AUTOLOGOUS RETINA TRANSPLANTATION FOR TREATMENT OF REFRACTORY DOUBLE FULL-THICKNESS MACULAR HOLE IN ALPORT SYNDROME.

PURPOSE: To report the structural and functional outcomes of autologous neurosensory retinal transplantation for closure of refractory double full-thickness macular hole in a patient diagnosed with Alport syndrome. METHODS: Patient with previous pars plana vitrectomy and a failed macular hole surgery (internal limiting membrane removal) underwent pars plana vitrectomy and autologous neurosensory retinal flap transplantation with silicone oil tamponade. Follow-up was performed after one year. The anatomic outcomes were evaluated mainly by fundus examination, optical coherence tomography (OCT), and microperimetry (MAIA). The functional changes were evaluated comparing best-corrected visual acuities preoperative and 1 year after surgery. RESULTS: A 35-year-old man with progressive visual loss of two years of evolution presented a double full-thickness macular hole in the left eye. After retinal flap transplantation, the macular hole appeared successfully closed during the entire follow-up. Integration of both retinal flaps into the surrounding retina and regeneration of the external retinal layers were observed in optical coherence tomography. Best-corrected visual acuities improved from 20/200 preoperatively to 20/80 one-year postoperatively. CONCLUSION: Pars plana vitrectomy combined with autologous neurosensory retinal flap transplantation is an effective option to achieve the anatomic closure of recurrent double full-thickness macular hole and significant visual recovery in Alport syndrome.

Racial disparities and trends in kidney transplant outcomes in patients with Alport syndrome.

BACKGROUND: Registry data from Europe has shown an increase in age at end-stage kidney disease for patients with Alport syndrome in recent years. Whether a similar delay in transplant age has occurred in the United States for Alport patients across all racial/ethnic groups is unknown. MATERIALS AND METHODS: We used data from the Scientific Registry of Transplant Recipients (SRTR) to identify 3,794 Alport patients transplanted between 12/1987 and 12/2017. We divided the study period into five equal eras to assess temporal trends in age at transplant, graft survival, and patient survival across racial groups using linear regression and Cox regression models. RESULTS: The mean age at transplant for Blacks (28.3 years; difference (Black vs. White): 8.9 years; p < 0.0001) and Hispanics (28.7 years; difference (Hispanics vs. White): 8.7 years; p < 0.0001) was significantly younger compared with that of Whites. We observed a temporal increase in age at transplant for Whites but not for Blacks and Hispanics (p-value for interaction: 0.001). Black recipients were at a higher risk of graft loss (aHR: 1.78; 95% CI: 1.47, 2.15; p < 0.0001) and death (aHR: 1.73; 95% CI: 1.11, 2.69; p = 0.02) compared with White recipients. We observed significant improvements in graft survival with each successive era (p < 0.01). Temporal trends in graft survival (interaction p = 0.46) were not modified by race. CONCLUSION: We found racial disparities in age at transplant and long-term graft survival for patients with Alport syndrome in the United States. The age at transplant increased over time for Whites but not Black and Hispanic patients.

Recurrent Postoperative Toxic Shock Syndrome in a Living Kidney Transplant Recipient.

Recurrent toxic shock syndrome (TSS) is uncommon. A certain level of clinical suspicion is indicated with a complex sepsis presentation in the postoperative kidney transplant patient. We present a case of presumed recurrent postoperative TSS in a living kidney transplant recipient. The patient was a 19-year-old Caucasian female with a 4-year prior single episode of toxin-mediated sepsis and chronic kidney disease (CKD) secondary to autosomal recessive Alport's syndrome (confirmed via renal biopsy and genetic testing). She received a human leukocyte antigen (HLA) 2A 2B 1DR MM, CMV -D/-R kidney from her 21-year-old friend. The patient received Campath and IV steroid induction after total cold ischemic time of 170 minutes with 40 minutes of revascularization. On postoperative day (POD) 5, she required re-exploration with reimplantation and stenting of the transplanted ureter. The patient subsequently spiked a fever of 101.6° with a generalized rash prompting collection of blood cultures which demonstrated no growth. Infectious Disease was consulted due to persistent fevers despite IV antibiotics. On POD 12, the patient returned to the operating room (OR) for evacuation of hematoma after decline in Hgb to 5.8 and CT confirmed perinephric hematomas. Kidney biopsy showed no rejection and donor specific antibodies (DSAs) were unremarkable. The patient underwent 1 treatment of empiric plasmapheresis for possible non-HLA antibodies followed by initiation of clindamycin. The patient's condition improved, and she was discharged home with a normal creatinine. Recurrent TSS is rare but should be added to the differential diagnoses of immuno-compromised patients undergoing kidney transplantation with a history of prior toxin-mediated sepsis.

Successful renal transplantation in a family with a novel mutation in COL4A3 gene and autosomal recessive Alport syndrome.

Alport syndrome (AS) is an inherited disorder of basement membranes caused by mutations affecting specific proteins of the type IV collagen family, presenting with nephropathy and extrarenal manifestations such as sensorineural deafness and ocular anomalies. Ten percentage to 15% of the patients with AS have autosomal recessive (ARAS) due to mutation in either COL4A3 or COL4A4 gene. We report a novel mutation in the COL4A3 gene in an Indian family with ARAS. The above-mentioned genetic anomaly was a missense variation in exon 26 of the COL4A3 gene (chr2:228137797G>A; c.1891G>A) that resulted in the amino acid substitution of Arginine for Glycine at codon 631 (p.Gly631Arg) that was present in the heterozygous state in the asymptomatic parents and homozygous state in the male offspring who presented with early-onset end-stage renal disease, lenticonus and hearing loss. The patient (male offspring) underwent successful renal transplantation with his mother as a donor.

Detection of Cryptic Mosaicism in X-linked Alport Syndrome Prompts to Re-evaluate Living-donor Kidney Transplantation.

BACKGROUND: Alport syndrome is a hereditary nephropathy caused by mutations in collagen IV genes and characterized by ultrastructural lesions of the glomerular basement membrane. Some patients have a negative family history with apparently de novo mutations. Although somatic mosaicism has been postulated, as cryptic mosaicism cannot be detected from mutational screening on peripheral blood samples, cases in kidney-confined mosaic form have been missed. METHODS: We report the case of a 24-year-old male patient with X-linked Alport syndrome diagnosis due to a COL4A5 pathogenic mutation (c.3334_3337dup [p.Gly1113Alafs25]). The same mutation had not been previously detected on a peripheral blood sample of maternal DNA. However, the mother, who was undertaking a clinical re-evaluation to take in consideration the possibility of a living-kidney transplantation, had experienced persistent microhematuria since the age of 10 years. RESULTS: A next-generation sequencing approach performed on maternal DNA from both peripheral blood sample and urine-derived podocyte-lineage cells unmasked the COL4A5 mutation only in the podocyte-lineage cells. CONCLUSIONS: This finding unveils an early postzygotic event which can explain both the renal involvement and germline mosaicism. It changes the inheritance risk for each pregnancy raising it to 50% and underlines the need for different clinical management in the mother. This seems to indicate that a case-by-case more cautious approach is needed with mother-to-son kidney transplants.

Alport-leiomyomatosis syndrome requiring subtotal esophagectomy for refractory gastroesophageal reflux disease after childhood partial esophagogastrectomy: a case report.

Alport-leiomyomatosis syndrome is an extremely rare condition occurring at a young age in which Alport syndrome coexists with diffuse leiomyomatosis of the digestive tract (primarily the esophagus). Most patients with diffuse esophageal leiomyomatosis require esophagectomy of variable extents. A 20-year-old man with Alport-leiomyomatosis syndrome was diagnosed with dysphasia and hematuria in childhood. Although he underwent partial esophagogastrectomy at 8 years of age, extremely severe gastroesophageal reflux symptoms were noted postoperatively. He was diagnosed with refractory severe reflux esophagitis associated with diffuse leiomyomatosis and esophagogastric anastomosis, for which he underwent subtotal esophagectomy, gastric tube reconstruction, and esophagogastric anastomosis in the left neck. The postoperative course was generally good, and he had no postoperative reflux symptoms. To achieve long-term control of symptoms, the lesion must be removed completely; nevertheless, unnecessarily extensive esophagectomy should be avoided.

Phacoemulsification in bilateral anterior lenticonus in Alport syndrome: A case report.

RATIONALE: To report the visual status and results of phacoemulsification cataract surgery in a young patient with Alport syndrome associated with bilateral anterior lenticonus. The milestone of this report is the use of anterior segment optical coherence tomography (AS-OCT) to confirm the central protrusion of the anterior surface of the crystalline lens. PATIENT CONCERNS: A 23-year-old young woman presented with severe progressive visual loss in both eyes, which started several years ago. DIAGNOSES: Refractive status was indicative of high myopia with astigmatism and vision was not improved with optimal correction to better than 0.1 in the right eye and 0.2 in the left eye (visual acuities given in decimal notation). Slit-lamp examination showed transparent cornea, anterior lenticonus and posterior sub-capsular cataract in both eyes. The classical appearance of oil droplet was evident using retro-illumination on the slit lamp. INTERVENTIONS: The natural lenses were replaced with intraocular lens (IOL). OUTCOMES: An excellent refractive status achieved associated with an uncorrected distance visual acuity 0.9 and 0.8 in the right and left eye, respectively. LESSONS: AS-OCT is a valuable device for confirming the budging of the anterior crystalline lens surface.

Retrospective genetic analysis illustrates the spectrum of autosomal Alport syndrome in a case of living-related donor kidney transplantation.

BACKGROUND: Kidney transplantation is the treatment of choice in end-stage renal disease due to Alport syndrome (AS). However, the chances of finding an adequate living-related donor in AS are much worse compared to non-heritable conditions. Successful cases of related living-donor transplantation mostly refer to X-linked AS but are rarely reported in genetically confirmed autosomal AS. CASE PRESENTATION: We describe the outcome of an exceptional AB0-incompatible kidney donation from father to son in a family with altered COL4A3. While decision-making was based on extensive clinical donor evaluation prior to transplantation, we analyzed the underlying genetic background in retrospect and associated these findings with the phenotype in all available family members. While biallelic COL4A3 variants caused autosomal recessive AS (ARAS) in the son (recipient), heterozygous family members, including the father (donor), showed minimal renal involvement and high-frequency sensorineural hearing impairment later in life indicating mild autosomal dominant Alport syndrome (ADAS). The recipient's successful participation in the European and World Transplant Games is a testament to the positive outcome of transplantation. CONCLUSIONS: In summary, living-related donor transplantation may be successful in autosomal AS, provided that thorough clinical and genetic evaluation of potential donors is performed. However, unrelated kidney transplantation should be given priority upon unpredictable genetic risk. Individual genetic variant interpretation is an important component of personalized donor assessment and will help to better predict genetic risk in the future.

Increased microvascular disease in X-linked and autosomal recessive Alport syndrome: a case control cross sectional observational study.

BACKGROUND: Retinal microvascular disease reflects, in part, poor blood pressure control and systemic microvascular disease contributes to renal failure progression. This study examined the retinal microvasculature in Alport syndrome. MATERIALS AND METHODS: Retinal images from 28 males and 28 females with X-linked Alport syndrome, and 13 individuals with autosomal recessive disease were reviewed retrospectively for microvascular/ hypertensive retinopathy (Wong and Mitchell classification), and small vessel calibre (using a computerised semiautomated method and revised Knudtson formula). Data were compared with age and gender-matched individuals with normal blood pressure and renal function. RESULTS: Microvascular/hypertensive retinopathy was more common in males and females with X-linked Alport syndrome than age- and gender-matched controls (23, 82% and 10, 36%, p < 0.01; and 21, 75% and 13, 48%, p = 0.05, respectively), and in individuals with autosomal recessive disease compared with controls (12, 92% and 16, 43%, p < 0.01). Moderate microvascular/hypertensive changes were present in males and females with X-linked or autosomal recessive disease but not controls. Arteriolar calibre was reduced in males with X-linked disease (142.5 ± 18.7 µm, and 150.7 ± 10.1 µm, p = 0.046) and in autosomal recessive disease (133.5 ± 11.10 µm and 149.1 ± 10.6 µm, p < 0.0001). Microvascular/hypertensive retinopathy and arteriolar narrowing in males with X-linked disease were not different after renal transplantation and before (p NS). CONCLUSIONS: Microvascular/hypertensive retinopathy was more common and more severe in Alport syndrome than normotensive controls. Improved BP levels may further slow the rate of renal functional decline in Alport syndrome.

Thin Glomerular Basement Membrane in a Kidney Transplant of an Alport's Syndrome Patient: A Case Report.

Alport syndrome (AS) and thin basement membrane lesions are caused by various mutations in type IV collagen genes. Although AS is considered a rare disease, thin basement membrane is a frequent pattern, especially in families with a history of persistent hematuria. We report a patient with a diagnosis of AS who developed end-stage kidney disease (ESKD) and received a kidney transplant from a living unrelated donor. The graft biopsy specimen surprisingly showed a pattern of thin basement membranes.

Low-dose Spinal Block With Continuous Epidural Infusion for Renal Transplantation in a Patient With Alport Syndrome: A Case Report.

OBJECTIVE: We aim to describe management of a patient receiving renal transplantation for chronic renal failure due to Alport syndrome with low dose of intrathecal bupivacaine and continuous epidural infusion of local anesthetic. CASE REPORT: A 38-years-old man with chronic renal failure secondary to Alport syndrome underwent kidney transplantation. Because of a high risk of respiratory and cardiovascular complications related to the patient's baseline lung disease and abnormalities in heart conduction, we selected combined spinal-epidural anesthesia. The block was ultrasound-guided and performed at the T12-L1 interspace with 4.5 mg of 0.5% intrathecal hyperbaric bupivacaine followed by a continuous epidural infusion of 0.5% levobupivacaine mixed with 25 µg of Fentanyl at the initial rate of 8 mL/h. Sensory block to T5-T6 was obtained within 10 minutes. The patient then received mild sedation with Propofol and Remifentanil. Methylprednisolone and diuretics were administered before vascular unclamping according to our internal protocol. Surgery lasted 3 hours with no clinical or procedural complication. CONCLUSIONS: Although renal transplantation is usually performed under general anesthesia, in a particularly complex patient with chronic renal failure, chronic obstructive pulmonary disease and a worsened respiratory mechanics, we applied a combined approach with a low dose of intrathecal bupivacaine and continuous epidural infusion of local anesthetic. The technique did not affect hemodynamics while having a positive impact on recovery of function of the transplanted organ with rapid improvement of urine output, serum creatinine, and blood urea nitrogen levels.

[Kidney allotransplantation from alive related donor in patients with Alport syndrome].

AIM: To evaluate the results of kidney transplantation from alive related donor in patients with Alport syndrome and to compare with those in patients with kidney hypoplasia. MATERIAL AND METHODS: We have analyzed 8 and 27 medical records of patients with Alport syndrome and kidney hypoplasia respectively. Following parameters were used - Kaplan-Meier survival analysis, Wilcox overall risk, percentage of transplants loss and mortality (Fisher's exact test calculation). RESULTS: It is concluded that percentage of transplants loss and mortality rate as well as overall survival and risk were similar in both groups. CONCLUSION: Despite risk of anti-GBM nephritis development in patients with Alport syndrome results are comparable with those after transplatation for chronic renal failure caused by other reasons.

Diffuse Alveolar haemorrhage: a fatal complication after alemtuzumab induction therapy in renal transplantation.

We report a fatal case of alemtuzumab-induced diffuse alveolar hemorrhage in an 18-year-old male with Alport syndrome. The patient developed acute onset shortness of breath, hemoptysis and fever after renal transplantation. Computed tomography findings were consistent with adult respiratory distress syndrome. Bronchoscopy and broncho-alveolar lavage was performed that showed no evidence of pathogenic bacteria or opportunistic infection. The patient was intubated and ventilated because of worsening respiratory function. The patient received plasma electrophoresis and was maintained on tacrolimus and steroids; however, unfortunately the patient died 31 days post-transplantation due to worsening respiratory function and declining graft function. Although the prevalence and the exact mechanism of this fatal complication remain unknown, an awareness of this complication is important to all clinicians using alemtuzumab. This is a second report of diffuse alveolar hemorrhage secondary to alemtuzumab induction in patients with Alport syndrome.

Successful treatment of hepatitis E virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin.

Hepatitis E virus genotype-3 (HEV3) infection can cause chronic hepatitis in immunosuppressed patients and induce extra-hepatic manifestations, such as neurological symptoms, kidney injuries, and immune-mediated thrombocytopenia. Very few cases of HEV-induced kidney manifestations have been reported. Herein, we report, for the first time, a case of de novo membranoproliferative glomerulonephritis that occurred in a kidney transplant patient who developed a chronic HEV3 infection, which was successfully treated with ribavirin.

Renal denervation in a patient with Alport syndrome and rejected renal allograft.

Renal denervation is a new intervention to treat resistant hypertension. By applying radiofrequency (RF) to renal arteries, sympathetic nerves in adventitia layer of vascular wall can be denervated. Sympathetic hyperactivity is an important contributory factor in hypertension of hemodialysis patients. Hyperactive sympathetic nervous system aggravates hypertension and it can cause complications like left ventricular hypertrophy, heart failure, arrhythmias and atherogenesis. Our report illustrates the use of renal denervation using conventional RF catheter for uncontrolled hypertension in a patient with Alport syndrome and rejected renal allograft. Progressive and sustained reduction of blood pressure was obtained post-procedure and at 24 months follow-up with antihypertensives decreased from 6 to 2 per day, thereby demonstrating the safety, feasibility, and efficacy of the procedure. There are some reports available on the usefulness of this technique in hemodialysis patients; however, there are no studies of renal denervation in patients with Alport syndrome and failed allograft situation.

Clear lens phacoemulsification in Alport syndrome: refractive results and electron microscopic analysis of the anterior lens capsule.

PURPOSE: To report the ocular findings of patients with Alport syndrome and the results of clear lens extraction in this patient group. METHODS: Twenty-three eyes of 15 patients with a diagnosis of Alport syndrome were included in this study. Clear corneal phacoemulsification and intraocular foldable lens implantation was performed in eyes with indeterminate refractive errors and/or poor visual acuity and anterior capsule samples were analyzed with electron microscopy. RESULTS: All patients had a history of hereditary nephritis and/or deafness as systemic involvement. Ophthalmologic examination revealed anterior lenticonus with high myopia and/or irregular astigmatism in all patients. The mean best-corrected visual acuity (BCVA) was 0.67 ± 0.17 logMAR (range 1.0-0.4) preoperatively and 0.17 ± 0.08 logMAR (range 0.3-0.0) postoperatively. Postoperative refractive lenticular astigmatism dramatically decreased and no ocular complications arose during the follow-up period. Transmission electron microscopic analysis of the lens capsules supported the diagnosis of Alport syndrome. CONCLUSIONS: Clear lens phacoemulsification and foldable intraocular lens implantation is a safe and effective therapeutic choice for the management of uncorrectable refractive errors and low visual acuity due to anterior lenticonus in patients with Alport syndrome.

[Hemophagocytic syndrome after kidney transplant in a patient with hereditary nephritis. Report of one case]. / Síndrome hemofagocítico en un trasplantado renal con síndrome de Alport.

We report a 28-year-old mole with a hereditary nephritis (Alport Syndrome) on hemodialysis for 5 years, who received a kidney graft from a deceased donor. Cyclosporine (CsA), mycophenolate mofetil (MMF) and steroids were prescribed. In the postoperative period the patient had thrombophlebitis and diarrhea. A CT sean showed splenomegaly, ascites, bilateral pleural effusion and bowel edema. Laboratory showed hypoalbuminemia, increased C reactive protein (CRP) and panhypogammaglobulinemia. At day 32 after transplantation, an acute rejection (Banff II b) was diagnosed and treated with methylprednisolone, replacing CsA by tacrolimus. The acute rejection was controlled but six days later, high fever, pancytopenia and hyperferritinemia appeared. A bone marrow smear showed numerous histiocytes and hemophagocytosis. Hemophagocytic syndrome was diagnosed. MMF and tacrolimus were withdrawn and CsA was reinstituted. Fever fell quickly, CPR normalized at 24 hours and white blood cell count at 72 hours. Days later, the concentrations of albumin, immunoglobulins and hematological parameters normalized. The patient was discharged on day 57 after admission in good condition.