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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2018  |  Volume : 29  |  Issue : 1  |  Page : 167-172
Alport’s syndrome with focal segmental glomerulosclerosis lesion – Pattern to recognize

1 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia
2 College of Medicine, King Saud bin Abdulaziz University for Health Sciences; Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center; King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia
3 College of Medicine, King Saud bin Abdulaziz University for Health Sciences; Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City; King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia
4 King Saud bin Abdulaziz University for Health Sciences; Department of Medicine, Division of Nephrology, King Abdulaziz Medical City, Riyadh, Saudi Arabia

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Date of Web Publication15-Feb-2018


The association between Alport’s syndrome (AS) and focal segmental glomerulosclerosis (FSGS) in the same patient is complex and rarely reported. We report a case of a 42-year-old male presenting with proteinuria, microscopic hematuria, elevated serum creatinine and hypertension with unremarkable physical examination apart from obesity. The renal biopsy showed well-established FSGS pattern of injury with mild interstitial fibrosis and tubular atrophy, while the electron microscopic examination demonstrated glomerular basement membranes (GBM) changes compatible with AS. AS can be complicated by segmental glomerular scarring, which can mimic primary FSGS, while familial FSGS can result from mutations in collagen IV network of the GBM. This overlap can complicate histopathological interpretation of renal biopsy, which should be accompanied by mutational analysis for accurate diagnosis and proper therapeutic intervention.

How to cite this article:
Alsahli AA, Alshahwan SI, Alotaibi AO, Alsaad KO, Aloudah N, Farooqui M, Al Sayyari AA. Alport’s syndrome with focal segmental glomerulosclerosis lesion – Pattern to recognize. Saudi J Kidney Dis Transpl 2018;29:167-72

How to cite this URL:
Alsahli AA, Alshahwan SI, Alotaibi AO, Alsaad KO, Aloudah N, Farooqui M, Al Sayyari AA. Alport’s syndrome with focal segmental glomerulosclerosis lesion – Pattern to recognize. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Sep 20];29:167-72. Available from: http://www.sjkdt.org/text.asp?2018/29/1/167/225193

   Introduction Top

Alport’s syndrome (AS) is a rare inherited disease caused by mutations in α3, α4, and α5 chains of type IV collagen, which are present in the glomerular basement membrane (GBM), cochlea and retina.[1],[2] It is clinically characterized by renal failure, sensorineural deafness and ocular abnormalities, and exhibits different modes of inheritance that can be X-linked, autosomal recessive, or autosomal dominant. The X-linked inheritance, which is the most common type, results from a mutation in COL4A5 gene,[2] whereas the autosomal recessive and autosomal dominant AS is due to mutations in COL4A3 and COL4A4 genes.[3]

Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular patterns of injury and diseases that lead to end-stage kidney disease, and can be primary or secondary to various immune-and nonimmune-mediated renal diseases.[4] Histologically, well-established FSGS injury is characterized by mesangial expansion by increased matrix and cellularity, adhesion of the glomerular tufts to the Bowman’s capsule, obliteration of the glomerular capillaries and variable amount of glomerular lipohyalinosis.[5] In familial FSGS, many podocyte-specific gene mutations have been identified, which indicates the importance of podocytes and their key role in the pathogenesis of FSGS.[6] However, as podocytes are part of the glomerular filtering system, they can be injured by a variety of the glomerular diseases,[7] including advanced stages of AS, in which the defective GBM leads to secondary pathological changes in the podocytes and subsequent evolving of FSGS pattern of glomerular injury.[8] On the other hand, studies on familial FSGS revealed that some of these families had no mutation in any of the genes involved in FSGS pathogenesis; instead, mutations in the COL4A3/COL4A4/COL4A5 genes, which typically seen in association with AS, were detected.[2],[8],[9],[10],[11]

Herein, we report a patient presented with persisting proteinuria and hematuria and describe the light microscopic findings of the renal biopsy, which demonstrated a morphological features of well-established FSGS pattern of injury, while electron microscopic analysis showed ultrastructural features typically encountered in AS.

   Case Report Top

A 42-year-old Saudi man was referred to the nephrology services to investigate proteinuria and microscopic hematuria. His medical history was unremarkable with no history of loss of hearing or problems in his vision and no history of previous illness or chronic disease. The patient was not smoker and his family history revealed a history of hypertension and cerebrovascular accident. He denied any family history of hearing loss, eye problems, or kidney disease.

On examination, the patient had normal vital signs with a blood pressure of 110/74 mm Hg, body temperature of 36.5°C, respiratory rate of 20 breaths/min, pulse rate of 77 beats/min and 97% O2 saturation in room air. He was obese with a body mass index (BMI) of 35 kg/m2. Examination of hearing and visual acuities was within normal limits and his respiratory, cardiovascular, musculoskeletal systems, and skin was all unremarkable.

Laboratory investigations revealed white blood cell count of 8.60 × 109/L, red blood cell (RBC) count of 4.68 × 1012/L, hemoglobin of 147 gm/L, and platelets count of 245 × 109/L. Serum electrolytes were within normal limits. The serum creatinine (SCr) concentration was 80 mmol/L, estimated glomerular filtration rate (eGFR) was 68 mL/min, and blood urea nitrogen was 7.7 mmol/L. Urine analysis showed protein of 300 mg/d and RBC of 17/hpf, while the remaining parameters of urine analysis were within normal limits. Twenty-four hour protein quantification was 2.55 g. The parathyroid hormone level was 11.09 pg/mL, and the total 25-hydroxy vitamin level was 32.6 ng/mL. His fasting glucose was slightly elevated (5.9 mmol/L).

The patient was advised to lose weight. He lost weight and reached a BMI of 32 kg/m2. However, he continued to have proteinuria, hematuria, and his SCr level increased to 111 mmol/L, and the eGFR dropped to 60 mL/min. Accordingly, the patient underwent renal biopsy.

The renal biopsy contained three cores of renal cortical and medullary tissue. Two μm thickness sections from the formalin-fixed, paraffin embedded tissue were stained with hematoxylin and eosin, periodic acid–Schiff (PAS), Masson’s Trichrome, and Methenamine silver special stains. For the direct immunofluorescence (IF) study, 3 μm cryostat sections were stained with fluorescein isothiocyanate-conjugated rabbit antihuman IgG, IgM, IgA, C3, C4, C1q, Kappa and Lambda light chains, albumin and fibrinogen (Dako, Carpinteria, CA, USA). The IF positivity was graded using a scale from 0, trace, and 1+ to 3+. Electron microscopy examination was performed on glutaraldehyde-fixed tissue after usual process cessing and staining with a JOEL1230 electron microscope (Akishima, Japan).

Light microscopic examination showed 12 glomeruli, of which two were globally sclerosed. No glomerulomegaly was noted. Some of the glomeruli demonstrated variable increase in mesangial matrix and mesangial cellularity. Well-developed FSGS in the form of obliteration of the glomerular capillaries and adhesion of the glomerular tufts to the Bowman’s capsule was readily identified in three glomeruli [Figure 1]. No glomerular hyalinosis was seen. The GBM showed segmental mild increase in thickness on PAS special stain and reduction in stain uptake on methenamine silver stain. No spike reaction, double contouring or discontinuity of the GBM was detected. There was no evidence of endocapillary hypercellularity, subendothelial deposits, fibrinoid necrosis, karyorrhexis, crescents formation, or microthrombi. Mild, nonspecific, predominantly lymphocytic, and medullary interstitial chronic inflammation was noted. No foam cell change was detected in the glomeruli or renal tubular epithelial cells. Mild interstitial fibrosis and tubular atrophy were seen [Figure 1], but there was no significant replication of the tubular basement membranes (TBM). No significant tubular epithelial cell degenerative changes were seen. There was no arteriolar hyalinosis and no arterial sclerosis. There was no evidence of interstitial vasculitis.
Figure 1: Light micrographs of the renal biopsy showing segmentally scarred glomerulus with mesangial alteration, obliteration of the glomerular capillaries and adhesion of the glomerular tufts to the Bowman's capsule (PAS ×400).

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Direct IF microscopy demonstrated diffuse linear and homogeneous, weak (1+) staining for IgG and strong staining (3+) for albumin along the GBM, Bowman’s capsules and TBM [Figure 2]. This was associated with trace staining for Kappa and Lambda light chains along the GBM and TBM. There was no staining for IgM, IgA, C3, C4, and C1q. Immunofluorescence study for collagen IV α-3, α-4, and α-5 subunits expression was unfortunately not performed.
Figure 2: Direct immunofluorescence microscopy demonstrating diffuse linear staining along the glomerular basement membranes, Bowman's capsules and tubular basement membranes for IgG and albumin, findings commonly seen in the setting of diabetic-related changes in kidney (DIF ×200).

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Ultrastructurally, the mesangium appeared segmentally expanded by increased mesangial matrix. Occasional obliterated glomerular capillaries were noted. No immune-type dense deposits were identified. The GBM showed segmental increase in thickness and attenuation (GBM thickness measured 163 nm) [Figure 3]a and [Figure 3]b. These were associated with loss of morphologic ultrastructural landmarks of the GBM, granular alteration, and reticulation of the texture of the GBM lamina densa [Figure 3]b and [Figure 3]c and segmental splitting [Figure 3]d. The foot processes of the glomerular visceral epithelial cells were effaced, predominantly over the sclerotic glomerular tufts (<50% effacement).
Figure 3: Electron microscopy micrographs showing segmental attenuation (A) and increase in thickness (B) of the glomerular basement membranes (GBM), granular alteration and reticulation of the GBM lamina densa (B and C, arrows) and segmental splitting of the GBM (D, arrows). These ultrastructural morphological features are compatible with hereditary nephritis/Alport syndrome (TEM, uranyl acetate, and lead citrate stain).

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The pathological findings were interpreted compatible with hereditary nephritis/Alport syndrome with secondary segmental glomerular scarring. The presence of diffuse and homogeneous linear IF weak staining of IgG and strong staining for albumin along the GBM and TBM suggested hyperglycemia effect/early diabetes mellitus-related changes.

Unfortunately, the patient did not show up for scheduled appointments for ophthalmic and audiological examinations, and genetic testing and he was lost to follow-up.

   Discussion Top

In this report, we described a patient who presented with persisting proteinuria and hematuria and discuss the clinical and pathological findings. The light microscopic findings of mesangial alterations with obliteration of the glomerular peripheral capillaries and adhesion of the glomerular tufts to the Bowman’s capsule is compatible with segmental glomerular scarring pattern of injury and can be interpreted as primary/idiopathic FSGS. However, ultrastructural analysis showed GBM changes typically seen in AS; these changes included variation in the thickness, and splitting of the GBM, and granular alteration and reticulation of GBM lamina densa, suggesting that the segmental glomerular scarring is a secondary form of FSGS, which can be seen as a chronic injury resulted from various glomerular diseases, including AS.[8] Secondary FSGS can be associated with obesity, have less amount of proteinuria typically seen in idiopathic FSGS and morphologically can exhibit glomerulomegaly and lipohyalinosis, which were not evident in our patient.[12],[13] In our case, the presence of subnephrotic range proteinuria and segmental but noticeable, rather than diffuse and total, effacement of the foot processes of the podocytes is consistent with secondary FSGS. The secondary glomerular scarring is most likely a result of AS, although obesity-related glomerulopathy cannot be completely excluded.

Conversely, the possibility that the histopathological and electron microscopic findings in renal biopsy represent a case of atypical FSGS that exhibits ultrastructural characteristics of AS should also be considered. Malone et al[8] described a cohort of 70 families diagnosed with familial FSGS, of which seven (10%) families had histological features of FSGS, but no mutation in any of the FSGS genes was identified, instead; mutations in the COL4A3/ COL4A4 genes typically causing AS were detected. However, ultrastructurally, thin GBM was detected in one family, while in four other families, variable findings, consistent with classical AS were seen. Using whole-genome sequencing and Sanger sequencing, Xie et al[9] reported heterozygous COL4A3 mutations in five (12.5%) families out of a cohort of 40 families diagnosed with familial FSGS. In addition, Wu et al[11] identify a missense mutation in COL4A4 in six patients from a single family of familial FSGS. Finally, Zhang et al[10] detected a missense mutation in COL4A5 gene in a male patient diagnosed with primary FSGS as well as in his asymptomatic mother. It is worth mentioning that mutations in genes known to cause familial FSGS and result in typical segmental glomerular scarring pattern of injury yet ultrastructural findings mimicking AS were described.[14]

Although our patient denied any family history of kidney disease and had no history of visual problems or deafness, electron microscopic examination of renal biopsy demonstrated ultrastructural features typical of AS. This can be due to the occurrence of a spontaneous mutation affecting the major type IV collagen network of the GBM. Such mutation may occur in up to 15% of X-linked AS. The absence of extrarenal manifestations in patients with COL4 genes mutations and ultrastructural features classical of AS was documented.[15],[16] Thus, the absence of family history of kidney disease and extrarenal manifestations of AS does not exclude AS and histopathological and meticulous ultrastructural examinations along with mutational analysis of COL4 genes still the gold standard for proper diagnosis.

In summary, the relationship between FSGS and AS is complex on light and electron microscopic levels as well as molecular pathogenesis and overlap between these two pathological entities complicates the diagnosis. AS can be complicated by secondary FSGS, especially at an advanced stage of the disease, while FSGS can result from mutations involving genes encoding collagen IV network and exhibits ultrastructural alterations in the GBM typically seen in AS. These cases of familial FSGS, as Miner stated in his commentary published in Kidney International,[2] might indeed fall in the expanding clinicopathological spectrum of AS. Nephropatho-logists should be aware of the complexity of this issue when interpreting renal biopsies showing FSGS pattern of injury. Mutational analysis for COL4 genes should be implemented to define the pathogenesis and to facilitate the selection of appropriate treatment modalities.

Funding: None.

Conflict of interest: None declared.

   References Top

Khoshnoodi J, Pedchenko V, Hudson BG. Mammalian collagen IV. Microsc Res Tech 2008;71:357-70.  Back to cited text no. 1
Miner JH. Pathology vs. Molecular genetics: (re)defining the spectrum of Alport syndrome. Kidney Int 2014;86:1081-3.  Back to cited text no. 2
Dagher H, Buzza M, Colville D, Jones C, Powell H, Fassett R, et al. A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport’s syndrome. Am J Kidney Dis 2001;38:1217-28.  Back to cited text no. 3
Bose B, Cattran D, Toronto Glomerulonephritis Registry. Glomerular diseases: FSGS. Clin J Am Soc Nephrol 2014;9:626-32.  Back to cited text no. 4
Angioi A, Pani A. FSGS: From pathogenesis to the histological lesion. J Nephrol 2016;29: 517-23.  Back to cited text no. 5
Wiggins RC. The spectrum of podocytopathies: A unifying view of glomerular diseases. Kidney Int 2007;71:1205-14.  Back to cited text no. 6
Reiser J, Altintas MM. Podocytes. F1000Res 2016;5. pii: F1000 Faculty Rev-114.  Back to cited text no. 7
Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int 2014;86:1253-9.  Back to cited text no. 8
Xie J, Wu X, Ren H, et al. COL4A3 mutations cause focal segmental glomerulosclerosis. J Mol Cell Biol 2014;6:498-505.  Back to cited text no. 9
Zhang J, Yang J, Hu Z. Study of a family affected with focal segmental glomerulosclerosis due to mutation of COL4A5 gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2017;34:373-6.  Back to cited text no. 10
Wu Y, Hu P, Xu H, et al. A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis. J Cell Mol Med 2016;20:2328-32.  Back to cited text no. 11
Kim JS, Han BG, Choi SO, Cha SK. Secondary focal segmental glomerulosclerosis: From podocyte injury to glomerulosclerosis. Biomed Res Int 2016;2016:1630365.  Back to cited text no. 12
Verani RR. Obesity-associated focal segmental glomerulosclerosis: Pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. Am J Kidney Dis 1992; 20:629-34.  Back to cited text no. 13
Rood IM, Bongers EM, Lugtenberg D, et al. Familial focal segmental glomerulosclerosis: Mutation in inverted formin 2 mimicking Alport syndrome. Neth J Med 2016;74:82-5.  Back to cited text no. 14
Zhou J, Hertz JM, Tryggvason K. Mutation in the alpha 5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: Detection by denaturing gradient gel electrophoresis of a PCR product. Am J Hum Genet 1992;50:1291-300.  Back to cited text no. 15
Atkin CL, Hasstedt SJ, Menlove L, et al. Mapping of Alport syndrome to the long arm of the X chromosome. Am J Hum Genet 1988;42:249-55.  Back to cited text no. 16

Correspondence Address:
Dr. Abdullah A Al Sayyari
Department of Medicine, Division of Nephrology, King Abdulaziz Medical City, P. O. Box 22490, Riyadh 11426
Saudi Arabia
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DOI: 10.4103/1319-2442.225193

PMID: 29456224

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