Aim
Apolipoprotein A‐I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe ...the clinical manifestations and pathologic features of kidney disease in three Irish families.
Methods
This observational study examines all known cases of chronic kidney disease due to hereditary apolipoprotein A‐I amyloidosis in Ireland. Patients were identified by physician interview. In all of the affected individuals the disease was caused by the Gly26Arg heterozygous mutation. Immunohistochemistry confirmed that amyloid deposits were composed of apolipoprotein A‐I fibrils. Family trees and clinical data were obtained via analysis of patient medical records.
Results
The vast majority of affected cases had demonstrable kidney disease, with variable liver disease. Renal disease most commonly manifested as slowly progressive renal impairment with mild proteinuria. In one kindred, a severe, debilitating peripheral neuropathy was common among affected family members. Histology demonstrated tubulointerstitial fibrosis with amyloid deposition in the medulla. There was very high penetrance within affected families. Of five patients who were transplanted, one transplant was lost after 5 years due to recurrent disease. One patient died from sepsis shortly after transplant.
Conclusion
Hereditary apolipoprotein A‐I amyloidosis is characterized by slowly progressive renal disease. Amyloid is deposited in the renal medulla highlighting the need to examine the medulla on renal biopsy. Overall, kidney transplantation conferred a survival advantage.
Summary at a glance
This is an interesting case series which described the clinical features of hereditary amyloidosis due to apolipoprotein A‐I deficiency. It will improve the awareness of this rare kind of hereditary amyloidosis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a ...suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease.
Histologic grading systems are used to guide diagnosis, therapy, and audit on an international basis. The reproducibility of grading systems is usually tested within small groups of pathologists who ...have previously worked or trained together. This may underestimate the international variation of scoring systems. We therefore evaluated the reproducibility of an established system, the Banff classification of renal allograft pathology, throughout Europe. We also sought to improve reproducibility by providing individual feedback after each of 14 small groups of cases. Kappa values for all features studied were lower than any previously published, confirming that international variation is greater than interobserver variation as previously assessed. A prolonged attempt to improve reproducibility, using numeric or graphical feedback, failed to produce any detectable improvement. We then asked participants to grade selected photographs, to eliminate variation induced by pathologists viewing different areas of the slide. This produced improved kappa values only for some features. Improvement was influenced by the nature of the grade definitions. Definitions based on "area affected" by a process were not improved. The results indicate the danger of basing decisions on grading systems that may be applied very differently in different institutions.
Leptospirosis is an exceptionally rare infectious disease in the Republic of Ireland. Leptospirosis can present with or mimic thrombotic microangiopathies (TTP/HUS). A 48-year-old male presented to a ...peripheral hospital with a short history of diarrhoea, anaemia, hyperbilirubinemia, raised lactate dehydrogenase, thrombocytopenia, and severe acute kidney injury and was transferred to our tertiary care kidney centre. A form of acute thrombotic microangiopathy (TMA) was suspected. However, no schistocytes were seen on the blood film, and the reticulocyte count was depressed. A kidney biopsy was performed before initiating any potential treatment which revealed acute interstitial nephritis (AIN). Leptospirosis was considered and subsequently serologically confirmed. The patient was managed with antimicrobials and supportive therapy. Acute kidney injury is common in leptospirosis and is often due to AIN. Initial presentation can mimic TMA; however, a differential diagnosis of leptospirosis should be considered even in nonendemic areas due to re-emergence of the disease.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
C3 glomerulopathy, a newly designated entity, is characterized by glomerular disease associated with dysregulation of the alternative complement pathway and is a rare cause of end-stage kidney ...disease. Overall disease characteristics that include clinical presentation, laboratory assessment, histopathology and genetic background have only been unravelled in recent years and have led to the development of anti-complement therapies targeting different levels of the alternative pathway. We describe the long-term outcomes following kidney transplantation in an Irish family with familial C3 glomerulopathy due to a hybrid CFHR3-1 gene.
Flow cytometric techniques are increasingly used in pretransplant crossmatching, although there remains debate regarding the clinical significance and predictive value of donor-specific antibodies ...detected by flow cytometry. At least some of the discrepancies between published studies may arise from differences in cutoffs used and lack of standardization of the test.
We selected cut-off values for pretransplant flow cytometric crossmatching (FCXM) based on the correlation of retrospective results with the occurrence of antibody-mediated rejection. The impact on long-term renal graft survival of prospective FCXM was determined by comparing graft survival between patients crossmatched with complement-dependent cytotoxicity (CDC) only with those prospectively crossmatched with both CDC and FCXM.
Chosen cut-off values gave a positive predictive value of FCXM for antibody-mediated rejection of 83%, and a negative predictive value of 90%. After the introduction of prospective B- and T-cell crossmatching by flow cytometry in addition to CDC in our center, there was a significant improvement in renal graft survival in highly sensitized patients (P=0.017). Four-year graft survival in highly sensitized patients after the introduction of FCXM was 89%, which did not differ significantly from that seen in nonsensitized patients (93%; P=0.638).
Our data demonstrate that prospective FCXM improves renal transplant outcome in highly sensitized patients, provided that cut-off values are carefully validated and results interpreted in the context of sensitization history and antibody screening results.
Abstract
Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder renowned for its clinical and genetic heterogeneity. Recently, variants in the ALG5 gene have ...been described as a cause of atypical ADPKD and interstitial fibrosis through the disruption of polycystin 1 maturation and trafficking via underglycosylation. In this report, we investigated genetic cause of the disease in two unrelated Irish families displaying late-onset ADPKD phenotype with atypical tubulointerstitial changes.
Method
Routine clinical and radiological evaluations were carried out. Available kidney biopsy specimens were reassessed. Genetic testing was performed on probands and all relatives with cystic kidneys. First, a custom-targeted gene panel of 227 genes associated with kidney disease was used, but the causal variant was not identified. Then reading frame-changing variants in variable number tandem repeats region of MUC1 were excluded by single-molecule real-time sequencing. Whole exome sequencing revealed a variant in the ALG5 gene, which is not included in the initial custom gene panel. By targeted Sanger sequencing, segregation of the variant with the disease phenotype was confirmed in both investigated families. Multiple bioinformatic tools were employed to predict the effect on protein structure and functions.
Results
The clinical diagnosis was consistent in most of the 20 affected individuals with non-enlarged cystic kidneys and few or no liver cysts. All but 1 individual underwent radiological assessment; 7 had kidney and liver cysts, 7 had only kidney cysts, and 5 had no kidney cysts at ages 68.6±14.4, 55.1±15.8, 46.8±15.6 years, respectively. Polycystic liver phenotype (>20 cysts) was present in two individuals. Biopsy-proven extensive kidney interstitial fibrosis and cystic tubular dilation were evident in four affected individuals with available kidney samples. Of the 20 genetically-defined individuals, 4 had end-stage kidney failure at a mean age of 70.25±3.1 years. Ten individuals were CKD stage 3 or greater, while 6 were CKD stage 4 or lower at ages 43.2±12.6 and 63.1±7.5 years (P value 0.004). A novel heterozygous missense variant in the ALG5 gene (NM_013338.5, c.235C>T, p.Arg79Trp) was identified in affected members from investigated families. Genetic screening of 20 affected and 10 unaffected individuals from both pedigrees revealed segregation of the variant with the disease phenotype. The novel ALG5 variant was classified as likely pathogenic as it was absent in the Genome Aggregation Database (gnomAD), is located in a conserved region and is predicted to be deleterious on protein stability.
Conclusion
This study expands the clinical and genetic spectrum of the identified range of ADPKD, considering the pathogenic ALG5 variants. Establishing a precise diagnosis of atypical cystic and interstitial kidney disease is crucial, with essential implications including follow-up, genetic counselling, prognostication, and therapeutic interventions.
Acute renal failure is a rare but serious complication of pregnancy. We describe a 31-year-old woman with haemolytic anemia, elevated liver enzymes, low platelets (HELLP syndrome) who developed acute ...peripartum renal failure. Renal biopsy performed 2 weeks later because of persistent oliguria revealed thrombotic microangiopathy and acute tubular necrosis. This case highlights the probable pathogenesis of acute renal failure in HELLP patients and explains why it resolves in the majority of cases. A review of the literature that describes renal histology in HELLP patients is presented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background. The natural history of idiopathic membranous nephropathy and recurrent disease in transplants is variable. We performed a retrospective cohort study of renal transplant recipients with a ...primary diagnosis of idiopathic membranous nephropathy. We aimed to establish patterns of disease recurrence and to identify factors associated with disease recurrence. Methods. We accessed the Irish renal transplant database to identify patients with biopsy-proven idiopathic membranous nephropathy in receipt of a renal transplant between 1982 and 2010. A detailed medical chart review was performed in all cases, and a senior renal histopathologist reviewed all histology specimens. Results. The outcomes of 32 patients, in receipt of 36 grafts, are reported. There was a male preponderance (n=29). Significant graft dysfunction, directly attributable to recurrent disease, was evident in 31% of cases at 10 years. There was no significant association between time on dialysis, HLA mismatch, occurrence of rejection, and the development of recurrent membranous disease. One patient was retransplanted twice; all three grafts were lost to aggressive recurrent membranous disease. Conclusions. It remains difficult to identify those that will develop recurrent membranous nephropathy. Almost one third of patients in this cohort developed clinically significant recurrent disease at 10 years.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Defective DNA repair pathways contribute to the development of chronic kidney disease (CKD) in humans. However, the molecular mechanisms underlying DNA damage induced CKD pathogenesis are not well ...understood. Here, we investigated the role of tubular cell DNA damage in the pathogenesis of CKD using mice in which the DNA repair protein Fan1 was knocked out. The phenotype of these mice is orthologous to the human DNA damage syndrome; karyomegalic interstitial nephritis (KIN). Inactivation of Fan1 in kidney proximal tubule cells sensitized the kidneys to genotoxic and obstructive injury characterized by replication stress and persistent DNA damage response activity. Accumulation of DNA damage in Fan1 tubular cells induced epithelial dedifferentiation and tubular injury. Characteristic to KIN, cells with chronic DNA damage failed to complete mitosis and underwent polyploidization. In vitro and in vivo studies showed that polyploidization was caused by the overexpression of DNA replication factors CDT1 and CDC6 in FAN1 deficient cells. Mechanistically, inhibiting DNA replication with Roscovitine reduced tubular injury, blocked the development of KIN and mitigated kidney function in these Fan1 knockout mice. Thus, our data delineate a mechanistic pathway by which persistent DNA damage in the kidney tubular cells leads to kidney injury and development of CKD. Furthermore, therapeutic modulation of cell cycle activity may provide an opportunity to mitigate the DNA damage response induced CKD progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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