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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 4  |  Page : 925-928
Dense deposit disease in a child with febrile sore throat

1 Pediatric Nephrology and Rheumatology Unit, University Hospital Gaetano Martino, Messina, Italy
2 Nephrology and Dialysis Unit, University Hospital Gaetano Martino, Messina, Italy

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Date of Web Publication21-Jul-2017


Dense deposit disease or membranoproliferative glomerulonephritis type II is a rare glomerulopathy characterized on renal biopsy by deposition of abnormal electron-dense material in the glomerular basement membrane. The pathophysiologic basis is uncontrolled systemic activation of the alternate pathway of the complement cascade. C3 nephritic factor, an autoantibody directed against the C3 convertase of the alternate pathway, plays a key role. In some patients, complement gene mutations have been identified. We report the case of a child who had persistent microscopic hematuria, proteinuria, and hypocomplementemia C3 for over 2 months. Renal biopsy confirmed the diagnosis of dense deposit disease.

How to cite this article:
Conti G, De Vivo D, Vitale A, Fede C, Santoro D. Dense deposit disease in a child with febrile sore throat. Saudi J Kidney Dis Transpl 2017;28:925-8

How to cite this URL:
Conti G, De Vivo D, Vitale A, Fede C, Santoro D. Dense deposit disease in a child with febrile sore throat. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2022 Dec 9];28:925-8. Available from: https://www.sjkdt.org/text.asp?2017/28/4/925/211328

   Introduction Top

Glomerulonephritis (GN) in children are in most cases postinfectious GN (PIGN), characterized by complement activation with reduction of serum C3 levels that usually normalizes within four to eight weeks. When serum C3 levels are persistently low, other GN needs to be ruled out such as membranoproliferative GN (MPGN). According to the type and site of the deposits, a new classification has been proposed. Immunofluorescence (IF) findings now play a crucial role in categorizing MPGN as immunoglobulin-mediated vs. nonimmunoglobulin (Ig)-mediated disease. Cases with MPGN and reduction of C3 levels in the absence of Ig are now classified as “C3 GN” a member of “C3 glomerulopathies” (C3Gs); this also includes dense deposit disease (DDD).[1],[2]

We describe the case of a child who had persistent microscopic hematuria, proteinuria, and hypocomplementemia C3 for over two months. These data indicated that PIGN was unlikely. Renal biopsy showed DDD, a very rare glomerulopathy, with an incidence of 2–3:1 million population.[1] This case report should help to suspect this type of GN in case of urinary abnormalities with persistent hypocomplementemia.

   Case Report Top

A previously healthy 12-year-old child was admitted to our unit with a two-day history of passing blood-stained urine. Two weeks before this, he had pharyngitis and amoxicillin was prescribed by his pediatrician. At the presentation, his blood pressure was 133/73 mm Hg, and there was no edema. Urinalysis showed proteinuria (3+) and dysmorphic erythrocytes in the urinary sediment. Laboratory tests showed hypocomplementemia C3 (9 mg/dL; normal value >85), antistreptolysin O antibodies (ASLO) of 830 U/L (normal value <200), and proteinuria of 1.5 g/24 h. The erythrocyte sedimentation rate, serum C-reactive protein, Igs, total proteins, albumin, C4, creatinine, and urea were normal. The initial diagnosis was acute poststreptococcal GN. Treatment with low-salt diet and monitoring of urine output and blood pressure was started. The blood pressure normalized after a day of hospitalization. Three days later, even the macrohematuria disappeared. However, hypocomplementemia C3 (12 mg/dL), significant microhematuria, and proteinuria 1 g/24-h persisted after 15 days of onset. ASLO was decreasing (580 U/L). To exclude secondary GN, more laboratory tests were performed including autoimmune workup (antinuclear antibody, antineutrophil cytoplasmic antibodies and nDNA); all were negative. Clinical and laboratory findings did not change in the next few weeks. Because of the persistence of low C3 beyond eight weeks, a renal biopsy was performed.

Light microscopy showed 19 glomeruli none of which were completely sclerotic. All the glomeruli showed a diffusely thick glomerular basement membrane (GBM) and mesangial hypercellularity with increased mesangial matrix. Mild tubular atrophy and interstitial fibrosis were present in less than 10% of the specimen [Figure 1]a. IF demonstrated prominent C3 (4+) deposits in the GBM with a ribbon-like pattern. The tubular basement membranes also showed linear deposits [Figure 1]b. Ultrastructural studies showed typical deposits in the lamina densa of GBM characterized by a very electron-dense appearance and foot process effacement in some glomerular capillaries [Figure 1]c. The biopsy suggested MPGN type II or DDD. Subsequently, genetic analysis was performed. No mutations in MCP, C3, CFH, CFB, or CFI were detected. Complement analysis revealed strong alternate pathway activation, very low levels of C3 and high levels of C5b-9 (545 ng/mL) and positive presence of C3 nephritic factor (C3Nef).

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   Discussion Top

GN in children is generally PIGN, characterized by complement activation with reduction of serum C3 levels. Typically, in PIGN, serum C3 normalizes within eight weeks. When serum C3 levels remain persistently low, other GN needs to be ruled out. These are characterized by the activation of the classical or alternate complement pathway and C3 deposits on renal biopsy such as MPGN. MPGN denotes a general pattern of glomerular injury that is easily recognized by light microscopy and classically classified into three types (I, II, and III). Recently, a new classification has been proposed.[2] The current approach is directed at IF findings and distinguishes MPGN with isolated C3 deposits from MPGN with Ig and complement deposits on biopsy. GN with isolated C3 deposits, defined as C3Gs, including DDD and C3GN, are characterized by alternate complement activation and differ from the MPGN (including MPGN type I and type III) that are mediated by the classical complement pathway.

C3Gs have a common pathogenesis, linked to a dysregulation in the activation of the alternate pathway of complement,[3] with low C3 levels but normal C4. However, in C3GN there is an increased activation of the alternate pathway by the C5 convertase, while in the DDD there is a greater activation by C3 convertase. Moreover, in C3GN, the electrondense deposits have paramesangial and subepithelial localization, while in the DDD the deposits are very dense and located in the middle layer of the GBM.

C3Gs and MPGN can be associated with a genetic mutation of the complement system. In particular, mutation of factor H is associated with DDD, C3GN, and MPGN type I, while mutation in factor I and MCP have been identified in patients with MPGN and C3GN.[4] Mutations in C3 of the complement have been identified in DDD.[5] The complement factor B is another protein potentially associated with MPGN.

The differential diagnosis between DDD and C3GN is essential both for the treatment and for prognosis. DDD is a very rare glomerulopathy with an incidence of 2–3:1 million people. The symptoms usually begin between 5 and 15 years, although some cases are described in adulthood. It is considered a more aggressive form compared to C3GN, and leads more rapidly to dialysis, probably due to the higher rate of C3Neph.[1]

There is no specific therapeutic indication. In patients with nephrotic syndrome and progressive decline of kidney function, current guidelines suggest oral cyclophosphamide or mycophenolate mofetil plus low-dose alternateday or daily corticosteroids with initial therapy limited to <6 months.[6] Recently, therapy with eculizumab, human monoclonal antibody, has been reported in MPGN characterized by high levels of C5b-9.[7],[8] Eculizumab blocks the cleavage of the C5 complement protein to C5a and C5b, and it prevents the generation of the proinflammatory peptide C5a and the membrane attack complex C5b-9.

This is an educational case focusing on GN with persistently low C3 levels beyond four weeks. The recognition of this specific glomerulopathy is important to initiate the appropriate treatment avoiding or slowing the progression to end-stage renal disease.

Conflict of interest: None declared.

   References Top

Sethi S, Fervenza FC, Zhang Y, et al. C3 glomerulonephritis: Clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 2012;82:465-73.  Back to cited text no. 1
Bomback AS, Appel GB. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol 2012;8:634-42.  Back to cited text no. 2
D’Agati VD, Bomback AS. C3 glomerulopathy: What’s in a name? Kidney Int 2012;82: 379-81.  Back to cited text no. 3
Servais A, Noël LH, Roumenina LT, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 2012;82:454-64.  Back to cited text no. 4
Martínez-Barricarte R, Heurich M, Valdes-Cañedo F, et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest 2010; 120:3702-12.  Back to cited text no. 5
KDIGO clinical practice guideline for glomerulonephritis. Idiopathic membranoproliferative glomerulonephritis. Kidney Int Suppl 2012;2: 198-9.  Back to cited text no. 6
Daina E, Noris M, Remuzzi G. Eculizumab in a patient with dense-deposit disease. N Engl J Med 2012;366:1161-3.  Back to cited text no. 7
Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 2012;7:748-56.  Back to cited text no. 8

Correspondence Address:
Giovanni Conti
Pediatric Nephrology and Rheumatology Unit, University Hospital Gaetano Martino, Viale Consolare Valeria, 98125 Messina
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Source of Support: None, Conflict of Interest: None

PMID: 28748900

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