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Retinal manifestations in patients with complement-mediated membranoproliferative glomerulonephritis
Manifestaciones retinianas en pacientes con glomerulonefritis membranoproliferativa mediada por complemento
L. de-Pablo-Gómez-de-Liañoa,
Corresponding author
depablo.lucia@gmail.com

Corresponding author.
, I. Cañas Zamarraa, J.I. Fernández-Vigob, M. Fernández Vidalc, C. Navarro-Pereab, T. Cavero Escribanoc
a Departamento de Oftalmología, Hospital Universitario 12 de Octubre, Madrid, Spain
b Departamento de Oftalmología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
c Departamento de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain
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subendothelial in type I&#44; intramembrane in type II and subendothelial and subepithelial in type III&#46; However&#44; at present MPGN is classified on the basis of its etiology according to immunofluorescence as immune-mediated MPGN &#40;most frequent&#41; when a majority of immunoglobulin deposits are observed&#44; or complement-mediated or glomerulopathy C3 if a predominantly C3 deposit is found at the glomerular level&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2&#8211;4</span></a> Glomerulopathy C3 comprises 2 diseases differentiated by morphology and location of deposits under electronic microscope&#46; Accordingly&#44; glomerulonephritis C3 features subendothelial and&#47;or subepithelial deposits &#40;formerly MPGN types I and III&#41; and dense deposit disease when deposits are found intramembrane &#40;formerly MPGN type II&#41;&#46; Several studies have described the association of MPGN type II or dense deposits disease with the presence of drusenoid deposits at the retinal level&#44; as well as the presence of choroidal neovascularization &#40;CNV&#41; and central serous choroidopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> However&#44; very few studies have assessed the presence of retinal alterations on the basis of the 2 MPGN subtypes of the new classification&#44; mediated by immune complexes and complement&#46; One of said studies&#44; of recent publication&#44; concludes that complement-mediated MPGN gives rise to retinopathy with greater frequency when compared to immune complex-mediated MPGN&#44; in which this association is rare&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">It has also been observed that the drusenoid deposits that appear in the retina of patients with MPGN are similar to those expressing at the subepithelial level in the glomerulus<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> because their physiopathology is the same&#44; i&#46;e&#46; hyperactivation of the alternative complement cascade pathway&#44; with the retina and glomerulus being vulnerable to damage by C3 deposits&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">It is important for ophthalmologists to be aware of said pathology and the modern classification thereof because complement-mediated MPGN patients could exhibit retinal alterations requiring ophthalmological examinations and an adequate differential diagnostic&#46; This is precisely the purpose of the present study&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">A transversal observational study of a case series comprising all patients in follow-up for complement-mediated MPGN at the Nephrology Dept&#46; of the authors&#8217; hospital&#46; Patients signed an informed consent and the study complied with the Helsinki Declaration standards&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Historical patient data comprised age&#44; sex&#44; age at nephropathy diagnostic and evolution time thereof&#46; In addition&#44; an ophthalmological examination was performed comprising visual acuity &#40;VA&#41;&#44; funduscopy and spectral domain optical coherence tomography &#40;OCT&#41; exploring the macular area &#40;Spectralis<span class="elsevierStyleSup">&#174;</span>&#44; Heidelberg Engineering&#44; Germany&#41; having a resolution of 4<span class="elsevierStyleHsp" style=""></span>&#956;m and a scan rate of 40&#44;000&#47;s&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">When spectral OCT alteration was observed&#44; a Swept Source domain OCT was also used &#40;Triton<span class="elsevierStyleSup">&#174;</span>&#44; Topcon&#44; Tokyo&#44; Japan&#41; as it features higher tissue penetration in order to evaluate the existence of choroidal changes&#46; Said device has a resolution of 2&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;m and a rate of 100&#44;000<span class="elsevierStyleHsp" style=""></span>A scans&#47;s applying the following modes&#58; linear&#44; with a 16<span class="elsevierStyleHsp" style=""></span>mm scanner&#44; and angio-OCT &#40;A-OCT&#41; with 12<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>mm protocol for an enhanced characterization of the lesions and to discard the presence of choroidal neovascularization&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Results</span><p id="par0040" class="elsevierStylePara elsevierViewall">Overall&#44; 8 out of 15 patients diagnosed with complement-mediated MPGN in follow-up at the authors&#8217; hospital were examined&#46; It was impossible to make contact with 4 of the remaining 7 while 2 declined participation and the remaining patient had passed away&#46; Mean age was 49&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;4 years &#40;range 21&#8211;82&#41;&#44; with predominance of females &#40;5&#47;8&#41;&#46; Mean agea at MPGN diagnostic was 30&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#46;2 years &#40;range&#58; 12&#8211;72&#41;&#44; with an evolution time at examination of 19&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;5 years &#40;range 2&#8211;41&#41;&#46; Right eye VA was&#44; 93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 &#40;range 0&#46;7&#8211;1&#41; and left eye VA was 0&#46;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;07 &#40;range&#58; 0&#46;8&#8211;1&#41;&#46; Two subjects required kidney transplant&#46; Seven subjects of the group &#40;87&#46;5&#37;&#41; exhibited normal funduscopic examination and OCT while one patient exhibited MPGN-related changes&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Said patient was a 42 year-old Caucasian with a history of hypothyroidism and tobacco smoking&#46; Baseline clinic comprised proteinuria &#40;0&#46;53<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41; and microhematuria&#44; and the complement-mediated MPGN diagnostic was concluded after kidney biopsy in 2014&#46; A genetic and immunological study was negative&#46; Treatment was initiated with corticoids and mycophenolate&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Ophthalmological examination was asymptomaticc with VA of 1 in both eyes&#44; while funduscopy and retinography revealed the presence of diffuse drusen-like deposits in posterior pole and externally to the arcades &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; appearing like RPE elevation in spectral OCT &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Superficial and deep retinal plexus and choriocapillary were evaluated with A-OCT&#44; discarding the presence of vascular membranes associated to pigment epithelium detachment &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">The present study analyzed 8 patients diagnosed with complement-mediated MPGN&#44; one of which exhibited drusenoid deposits&#46; In this case the lesions did not compromise VA despite a 4-year evolution of the kidney disease&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Macular changes in MPGN can range from small drusenoid deposits in patients preserving excellent VA<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;4</span></a> to the development of large pigment epithelium detachments&#44; retinal atrophy&#44; CNV and central serous choroidopathy that could involve the appearance of scotoma and central vision distorsion&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;5&#8211;7</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The above described patient had been erroneously diagnosed with age-related macular degeneration &#40;AMD&#41; in a routine ophthalmological checkup&#46; This was because both pathologies exhibit small diffuse yellowish lesions that generally compromise the posterior pole and have a similar composition&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> The differential characteristics between both entities are that in MPGN drusenoid lesions emerge at earlier ages and in larger quantity and covering a larger retinal extension than in AMD&#46; In addition&#44; according to the study by Savige et al&#46;&#44; complications compromising vision appear earlier and more frequently&#46; Accordingly&#44; said authors recommend discarding renal disease in patients under 50 years and could exhibit the presence of AMD&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">It has been described that the presence of drusen is more frequent in the complement-mediated MPGN type<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2&#44;4</span></a> as observed in 39&#37; of cases &#40;9&#47;23&#41; of the series by Dalvin et al&#46;&#44; where 5 patients exhibited VA loss due to associated complications&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Said study reported that&#44; in a series of patients with immune complex-mediated MPGN&#44; only 9&#37; &#40;2&#47;23&#41; of cases exhibited drusen&#44; without associated visual alterations&#46; The severity of ocular compromise is not always correlated to the severity of the kidney disease&#46; However&#44; when the renal disease is more evolved&#44; ophthalmological compromise risk is higher&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;5&#44;9</span></a> Kheir et al&#46; have described that various treatments utilized for nephropathy such as corticoids&#44; immunosuppresants and&#47;or plasmapheresis failed to improve the retinal disease&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Accordingly and as proposed by other authors<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2&#44;5&#44;10</span></a> it would be interesting to evaluate complement-mediated MPGN patient referrals in order to carry out the retinal examination at diagnostic&#44; following up patients with large drusen so as to detect possible complications&#46; In contrast&#44; Dalvin et al&#46;&#44; maintain this would not be necessary in the case of immune complex-mediated MPGN because the association between this pathology and eye fundus alterations is very small and the risk of diminished VA is lower&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> In turn&#44; McAvoy et al&#46; indicate that&#44; considering the rarity of ocular complications&#44; routine screening of patients with MPGN type II would not be necessary as only 1 exhibited diminished VA &#40;due to CNV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In addition&#44; it is important to point out the possible usefulness of A-OCT in this disease to discard associated CNV without requiring the injection of contrast which in these patients could worsen pre-existing kidney damage&#44; although this complication was not observed in the present series&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Limitations of the present study include being its transversal nature without follow-up of patients affected by retinal alterations&#46; Accordingly&#44; studies with larger amount of patients and follow-up would be necessary to achieve a better characterization of this disease and its ocular complications&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">MPGN can give rise to retinal alterations with drusen or pigment epithelium detachment&#44; for which reason it is necessary to perform an adequate differential diagnostic with AMD&#44; with follow-up for these patients due to the possibility of complications which could cause loss of vision&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interests</span><p id="par0100" class="elsevierStylePara elsevierViewall">No conflict of interests was declared by the authors&#46;</p></span></span>"
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            0 => "Membranoproliferative glomerulonephritis"
            1 => "Drusen-like deposits"
            2 => "Retinal pigment epithelium detachment"
            3 => "Optical coherence tomography"
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          "clase" => "keyword"
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            0 => "Glomerulonefritis membranoproliferativa"
            1 => "Dep&#243;sitos drusenoides"
            2 => "Desprendimiento del epitelio pigmentario"
            3 => "Tomograf&#237;a de coherencia &#243;ptica"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Complement-mediated membranoproliferative glomerulonephritis is a rare progressive glomerular disease&#46; In some patients it can be associated with retinal lesions&#46; Therefore&#44; the purpose of this study was to assess a case series with this diagnosis in our hospital&#46; A cross-sectional study was conducted on 8 patients diagnosed with complement-mediated membranoproliferative glomerulonephritis&#46; Funduscopy&#44; optical coherence tomography &#40;OCT&#41; and Swept Source domain OCT angiography were performed&#46; Only 1 of the 8 patients showed drusen-like deposits that were located under the retinal pigment epithelium in the OCT&#44; with the presence of associated choroidal neovascularization being ruled out in OCT angiography&#46; Therefore&#44; membranoproliferative glomerulonephritis may produce retinal alterations with drusen or retinal pigment epithelium detachment&#44; and requires an appropriate differential diagnosis to be made with age-related macular degeneration&#46; The follow-up of these patients is important in order to detect vision-threatening complications&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La glomerulonefritis membranoproliferativa mediada por complemento es una enfermedad rara&#44; pero puede asociarse a alteraciones retinianas&#46; Por ello&#44; el prop&#243;sito de este estudio fue valorar una serie de casos con dicho diagn&#243;stico en seguimiento por nefrolog&#237;a en nuestro centro&#46; Se realiz&#243; un estudio transversal de 8 pacientes diagnosticados de glomerulonefritis membranoproliferativa mediada por complemento&#46; Se realiz&#243; funduscopia&#44; tomograf&#237;a de coherencia &#243;ptica &#40;OCT&#41; y angio-OCT de dominio <span class="elsevierStyleItalic">Swept Source</span>&#46; Uno de los 8 pacientes presentaba dep&#243;sitos drusenoides que se localizaron bajo el epitelio pigmentario retiniano en la OCT&#44; descart&#225;ndose la presencia de neovascularizaci&#243;n coroidea asociada en la angio-OCT&#46; Por tanto&#44; la glomerulonefritis membranoproliferativa puede producir alteraciones retinianas con drusas o desprendimientos del epitelio pigmentario retiniano&#44; por lo que debe hacerse un adecuado diagn&#243;stico diferencial con la degeneraci&#243;n macular asociada a la edad&#46; Es crucial realizar un seguimiento en estos pacientes ante las posibles complicaciones que pueden desembocar en una p&#233;rdida de visi&#243;n&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; de-Pablo-G&#243;mez-de-Lia&#241;o L&#44; Ca&#241;as Zamarra I&#44; Fern&#225;ndez-Vigo JI&#44; Fern&#225;ndez Vidal M&#44; Navarro-Perea C&#44; Cavero Escribano T&#46; Manifestaciones retinianas en pacientes con glomerulonefritis membranoproliferativa mediada por complemento&#46; Arch Soc Esp Oftalmol&#46; 2019&#59;94&#58;95&#8211;99&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Retinography showing drusenoid deposits in posterior pole and exteriorly to the vascular arcades in both eyes&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Spectral domain optical coherence tomography showing drusenoid deposits below the retina pigment epithelium&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Swept Source domain optical coherence tomography&#44; with the location of these deposits being shown in higher resolution between the retina pigment epithelium and Bruch&#39;s membrane&#46; Bottom&#58; angio-OCT images that discarded the presence of CNV&#46;</p>"
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                      "titulo" => "Retinal disease in the C3 glomerulopathies and the risk of impaired vision"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Savige"
                            1 => "L&#46; Amos"
                            2 => "F&#46; Lerino"
                            3 => "H&#46;G&#46; Mack"
                            4 => "R&#46;C&#46; Symons"
                            5 => "P&#46; Hughes"
                          ]
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                    0 => array:2 [
                      "doi" => "10.3109/13816810.2015.1101777"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26915021"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Manifestations of complement-mediated and immune complex-mediated membranoproliferative glomerulonephritis&#58; a comparative consecutive series"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "L&#46;A&#46; Dalvin"
                            1 => "F&#46;C&#46; Fervenza"
                            2 => "S&#46; Sethi"
                            3 => "J&#46;S&#46; Pulido"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.ophtha.2016.02.018"
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                ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multimodal imaging of retinal pigment epithelial detachments in patients with C3 glomerulopathy&#58; case report and review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "V&#46; Kheir"
                            1 => "A&#46; Dirani"
                            2 => "M&#46; Halfon"
                            3 => "J&#46;P&#46; Venetz"
                            4 => "G&#46; Halabi"
                            5 => "Y&#46; Guex-Crosier"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12886-017-0602-4"
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