glomerular basement mem-brane thickness and the diaphragms at the base of the epi-thelial filtration slits. They found no significant differencebetween glomerular basement membrane thickness inMCNS patients and controls [14, 30]. However, they not-ed a marked reduction in the filtration slit frequency as aconsequence of broadening of the epithelial foot process-es, indicating that the reduced Kf is caused by decreasedhydraulic permeability. The lower GFR found in patientsinvestigated close to the onset of the nephrotic syndrome,compared with those investigated in connection with a re-currence, might be caused by more-pronounced foot pro-cess fusion at the onset of the disease.

The later onset of the disease in children with MCGNthan in children with MCNS found in the present studyagrees with the (ISKDC) results from the InternationalStudy of Kidney Disease in Children [31]. In that study,the onset of FSGS also occurred at a later age than that ofMCNS, a finding that was not consistent with our study.

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Hypertension occurred in 49/117 (42%) of our pa-tients. In the ISKDC study, lower frequencies of hyper-tension were reported, i.e., 13.5% of MCNS, 33.3% ofFSGS, and 27% of MCGN with diastolic blood pressures>98th percentile at the time of diagnosis. We found simi-lar frequencies in our patients, except for a higher fre-quency in the MCNS group, including the MCNS?(44%). Kster et al. [25] report an even higher frequency

(95%) in nephrotic children before the institution of cor-ticosteroids. They found a similar prevalence of hyper-tension in children with FSGS, although, after completeremission, a higher proportion of FSGS patients werehypertensive compared with MCNS children [25].Among the few patients in the present study who werestill on antihypertensive treatment at the last investiga-tion, all had histological lesions and also showed de-creased renal function at that time.

In conclusion,we have shown that patients in thenephrotic stage have a reduced GFR and FF which nor-malize in recovery and remission. The low GFR was notdependent on hypoperfusion. Instead an increased ERPF

was found in the nephrotic stage in patients with histo-logical lesions. A low GFR has previously been reportedto be related to epithelial foot process fusion [14, 29,30], reducing the total slit pore length and thereby the ul-trafiltration coefficient. The direct relationship betweenGFR and serum albumin and the indirect relationship be-tween GFR and MAP suggest the presence of compensa-tory mechanisms to increase the ultrafiltration pressurein order to counteract the greatly reduced ultrafiltrationcoefficient.

&p.2:Acknowledgement The results have been presented at the Inter-national Congress of Pediatric Nephrology, Santiago, Chile, Sep-tember 1995. Financial support was received from the Swedish

Medical Research Foundation (no. 6864), the Karolinska Institute,The Samariten Foundation, and Tornspiran Foundation.

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