Case 4 -
Focal Segmental and Global Glomerulosclerosis and Hyalinosis, Glomerulomegaly, Patchy Tubular Atrophy and Interstitial Fibrosis, and Arteriolosclerosis
Theodore J. Pysher
Primary Children's Medical Center
Salt Lake City, UT
Click on each slide thumbnail image for an enlarged view
A percutaneous renal biopsy was performed in an adolescent female with nephrotic range proteinuria.
A 19 year old Caucasian female was referred for evaluation of proteinuria that was discovered in the
course of a routine physical examination. She had not noticed facial or extremity edema, skin rash,
joint pain or swelling, or discolored urine. She was overweight, complained of intermittent heartburn,
and was being treated for obstructive sleep apnea. Neither the patient nor her family members had
hearing problems, and there was no family history of renal disease, but both parents were on
antihypertensives. Physical examinations on several occassions were remarkable only for pulse rates that
ranged from 100-108/minute, blood pressures that ranged from 126/65-150/90 Torr, and height at the
50th percentile for age but weight greater than the 95th percentile with a body
mass index of 40 kg/M2.
Urinalyses showed 3+-4+ protein and negative or trace blood, the protein:creatinine ratio ranged from
0.49-1.67 (expected <0.2), and a timed urine collection revealed 2.3 grams of protein/24 h and a
creatinine clearance of 85 mL/min/1.73 M2. Abnormal laboratory studies included cholesterol
233 mg/dL, triglycerides 246 mg/dL, LDL cholesterol 141 mg/dL, non-fasting glucose levels that ranged
from 87-136 mg/dL, and alanine aminotransferase 58 IU. Normal studies included blood urea nitrogen,
creatinine, total protein, albumin, sodium, potassium, chloride, total bicarbonate, calcium, inorganic
phosphate, complete blood count, C3 and C4 complement levels, anti-nuclear, anti-smooth muscle and
anti-neutrophil cytoplasmic antibodies, hemoglobin A1C, thyroid stimulating hormone, and serologic
studies for hepatitis A, B and C.
Case 4 - Figure 1 -
This low magnification photomicrograph shows five glomeruli. The glomeruli at the left and top are large and the other three show segmentally increased mesangial matrix. PAS
Case 4 - Figure 2 -
At higher magnification the increased mesangial matrix in the three smaller glomeruli and the large glomerulus at the top is more evident. The glomerulus at the lower right also shows segmental proliferation of visceral epithelial cells (between 6 and 9 o’clock). Jones
Case 4 - Figure 3 -
The glomerulus in the center is enlarged, the glomerulus at the left shows segmental tuft sclerosis, and the intervening parenchyma shows tubular atrophy and interstitial fibrosis. PAS
Case 4 - Figure 4 -
This glomerulus shows segmental sclerosis (6 to 9 o’clock) and increased mesangial matrix and cellularity in the remaining tufts. Hyaline material can be seen at the interface of the sclerotic tuft and Bowman’s capsule. PAS
Case 4 - Figure 5 -
Beginning at the upper left there is an area of tubular atrophy and interstitial fibrosis, then a globally sclerotic glomerulus, and then a glomerulus that shows extensive segmental sclerosis involving at least 50% of the glomerular area. PAS
Case 4 - Figure 6 -
This glomerulus shows several features of diabetic nephropathy – a capsular drop at 11 o’clock, a hyaline cap at 12 o’clock, and an area of mesangial expansion near 7 o’clock. PAS
Case 4 - Figure 7 -
This arteriole shows eccentric sub-intimal hyalinosis. PAS
Case 4 - Figure 8 -
Approximately 15% of the cortical area showed interstitial fibrosis. Trichrome
Case 4 - Figure 9 -
Immunofluorescent microscopy showed only non-specific staining for IgG (shown here), IgM and C3. Fluoresceinated anti-IgG
Case 4 - Figure 10 -
This electron micrograph shows a widely patent capillary loop at the upper left and a collapsed tuft at the lower right with electron dense material of uncertain significance in the sclerotic area at the upper right. No deposits consistent with immune complexes, or alterations of the capillary basement membrane are evident.
Renal Biopsy Findings
The tissue submitted for light microscopy contained 25 glomeruli, two of which were globally sclerotic
and 8 of which showed segmental tuft sclerosis with hyaline material in many of the adhesions between
sclerotic tufts and Bowman's capsule. The non-sclerotic glomeruli were enlarged and showed slightly
increased mesangial matrix, but normal cellularity. There was proliferation of visceral epithelial cells
over collapsed or sclerotic tufts, but no crescent was seen. Bowman's capsule was slightly thickened and
focally contained a hyaline capsular drop. Approximately 10%-15% of cortical tubules were atrophic, and
a similar proportion of the cortical area was fibrotic. Large arteries at the corticomedullary junction
were unremarkable, but intracortical arteries and arterioles showed segmental to circumferential
Immunofluorescent microscopy showed only blotchy segmental staining for IgG, IgM, and C3 consistent
with serum trapping in the areas of histologically-observed hyalinosis. The tissue submitted for
electron microscopy contained two globally sclerotic glomeruli and one that showed segmental sclerosis
with hyalinosis, and examination of the latter showed irregular accumulations of electron dense material
in collapsed or sclerotic tufts that was most likely insudated protein, but there were no deposits
consistent with immune complexes, and the glomerular capillary basement membrane was normal in caliber
Focal Segmental and Global Glomerulosclerosis and Hyalinosis, Glomerulomegaly, Patchy Tubular Atrophy and Interstitial Fibrosis, and Arteriolosclerosis.
Differential Diagnosis and Discussion
The cardinal lesions in this renal biopsy are glomerulomegaly and focal segmental glomerulosclerosis.
The differential diagnosis of glomerulomegaly includes several extra-renal and primary renal disorders.
The association that is perhaps best known to pediatric pathologists is with cyanotic congenital heart
disease. As reviewed by Cohen, this was first described by Meessen and Litton 1953 and quantitated by
Bauer and Rosenberg in 1960. Spear also reported on this association and noted arteriolar
hyalinization. Cohen also noted that Naeye described glomerulomegaly in children living at high
altitudes, and that this lesion had been described in chronic lung disease, cor pulmonale, and right
sided congestive heart failure due to a variety of causes.  Fogo and co-workers noted significantly
larger glomeruli in 10 children with minimal change disease (MCD) who subsequently developed focal
glomerulosclerosis than in 32 children with MCD who had a more favorable clinical course,  and based on
experimental and clinical observations, Fogo and Ichikawa proposed that glomerular hypertrophy was an
early response to nephron loss, but that the growth-promoting factors that caused the hypertrophy also
caused increased matrix to be laid down, eventually occluding the glomerular capillary bed and leading to
Focal segmental glomerulosclerosis (FSGS) is a name applied to what has become the most common cause
of the idiopathic nephrotic syndrome in children  and
adults , and to a lesion that is seen in a
growing number of familial and infectious diseases, drug toxicities, and stages in the evolution of
nearly all other primary and secondary glomerulopathies. It has been aptly described as
clinicopathologic syndrome rather than a specific disease, and several morphologic patterns have been
recognized.  However, no pattern is diagnostic of a single disease, and many diseases can produce
more than one pattern. FSGS has been recognized for many years as the hallmark of injury due to
glomerular hyperfiltration , but more recent studies have identified absent or altered gene expression
in podocytes in familial  and
HIV-related  FSGS and other studies suggest that the idiopathic
nephrotic syndrome is a T-cell disorder that leads to podocyte dysfunction. 
Clinically, primary FSGS typically presents with acute onset of the nephrotic syndrome, while
secondary forms of FSGS are more insidious, have less severe proteinuria, and do not manifest
hypoalbuminemia or edema even if urine protein excretion exceeds 3.5 grams per day. The practical effect
of this distinction is that primary FSGS is usually treated with immunosuppressive drugs, while secondary
forms are treated with agents that lower intraglomerular pressure such as angiotensin converting enzyme
inhibitors.  Pathologically, secondary FSGS is more likely to show perihilar sclerosis attributed to
increased glomerular perfusion pressure, trapping of IgM and other immunoreactants attributed to less
severe podocyte dysfunction allowing the solvent drag from the leaky membrane to pull albumin through
while larger proteins become trapped, and less extensive foot process retraction.
The insidious onset and absence of clinical stigmata of the nephrotic syndrome in the present case
suggest a secondary form of FSGS, and the most likely cause based on the clinical history and extensive
but largely negative laboratory studies is obesity-related glomerulopathy (O-RG). In a report in 1923 of
clinical observations in 1000 obese patients, Preble noted that 410 had proteinuria. A much lower
prevalence of proteinuria has been reported in more recent surveys, but since 1970, there have been
several case reports
and more detailed analyses of
findings of the renal lesions in obese patients with proteinuria.
Obesity in children is defined from age and sex specific charts of body mass index (BMI), which is the
weight in kilograms divided by the square of the height in meters. Values above the 85th
percentile are categorized as "at risk for overweight" and those above the 95th percentile as
"overweight", and these are roughly comparable to the categories of "overweight" and "obese" in adults.
Applying these categories to data collected in the most recent National Health and Nutrition Examination
Survey (NHANES) revealed that the prevalence of obesity among children and adolescents in the United
States has doubled in the past 20 years,  and tripled in the
past 40.  This increase in the
prevalence of obesity has been accompanied by two- to five-fold increase in various obesity-related
hospitalizations based on a comparison of data in the National Hospital Discharge Survey , but neither
that report nor two recent reviews that tabulated medical complications of obesity
O-RG. However, Kambham et al. noted a ten-fold increase in the prevalence of O-RG in their biopsy
practice between 1986-90 (0.2%) and 1996-2000 (2.0%).
Autopsy studies identified the importance of glomerulomegaly in obesity-related glomerulopathy.
Suzuki first noted glomerulomegaly in the autopsy of a massively obese 52 year old woman who also had
endocardial fibroelastosis,  and Cohen identified glomerulomegaly in a review of the autopsies of 5
obese patients, including 3 year old, 14 year old, and 22 year old males with Prader-Willi syndrome, and
two other males 26 and 30 years old. The 14 and 26 year old patients had diabetes, and all of the
patients had fatty livers – 5 years before Ludwig and co-workers described non-alcoholic
steatohepatitis.  Kassiske and co-workers reviewed the autopsies of 46 obese patients
(mean age 50
years) and 46 age, sex and height matched controls, and found no FSGS (and only rare global sclerosis) in
the obese group. However measurements of glomeruli in a subset of 10 obese and 10 control kidneys showed
glomerulomegaly in the obese group that was proportional to body and kidney weight.  Verani found
FSGS in a review of autopsy kidneys of 7/22 obese but 0/15 age and sex matched control patients.
Glomeruli were larger than controls in patients with FSGS, but not in those with obesity without FSGS,
and glomerular size correlated with lipid levels and heart weight, but not body or kidney weight. 
The reports of 5 patients at Stanford (25 year old female, 37 year old male, 49 year old male,
49 year old female, and 53 year old male}, 3 of whom had biopsies,
and single cases by
Wesson et al. (41 year old male),
 Jennette et al. (49 year old male},
 Bailey et al.
old male],  Lamas et al.
(39 year old female),
 and Faustinella et al.
(34 year old female)
have generally shown FSGS with hyalinosis and glomerulomegaly. Arteriolar hyaline was noted in one of
the cases reported by Warnke et al.  and in the reports of Jennette
et al.  and Bailey
et al. 
Neutrophils and fibrin were noted in the Stanford reports,
but have not been described by
others. The report by Wesson et al. described the renal biopsy as normal.  Several of these reports
noted reduction of proteinuria with weight loss.
Larger biopsy series' have been reported from Minneapolis, 
New York. 
Kasiske et al. collected 17 patients over 4 years and compared them to 34 age and sex matched nephrotic
but non-obese "controls" (14 with membranous nephropathy, 6 with minimal change disease, and the others
with a variety of lesions). Focal glomerulosclerosis was seen in 9/17 obese patients, but only 2/34
controls, and 4 of the obese patients but none of the controls had "occult diabetic nephropathy". The
obese patients had normal albumin levels despite similar levels of proteinuria. Glomerular size was not
Praga et al.
and Kambham et al.  compared patients with obesity-related
(O-FSGS) and idiopathic FSGS (I-FSGS) and found that O-FSGS patients tended to be older with less severe
proteinuria and impairment of renal function, and only rarely manifested clinical or laboratory features
of nephrotic syndrome. Nevertheless, both of these studies showed a progressive loss of renal function
on follow-up and predicted that approximately 50% of patients would progress to end stage renal disease
over 10 years. Kambham et al. found glomerulomegaly (by definition) in all patients with O-RG and
O-FSGS, but only in 10% of I-FSGS biopsies. The O-FSGS group showed a predominantly classic pattern of
FSGS with only a few examples of tip, cellular or collapsing lesions (the latter two of which were
excluded from the I-FSGS group); and a mixed distribution of sclerotic lesions (exclusive perihilar
involvement in only 19%) . A smaller proportion of glomeruli in the O-FSGS group were affected by
segmental or global glomerulosclerosis and a smaller proportion of the glomerular capillary surface
showed foot process retraction. Arteriosclerosis and "diabetoid" changes in glomeruli were more common
in the O-FSGS group.  Praga et al. found that the percentage of segmentally sclerotic glomeruli
correlated with the level of proteinuria, while the percentage of globally sclerotic glomeruli correlated
with serum creatinine and creatinine clearance results. They noted no difference in the prevalence of
arteriolosclerosis in the O-FSGS and I-FSGS groups. 
FSGS is presumed to be a consequence of glomerular hyperperfusion, usually in response to a congenital
or acquired reduction of glomerular mass, but in O-RG this could be due to increased perfusion of a
normal nephron mass as it has been known for some time that obese patients have increased blood
volumes.  The "diabetoid" features of O-FSGS raise the question of whether some of the proposed
pathogenetic mechanisms of diabetic nephropathy, such as mesangial cell or podocyte injury due to
hyperglycemia and advanced glycation end-products, and upregulation of the fibroblastic activity of
mesangial cells by transforming growth factor beta (TGF-b) might play a role in the development of O-RG.
Uriu and co-workers showed glomerulomegaly (increased over controls, but proportional to body weight),
mesangial matrix expansion, and glomerulosclerosis in obese non-insulin dependent diabetic rats compared
to lean non-diabetic controls,  and Scaglione and co-workers have shown a correlation between BMI and
higher circulating levels of TGF-b and urinary albumin excretion in obese and overweight hypertensive
subjects compared to lean hypertensive subjects.  Verani noted lipid in the kidneys of obese patients
with FSGS,  and recent reports of increased renal accumulation of cholesterol and triglyceride in
diet-induced obese mice that was associated with glomerulosclerosis and proteinuria,  suggest that
altered renal lipid metabolism plays a role in the development of glomerulosclerosis.
However, a study of glomerular filtration rate (GFR) and renal plasma flow (RPF) in 12 non-diabetic
obese subjects and 9 controls showed significantly greater GFR and RPF in the obese subjects that
correlated with insulin resistance,  and a gene array study of glomeruli microdissected from the renal
biopsies from six patients with O-RG and two control donor kidneys found increased expression of genes
related to lipid metabolism, inflammatory cytokines, and insulin resistance in the O-RG kidneys. 
Insulin resistance is also related to obesity-related hypertension, which may contribute to O-RG, as
animal and in vitro studies have shown that insulin upregulates AT1 and AT2 receptors in the kidney. 
The strong relationship between insulin resistance and progressive renal disease in hypertensive
patients, and the emergence of FSGS as the major lesion in hypertensive nephrosclerosis, led
Kincaid-Smith to recently propose that obesity and insulin resistance, rather than blood pressure, are
responsible for hypertensive nephrosclerosis.  Finally, while both obesity-related increased
and proteinuria  have been shown to improve with weight loss, a study of obese Zucker rats showed
that while hypertriglyceridemia and glomerular hyperfiltration could be reversed by food restriction at
any age, food restriction at 6 or 12 weeks of age prevented glomerular injury, whereas food restriction
at 26 weeks of age reduced proteinuria and food restriction at 50 weeks of age prevented further
increases in proteinuria without reducing pre-existing hypercholesterolemia, hypertension, or
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