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Updated genetic testing of Italian patients referred with a clinical diagnosis of primary hyperoxaluria.

Thu, 10/12/2017 - 10:01
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Updated genetic testing of Italian patients referred with a clinical diagnosis of primary hyperoxaluria.

J Nephrol. 2017 Apr;30(2):219-225

Authors: Pelle A, Cuccurullo A, Mancini C, Sebastiano R, Stallone G, Negrisolo S, Benetti E, Peruzzi L, Petrarulo M, De Marchi M, Marangella M, Amoroso A, Giachino D, Mandrile G

Abstract
BACKGROUND: Primary hyperoxaluria (PH) is a rare autosomal recessive disease commonly arising in childhood and presenting with nephrolithiasis, nephrocalcinosis and/or chronic renal failure. Three genes are currently known as responsible: alanine-glyoxylate aminotransferase (AGXT, PH type 1), glyoxylate reductase/hydroxypyruvate reductase (GRHPR, PH type 2), and 4-hydroxy-2-oxoglutarate aldolase (HOGA1, PH type 3). In our Centre, at the end of 2014 molecular diagnosis of PH1 had been performed in 80 patients, while one patient received a PH2 diagnosis.
MATERIALS AND METHODS: Fifteen patients referred to our Centre and suspected to have PH on clinical grounds were negative for pathogenic variants in the entire coding sequence and exon-intron boundaries of the AGXT gene. Therefore, we extended the analysis to the AGXT promoter region and the GRHPR and HOGA1 genes.
RESULTS: Two patients were heterozygous for two novel AGXT-promoter variants (c.-647C > T, c.-424C > T) that were probably non pathogenic. One patient was homozygous for a novel HOGA1 variant of intron 2 (c.341-81delT), whose pathogenicity predicted by in silico splicing tools was not confirmed by a minigene splicing assay in COS-7 and HEK293T cells.
CONCLUSION: New genetic subtypes of PH can be hypothesized in our patients, that may be caused by mutations in other gene encoding proteins of glyoxylate metabolism. Alternatively, some kind of mutations (e.g., deletions/duplications, deep intronic splicing regulatory variants) could be missed in a few cases, similarly to other genetic diseases.

PMID: 26946417 [PubMed - indexed for MEDLINE]

Hopes and Difficulties for Blastocyst Complementation.

Wed, 10/11/2017 - 15:45

Hopes and Difficulties for Blastocyst Complementation.

Nephron. 2017 Oct 10;:

Authors: Freedman BS

Abstract
CONTEXT: The clinical need for organ replacement therapies has inspired the idea of growing human organs in animal hosts. The injection of human pluripotent stem cells into animal blastocysts provides a possible strategy to accomplish this goal. Subject of Review: A recent study [Wu et al. Cell 2017;168:473-486.e415] tests the feasibility of this approach by creating chimeric embryos between humans and large domestic animals, including pigs and cattle. The study further examines the potential of combining CRISPR-Cas9 gene editing with blastocyst complementation to grow fully foreign organs in chimeric hosts. Second Opinion: Here, we consider what this report and related studies reveal about the likelihood of human-animal chimeras reaching the clinic and translating into therapies. A careful look suggests hope for eventual success in this area but also underscores important challenges that will require dedicated effort to resolve.

PMID: 29017167 [PubMed - as supplied by publisher]

Effectiveness of IHD with Adsorptive PMMA Membrane in Myeloma Cast Nephropathy: A Cohort Study.

Wed, 10/11/2017 - 15:45

Effectiveness of IHD with Adsorptive PMMA Membrane in Myeloma Cast Nephropathy: A Cohort Study.

Am J Nephrol. 2017 Oct 10;46(5):355-363

Authors: Sens F, Chaintreuil D, Jolivot A, Guebre-Egziabher F, Robinson P, Karlin L, Bridoux F, Juillard L

Abstract
BACKGROUND: In patients with cast nephropathy and acute kidney injury (AKI) requiring dialysis, the reduction of serum free light chains (FLC) using chemotherapy and intensive hemodialysis (IHD) with a high cut-off filter may improve renal and patient outcomes. We evaluated the effectiveness of a combination of chemotherapy and IHD with an adsorbent polymethylmethacrylate membrane (IHD-PMMA) on renal recovery and survival.
METHODS: A single-center retrospective cohort-study was conducted. Between 2007 and 2014, patients with dialysis-dependent acute cast nephropathy treated with chemotherapy and IHD-PMMA were included. Patients had six 6-h hemodialysis sessions a week, until predialysis serum FLC fell below 200 mg/L, for a maximum of 3 weeks. Primary outcomes were renal recovery, defined as dialysis independence, and survival.
RESULTS: Seventeen patients were included, all with stage 3 AKI. All received chemotherapy, mostly based on bortezomib and steroids (88%). Twelve patients (71%) achieved renal recovery, usually within 60 days (92%). At 3 months, the overall hematological response rate was 57%; hematological response was maintained for at least 2 years in 86% of responders. At 6, 12, and 24 months, 76, 75, and 62% of patients were alive, respectively. Higher reduction in involved FLC by day 12 (p = 0.022) and day 21 (p = 0.003) was associated with renal recovery. Patients with FLC reduction rate >50% by day 21 experienced a lower mortality (hazard ratio 0.10, 95% CI 0.02-0.63).
CONCLUSION: In patients with dialysis-dependent myeloma cast nephropathy, early FLC removal by IHD-PMMA combined with chemotherapy was associated with high rates of renal recovery and survival.

PMID: 29017155 [PubMed - as supplied by publisher]

Is Visceral Leishmaniasis Different in Immunocompromised Patients Without Human Immunodeficiency Virus? A Comparative, Multicenter Retrospective Cohort Analysis.

Wed, 10/11/2017 - 15:45

Is Visceral Leishmaniasis Different in Immunocompromised Patients Without Human Immunodeficiency Virus? A Comparative, Multicenter Retrospective Cohort Analysis.

Am J Trop Med Hyg. 2017 Sep 05;:

Authors: Ramos JM, León R, Merino E, Montero M, Aljibe A, Blanes M, Reus S, Boix V, Salavert M, Portilla J

Abstract
Although visceral leishmaniasis (VL) can affect immunocompromised patients, data from the human immunodeficiency virus (HIV) infection context are limited, and the characteristics of VL in other immunosuppression scenarios are not well defined. A retrospective review of all cases of VL in immunocompromised patients from January 1997 to December 2014 in two Spanish hospitals on the Mediterranean coast was performed. We included 18 transplant recipients (kidney: 7, liver: 4, lung: 3, heart: 2, and blood marrow: 2), 12 patients with other causes of immunosuppression (myasthenia gravis: 3 and rheumatoid arthritis: 2), and 73 VL HIV-positive patients. Fever was more common in transplant patients (94.4%) and patients with other types of immunosuppression (100%) than in HIV-positive individuals (73.3%). Hepatomegaly was less common in transplant recipients (27.8%) and patients with other types of immunosuppression (41.7%) compared with HIV-positive patients (69.9%) (P = 0.01; P = 0.001, respectively). Patients with other types of immunosuppression had a median leukocyte count of 1.5 × 10(9)/L, significantly lower than HIV-positive patients (2.5 × 10(9)/L) (P = 0.04). Serology was more commonly positive in nontransplant immunosuppressed individuals (75%) and transplant recipients (78.6%) than in HIV-patients (13.8%) (P < 0.001). Antimonial therapy was rarely used in transplant recipients (1.9%) and never in patients with other immunosuppressive conditions, whereas 34.2% of HIV-positive patients received it (P = 0.05 and P = 0.01, respectively). Mortality was 16.7% in both transplant recipients and patients with other immunosuppressive conditions and 15.1% in HIV-positive patients. The features of VL may be different in immunosuppressed patients, with more fever and less hepatomegaly and leukopenia than in HIV-infected patients.

PMID: 29016284 [PubMed - as supplied by publisher]

Subcutaneous phaeohyphomycosis in kidney transplant recipients: A series of seven cases.

Wed, 10/11/2017 - 15:45

Subcutaneous phaeohyphomycosis in kidney transplant recipients: A series of seven cases.

Transpl Infect Dis. 2017 Oct 09;:

Authors: Satish H, Parameswaran S, Srinivas BH, Laxmisha C, Bibilash BS, Rakesh S, Jayasurya R, Rajesh P, Ezhilnilavan S, Avinash DK, Priyamvada PS

Abstract
BACKGROUND: Superficial and deep fungal infections are more frequent in transplant recipients primarily because of the failure of cell-mediated immunity and lesser amount of antigen-presenting Langerhans cells in their epidermis. Here we report seven cases of post-renal transplant subcutaneous phaeohyphomycosis, all of which manifested within 1 year after transplantation and were unresponsive to prolonged courses of itraconazole. This is the first case series, to our knowledge, of phaeohyphomycosis in transplant recipients in India.
METHOD: We performed a retrospective review of cases of phaeohyphomycosis among kidney transplant recipients for type of transplant, immunosuppression, histopathology, and treatment, with prospective follow-up of healed lesion.
RESULTS: An overall incidence of 8.3% was noted, with a median duration of approximately 6 months post transplant to the onset of skin lesion. None of the lesions responded to itraconazole alone and 6/7 lesions were surgically excised. Histopathology showed various lesions and culture could isolate Neocytalidium and Exophiala jeanselmi in two cases.
CONCLUSION: Dematiaceous fungi are increasingly implicated in cutaneous lesions in transplant recipients. Respectively, histopathology and surgical excision are the appropriate tools for diagnosis and treatment. This article is protected by copyright. All rights reserved.

PMID: 28994174 [PubMed - as supplied by publisher]

Thrombotic microangiopathy following haematopoietic stem cell transplant.

Wed, 10/11/2017 - 15:45

Thrombotic microangiopathy following haematopoietic stem cell transplant.

Pediatr Nephrol. 2017 Oct 09;:

Authors: Seaby EG, Gilbert RD

Abstract
Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.

PMID: 28993886 [PubMed - as supplied by publisher]

Precision Transplant Medicine: Biomarkers to the Rescue.

Wed, 10/11/2017 - 15:45

Precision Transplant Medicine: Biomarkers to the Rescue.

J Am Soc Nephrol. 2017 Oct 09;:

Authors: Naesens M, Anglicheau D

Abstract
The concept that individuals with the same disease and a similar clinical presentation may have very different outcomes and need very different therapies is not novel. With the development of many innovative tools derived from the omics technologies, transplant medicine is slowly entering the era of precision medicine. Biomarkers are the cornerstone of precision medicine, which aims to integrate biomarkers with traditional clinical information and tailor medical care to achieve the best outcome for an individual patient. Here, we discuss the basic concepts of precision medicine and biomarkers, with a specific focus on progress in renal transplantation. We delineate the different types of biomarkers and provide a general assessment of the current applications and shortcomings of previously proposed biomarkers. We also outline the potential of precision medicine in transplantation. Moving toward precision medicine in the field of transplantation will require transplant physicians to embrace the increased complexity and expanded decision algorithms and therapeutic options that are associated with improved disease nosology.

PMID: 28993504 [PubMed - as supplied by publisher]

A rare case of extra-adrenal bilateral perirenal and periureteric myelolipoma.

Wed, 10/11/2017 - 15:45

A rare case of extra-adrenal bilateral perirenal and periureteric myelolipoma.

BMJ Case Rep. 2017 Oct 09;2017:

Authors: Yugandhar S, Sureka SK, Yadav P, Lal H

Abstract
A 30-year-old immunocompetent female presented with right flank pain since 3 years. MRI revealed a large well-defined T1 and T2 hypointense mildly enhancing lesion in the right anterior pararenal space displacing the right kidney and encasing the right ureter with T2 hyperintense wall thickening of the left renal pelvis and ureter. A provisional diagnosis of solitary fibrous tumour was kept. Bilateral double J stenting was done for hydronephrosis. Surgical debulking of the lesion was done with biopsy from the left periureteral wall thickening and was found to be myelolipoma on histopathological examination. This case is a novel variety of myelolipoma which is lipid poor, extra-adrenal and in bilateral perirenal and periureteric location.

PMID: 28993361 [PubMed - in process]

The Lived Experience of "Being Evaluated" for Organ Donation: Focus Groups with Living Kidney Donors.

Wed, 10/11/2017 - 15:45

The Lived Experience of "Being Evaluated" for Organ Donation: Focus Groups with Living Kidney Donors.

Clin J Am Soc Nephrol. 2017 Oct 09;:

Authors: Hanson CS, Ralph AF, Manera KE, Gill JS, Kanellis J, Wong G, Craig JC, Chapman JR, Tong A

Abstract
BACKGROUND AND OBJECTIVES: Comprehensive evaluations are required to safeguard voluntarism and minimize harm to living kidney donors. This process is lengthy, invasive, and emotionally challenging, with up to one fifth of potential donors opting out. We aimed to describe donors' experiences of the evaluation process.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted 14 focus groups involving 123 kidney donors who completed donation from three transplant centers (Australia and Canada). Transcripts were analyzed thematically.
RESULTS: We identified six themes reflecting donors' experiences of evaluation. The themes that related to perseverance included emotional investment (prioritizing the recipient's health, desperation for a normal life, protecting eligibility, shame of disappointing others, and overcoming opposition), undeterred by low risks (medical confidence and protection, worthwhile gamble, inherent invincibility, and normalizing risks), and mental preparation (avoiding regret, resolving decisional ambivalence, and managing expectations of recovery). The challenges included underlying fears for health (processing alarming information, unsettling uncertainty, and preoperative panic), system shortfalls (self-advocacy in driving the process, stressful urgency, inconsistent framing of safety, unnerving bodily scrutiny, questioning risk information, and draining finances); and lifestyle interference (living in limbo, onerous lifestyle disruption, and valuing flexibility).
CONCLUSIONS: Previous donors described an emotional investment in donating and determination to protect their eligibility, despite having concerns for their health, financial and lifestyle disruption, and opposition from their family or community. Our findings suggest the need to prepare donors for surgery and recovery, minimize anxiety and lifestyle burdens, ensure that donors feel comfortable expressing their fears and concerns, reduce unnecessary delays, and make explicit the responsibilities of donors in their assessment process.

PMID: 28993303 [PubMed - as supplied by publisher]

Outcomes of Organ Transplants When the Donor Is a Prior Recipient.

Wed, 10/11/2017 - 15:45

Outcomes of Organ Transplants When the Donor Is a Prior Recipient.

Am J Transplant. 2017 Oct 09;:

Authors: Lee GS, Goldberg DS, Levine MH, Abt PL

Abstract
Organ shortage continues to challenge the field of transplantation. One potential group of donors are those who have been transplant recipients themselves, or Organ Donor After Transplant (ODAT). We conducted a retrospective cohort study to describe ODAT donors and to compare outcomes of ODAT grafts versus conventional grafts. From 10/1/87 to 6/30/15, 517 former recipients successfully donated 803 organs for transplant. Former kidney recipients generally survived a median of approximately four years before becoming an ODAT donor whereas liver, lung, and heart recipients generally survived less than a month prior to donation. In the period 1/1/05 to 12/31/14, liver grafts from ODAT donors had a significantly higher risk of graft failure compared to non-ODAT liver transplants (p = 0.008). Kidney grafts donated by ODAT donors whose initial transplant occurred >1 year prior were associated with significantly increased graft failure (p = 0.012). Despite increased risk of graft failure amongst certain ODAT grafts, five year survival was still high. ODAT donors should be considered another form of expanded criteria donor under these circumstances. This article is protected by copyright. All rights reserved.

PMID: 28992380 [PubMed - as supplied by publisher]

Obesity and synergistic risk factors for chronic kidney disease in African American adults: the Jackson Heart Study.

Wed, 10/11/2017 - 15:45

Obesity and synergistic risk factors for chronic kidney disease in African American adults: the Jackson Heart Study.

Nephrol Dial Transplant. 2017 Aug 30;:

Authors: Olivo RE, Davenport CA, Diamantidis CJ, Bhavsar NA, Tyson CC, Hall R, Bidulescu A, Young B, Mwasongwe SE, Pendergast J, Boulware LE, Scialla JJ

Abstract
Background: African Americans are at high risk for chronic kidney disease (CKD). Obesity may increase the risk for CKD by exacerbating features of the metabolic syndrome and promoting glomerular hyperfiltration. Whether other factors also affecting these pathways may amplify or mitigate obesity-CKD associations has not been investigated.
Methods: We studied interactions between obesity and these candidate factors in 2043 African Americans without baseline kidney disease enrolled in the Jackson Heart Study. We quantified obesity as body mass index (BMI), sex-normalized waist circumference and visceral adipose volume measured by abdominal computed tomography at an interim study visit. Interactions were hypothesized with (i) metabolic risk factors (dietary quality and physical activity, both quantified by concordance with American Heart Association guidelines) and (ii) factors exacerbating or mitigating hyperfiltration (dietary protein intake, APOL1 risk status and use of renin-angiotensin system blocking medications). Using multivariable regression, we evaluated associations between obesity measures and incident CKD over the follow-up period, as well as interactions with metabolic and hyperfiltration factors.
Results: Assessed after a median of 8 years (range 6-11 years), baseline BMI and waist circumference were not associated with incident CKD. Higher visceral adipose volume was independently associated with incident CKD (P   =   0.008) in a nonlinear fashion, but this effect was limited to those with lower dietary quality (P   =   0.001; P-interaction = 0.04). In additional interaction models, higher waist circumference was associated with greater risk of incident CKD among those with the low-risk APOL1 genotype (P   =   0.04) but not those with a high-risk genotype (P-interaction = 0.02). Other proposed factors did not modify obesity-CKD associations.
Conclusions: Higher risks associated with metabolically active visceral adipose volume and interactions with dietary quality suggest that metabolic factors may be key determinants of obesity-associated CKD risk. Interactions between obesity and APOL1 genotype should be considered in studies of African Americans.

PMID: 28992354 [PubMed - as supplied by publisher]

Serum-to-dialysate potassium gradient and its association with short-term outcomes in hemodialysis patients.

Wed, 10/11/2017 - 15:45

Serum-to-dialysate potassium gradient and its association with short-term outcomes in hemodialysis patients.

Nephrol Dial Transplant. 2017 Aug 19;:

Authors: Brunelli SM, Spiegel DM, Du Mond C, Oestreicher N, Winkelmayer WC, Kovesdy CP

Abstract
Background: A high serum-to-dialysate potassium (K + ) gradient at the start of dialysis leads to rapid lowering of serum K + and may confer a greater risk of adverse events. Here, we examined the near-term association of K + gradient with clinical outcomes.
Methods: This retrospective (2010-11) event-based study considered 830 741 patient-intervals, each defined by a pre-dialysis measurement of serum K + made among adult Medicare Parts A and B enrollees who received in-center hemodialysis on a Monday/Wednesday/Friday schedule at a large US dialysis organization. K + gradient was considered based on the difference in K + concentration (serum-dialysate) on the date of measurement; analyses accounted for multiple observations per patient. Outcomes considered were: all-cause and cardiovascular hospital admissions, emergency department (ED) visits and deaths.
Results: Higher K + gradient was associated with younger age, greater fistula use, lower comorbidity scores and better nutritional indices. Adjusting for patient differences, there was a dose-response relationship between higher K + gradient and greater risks of all-cause hospitalization and ED visit. A similar trend was seen for cardiovascular hospitalization but did not achieve statistical significance. No associations were observed with mortality, potentially due to a low number of events.
Conclusions: Higher K + gradient is independently associated with greater risk of all-cause hospitalizations and ED visits. Further research is needed to determine whether interventions that reduce the K + gradient ameliorate this risk.

PMID: 28992343 [PubMed - as supplied by publisher]

Gremlin and renal diseases: ready to jump the fence to clinical utility?

Wed, 10/11/2017 - 15:45

Gremlin and renal diseases: ready to jump the fence to clinical utility?

Nephrol Dial Transplant. 2017 Jul 08;:

Authors: Mezzano S, Droguett A, Lavoz C, Krall P, Egido J, Ruiz-Ortega M

Abstract
The current therapeutic strategy for the treatment of chronic kidney diseases only ameliorates disease progression. During renal injury, developmental genes are re-expressed and could be potential therapeutic targets. Among those genes reactivated in the adult damaged kidney, Gremlin is of particular relevance since recent data suggest that it could be a mediator of diabetic nephropathy and other progressive renal diseases. Earlier studies have shown that Gremlin is upregulated in trans-differentiated renal proximal tubular cells and in several chronic kidney diseases associated with fibrosis. However, not much was known about the mechanisms by which Gremlin acts in renal pathophysiology. The role of Gremlin as a bone morphogenetic protein antagonist has clearly been demonstrated in organogenesis and in fibrotic-related disorders. Gremlin binds to vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial and tubular epithelial cells. Activation of the Gremlin-VEGFR2 axis was found in several human nephropathies. We have recently described that Gremlin activates the VEGFR2 signaling pathway in the kidney, eliciting a downstream mechanism linked to renal inflammatory response. Gremlin deletion improves experimental renal damage, diminishing fibrosis. Overall, the available data identify the Gremlin-VEGFR2 axis as a novel therapeutic target for kidney inflammation and fibrosis and provide a rationale for unveiling new concepts to investigate in several clinical conditions.

PMID: 28992340 [PubMed - as supplied by publisher]

STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model.

Wed, 10/11/2017 - 15:45

STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model.

Nephrol Dial Transplant. 2017 Aug 17;:

Authors: Yokota T, Omachi K, Suico MA, Kamura M, Kojima H, Fukuda R, Motomura K, Teramoto K, Kaseda S, Kuwazuru J, Takeo T, Nakagata N, Shuto T, Kai H

Abstract
Background: Alport syndrome (AS) is a hereditary, progressive nephritis caused by mutation of type IV collagen. Previous studies have shown that activation of signal transducer and activator of transcription 3 (STAT3) exacerbates other renal diseases, but whether STAT3 activation exacerbates AS pathology is still unknown. Here we aim to investigate the involvement of STAT3 in the progression of AS.
Method: Phosphorylated STAT3 expression was assessed by immunoblotting analysis of kidneys and glomeruli of an AS mouse model ( Col4a5 G5X mutant). To determine the effect of blocking STAT3 signaling, we treated AS mice with the STAT3 inhibitor stattic (10 mg/kg i.p., three times per week for 10 weeks; n  = 10). We assessed the renal function [proteinuria, blood urea nitrogen (BUN), serum creatinine] and analyzed the glomerular injury score, fibrosis and inflammatory cell invasion by histological staining. Moreover, we analyzed the gene expression of nephritis-associated molecules.
Results: Phosphorylated STAT3 was upregulated in AS kidneys and glomeruli. Treatment with stattic ameliorated the progressive renal dysfunction, such as increased levels of proteinuria, BUN and serum creatinine. Stattic also significantly suppressed the gene expression levels of renal injury markers ( Lcn2 , Kim-1 ), pro-inflammatory cytokines ( Il-6 , KC ), pro-fibrotic genes ( Tgf-β , Col1a1 , α-Sma ) and Mmp9 . Stattic treatment decreased the renal fibrosis congruently with the decrease of transforming growth factor beta (TGF-β) protein and increase of antifibrosis-associated markers p-Smad1, 5 and 8, which are negative regulators of TGF-β signaling.
Conclusion: STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression and provides a promising therapeutic target for AS.

PMID: 28992339 [PubMed - as supplied by publisher]

The association of donor and recipient age with graft survival in paediatric renal transplant recipients in a European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplantation Association Registry study.

Wed, 10/11/2017 - 15:45

The association of donor and recipient age with graft survival in paediatric renal transplant recipients in a European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplantation Association Registry study.

Nephrol Dial Transplant. 2017 Sep 15;:

Authors: Chesnaye NC, van Stralen KJ, Bonthuis M, Groothoff JW, Harambat J, Schaefer F, Canpolat N, Garnier A, Heaf J, de Jong H, Schwartz Sørensen S, Tönshoff B, Jager KJ

Abstract
Background: The impact of donor age in paediatric kidney transplantation is unclear. We therefore examined the association of donor-recipient age combinations with graft survival in children.
Methods: Data for 4686 first kidney transplantations performed in 13 countries in 1990-2013 were extracted from the ESPN/ERA-EDTA Registry. The effect of donor and recipient age combinations on 5-year graft-failure risk, stratified by donor source, was estimated using Kaplan-Meier survival curves and Cox regression, while adjusting for sex, primary renal diseases with a high risk of recurrence, pre-emptive transplantation, year of transplantation and country.
Results: The risk of graft failure in older living donors (50-75 years old) was similar to that of younger living donors {adjusted hazard ratio [aHR] 0.74 [95% confidence interval (CI) 0.38-1.47]}. Deceased donor (DD) age was non-linearly associated with graft survival, with the highest risk of graft failure found in the youngest donor age group [0-5 years; compared with donor ages 12-19 years; aHR 1.69 (95% CI 1.26-2.26)], especially among the youngest recipients (0-11 years). DD age had little effect on graft failure in recipients' ages 12-19 years.
Conclusions: Our results suggest that donations from older living donors provide excellent graft outcomes in all paediatric recipients. For young recipients, the allocation of DDs over the age of 5 years should be prioritized.

PMID: 28992338 [PubMed - as supplied by publisher]

How to set the stage for a full-fledged clinical trial testing 'incremental haemodialysis'.

Wed, 10/11/2017 - 15:45

How to set the stage for a full-fledged clinical trial testing 'incremental haemodialysis'.

Nephrol Dial Transplant. 2017 Jul 21;:

Authors: Casino FG, Basile C

Abstract
Most people who make the transition to maintenance haemodialysis (HD) therapy are treated with a fixed dose of thrice-weekly HD (3HD/week) regimen without consideration of their residual kidney function (RKF). The RKF provides an effective and naturally continuous clearance of both small and middle molecules, plays a major role in metabolic homeostasis, nutritional status and cardiovascular health, and aids in fluid management. The RKF is associated with better patient survival and greater health-related quality of life. Its preservation is instrumental to the prescription of incremental (1HD/week to 2HD/week) HD. The recently heightened interest in incremental HD has been hindered by the current limitations of the urea kinetic model (UKM), which tend to overestimate the needed dialysis dose in the presence of a substantial RKF. A recent paper by Casino and Basile suggested a variable target model (VTM), which gives more clinical weight to the RKF and allows less frequent HD treatments at lower RKF as opposed to the fixed target model, based on the wrong concept of the clinical equivalence between renal and dialysis clearance. A randomized controlled trial (RCT) enrolling incident patients and comparing incremental HD (prescribed according to the VTM) with the standard 3HD/week schedule and focused on hard outcomes, such as survival and health-related quality of life of patients, is urgently needed. The first step in designing such a study is to compute the 'adequacy lines' and the associated fitting equations necessary for the most appropriate allocation of the patients in the two arms and their correct and safe follow-up. In conclusion, the potentially important clinical and financial implications of the incremental HD render it highly promising and warrant RCTs. The UKM is the keystone for conducting such studies.

PMID: 28992335 [PubMed - as supplied by publisher]

Effect of human leukocyte antigen mismatching on the outcomes of pediatric kidney transplantation: a systematic review and meta-analysis.

Wed, 10/11/2017 - 15:45

Effect of human leukocyte antigen mismatching on the outcomes of pediatric kidney transplantation: a systematic review and meta-analysis.

Nephrol Dial Transplant. 2017 Aug 23;:

Authors: Shi X, Liu R, Xie X, Lv J, Han W, Zhong X, Ding J

Abstract
Background: Kidney transplantation is regarded as the optimal treatment for pediatric patients with end-stage renal disease. Here, we address a controversial topic in pediatric kidney transplantation by performing a quantitative evaluation of the effect of human leukocyte antigen (HLA) mismatching on the outcomes of pediatric kidney transplantation.
Methods: We systematically searched PubMed, EMBASE and the Cochrane Library from their inception to 31 December 2016 for cohort studies assessing the risk ratio (RR) of HLA mismatching on pediatric kidney transplantation. Outcome measures included graft failure, rejection and all-cause mortality. RRs and 95% confidence intervals (CIs) were used as estimates of effect size in random-effect models.
Results: Eighteen studies comprising a total of 26 018 pediatric recipients were included in the evaluation. Compared with 0-1 HLA-DR mismatch, 2 mismatches significantly increased the risk of graft failure at 1 year (RR: 1.41, 95% CI: 1.11-1.80), 3 years (RR: 1.28, 95% CI: 1.08-1.52), 5 years (RR: 1.21, 95% CI: 1.04-1.41) and 10 years (RR: 1.30, 95% CI: 1.02-1.67). For HLA-A + B, the 5-year graft failure risk was higher for 2-4 mismatches compared with 0-1 mismatch (RR: 3.17, 95% CI: 1.20-8.36), but not for 3-4 compared with 0-2 mismatches (RR: 1.49, 95% CI: 0.79-2.80).
Conclusions: Based on pooled analysis, HLA-DR and HLA-A + B are important factors affecting post-transplant outcomes, especially graft failure, in pediatric recipients. Additional randomized controlled trials with higher quality evidence are needed for further investigation.

PMID: 28992320 [PubMed - as supplied by publisher]

Atrial fibrillation in kidney transplant recipients: is there a place for the novel drugs?

Wed, 10/11/2017 - 15:45

Atrial fibrillation in kidney transplant recipients: is there a place for the novel drugs?

Nephrol Dial Transplant. 2017 Sep 07;:

Authors: Malyszko J, Lopatowska P, Mlodawska E, Musialowska D, Malyszko JS, Tomaszuk-Kazberuk A

Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia of high clinical importance, occurring in 2% of the general population and in 19-24% in patients with chronic kidney disease. It is a well-known risk factor for cardiovascular morbidity and mortality. Kidney transplant recipients with a history of AF were associated with significantly higher rate of ischaemic strokes, graft failure and post-transplant mortality. AF occurs in over 7% of kidney transplant recipients in the first 3 years after transplantation and is associated with reduced graft and patient survival. The incidence of stroke in patients after kidney transplantation (KTx) is higher than the general population, but markedly lower than those on dialysis. Oral anticoagulation (OAC) therapy is recommended in AF patients at high risk of stroke. There are no randomized studies assessing OAC in patients after KTx and there are no specific recommendations and guidelines on therapeutic strategies in these patients. KTx recipients are a vulnerable population, exposed to variations in renal function, being at higher risk of bleeding and thrombotic complications, with possible interactions with immunosuppression. Surely, there is a place for novel oral anticoagulants (NOACs) in this group of patients as long as the summary of product characteristics is followed, as they are a valuable anticoagulation therapy. On one hand, they are at least as effective as warfarin; on the other hand NOACs are safer, especially when it comes to intracranial haemorrhages. However, NOACs seem to be underused in this population as they are excreted via kidney, may interact with immunosuppressive therapy and physicians need more experience and confidence in their administration. Percutaneous left atrial appendage occlusion procedure may also be considered as an opportunity for this group of patients, in particular in the presence of contraindications to anticoagulation.

PMID: 28992319 [PubMed - as supplied by publisher]

Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease.

Wed, 10/11/2017 - 15:45

Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease.

Nephrol Dial Transplant. 2017 Jul 11;:

Authors: Di Iorio BR, Marzocco S, Bellasi A, De Simone E, Dal Piaz F, Rocchetti MT, Cosola C, Di Micco L, Gesualdo L

Abstract
Background: Protein carbamylation is one of the non-enzymatic reactions involved in protein molecular ageing. We sought to investigate the relationship between urea levels and protein carbamylation, and whether a Mediterranean diet (MD) and a very low protein diet (VLPD) reduce protein carbamylation through reduction in urea levels in patients with chronic kidney disease (CKD).
Methods: This is a prospective, randomized, crossover controlled trial that investigated 60 patients with CKD grades 3B-4 (46 males, mean age of 67 years). The enrolled CKD patients were randomly assigned (1:1) to two different nutritional treatment arms: (i) 3 months of free diet (FD), 6 months of VLPD, 3 months of FD and 6 months of MD; and (ii) 3 months of FD, 6 months of MD, 3 months of FD and 6 months of VLPD. Blood levels of lysine (Lys) and homocitrulline (Hcit) and their ratio were used as markers of cyanate levels. Due to a lack of pre-existing data on the potential effects of different dietary regimens and in light of the exploratory nature of the study, no formal sample size estimation was carried out.
Results: At study completion, lower diastolic blood pressure and decreased serum levels of urea, sodium, phosphorus and parathyroid hormone, but higher serum levels of bicarbonate and haemoglobin, were noted with MD and VLPD. When compared with FD, both MD and VLPD were also associated with a decrease in serum Hcit levels and Hcit/Lys ratios (P < 0.001). Notably, reductions in urea levels correlated with substantial reductions in Hcit levels ( R 2 = 0.16 and 0.17 for VLPD and MD, respectively).
Conclusion: In conclusion, nutritional treatments that significantly decrease serum levels of urea are associated with reduced protein carbamylation.

PMID: 28992314 [PubMed - as supplied by publisher]

Secular trends in the incidence of end-stage renal disease and its risk factors in Japanese patients with immunoglobulin A nephropathy.

Wed, 10/11/2017 - 15:45

Secular trends in the incidence of end-stage renal disease and its risk factors in Japanese patients with immunoglobulin A nephropathy.

Nephrol Dial Transplant. 2017 Jul 19;:

Authors: Tanaka S, Ninomiya T, Katafuchi R, Masutani K, Tsuchimoto A, Tokumoto M, Hirakata H, Ooboshi H, Kitazono T, Tsuruya K

Abstract
Background: There are limited data on secular trends in the incidence of end-stage renal disease (ESRD) and frequencies of its risk factors or treatment modalities in patients with immunoglobulin A nephropathy (IgAN).
Methods: This study divided 1255 patients with IgAN into three groups according to the timing of renal biopsy: 1979-89 ( n  = 232), 1990-99 ( n  = 574) and 2000-10 ( n  = 449). The age-adjusted incidence rates, incidence rate ratios and 95% confidence intervals (CIs) for ESRD were calculated by the person-year method and compared using Poisson regression analysis.
Results: A total of 63 patients (5.0%) developed ESRD. The age-adjusted incidence of ESRD decreased significantly over time, i.e. 11.5 per 1000 person-years (95% CI 5.4-24.6) in 1979-89, 6.5 per 1000 person-years (95% CI 1.0-25.2) in 1990-99 and 4.2 per 1000 person-years (95% CI 1.0-17.7) in 2000-10. The proportions of patients with preserved renal function and acute-stage inflammatory histologic changes (i.e. endocapillary hypercellularity and extracapillary proliferation) at the timing of biopsy increased over time, as did the rates of prescriptions of renin-angiotensin system blockers and corticosteroids (all P for trend <0.05). The effect of acute inflammatory histologic lesions on renal prognosis was drastically reduced over time.
Conclusions: These findings suggest that early diagnosis in the acute inflammatory phase and subsequent aggressive treatment may have contributed to the significant downward trend in the incidence of ESRD in patients with IgAN over three decades.

PMID: 28992313 [PubMed - as supplied by publisher]

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