SUMMARY OBJECTIVE: Chronic kidney disease (CKD) remains one of the major common health problems, and the number of people affected by the disease is progressively increasing in Turkey and worldwide. This study aimed to investigate molecular defects in Alport syndrome (AS) and other genes in patients with clinically suspected CKD using whole-exome sequencing (WES). METHODS: Patients with clinical suspicion of CKD were included in the study. Molecular genetic analyses were performed on genomic DNA by using WES. RESULTS: A total of 15 with 5 different pathogenic or likely pathogenic variants were identified in CKD patients, with a diagnostic rate of 30%. Eight variants of uncertain significance were also detected. In this study, 10 variants were described for the first time. As a result, we detected variants associated with CKD in our study population and found AS as the most common CKD after other related kidney diseases. CONCLUSIONS: Our results suggest that in heterogeneous diseases such as CKD, WES analysis enables accurate identification of underlying molecular defects promptly. Although CKD accounts for 10–14% of all renal dysfunction, molecular genetic diagnosis is necessary for optimal long-term treatment, prognosis, and effective genetic counseling.

Resumen Los pacientes con insuficiencia renal crónica hacen de la diálisis una forma de vida, muchos describen la cicladora de peritoneal, como “tu pareja” de noche y la hemodiálisis, un trabajo a media jornada días alternos. Pero la mayoría vive pensando en cambiar esa involuntaria vida nocturna de pareja o laboral y volver a la libertad que te da el trasplante renal. Este relato narra la lucha constante de una mujer cuya “enfermedad rara”, el síndrome de Alport, la llevó a recibir ambos tratamientos dialíticos antes de los veinte años. Tres décadas después, aun con sus limitaciones auditivas y visuales, tres trasplantes y varios hospitales en los que ha ido dejando amigos, no pierde la sonrisa y el optimismo, a la espera de que su sueño de un cuarto trasplante “biónico” vuelva a dejarla en la lista del paro del oficio de dializarse.

Abstract Patients with chronic kidney failure make dialysis a way of life, many describe the peritoneal cycler as “your partner” at night and hemodialysis, a part-time job every other day. But most of them live thinking about changing that involuntary night life as a couple or work and return to the freedom that kidney transplantation gives you. This story recounts the constant struggle of a woman whose “rare disease”, Alport syndrome, led her to receive both dialysis treatments before she was twenty. Thirty years later, even with her hearing and visual limitations, three transplants and several hospitals where she has been leaving friends, she does not lose her smile and optimism, waiting for her dream of a fourth “bionic” transplant to leave her again, on the list of unemployment of the trade of dialysis.

Abstract Introduction: Levamisole is an anthelmintic drug, also known for its use as an immunomodulator which, because of its toxic effects, was withdrawn at the end of the 20th century. In 2005, because of an increase in the diagnosis of pauci-immune vasculitis among the population that uses psychoactive substances, the adulteration of cocaine for commercial purposes by combining it with levamisole was documented. Case Report: The case of a young adult with a history of Alport Syndrome and recent consumption of psychoactive substances is presented. A renal biopsy is performed, demonstrating the presence of pauci-immune crescentic glomerulonephritis. Therefore, this type of small vessel vasculitis with kidney involvement and immune complex deposition was associated with the use of cocaine adulterated with levamisole. Discussion: Levamisole, a drug approved by the FDA in 1991, acts as an immunomodulator, antiparasitic and adjuvant in chemotherapy. Levamisole produces a rheumatic syndrome characterized by the presence of glomerulonephritis, alveolar hemorrhage, retinal purpura, neutropenia, and agranulocytosis in association with the presence of anti-neutrophil cytoplasmic antibodies. Conclusion: levamisole is known for its anthelmintic and immunomodulatory properties, additionally it can produce ostensible toxic effects. Given the high consumption of cocaine among the indigent population, the presence of this adulterant constitutes a growing public health problem.

Resumen Introducción: El levamisol es un fármaco antihelmíntico, también conocido por su uso como inmunomodulador el cual, como consecuencia de sus efectos tóxicos, fue retirado a finales del siglo XX. En el 2005, producto de un incremento en el diagnóstico de vasculitis pauci-inmune entre la población usuaria de sustancias psicoactivas, se documentó la adulteración con fines comerciales de la cocaína combinándola con levamisol, a partir de un aumento de manifestaciones reumáticas asociadas al consumo de dicha droga. Reporte de caso: Se presenta el caso de un adulto joven con antecedentes de síndrome de Alport y consumo reciente de sustancias psicoactivas. Se realiza biopsia renal demostrándose la presencia de glomerulonefritis crescéntica pauci-inmune. Por lo anterior, se relacionó este tipo de vasculitis de pequeño vaso con afectación renal y depósito de complejos inmunes al consumo de cocaína adulterada con levamisol. Discusión: El levamisol, medicamento aprobado por la FDA en 1991, actúa como inmunomodulador, antiparasitario y coadyuvante en quimioterapia. El levamisol produce un síndrome reumático caracterizado por la presencia de glomerulonefritis, hemorragia alveolar, púrpura retiforme, neutropenia y agranulocitosis en relación con la presencia de anticuerpos anticitoplasma de neutrófilo. Conclusión: El levamisol es conocido por sus propiedades antihelmínticas e inmunomoduladoras, adicionalmente puede producir efectos tóxicos ostensibles. Dado el alto consumo de cocaína entre la población indigente, la presencia de este adulterante constituye un problema de salud pública creciente.

ABSTRACT Alportsyndromeis a renal hereditarydisease of progressivecourse, causedby geneticdefects in the genes responsible for the constitution of the glomerular basementmembrane. Mutation in genes fortype IV collagen occurs at COL 4A3/4/5, whichproducesinterference in thecorrectmembranearrangement. Clinicalpresentationmayvarydependingonmutationtype. Afterconfirming diagnosis, withgenetic studiesorbiopsies, managementincludesidentification of risk and treatment. Reduction of proteinuria, as managementguidelinessuggest, has resulted in delay in progressiontochronickidneydisease. In themeantime, studiesfor new treatmentdevelopments are in progress, directedtospecificreceptors.

RESUMEN El síndrome de Alport es una enfermedad renal hereditaria de curso progresivo, que ocurre por defectos genéticos en los genes responsables de la constitución de la membrana basal glomerular. Las mutacionespatogénicas en los genes para el colágeno tipo IV (COL 4A3/4/5) producen una alteración en el arreglo correcto de la membrana basal a nivel glomerular.La presentación clínica puede variar dependiendo de la mutación que presente el paciente. Luego de confirmar el diagnóstico,con estudios genéticoso mediante biopsia, se hace necesaria la correlación genotipo-fenotipo para determinar pronóstico y tratamiento. La reducción de la proteinuria, según sugieren las guías de manejo, ha resultado en un retraso en la progresión a enfermedad renal crónica, mientras se concluyen los estudios con medicamentos innovadores dirigidos a receptores específicos.

RESUMO Objetivos: Descrever os achados na angiografia por tomografia de coerência óptica associada à síndrome de Alport. Métodos: Estudo descritivo de um serviço de referência em Oftalmologia (Hospital Evangélico de Vila Velha, Brasil). Os pacientes diagnosticados com síndrome de Alport, foram incluídos. Resultados: O grupo de estudo foi composto por quatro pacientes (um feminino e três homens) com diagnóstico de síndrome de Alport. A acuidade visual no pior olho estava entre 20/40 a 20/60. Todos os pacientes do sexo masculino apresentaram lenticone anterior à biomiscroscopia. Os achados da retina observados incluíram pontos e manchas e alterações pigmentares na mácula. Na angiotomografia de coerência óptica, as camadas internas da retina de todos os pacientes apresentaram afinamento (especialmente na região temporal da mácula) e aumento da zona avascular foveal. Uma coroide espessa foi observada em ambos os olhos dos dois pacientes mais jovens. Conclusões: Em pacientes com síndrome de Alport, as camadas internas da retina sofrem alterações devido à mutação do colágeno tipo IV. A angiotomografia de coerência óptica permite visualizar esses achados, tornando-o uma ferramenta útil na detecção de achados iniciais da retina associados à síndrome de Alport.

ABSTRACT Purpose: To describe the findings on optical coherence tomography angiography associated with Alport syndrome. Methods: Descriptive study from a referral ophthalmology service (Hospital Evangélico de Vila Velha, Brazil). Patients diagnosed with Alport syndrome were included. Results: The study group consisted of four patients (one female and three males) diagnosed with Alport syndrome. Visual acuity in the worst eye was between 20/40 and 20/60. All male patients had anterior lenticonus on biomicroscopy. The observed retinal findings included dots and flecks and pigmentary changes in the macula. On optical coherence tomography angiography, the inner retinal layers of all patients displayed thinning (especially in the temporal quadrant of the macula) and an increase in the foveal avascular zone. A thick choroid was observed in both eyes of the two youngest patients. Conclusions: In patients with Alport syndrome, the inner retinal layers suffer changes due to type IV collagen mutations. Optical coherence tomography angiography makes it possible to visualize and document these findings, making it a useful tool in the detection of early retinal findings associated with Alport syndrome.

Resumen El síndrome de Alport es un trastorno genético raro causado por mutaciones en los genes del colágeno tipo IV, caracterizado por insuficiencia renal, hipoacusia neurosensorial y anomalías oculares. Se presenta el caso de un paciente de 24 años con un cuadro de un día de disminución súbita de la agudeza visual en el ojo izquierdo, posterior a ruptura espontánea de la cápsula anterior del cristalino, asociado a catarata, uveítis facolítica e hipertensión ocular. En la anamnesis se encontraron antecedentes personales de hipoacusia e insuficiencia renal y, dos familiares con el diagnóstico clínico de síndrome de Alport. El heredograma sugirió una herencia dominante ligada al cromosoma X. Se inició el tratamiento tópico con prednisolona, atropina y brimonidina/timolol. Posteriormente, se realizó facoemulsificación y aspiración de restos de cristalino, con mejoría del cuadro clínico.

Abstract Alport syndrome is a rare genetic disorder due to mutations involving the coding genes for type IV collagen characterized by renal failure, sensorineural hearing loss and ocular abnormalities. This article presents a 24-year-old man with one day of sudden decrease in visual acuity in left eye due to spontaneous rupture of anterior lens capsule, related to cataract, phacolytic uveitis and ocular hypertension. In the anamnesis, personal history of hearing loss, renal failure and two-family members with a clinical diagnosis of Alport syndrome were found. The inheritance map was suggestive of a dominant inheritance X-linked pattern. Topical treatment was initiated with prednisone, atropine and brimonidine/timolol. Subsequently, phacoemulsification and aspiration of lens residues was performed, obtaining clinical relief.

Alport syndrome is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. We report two men with Alport syndrome. Both had chronic kidney disease and consulted for long-term loss of visual acuity. One had auditory abnormalities. On the ophthalmological examination, both had anterior lenticonus and one had dot or fleck retinopathy. Those findings are described in up to 50% and 70% of men with X-linked Alport syndrome, respectively. Both patients had a family history of Alport syndrome or suggestive signs and symptoms.

Introduction: Alport syndrome is a glomerular genetic disease progressing to chronic renal failure associated with deafness and ocular changes. Clinical presentation is usually in the first decade of life with microscopic haematuria and/or persistent proteinuria without hypertension or renal dysfunction. Case Report: Male, 4.5 years old, with an acute nephritic syndrome characterized by macroscopic haematuria, oedema, non-oliguric acute renal failure (maximal urea and creatinine of 25mmol/L and 150μmol/L, respectively), anaemia and proteinuria. Blood pressure normal. Normal immunoglobulins and complement fractions; anti-neutrophil cytoplasmic antibody, anti-nuclear antibody and anti-basal membrane antibody negative. History of recurrent episodes of macroscopic haematuria since the age of eighteen months associated with respiratory infections. No family history of renal disease or deafness. Renal biopsy showed proliferative glomerulonephritis with extracapillary crescentic activity, complete fragmentation of glomerular basement membranes and negative immunofluorescence. Pulse methylprednisolone was given followed by oral prednisolone and cyclophosphamide. Renal function recovered, microscopic haematuria persisted. At age 5, there was reappearance of proteinuria, worsening progressively and two years later he started treatment with enalapril. At age 11, a second renal biopsy revealed mesangial proliferative glomerulonephritis, small foci of glomerular sclerosis and few deposits of IgM on immunofluorescence. He started oral corticosteroids with partial response. Nine months later, bilateral sensorineural deafness was detected. At age 16, he maintains normal renal function, microscopic haematuria with manifest proteinuria. A mutation in homozygosity in the COL4A3 gene, compatible with autosomal recessive Alport syndrome, was identified. Conclusions: This case draws attention to an uncommon early course and clinical/pathological findings of a patient later diagnosed with Alport syndrome, with an initial good response to corticosteroids and cyclophosphamide. The case also illustrates the importance of kidney biopsy, including electron microscopy, in the diagnostic, classification and therapy in kidney diseases with unusual clinical course

RESUMO Descrevemos um paciente de 6 anos de idade com história de hematúria, distrofia corneana polimorfa posterior e retinopatia em "dots and flecks". Síndrome de Alport deve ser excluída se o paciente apresentar com distrofia corneana polimorfa posterior ou lenticone anterior com historia familiar de doença renal.

ABSTRACT We describe a six-year-old boy with a history of hematuria, posterior polymorphous corneal dystrophy and dots and fleck retinopathy. Alport syndrome should be ruled out in patients presenting with posterior polymorphous corneal dystrophy or anterior lenticonus and a family history of renal disease.

RESUMO A síndrome de Alport é descrita como uma doença hereditária que afeta um gene relacionado à produção de colágeno das membranas basais causando nefrite hemorrágica associada com surdez e alterações oculares. A forma ligada ao X é a mais comum e afeta principalmente homens. Os achados oculares típicos são retinopatia em ponto-mancha, lenticone anterior e distrofia polimorfa posterior. Alguns casos foram descritos de associação entre a distrofia polimorfa posterior e ectasia corneana. Nós apresentamos um caso de paciente do sexo feminino, 33 anos, diagnóstico de síndrome de Alport, distrofia polimorfa posterior e astigmatismo irregular, que apresenta melhora da acuidade visual após adaptação com lentes de contato rígidas gás permeáveis.

ABSTRACT Alport Syndrome is a hereditary disease that is caused by a gene mutation and affects the production of collagen in basement membranes; this condition causes hemorrhagic nephritis associated with deafness and ocular changes. The X-linked form of this disease is the most common and mainly affects males. Typical ocular findings are dot-and-fleck retinopathy, anterior lenticonus, and posterior polymorphous corneal dystrophy. Some cases involving polymorphous corneal dystrophy and corneal ectasia have been previously described. Here we present a case report of a 33-year-old female with Alport syndrome, posterior polymorphous corneal dystrophy, and irregular astigmatism, whose visual acuity improved with a rigid gas permeable contact lens.

Se presenta el caso de una paciente de 4 años de edad, con hermano gemelo dicigoto asintomático, hija de padres no consanguíneos y sin antecedentes familiares de enfermedad renal. Inicia su cuadro clínico con edemas y proteinuria severa como manifestación de un síndrome nefrótico primario de cambios mínimos; este se diagnosticó por biopsia renal y, en un principio, se manejó con esteroides. Su evolución no fue adecuada debido a múltiples recaídas que la clasificaron como síndrome nefrótico corticorresistente. Por ello, se requirió un cambio en su tratamiento y una segunda biopsia renal, cuyo resultado histológico sorprendió al grupo médico tratante porque los cambios en la membrana basal glomerular confirmaban que se trataba de un Síndrome de Alport.

We present the case of a 4 year-old girl patient, with an asymptomatic dizygotic twin brother, child of non-consanguineous parents and with no family history of renal disease. Her clinical picture started with edema and severe proteinuria as manifestations of a minimal change nephrotic syndrome that was diagnosed by renal biopsy and initially treated with steroids. Her clinical course was complicated by multiple relapses that classified her as a patient presenting a steroid-resistant nephrotic syndrome, her treatment was changed and a second renal biopsy was needed. Histology outcome of biopsy surprised the treating medical group because changes in glomerular basal membrane revealed that it was in fact an Alport syndrome.