Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less ...extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Staphylococcus aureus bloodstream infection can have potentially catastrophic consequences for patients on hemodialysis. Consequently, an effective vaccine to prevent S aureus infection would have a ...significant influence on morbidity and mortality in this group. To date, however, efforts to develop a vaccine have been unsuccessful. Previous antibody-inducing vaccine candidates did not prevent or attenuate S aureus infection in clinical trials. Recent advances have helped to elucidate the role of specific T-cell subsets, notably T-helper cell 1 and T-helper cell 17, in the immune response to S aureus. These cells are essential for coordinating an effective phagocytic response via cytokine production, indirectly leading to destruction of the organism. It is now widely accepted that next-generation S aureus vaccines must also induce effective T-cell–mediated immunity. However, there remains a gap in our knowledge: how will an S aureus vaccine drive these responses in those patients most at risk? Given that patients on hemodialysis are an immunocompromised population, in particular with specific T-cell defects, including defects in T-helper cell subsets, this is likely to affect their ability to respond to an S aureus vaccine. We urgently need a better understanding of T-cell–mediated immunity in this cohort if an efficacious vaccine is ever to be realized for these patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose of the Study. Antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is a rare multisystem autoimmune condition with an incidence of 0.4–24 per 1 million person- years. The ...severity of renal involvement predicts prognosis. Limited data are available on its management and outcomes; thus, we aim to assess this at our tertiary-care renal facility. Study Design. Retrospective data were collected using our national renal electronic database (eMED) to identify AAV patients over a period of 6 years. Outcomes included progression to end-stage renal disease (ESRD) or death, chronic kidney disease (CKD), and preservation of renal function. Results. Thirty-six patients were included in the final study. Cyclophosphamide was used in 24 patients (66.7%) and, comparatively, rituximab in 7 patients (19.4%) for induction. Seven patients (19.4%) had a documented relapse, and six patients (85.7%) had rituximab as induction therapy for relapse. The majority of patients were on azathioprine (61.1%, 57.1% relapse population) as maintenance therapy. Progression to ESRD occurred in 11 (30.6%), death in 4 (11.1%), established CKD in 15 (41.7%), and preservation of renal function in 6 (16.7%) patients by the end of the follow-up period. Conclusions. While cyclophosphamide remains the choice of induction immunosuppression therapy, we favour rituximab as an induction agent in the relapse of AAV. Despite aggressive immunosuppression therapy, the incidence of ESRD and death remains high in these patients.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
In the absence of immunosuppression, transplanted organs invariably undergo progressive immune-mediated injury. Future immunosuppressive strategies are discussed.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: A pathologic analysis.
Acquired renal cystic disease (ARCD), renal adenoma (AD), and renal cell carcinoma (RCC) are more ...common in patients with end-stage renal disease (ESRD). However, the prevalence of these conditions in patients undergoing transplantation, and the clinical characteristics associated with their occurrence are unclear.
At our institution, the majority of patients undergo an ipsilateral native nephrectomy at the time of transplantation, providing a unique opportunity to study the prevalence and pathology of ARCD, AD and RCC in ESRD. We retrospectively reviewed all consecutive nephrectomy pathology reports over a six year period. Demographic and clinical characteristics associated with these lesions were identified.
Two hundred and sixty nephrectomy reports were reviewed: ARCD, AD, RCC and oncocytoma were found in 33%, 14%, 4.2% and 0.6% of cases, respectively. On multivariable analysis, ARCD was positively associated with male sex and longer dialysis duration and negatively associated with peritoneal dialysis. Similarly, AD was positively associated with male sex, longer dialysis duration and greater age. There was a trend for RCC cases to share similar associations although the small total number of cases precluded findings of statistical significance.
By pathologic analysis, renal tumors are more common in the pre-transplant ESRD population than previously reported (using radiologic methods). Our study also identifies risk factors for their occurrence. This may prove useful in designing screening studies for renal tumors in this patient population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Factor H autoantibodies are found in ∼10% of aHUS patients. Most are associated with complete deficiency of factor H related proteins 1/3 and bind to the C terminal recognition domain. MPGN, like ...aHUS, is characterised by complement activation. In this study we, therefore, examined the hypothesis that factor H autoantibodies are associated with MPGN. We screened sera from 16 MPGN patients and 100 normal controls using ELISA and detected strongly positive IgG factor H autoantibodies in 2 patients. One patient had type II (DDD) MPGN (male aged 24 yrs) with C3NeF and the other type I (female aged 26 yrs) with no detectable C3NeF. We identified the binding site of the autoantibodies using small SCR domain fragments in the ELISA and showed that the autoantibodies in both patients bound predominately to the N terminal complement regulatory domain of factor H. We measured CFHR 1/3 copy number using MLPA and showed that both patients had 2 copies of CFHR1 and 3. Finally, we examined the functionality of detected factor H autoantibodies using purified patient IgG and observed increased haemolysis when purified IgG from both patients was added to normal human sera prior to incubation with rabbit red blood cells. Thus, in a cohort of MPGN patients we have found a high titre of functionally significant factor H autoantibodies in two patients with MPGN. Antibody depleting therapy may have a role in such patients and we suggest that screening for factor H autoantibodies should be undertaken in all patients with MPGN.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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
The kinetic characteristics of the column were necessary property to be understood before actual operation. Hence, a functional small-scale zeolite column system was installed for conducting the ...experiments to understand decontamination behaviors. Each column has a 2 cm inner diameter and a 12 cm height, and 12 g of zeolite-type media was packed into the column. The column experiments were carried out with Kurion-zeolite, herschelite, at different feed rates of simulated water with different concentrations of Cs and sea salt. As expected from equilibrium ion-exchange isotherms obtained for KURION-herschelite, the adsorption of Cs is hampered by the existence of sea salt ratio. The difference in breakthrough behaviors can be ascribed to the difference in sea salt ratio. Above 1000 bed volumes, the adsorption rate of Cs was the same at a solution velocity of between 14 and 81 cm/min. Under the condition of a 3.4 wt% sea salt ratio, the performance of the media supplied by KURION was in the order surfactant modified zeolite < silver-impregnated engineered herschelite = herschelite (H). This result was suggested to evaluate the performance of KURION media on the actual columns.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
For the safe storage of zeolite wastes generated by the treatment of radioactive saline water at the Fukushima Daiichi Nuclear Power Station, this study investigated the fundamental properties of ...herschelite adsorbent and evaluated its adsorption vessel for hydrogen production and corrosion. The hydrogen produced by the herschelite sample is oxidized by radicals as it diffuses to the water surface and thus depends on the sample's water level and dissolved species. The hydrogen production rate of herschelite submerged in seawater or pure water may be evaluated by accounting for the water depth. From the obtained fundamental properties, the hydrogen concentration of a reference vessel (decay heat = 504 W) with or without residual pure water was evaluated by thermal-hydraulic analysis. The maximum hydrogen concentration was below the lower explosive limit (4%). The steady-state corrosion potential of a stainless steel 316L increased with the absorbed dose rate, but the increase was repressed in the presence of herschelite. The temperature and absorbed dose at the bottom of the 504 W vessel were determined as 60 °C and 750 Gy/h, respectively. Under these conditions, localized corrosion of a herschelite-contacted 316L vessel would not immediately occur at Cl
−
concentrations of 20,000 ppm.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Background. We present our experience of a controlled non-heart beating donation (CNHBD) programme in a University Hospital. Methods. Data from all referrals for CNHBD between January 2005 and ...January 2008 were collected prospectively. Donor and recipient data were analysed and compared to other cadaveric and HBD transplants performed during the same period. Results. During the period, 79 donors were referred resulting in 35 proceeding to retrieval and 61 kidneys being successfully transplanted. The median time from withdrawal of therapy to asystole was 15 min (IQR 10.0–23.0). The median primary warm ischaemic time was 20 min (IQR 16.0–27.0). The mean cold ischaemia time was 16.6 ± 4.21 h for CNHBD (16.6 ± 5.91 for HBD) kidneys. Compared to HBD kidneys, CNHBD kidneys had more HLA mismatches and significantly more delayed graft function (44% versus 14%), and the mean time to halving of serum creatinine was significantly greater (12.8 versus 5 days). However, 1-year patient and graft survival (88% and 93%) were excellent and mean creatinine at 12 months for CNHB kidneys was not significantly different from HBD kidneys (141 μmol/l versus 131 μmol/l). Conclusions. Structured implementation resulted in a successful CNHBD programme providing 61 successful renal transplants from 35 donors in 3 years—contributing to ∼50% of the total number of cadaveric renal transplants during the period. At 12 months, CNHBD kidney graft function was equivalent to HBD organs.
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