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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 3  |  Page : 676-680
A rare cause of nephrotic syndrome

Department of Nephrology, Government Kilpauk Medical College, Chennai, Tamil Nadu, India

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Date of Submission08-Jun-2019
Date of Acceptance24-Jul-2019
Date of Web Publication10-Jul-2020


Classical Alport syndrome is a rare X-linked disease of males (85%) presenting early with hematuria, ocular, and hearing defects. Proteinuria and renal failure are less common in the early stages. Here, we report the case of a young female with nephrotic range proteinuria, microscopic hematuria, and renal failure. A keen observation of abundant interstitial foam cells with suspicious glomerular basement membrane changes on kidney biopsy hinted the possibility of Alport syndrome. Further directed testing of the index patient and her family members including genetic analysis revealed a rare pathogenic variant of COL4A homozygous autosomal recessive Alport syndrome. Pedigree analysis showed that the peculiar inheritance could be due to maternal gonadal mosaicism or uniparental isodisomy of paternal genes alone.

How to cite this article:
Thomas RG, Senthilkumar R P, Velayudham B, Vasudevan C, Murugesan T. A rare cause of nephrotic syndrome. Saudi J Kidney Dis Transpl 2020;31:676-80

How to cite this URL:
Thomas RG, Senthilkumar R P, Velayudham B, Vasudevan C, Murugesan T. A rare cause of nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2022 Oct 3];31:676-80. Available from: https://www.sjkdt.org/text.asp?2020/31/3/676/289453

   Case Report Top

A 26-year-old female, born of second degree consanguineous marriage, presented to our department with complaints of generalized edema and frothy urine of two weeks’ duration. She did not have fever, joint pains, high colored urine, oral ulcers, rash, or any native medicine usage. She was married for five years, but had not conceived yet. There was no past history of similar episodes, dysuria, hematuria, or a family history of kidney disease. Her blood pressure was normal (130/80 mm Hg), and general examination revealed facial and periorbital puffiness and pitting pedal edema. Urine analysis showed 4+ proteinuria, 5-10 red blood cells, and no pus cells. Urine protein creatinine ratio (PCR) was 6.2, and 24- h urine protein was 4226 mg. Serum creatinine was elevated (2.1); serum albumin was low (2.9); and cholesterol (226), ANA, HBsAg, HIV, and HCV serologies were negative. An ultrasonogram showed normal sized kidneys and so a renal biopsy was performed after obtaining informed consent. The light microscopy showed six glomeruli, out of which two were globally sclerotic. Another two glomeruli showed segmental sclerosis with adhesions to the Bowmans capsule in the perihilar region, mild increase in mesangial cellularity, and matrix with interstitial fibrosis and tubular atrophy (IFTA) in 30%–40% of the field, clinching the diagnosis of focal segmental glomerulosclerosis (FSGS) – perihilar variant with moderate IFTA. The pathologist made a keen observation of numerous clusters of foam cells in the interstitium and suggested to rule out Alport syndrome [Figure 1]. Ophthalmological evaluation of the patient revealed anterior lenticonus of both eyes [Figure 2] and [Figure 3]. Fundal flecks were absent, and there was no sensorineural hearing loss by pure-tone audio-gram and brainstem-evoked response audiometry (BERA). A gynecological evaluation for primary infertility did not show evidence of leiomyomas in the uterus. Her parents and siblings were evaluated for features of Alport syndrome. None of them had complaints of hematuria or edema although her father had mild renal failure (serum creatinine 1.4). His eye examination revealed unilateral anterior lenticonus and a flecked retina. Her father consented to a renal biopsy. Light microscopy did not show foam cells, but electron microscopy revealed mild glomerular basement membrane (GBM) alteration [Figure 4] and [Figure 5]. We now entertained the possibility of an inherited mutation and considering that our index patient is a female with features of Alport syndrome, we suspected an auto-somally inherited form of disease. A genetic analysis was done of the index patient (as she was unwilling for a repeat renal biopsy and electron microscopic examination), and she was found to carry homozygous COL4A4 mutation (intron 10) on chromosome 2, making the final diagnosis of autosomal recessive (AR) Alport syndrome with secondary FSGS, nephrotic syndrome, and renal failure. Sanger sequencing for this new mutation is underway, and the patient and her family members were provided genetic counseling.
Figure 1: Massons trichrome stain of the index case showing abundant foam cells in the interstitium.

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Figure 2: Anterior lenticonus of the right eye (index case).

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Figure 3: Anterior lenticonus of the left eye (index case).

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Figure 4: Renal biopsy of the father of the index case. Normal light microscopy.

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Figure 5: Electron microscopy of the father of the index case shows mild glomerular basement membrane alteration.

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   Discussion Top

Alports syndrome, first identified by Dr. Cecil A. Alport in 1927, is a hereditary nephritis due to abnormalities in Type IV collagen, a key component of the glomerular basement membrane.[1] The worldwide prevalence of Alports syndrome is 1 in 50,000.[2] The triple helical structure of Type IV collagen is formed by six possible alpha chains encoded on chromosomes 13 (COL4A1 and COL4A2), chromosome 2 (COL4A3 and COL4A4), and chromosome X(COL4A5 and COL4A6).[3] Depending on the site of the mutation, variants of Alports syndrome are classified as X-linked (85%), AR (10%–15%), and autosomal dominant (5%). The phenotype of X-linked and AR variants is similar with rapid progression to end-stage renal disease (ESRD) between the ages of 16 and 35 years,[4] ocular defects, and sensorineural hearing loss. However, an equal predilection for males and females is seen among AR variants, whereas a male predominance is seen among X-linked Alport.

Our patient is a female who presented with nephrotic syndrome, hypoalbuminemia, dys-lipidemia, and renal failure without any family history of renal disease. The initial clinical suspicion was of MCD, FSGS, or lupus membranous nephropathy. Renal biopsy showed perihilar variant of FSGS and numerous interstitial foam cells, leading the pathologist to raise a suspicion of Alport syndrome. Although foam cells are not pathognomonic of Alport syndrome, their predominant interstitial location makes Alport syndrome more likely in the absence of diabetic nephropathy and atheroembolic disease. Other sites of foam cells are in the capillary loops of glomeruli commonly seen with cellular variant of FSGS and LCAT (lecithin-cholesterol acyltransferase) deficiency. To confirm the diagnosis in our patient, an electron microscopy was required, but as the patient was unwilling, we counseled and performed genetic analysis. Simultaneously, her family members were evaluated clinically for Alport syndrome. Anterior lenticonus in both eyes of the index patient with evidence of chronicity on renal biopsy indicated a severe phenotype of Alport syndrome, which was more likely to be due to AR inheritance as the patient is a female. However, the presence of unilateral anterior lenticonus and flecked retina in the father but normal urinalysis and ophthalmological evaluation in the mother and other siblings was confusing. A renal biopsy was performed on the patient’s father, which showed mild Glomerular Basement Membrane disease alterations in thickness without podocyte abnormalities, strengthening our doubts about an inherited form of disease. The genetic analysis of the patient for Alport panel genes by targeted gene sequencing identified a homozygous AR pathogenic mutation in intron 10 of COL4A4, resulting in truncated gene transcript. The observed variant (c.657 + 1dupG- 5-splice site) has never been reported in the 1000 genomes,[5] ExAC and internal Indian population database. As per the recommendations of the American College of Medical Genetics,[6] the clinical significance of the variant was tested on MutationTaster2 and found to be damaging. Further validation of the variant by Sanger sequencing has been initiated.

Among the extrarenal manifestations of Alport syndrome, anterior lenticonus is the most common among all inherited forms and is pathognomonic of the disease. Bilateral sensorineural hearing loss does not occur until late in adulthood and usually progresses with increasing severity of renal failure.[4] Sometimes, pure-tone audiogram may miss out on cases of early hearing loss, whereas BERA detects acoustic nerve lesions in Alports syndrome, which precedes cochlear dysfunction and clinical hearing loss.[7] Leiomyomas are present in 2%–5% of cases and carriers of X-linked Alports syndrome and are not seen among autosomal variants.[8] Another cause of thinning of GBM is thin basement membrane nephropathy (TBMN), but this is usually a benign disease without extrarenal manifestations and renal failure. Family history of microscopic hematuria without renal failure may be present in TBMN as it is inherited as autosomal dominant pattern by COL4A3 and COL4A4.[9]

With regard to management, Angiotensin-converting-enzyme inhibitors and Angiotensin II receptor blockers are the cornerstone of proteinuria reduction as there is no specific treatment for Alports syndrome. Uncontrolled studies have shown benefits of cyclosporine therapy to retard the progression of renal failure.[10] Once patients develop ESRD, transplantation is the treatment of choice. Posttransplant course is complicated by the possibility of de novo anti-GBM disease in 3% of patients.[11] In our case, the patient and family members were provided genetic counseling. Although genetic analysis was not performed on the parents, parental consanguinity and presence of unilateral anterior lenticonus in the father and unaffected mother suggest the presence of COL4A4 mutation in the father and the second mutant provided by maternal gonadal mosaicism or a case of uniparental isodisomy from the father alone [Figure 6].[12] In view of the high risk of progression to renal failure, the couple were advised against pregnancy and to consider adoption. The patient is on follow-up with serum creatinine 1.4 and urine PCR reduced to 0.7.
Figure 6: Limited pedigree chart.

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   Acknowledgment Top

We would like to acknowledge the contribution from Dr. Anila Abraham Kurien, Renopath, Centre for Renal and Urological Pathology Pvt Ltd., Chennai, who hinted the possibility of Alport syndrome from renal biopsy.

   Source of Support Top

Financial support was provided by Dr. R. P. Senthil Kumar.

Conflict of interest: None declared.

   References Top

Alport AC. Hereditary familial congenital haemorrhagic nephritis. Br Med J 1927;1:504-6.  Back to cited text no. 1
Feingold J, Bois E, Chompret A, Broyer M, Gubler MC, Grünfeld JP. Genetic heterogeneity of Alport syndrome. Kidney Int 1985; 27:672-7.  Back to cited text no. 2
Hudson BG. The molecular basis of Good-pasture and Alport syndromes: Beacons for the discovery of the collagen IV family. J Am Soc Nephrol 2004;15:2514-27.  Back to cited text no. 3
Cheungpasitporn W, Kaewpoowat Q, Suksaranjit P, et al. Autosomal dominant Alport syndrome presenting as proteinuria at marine corps physical fitness test: A case report and review. J Nephrol Therapeut 2012; S8:1.  Back to cited text no. 4
1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, et al. A global reference for human genetic variation. Nature 2015;526:68-74.  Back to cited text no. 5
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17: 405-24.  Back to cited text no. 6
Di Paolo B, Di Marco T, Palmieri PF, Spisni C, Albertazzi A. The brainstem auditory evoked responses in Alports syndrome. Nephrol Dial Transplant 1987;2:323-6.  Back to cited text no. 7
Dahan K, Heidet L, Zhou J, et al. Smooth muscle tumors associated with X-linked Alport syndrome: Carrier detection in females. Kidney Int 1995;48:1900-6.  Back to cited text no. 8
Tiebosch AT, Frederik PM, van Breda Vriesman PJ, et al. Thin-basement-membrane nephropathy in adults with persistent hematuria. N Engl J Med 1989;320:14-8.  Back to cited text no. 9
Callis L, Vila A, Carrera M, José Nieto J. Long-term effects of cyclosporin A in Alports syndrome. Kidney Int 1999;55:1051-6.  Back to cited text no. 10
Kashtan CE, Michael AF. Alport syndrome. Kidney Int 1966;50:1445-63.  Back to cited text no. 11
Anazi S, Al-Sabban E, Alkuraya FS. Gonadal mosaicism as a rare cause of autosomal recessive inheritance. Clin Genet 2014;85:278-81.  Back to cited text no. 12

Correspondence Address:
Remi George Thomas
Department of Nephrology, Government Kilpauk Medical College, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.289453

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]


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