Focal
Segmental
Glomerulosclerosis
and
Progressive
Renal
Failure
Associated
with a
Unilateral
Kidney
Paul S. Thorner,
MD, Gerald
S. Arbus,
MD, David
S. Celermajer,
and
Reuben
Baumal,
MD, PhD
From the Departments of Pathology and Pediatrics, The Hospital for Sick Children, Toronto
ABSTRACT.
Persistent proteinuria, chronic renal failure, and focal segmental glomerulosclerosis developed in three children with solitary kidneys. Two of these children were born with unilateral kidneys. The third had bilateral reflux and underwent a unilateral nephrectomy and reim-plantation of the remaining ureter; persistent proteinuria developed 7 years later. It is postulated thathyperperfu-sion of a critical number of glomeruli during childhood
may be the mechanism responsible for the production of
focal segmental glomerulosclerosis in these patients.
Pe-diatrics 1984;73:806-810; unilateral kidneys, focal
segmen-tal glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is the second most common cause of idiopathic nephrotic syndrome in childhood and often progresses to renal insufficiency.’ Although FSGS has been widely recognized in laboratory animals with uni-lateral kidneys,27 this association has only recently been reported in man.8 Kiprov et a!8 showed that FSGS was present in adults born with a solitary kidney but not in adults who had undergone uni-lateral nephrectomy. We report the development of proteinuria, chronic renal failure, and FSGS in three children with solitary kidneys.
CASE REPORTS
Case I
A 15-year-old male adolescent was found to have 2+
proteinuria during a routine presummer camp
examina-Received for publication June 1, 1983; accepted July 18, 1983. Reprint requests to (R.B.) Department of Pathology, The Hos-pital for Sick Children, 555 University Aye, Toronto, Ontario,
Canada M5G 1X8.
PEDIATRICS (ISSN 0031 4005). Copyright © 1984 by the
American Academy of Pediatrics.
tion when he was 1 1 years old. He was otherwise normal with height and weight at the 25th percentile. Investiga-tions revealed BUN of 23 mg/dL and serum creatinine
level was consistently about 1.6 mg/dL. The urine did not contain any blood or casts. A 24-hour urine showed
2.5 g of protein, and creatinine clearance was 64 mL/
min/1.73 m2. Values for serum electrolytes, lipids, and
proteins were normal. An intravenous pyelogram (IVP) showed that the kidney was in the right iliac fossa, but
there was no evidence of a left kidney on ultrasound examination. Cystourethogram indicated a normal
blad-der and urethra with no reflux. The patient has remained well without therapy, and at no time has he been hyper-tensive or edematous; however, the proteinuria has
per-sisted and there has been a slight reduction in growth
rate. At his most recent visit, the serum creatinine level
was 2.7 mg/dL, creatinine clearance was 19 mL/min/1.73
m’, and 24-hour urinary protein was 2.5 g. An open renal
biopsy was performed.
Case 2
An 8-year-old boy was admitted to the hospital on
numerous occasions from 6 months of age onward with pneumonia and asthma. During one of these stays (at 3#{189}
years of age), he was found to have proteinuria; there was
no hypertension. An IVP and ultrasound demonstrated an absent left kidney and compensatory hypertrophy of the right kidney. Cystoscopy showed a hemitrigone of the
bladder with a single ureteric orifice. There was no reflux
on a voiding cystourethrogram. Over the next 4 years, he
was followed by his family doctor; the boy’s urine was
normal except for persistent 2 to 4+ proteinuria. At no
time was edema present. Values for BUN and serum creatinine were in the normal range. The patient’s serum creatinine level was first noted to be elevated (1.3 mgI
dL) when he was 7 years old and he was referred to The
Hospital for Sick Children. Creatinine clearance was 43 mL/min/1.73 m2, and 24-hour urine protein was 0.75 g. Nine months later, the serum creatinine level was 1.6 mg/dL and creatinine clearance was 31 mL/min/1.73 m2.
Fig I. Renal biopsy from case 1, showing focal segmen- tubular atrophy and interstitial fibrosis. (hematoxylin-tal sclerotic lesions in glomerulus against background of phloxine-saffron, x140).
Case 3
MATERIALS
AND
METHODS
A 16-year-old male adolescent was first seen at 6 years
of age with a 1-week history of diarrhea and fever. Inves-tigations at that time revealed bilateral costovertebral
angle tenderness, pyuria, and Gram-negative bacilli in
the urine. There was no proteinuria. He was treated for pyelonephritis and dehydration, and the initial serum creatinine level of 3.8 fell to 1.5 mg/dL. IVP showed no function of the left kidney. Voiding cystourethrogram showed bilateral vesicoureteral reflux. Because of its poor function, the left kidney was surgically removed.
Histo-logic examination revealed renal dysplasia; no evidence
of FSGS was seen. Five months later, the patient’s re-maining ureter was reimplanted. At this time, creatinine clearance was 50 mL/min/1.73 m’. Over the next 7 years,
the patient remained asymptomatic; renal function was stable and no evidence of reflux, urethral obstruction,
edema, or proteinuria (checked twice annually) was ever
noted. He maintained normal height and weight (50th to
75th percentile) and was not hypertensive. Proteinurea (1 to 2+) with a rising serum creatinine level first
ap-peared when he was 13 years old. When last seen, his serum creatinine level was 2.7 mg/dL and a 24-hour urine sample contained 2.7 g of protein. An open renal biopsy was performed.
Open renal biopsies were performed on the three
patients and each specimen was divided into three
parts. The first was fixed in Helly’s solution and processed for routine paraffin sections; 3-j.m sec-tions were stained for light microscopy. The second
part was snap-frozen in liquid nitrogen, sectioned at 5 tm, and stained with fluorescein-conjugated rabbit antisera to immunoglobulins G, A, M, and C3. The third part was fixed in universal fixative
and processed for electron microscopy.
RESULTS
A!! three biopsies demonstrated similar features and are described together.
Light microscopy showed extensive areas of tu-bular atrophy, interstitial fibrosis, and a chronic interstitial inflammatory cell infiltrate (Fig 1). A spectrum of changes was seen in the g!omeru!i, ranging from normal (25%) to global sclerosis (25%
to 50%). The remaining glomeruli demonstrated
Renal biopsies were performed on three children with solitary kidneys, in order to ascertain whether
2.
(
Lomeru om case 3, showing segmental sclerotic 1and hyaline deposit (arrowhead) (hematoxylin-phloxine-saffron, x350).
loop collapse, and foci of hyalinosis (Fig 2). The
scierosed segments were adherent to Bowman’s
capsule with overlying areas of prominent parieta! epithelium. In some cases, these changes were most marked at the vascular pole, but they were also seen in other portions of the glomeruli. Away from the
segmental lesions, glomerular capillary loops and
mesangial regions appeared normal. The affected glomeruli were often surrounded by fibrosis. None of the biopsies showed evidence of renal dysplasia or other congenital anomaly.
Immunofluorescence studies revealed focal seg-mental granular staining for 1gM and C3 in
gb-meruli, mainly in mesangia! regions.
Electron microscopy showed extensive fusion of foot processes of visceral epithe!ial cells and pseu-dovilbous transformation. Gbomerular capillary
basement membranes were wrinkled and thickened
in the areas of sclerosis. No electron-dense deposits were identified, but foam cells and osmiophi!ic
de-bris were occasionally found in a subendothelial
location.
DISCUSSION
their proteinuria and renal failure were a
conse-quence of FSGS. It is known that FSGS may be primary or secondary to a number of other diseases
including heroin abuse,9 segmental hypoplasia,’#{176} oligomeganephronia,1 Alport’s 12 and
re-flux nephropathy.’3 Recently, unilateral renal
agen-esis (ie, patients born with a solitary kidney) has
been described as a secondry cause of FSGS. In a
retrospective review of 586 renal biopsies and 9,200 autopsies, Kiprov et a!8 found five and two cases, respectively, of unilateral renal agenesis associated with FSGS. An eighth case was the father of one of the other seven cases. Seven of these cases were males; the youngest was 18 years old. In six cases,
terminal renal failure led to death. In one case, the patient was in chronic renal failure. No cases of FSGS were found in adults who had undergone
unilateral nephrectomy.
In our study, all three patients were male. They
were first seen with proteinuria at 3#{189}to 13 years
of age, with no evidence of a renal tubular defect.
Two ofthe patients were born with solitary kidneys; at no time did they have evidence of reflux and/or
pyebonephritis, yet both demonstrated FSGS on renal biopsy. The third patient was seen with reflux
poorly functioning kidney removed surgically; it
showed no evidence of FSGS. An antireflux proce-dure was performed on the remaining kidney.
Al-though the creatinine clearance was reduced at the time of ureteral reimplantation, there was no fur-ther reflux. Proteinuria
did
not appear until 7 years later, suggesting that FSGS did not develop untilthis time.
What factor(s) may be responsible for the
initi-ation and progression of secondary FSGS, as seen in our three patients? Studies in animals27 have shown that the situation of a solitary kidney in
man can be simulated by performing renal ablation
experiments, which result in functional overload of
the remaining renal ti55ue.3’4’6”4 Although overall gbomerular filtration rate drops, the gbomerular fib-tration rate per individual nephron rises.3’4 This hyperperfusion per nephron leads to gbomerular
damage, heralded by proteinuria, and, in time,
FSGS which becomes well established within 2 to
50 weeks.3’4 The process is self-perpetuating,
be-cause with every glomerulus that becomes sclerotic, there is a further increase in perfusion of the re-maining nephrons. This may explain why renal injury occurring at one time progresses in the future to renal failure. Why the gbomerular lesion is
mi-tially segmental and begins in the juxtamedulbary region is not known. It has been postulated thatjuxtamedullary gbomeruli have a higher filtration rate and thus are more susceptible than superficial
glomeruli to damage as a result of
hyperperfu-sion.2”5
An additional factor in the development of FSGS
has become clear from animal and human data. In uninephrectomized or /6 renal-ablated rats, several investigators’’9 observed that high protein diets
(up to 40% of calories) increased the severity of
FSGS, whereas a protein-restricted diet (6% of calories) minimized the development of FSGS.4’2#{176} Improved renal function was also noted in patients with progressive renal failure when their dietary
protein intake was reduced.2’ Studies have shown
that increasing the protein or amino acid content of the diet increases renal perfusion, perhaps via glucagon release.2#{176} This increase would aggravate
the hyperfusion per nephron already occurring
when renal mass is reduced.
What makes some children with one kidney
sus-ceptible to the development of FSGS and not others
is not clear. Although the incidence of solitary
kidneys in the general population is about 1/1,000,
the majority of affected individuals do not acquire renal disease. In addition, the effect of unilateral nephrectomy in adults is controversial. Some investigators have concluded that renal damage
does not occur after nephrectomy3’2224 whereas
others25’26 have detected subtle deterioration in
renal function, suggesting that such patients be followed closely for more obvious renal
abnormali-ties. One explanation that may account for the
progressive renal disease that ensues in some chil-dren with a solitary kidney is that there is a critical number of nephrons below which the kidney is at
risk to develop FSGS. If one is born with a solitary
kidney and appreciably less than 1 million neph-rons, perhaps the case in our first two patients, or if a kidney is removed from an individual and the remaining kidney has a significant number of
neph-rons destroyed (from reflux and/or pyebonephritis) as in our third patient, then in time, FSGS will
occur. Similarly, patients with oligomeganephronia or segmental hypoplasia may be at risk, while the
majority of patients born with solitary kidneys or
undergoing unilateral nephrectomy, yet who
pos-sess a full complement of 1 million functioning
nephrons would not be at risk. We believe that this mechanism may explain the development of FSGS
in our three patients.
It would appear that proteinuria and renal failure were a consequence of FSGS in patients 1 and 2, who were born with a solitary kidney, and in patient
3, who was left with a single kidney as a result of surgery. We feel that performance of renal biopsies was justified because it allowed us to determine that
FSGS was present, presumably as a result of
hy-perperfusion of the remaining nephrons.
Restric-tion ofprotein has been instituted in these children,
who had been receiving regular diets, because it has been shown that a high protein diet increases gb-merular filtration rate and would potentially aggra-vate the FSGS.2#{176}It is conceivable that restricting dietary protein early in life might be more beneficial to these patients than doing so after renal failure
has developed.
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MEETING: BEHAVIORAL PEDIATRICS FOR THE PRACTITIONER
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