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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 6  |  Page : 1274-1278
C1q nephropathy and isolated CD59 deficiency manifesting as necrotizing crescentic glomerulonephritis: A rare association of two diseases

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India

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Date of Web Publication30-Oct-2015


C1q nephropathy is a recently described clinico-pathologic entity with a variable clinical presentation and pathology. Crescentic glomerulonephritis (GN) has been reported in only two patients in the available literature. CD59 deficiency, along with lack of CD55, is responsible for paroxysmal nocturnal hemoglobinuria (PNH). Few cases of isolated CD59 deficiency have been described with PNH-like features. A middle-aged adult male presented with rapidly progressive renal failure. Serological investigations were negative. A renal biopsy revealed necrotizing crescentic GN with rupture of Bowman's capsule. Immunofluorescence on the frozen sections showed dominant mesangial deposits of C1q along with IgM. Hematological work-up of the patient revealed isolated CD59 deficiency. Hence, a final diagnosis of C1q nephropathy and CD59 deficiency manifesting as crescentic GN and hemolytic anemia was made. The co-existence of two rare disorders, C1q nephropathy and CD59 deficiency, in a patient with necrotizing crescentic GN is described for the first time to the best of our knowledge. The pathogenetic link of these two entities with the clinical manifestation requires further study.

How to cite this article:
Gupta R, Sharma A, Agarwal SK, Dinda AK. C1q nephropathy and isolated CD59 deficiency manifesting as necrotizing crescentic glomerulonephritis: A rare association of two diseases. Saudi J Kidney Dis Transpl 2015;26:1274-8

How to cite this URL:
Gupta R, Sharma A, Agarwal SK, Dinda AK. C1q nephropathy and isolated CD59 deficiency manifesting as necrotizing crescentic glomerulonephritis: A rare association of two diseases. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2022 Dec 8];26:1274-8. Available from: https://www.sjkdt.org/text.asp?2015/26/6/1274/168671

   Introduction Top

Jenette and Hipp described C1q nephropathy as an immune complex-mediated glomerulonephritis (GN) with dominant mesangial deposits of C1q in the absence of evidence of lupus erythematosus. [1] The clinical presentation of C1q nephropathy may range from steroidresistant nephrotic syndrome to nephritic- nephrotic picture. Likewise, the pathologic correlates include minimal change lesion (MNCS), focal segmental glomerulosclerosis (FSGS) to various proliferative GN. [2],[3] Crescentic GN in C1q nephropathy has been described in only two reports in the available literature. [3],[4]

CD59, in conjunction with CD55 (decay accelerating factor), is deficient in paroxysmal nocturnal hemoglobinuria (PNH). Isolated deficiency of CD59 has also been reported in a few patients with PNH-like clinical picture. [5] Experimental studies have shown enhancement of glomerular injury in the CD59a-deficient mouse model of nephrotoxic nephritis. [6] The co-existence of C1q nephropathy and CD59 deficiency has not been described in the literature so far to the best of our knowledge. This report describes a necrotizing crescentic GN in a patient with a C1q nephropathy and an isolated CD59 deficiency.

   Case Report Top

A 34-year-old man was referred to the nephrology department with a two-week history of anorexia, vomiting, reduced urine output and generalized weakness. He was detected to have advanced azotemia (serum creatinine 25.2 mg/dL) at a private hospital and initiated on hemodialysis. There was a history of high-grade fever one month back, which was managed by antipyretics. There was no other significant medical or surgical illness, including rash or joint pains. He was normotensive at admission. The general physical and systemic examination was unremarkable, except for pallor.

The hematological investigations revealed anemia (hemoglobin 7.5 g/dL) with normal leukocyte (7.8 × 10 6/L) and platelet (2.09 × 10 9/L) counts. Renal function tests showed serum urea 120 mg/dL and creatinine 13.2 mg/dL. Serological investigations for antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (anti-GBM) antibodies were negative. Serum complement component (C3) levels were also normal. Urinalysis revealed proteinuria (2+ spot) with microscopic hematuria. Ultrasonography of the abdomen showed normal-sized kidneys with increased echogenecity and partial loss of cortico-medullary distinction. The salient investigations are tabulated in [Table 1]. A renal biopsy was performed with a clinical diagnosis of rapidly progressive renal failure.
Table 1: Salient biochemical and serological investigations.

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The renal biopsy contained ten glomeruli, of which nine showed cellular to fibrocellular crescents with variable compression of glomerular tufts [Figure 1]a. The crescents as well as glomerular tufts showed neutrophil infiltration with focal fibrin deposition [Figure 1]b. Two glomeruli showed focal tuft necrosis. Rupture of the Bowman's capsule was also noted [Figure 1]c and d.
Figure 1: A panel of photomicrographs showing glomerular crescent, tubular atrophy and intersitital fibrosis with inflammation (a, H&E, ×100). The crescent can be better appreciated at higher magnification (b, H&E, ×200). Periodic acid Schiff stain shows a cellular crescent with rupture of glomerular basement membranes (c, PAS, ×200). Methenamine silver stain delineates the crescent and the fragmentation of basement membranes (d, ×200).

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Immunofluorescence examination showed strong mesangial deposits of C1q (3+ staining, [Figure 2]a and b along with IgM. Staining for IgA, IgG, C3 and kappa and lambda antibody chains were negative.
Figure 2: Photomicrographs showing strong mesangial staining for C1q in a glomerulus with crescent (a and b, FITC-conjugated stain, ×200). The tubular epithelial cells demonstrate golden-brown refractile cytoplasmic pigment (c, H&E, ×200). Higher magnification shows the fine granular nature of the pigment (d, H&E, ×400).

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Focal tubular atrophy and interstitial fibrosis were detected. In addition, many tubules, especially those in the medulla, demonstrated cytoplasmic deposition of fine granular, golden-brown refractile pigment [Figure 2]c and d. The Prussian blue staining revealed the pigment to be hemosiderin. Tubular red cell casts were also noted.

A final pathologic diagnosis of C1q nephropathy manifesting as necrotizing crescentic GN with tubular hemosiderin deposition was reported and diagnostic work-up for etiology of hemolytic anemia was advised.

The serology tests for HIV, anti-HCV and HBsAg were negative. A hematological workup for hemolytic anemia was performed. G6PD (qualitative) screening test, direct Coombs' test and high-performance liquid chromatography for hemoglobinopathy diagnosis were all negative. The Gel card test for paroxysmal nocturnal hemoglobinuria showed isolated deficiency of CD59, while CD55 was normal.

Hence, the final diagnosis was C1q nephropathy and isolated CD59 deficiency presenting as necrotizing crescentic GN.

The patient was started on oral prednisolone 1 mg/kg with monthly intravenous cyclophosphamide 12 mg/kg. A total of three doses of cyclophosphamide was given. The prednisolone dose was tapered by 10 mg every month. However, the patient did not show any response and continued to require dialysis support. After three months, in view of no response to immunosuppressive therapy, all the immunosuppressive drugs were stopped and the patient was prepared for renal transplantation.

   Discussion Top

C1q nephropathy, an immune complex glomerulonephritis characterized by dominant or co-dominant mesangial deposits of C1q in the absence of evidence of systemic lupus erythematosus, was described as a distinct entity by Jennette and Hip in 1985. [1] The majority of the cases of C1q nephropathy have been reported in older children and young adults as steroidresistant nephrotic syndrome with a poor long-term prognosis. [1],[2] The histologic appearance of C1q nephropathy ranges from no appreciable change (minimal change, MCNS) to FSGS to proliferative GN. Iskandar et al, in their pediatric series, concluded that C1q nephropathy was clearly distinguished from the usual cases of MCNS or FSGS due to the poor response to steroids. [2] On the other hand, Markowitz et al suggested that C1q deposition in FSGS may be non-specific and does not indicate an ongoing immune-mediated process. [7] In a study by Vizjak et al, the patients with MCD or FSGS were younger than those with proliferative GN. In their study, the podocyte foot process effacement and cytoskeleton condensation were not associated with glomerular capillary wall deposits in the MCD and FSGS groups. [8]

Proliferative GN has been reported in C1q nephropathy with a variable frequency. [1],[3],[8],[9] Because membranoproliferative GN may show deposition of C1q, this form of GN has been recommended as an exclusion criterion for C1q nephropathy by Jennette and co-workers. [1] Various histologic findings, including the focal or diffuse proliferative GN, mesangial or proliferative GN or membranous GN have been reported in the patients with C1qN and "full house" immunofluorescence staining. [3] An extensive review of the available English literature yielded only two cases of crescentic GN in the C1qN. [3],[4] Srivastava et al. described the crescentic GN in a 3-year-old girl with C1qN. This patient progressed to end-stage renal disease within 14 weeks of the initial presentation. [4] Our patient, a middle-age adult, presented with rapidly progressive renal failure. A renal biopsy revealed a necrotizing crescentic GN with mesangial deposits of C1q and IgM. He was started on maintenance hemodialysis and planned for renal transplantation.

Although the exact etiology and pathogenesis of C1q nephropathy are still not clear, it is postulated that C1q deposition occurs as a result of the activation of the classical complement pathway through the formation of antigen-antibody complexes. In addition to the classical pathway, the alternative and lectin pathways are also involved. [10] Another hypothesis suggests that C1q binds to polyanionic substances such as DNA and RNA and to cells like macrophages, neutrophils and mesangial cells through the C1q receptors, and this binding is involved in the onset of C1q nephropathy. [11]

CD59, an 18-20 kD glycosyl-phosphatidylinositol (GPI)-anchored protein, prevents the formation of membrane attack complex (C5b-9) of the complement system. [12] Deficiency of CD59 and CD55 (decay accelerating factor) have been pathogenetically related to PNH. The isolated deficiency of CD59 has also been reported in few individuals with a PNH-like syndrome. [5] Our patient also demonstrated isolated deficiency of CD59 on red blood cells and leukocytes in the setting of PNH-like hemolytic anemia. Recent experiments on a mouse model of CD59 deficiency have demonstrated the protective effects exerted by CD59 on glomerular mesangial cells. Turnberg et al demonstrated that the CD59 deficiency in a mouse model of accelerated nephrotoxic nephritis resulted in enhanced glomerular hypercellularity and glomerular thrombosis. [6] Although more extensive studies are ongoing in this subject, the existing observations strongly suggest a role of the CD59 deficiency in the exacerbation of immune-mediated glomerular disease.

In our patient, we hypothesize that the isolated CD59 deficiency resulted in aggravation of the complement-mediated glomerular injury initiated with C1q deposition, as this deficiency may have resulted in an unchecked formation of a membrane attack complex. This combination of complement system disorders probably resulted in the extensive renal involvement at presentation. However, the exact mechanism of the renal injury in this unusual association is still conjectural, given that this is probably the first of such cases.

In conclusion, this report described for the first time the presentation of a crescentic glomerulonephritis in a C1q nephropathy in a patient with an isolated CD59 deficiency. The pathogenetic role of the co-existence of these two disorders warrants further study.

Conflict of interest: None declared.

   References Top

Jennette JC, Hipp CG. C1q nephropathy: A distinct pathologic entity usually causing nephrotic syndrome. Am J Kidney Dis 1985;6: 103-10.  Back to cited text no. 1
Iskandar SS, Browning MC, Lorentz WB. C1q nephropathy: A pediatric clinicopathologic study. Am J Kidney Dis 1991;18:459-65.  Back to cited text no. 2
Sharman A, Furness P, Feehally J. Distinguishing C1q nephropathy from lupus nephritis. Nephrol Dial Transplant 2004;19:1420-6.  Back to cited text no. 3
Srivastava T, Chadha V, Taboada EM, Alon US. C1q nephropathy presenting as rapidly progressive crescentic glomerulonephritis. Pediatr Nephrol 2000;14:976-9.  Back to cited text no. 4
Yamashina M, Ueda E, Kinoshita T, et al. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinnuria. N Engl J Med 1990;323:1184-9.  Back to cited text no. 5
Turnberg D, Botto M, Warren J, Morgan BP, Walport MJ, Cook HT. CD59a deficiency exacerbates accelerated nephrotoxic nephritis in mice. J Am Soc Nephrol 2003;14:2271-9.  Back to cited text no. 6
Markowitz GS, Schwimmer JA, Stokes MB, et al. C1q nephropathy: A variant of focal segmental glomerulosclerosis. Kidney Int 2003; 64:1232-40.  Back to cited text no. 7
Vizjak A, Ferluga D, Rozic M, et al. Pathology, clinical presentations, and outcomes of C1q nephropathy. J Am Soc Nephrol 2008;19:2237-44.  Back to cited text no. 8
Lau KK, Gaber LW, Delos Santos NM, Wyatt RJ. C1q nephropathy: Features at presentation and outcome. Pediatr Nephrol 2005;20:744-9.  Back to cited text no. 9
Hisano S, Matsushita M, Fujita T, Uesugi N, Iwasaki H. Activation of the lectin complement pathway in C1q nephropathy. J Am Soc Nephrol 2006;17:256A. [Abstract].  Back to cited text no. 10
Eggleton P, Tenner AJ, Reid KB. C1q receptors. Clin Exp Immunol 2000;120:406-12.  Back to cited text no. 11
Meri S, Morgan BP, Davies A, et al. Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology 1990;71:1-9.  Back to cited text no. 12

Correspondence Address:
Amit K Dinda
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.168671

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  [Figure 1], [Figure 2]

  [Table 1]

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