—  SPECIALTY CONFERENCE  —

Pediatric Pathology

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
Case History
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 subintimal hyaline.

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 and consistency.

Biopsy Diagnosis
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. [1] 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, [2] 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 sclerosis. [3]

Focal segmental glomerulosclerosis (FSGS) is a name applied to what has become the most common cause of the idiopathic nephrotic syndrome in children [4] and adults [5], 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. [6] 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 [7], but more recent studies have identified absent or altered gene expression in podocytes in familial [8] and HIV-related [9] FSGS and other studies suggest that the idiopathic nephrotic syndrome is a T-cell disorder that leads to podocyte dysfunction. [4]

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. [10] 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 [11, 12, 13, 14, 15, 16, 17, 18] and more detailed analyses of autopsy [1, 19, 20] and biopsy [10, 21-23] 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, [24] and tripled in the past 40. [25] 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 [26], but neither that report nor two recent reviews that tabulated medical complications of obesity [25, 27] included 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%). [21]

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, [15] 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. [1] 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. [19] 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. [20]

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, [16, 17] and single cases by Wesson et al. (41 year old male), [18] Jennette et al. (49 year old male}, [13] Bailey et al. (40 year old male], [11] Lamas et al. (39 year old female), [14] and Faustinella et al. (34 year old female) [12] have generally shown FSGS with hyalinosis and glomerulomegaly. Arteriolar hyaline was noted in one of the cases reported by Warnke et al. [16] and in the reports of Jennette et al. [13] and Bailey et al. [11] Neutrophils and fibrin were noted in the Stanford reports, [16, 17] but have not been described by others. The report by Wesson et al. described the renal biopsy as normal. [18] Several of these reports noted reduction of proteinuria with weight loss. [14, 17, 18]

Larger biopsy series' have been reported from Minneapolis, [22] Madrid, [10, 23] and New York. [21] 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 measured. [22] Praga et al. [10, 23] and Kambham et al. [21] 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. [21] 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. [23]

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. [28] 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, [29] 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. [30] Verani noted lipid in the kidneys of obese patients with FSGS, [20] and recent reports of increased renal accumulation of cholesterol and triglyceride in diet-induced obese mice that was associated with glomerulosclerosis and proteinuria, [31] 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, [32] 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. [33] 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. [34] 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. [35] Finally, while both obesity-related increased GFR [36] and proteinuria [37] 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 hyperinsulinemia. [38]

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