DNAJB11-Related Atypical ADPKD in a Kidney Transplant Donor.
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ABSTRACT:
SUBMITTER: Wilson GJ
PROVIDER: S-EPMC7403562 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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<i>DNAJB11</i>-Related Atypical ADPKD in a Kidney Transplant Donor.
Wilson Gregory J GJ Wood Simon S Patel Chirag C Oliver Kimberley K John George G Ranganathan Dwarakanathan D Mallett Andrew A Isbel Nicole N
Kidney international reports 20200602 8
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Project description:Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.
| S-EPMC5986722 | biostudies-literature
Project description:BackgroundPolycystic kidney diseases (PKD) are an important cause of chronic kidney disease (CKD). Autosomal dominant polycystic kidney disease (ADPKD) due to PKD1 or PKD2 mutations is the most common form, but other genes can be responsible for ADPKD and its phenocopies. Among them, a form of atypical ADPKD caused by DNAJB11 mutations (DNAJB11-PKD) has been recently described.MethodsWe retrospectively recruited a cohort of 27 patients from six different families sharing common ancestries and harboring the same DNAJB11 mutation (c.100C>T, p.Arg34*) and we compared it with a cohort of 42 typical ADPKD patients.ResultsDNAJB11-PKD patients show small/normal-sized kidneys, with significantly smaller cysts and a slower progression to end-stage kidney disease (ESKD) than ADPKD patients. In the DNAJB11-PKD cohort, the cystic phenotype could not be detected by ultrasound in about half of the patients, but all cases with available computed tomography/magnetic resonance scans displayed cysts. Clinically, DNAJB11-PKD patients displayed proteinuria (mostly albuminuria). Compared with ADPKD, DNAJB11-PKD patients were older and had a higher prevalence of type 2 diabetes mellitus (19% versus 0%; P = 0.007) and nephrolithiasis (62% versus 29%; P = 0.01), whereas the prevalence of cardiac valvular defects was lower (4% versus 51%; P < 0.001).ConclusionsOverall, clinical features of DNAJB11-PKD were more subtle compared with those of ADPKD. DNAJB11-PKD shows a unique renal and extrarenal phenotype, clinical presentation and natural history. Therefore our data support that this genetic disease is classified separately from ADPKD.
| S-EPMC9155219 | biostudies-literature
Project description:IntroductionCardiovascular disease leads to high morbidity and mortality in patients with kidney failure. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease with various cardiac abnormalities. Details on the cardiovascular profile of patients with ADPKD who are undergoing kidney transplantation (KT) and its progression are limited.MethodsEchocardiographic data within 2 years before KT (1993-2020), and major adverse cardiovascular events (MACEs) after transplantation were retrieved. The primary outcome is to assess cardiovascular abnormalities on echocardiography at the time of transplantation in ADPKD as compared with patients without ADPKD matched by sex (male, 59.4%) and age at transplantation (57.2 ± 8.8 years).ResultsCompared with diabetic nephropathy (DN, n = 271) and nondiabetic, patients without ADPKD (NDNA) (n = 271) at the time of KT, patients with ADPKD (n = 271) had lower rates of left ventricular hypertrophy (LVH) (39.4% vs. 66.4% vs. 48.6%), mitral (2.7% vs. 6.3% vs. 7.45) and tricuspid regurgitations (1.8% vs. 6.6% vs. 7.2%). Patients with ADPKD had less diastolic (25.3%) and systolic (5.6%) dysfunction at time of transplantation. Patients with ADPKD had the most favorable post-transplantation survival (median 18.7 years vs. 12.0 for diabetic nephropathy [DN] and 13.8 years for nondiabetic non-ADPKD [NDNA]; P < 0.01) and the most favorable MACE-free survival rate (hazard ratio = 0.51, P < 0.001). Patients with ADPKD had worsening of their valvular function and an increase in the sinus of Valsalva diameter post-transplantation (38.2 vs. 39.9 mm, P < 0.01).ConclusionADPKD transplant recipients have the most favorable cardiac profile pretransplantation with better patient survival and MACE-free survival rates but worsening valvular function and increasing sinus of Valsalva diameter, as compared with patients with other kidney diseases.
| S-EPMC9459062 | biostudies-literature
Project description:Simultaneous deceased donor pancreas and living donor kidney transplant (SPLK) has certain advantages over conventional simultaneous pancreas-kidney transplant (SPK) and may be beneficial for overcoming the paucity of organs needed for diabetic patients requiring transplant. We compared the clinical outcomes of patients who underwent either SPK (n = 149) or SPLK (n = 46) in terms of pre- and post-transplantation variables, development of de novo DSA, occurrence of biopsy-proven acute rejection (BPAR), and graft survival rates. There were no significant differences in the baseline characteristics between the SPK and SPLK groups except for the shorter cold ischemic time of kidney grafts, shorter duration of diabetes, older age of pancreas graft-donors, and younger age of kidney graft-donors in the SPLK group. Our results showed that the death-censored pancreas graft survival rate was lower in the SPLK group. In addition, the incidence of BPAR of the pancreas graft was higher in the SPLK group. There was no significant difference in the presence of de novo DSA and the rates of kidney graft failure, kidney BPAR, and mortality. Our results show that SPLK can be considered an alternative option for SPK although higher incidences of BPAR and graft failure of pancreas after SPLK need to be overcome.
| S-EPMC9807579 | biostudies-literature
Project description:IntroductionCyst infection is a known complication of autosomal dominant polycystic kidney disease (ADPKD). Here, we describe incidence, risk factors, clinical presentation, and outcomes of cyst infection in kidney transplant recipient.MethodsWe conducted a single-center retrospective cohort study of patients with ADPKD with renal allografts between January 1, 2009, and October 31, 2020. Cyst infection diagnosis was based on previously described clinical and radiological criteria, using positron emission tomography when available.ResultsA total of 296 patients with ADPKD with renal allografts were included, and 21 patients experienced 22 episodes of cyst infection over a median follow-up of 4 (2-7) years. The cumulative incidence rate was 3% at 1 year, 6 % at 5 years, and 12% at 10 years after transplantation. In multivariate analysis, history of cyst infection before transplantation was the only significant risk factor identified to predict the occurrence of cyst infection after kidney transplantation (hazard ratio [HR] 3.47, 95% CI 1.29-9.31). The clinical presentation at diagnosis of cyst infection included isolated fever in 5 (23%) episodes, acute kidney injury in 12 (55%), and severe sepsis/septic shock in 3 (14%) episodes. Among the 16 (73%) episodes with culture positivity, Escherichia coli was the most common pathogen. There was no difference between early (≤1 year after transplantation) and late (>1 year) cyst infection episodes in terms of clinical presentation and outcomes. Cyst infection was significantly associated with graft loss (HR 3.93, 95% CI 1.21-12.80), but no causal relationship could be established.ConclusionIncidence of cyst infection in ADPKD after kidney transplantation is low, history of cyst infection representing the main risk factor.
| S-EPMC9039903 | biostudies-literature
Project description:African Americans are at greater risk to reach end-stage renal disease and this risk may carry over in a kidney transplant recipient after kidney transplantation.Linking the five-yr patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, we identified 13 692 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function risks were estimated by Cox's regression (hazard ratio [HR] and 95% confidence interval) and logistic regression, respectively.Patients were 48 ± 14 yr old and included 39% women and 26% patients with diabetes. After adjusting for several relevant clinical and transplant-related variables, African American donor race was associated with higher all-cause mortality, with HR of 1.39 (1.09-1.78) for all-cause mortality, 1.80 (1.17-2.76) for cardiovascular mortality, 1.30 (1.03-1.64) for death-censored graft loss and 1.31 (1.10-1.57) for combined outcome over the six-yr observation period. In the non-African American recipient subcohort, but not in the African American recipient subcohort, African American donor race was associated with higher risk of death-censored graft loss (2.24 [1.44-3.49]) in our fully adjusted model.African American donor race was associated with increased all-cause and cardiovascular mortality and graft loss.
| S-EPMC3593049 | biostudies-literature
Project description:Kidney transplantation is regarded as the best treatment option for patients with end-stage renal disease. However, living-donor recipients (LDRs) and deceased-donor recipients (DDRs) still face challenges in transplant-specific emotional adjustment post-transplantation. Research distinguishing emotional adjustment between transplant groups has been limited to Western settings, with little attention given to Asian populations. As such, documenting and comparing the emotional adjustment of LDRs and DDRs in an ethnically diverse Asian setting in Singapore and identifying factors associated with emotional adjustment are of interest. Methods:One hundred eighty-two kidney transplant patients (106 LDRs and 76 DDRs) completed measures of generic distress (Depression, Anxiety, Stress Scale-21) and transplantation-specific emotional and behavioral outcomes (Transplant Effects Questionnaire). Results:LDRs were significantly younger (P = 0.019) and had higher education levels (P = 0.007), higher personal income (P < 0.001), shorter dialysis vintage (P < .001), and higher estimated glomerular filtration rates (eGFRs) (P = 0.002) compared with DDRs. Generic symptoms of depression and stress were very low; however, 29.2% of LDRs and 19.7% of DDRs experienced moderate to severe symptoms of anxiety. Similarly, 83.0% of LDRs and 72.4% of DDRs reported high levels of transplant-specific worry. Multivariate models showed younger patients expressing greater generic distress, and transplant-specific worry (P < 0.01), despite higher eGFRs (P < 0.05). ANCOVA controlling for casemix differences showed that LDRs experienced higher feelings of guilt (P = 0.004) and greater willingness to disclosure (P = 0.041). Conclusions:Clinicians should be vigilant of younger kidney transplant patients who have greater risk of poorer emotional adjustment. Future interventions should target alleviating anxiety and transplant-specific worry.
| S-EPMC7004627 | biostudies-literature
Project description: Not available
| S-EPMC7608998 | biostudies-literature
Project description:Socioeconomically deprived individuals with renal disease are less likely to receive a live-donor kidney transplant than less-deprived individuals. This qualitative study aimed to identify reasons for the observed socioeconomic disparity in live-donor kidney transplantation.A qualitative study using face-to-face in-depth semistructured interviews.A UK tertiary renal referral hospital and transplant centre.Purposive sampling was used to select deceased-donor transplant recipients from areas of high socioeconomic deprivation (SED) (19 participants), followed by a low SED comparison group (13 participants), aiming for maximum diversity in terms of age, gender, ethnicity, primary renal disease and previous renal replacement therapy.Participants were interviewed following their routine transplant clinic review. Interviews were digitally audio-recorded and transcribed verbatim. Transcripts were coded using NVivo software and analysed using the constant comparison method described in Grounded Theory.Themes common and distinct to each socioeconomic group emerged. 6 themes appeared to distinguish between individuals from areas of high and low SED. 4 themes were distinct to participants from areas of high SED: (1) Passivity, (2) Disempowerment, (3) Lack of social support and (4) Short-term focus. 2 themes were distinct to the low SED group: (1) Financial concerns and (2) Location of donor.Several of the emerging themes from the high SED individuals relate to an individual's lack of confidence and skill in managing their health and healthcare; themes that are in keeping with low levels of patient activation. Inadequate empowerment of socioeconomically deprived individuals by healthcare practitioners was also described. Financial concerns did not emerge as a barrier from interviews with the high SED group. Interventions aiming to redress the observed socioeconomic inequity should be targeted at both patients and clinical teams to increase empowerment and ensure shared decision-making.
| S-EPMC4785291 | biostudies-other
Project description:ImportanceIn the US, live donor (LD) kidney transplant rates have decreased in pediatric recipients. Pediatric patients with kidney failure will likely need more than 1 kidney transplant during their lifetime, but the optimal sequence of transplant (ie, deceased donor [DD] followed by LD or vice versa) is not known.ObjectiveTo determine whether pediatric recipients should first receive a DD allograft followed by an LD allograft (DD-LD sequence) or an LD allograft followed by a DD allograft (LD-DD sequence).Design, setting, and participantsThis decision analytical model examined US pediatric patients with kidney failure included in the US Renal Data System 2019 Report who were waiting for a kidney transplant, received a transplant, or experienced graft failure.InterventionsKidney transplant sequences of LD-DD vs DD-LD.Main outcomes and measuresDifference in projected life-years between the 2 sequence options.ResultsAmong patients included in the analysis, the LD-DD sequence provided more net life-years in those 5 years of age (1.82 [95% CI, 0.87-2.77]) and 20 years of age (2.23 [95% CI, 1.31-3.15]) compared with the DD-LD sequence. The net outcomes in patients 10 years of age (0.36 [95% CI, -0.51 to 1.23] additional life-years) and 15 years of age (0.64 [95% CI, -0.15 to 1.39] additional life-years) were not significantly different. However, for those aged 10 years, an LD-DD sequence was favored if eligibility for a second transplant was low (2.09 [95% CI, 1.20-2.98] additional life-years) or if the LD was no longer available (2.32 [95% CI, 1.52-3.12] additional life-years). For those aged 15 years, the LD-DD sequence was favored if the eligibility for a second transplant was low (1.84 [95% CI, 0.96-2.72] additional life-years) or if the LD was no longer available (2.49 [95% CI, 1.77-3.27] additional life-years). Access to multiple DD transplants did not compensate for missing the LD opportunity.Conclusions and relevanceThese findings suggest that the decreased use of LD kidney transplants in pediatric recipients during the past 2 decades should be scrutinized. Given the uncertainty of future recipient eligibility for retransplant and future availability of an LD transplant, the LD-DD sequence is likely the better option. This strategy of an LD transplant first would not only benefit pediatric recipients but allow DD kidneys to be used by others who do not have an LD option.
| S-EPMC8739763 | biostudies-literature