Dual-task kidney MR segmentation with transformers in autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease is a prevalent genetic disorder characterized by the development of renal cysts, leading to kidney enlargement and renal failure. Accurate measurement of total kidney volume through polycystic kidney segmentation is crucial to assess disease severity, predict progression and evaluate treatment effects. Traditional manual segmentation suffers from intra- and inter-expert variability, prompting the exploration of automated approaches. In recent years, convolutional neural networks have been employed for polycystic kidney segmentation from magnetic resonance images. However, the use of Transformer-based models, which have shown remarkable performance in a wide range of computer vision and medical image analysis tasks, remains unexplored in this area. With their self-attention mechanism, Transformers excel in capturing global context information, which is crucial for accurate organ delineations. In this paper, we evaluate and compare various convolutional-based, Transformers-based, and hybrid convolutional/Transformers-based networks for polycystic kidney segmentation. Additionally, we propose a dual-task learning scheme, where a common feature extractor is followed by per-kidney decoders, towards better generalizability and efficiency. We extensively evaluate various architectures and learning schemes on a heterogeneous magnetic resonance imaging dataset collected from 112 patients with polycystic kidney disease. Our results highlight the effectiveness of Transformer-based models for polycystic kidney segmentation and the relevancy of exploiting dual-task learning to improve segmentation accuracy and mitigate data scarcity issues. A promising ability in accurately delineating polycystic kidneys is especially shown in the presence of heterogeneous cyst distributions and adjacent cyst-containing organs. This work contribute to the advancement of reliable delineation methods in nephrology, paving the way for a broad spectrum of clinical applications.

An Artificial Intelligence Generated Automated Algorithm to Measure Total Kidney Volume in ADPKD.

Introduction: Accurate tools to inform individual prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Here, we report an artificial intelligence (AI)-generated method for routinely measuring total kidney volume (TKV). Methods: An ensemble U-net algorithm was created using the nnUNet approach. The training and internal cross-validation cohort consisted of all 1.5T magnetic resonance imaging (MRI) data acquired using 5 different MRI scanners (454 kidneys, 227 scans) in the CYSTic consortium, which was first manually segmented by a single human operator. As an independent validation cohort, we utilized 48 sequential clinical MRI scans with reference results of manual segmentation acquired by 6 individual analysts at a single center. The tool was then implemented for clinical use and its performance analyzed. Results: The training or internal validation cohort was younger (mean age 44.0 vs. 51.5 years) and the female-to-male ratio higher (1.2 vs. 0.94) compared to the clinical validation cohort. The majority of CYSTic patients had PKD1 mutations (79%) and typical disease (Mayo Imaging class 1, 86%). The median DICE score on the clinical validation data set between the algorithm and human analysts was 0.96 for left and right kidneys with a median TKV error of -1.8%. The time taken to manually segment kidneys in the CYSTic data set was 56 (±28) minutes, whereas manual corrections of the algorithm output took 8.5 (±9.2) minutes per scan. Conclusion: Our AI-based algorithm demonstrates performance comparable to manual segmentation. Its rapidity and precision in real-world clinical cases demonstrate its suitability for clinical application.

Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.

Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.

[Prevalence of iron deficiency in patients with non-dialysis chronic kidney disease: The CARENFER national, multicentre, observational study]. / Prévalence de la carence martiale dans une population de patients insuffisants rénaux chroniques non dialysés : étude nationale multicentrique observationnelle CARENFER.

INTRODUCTION: Iron deficiency is common and associated with worse outcomes in patients with non-dialysis chronic kidney disease. We performed a national, multicentre, observational and transversal study to assess the prevalence of iron deficiency as well as current iron deficiency screening practices in this population. PATIENTS AND METHODS: A total of 25 nephrology centres in France participated in the study. All adult non-dialysis chronic kidney disease patients who met the inclusion (GFR>15mL/min/1.73m2) and exclusion criteria and provided consent were systematically recruited over a 4-week inclusion period. Investigators were asked to perform a blood test (hemoglobin concentration, serum iron, serum ferritin and transferrin saturation) and to complete a questionnaire about their iron status monitoring practices. The primary objective was to assess the prevalence of iron deficiency (serum ferritin<100µg/L and/or transferrin saturation<20%). Secondary objectives were to evaluate the prevalence of absolute iron deficiency (serum ferritin<100µg/L and transferrin saturation<20%) and functional iron deficiency (serum ferritin≥100µg/L and transferrin saturation<20%), the prevalence of iron deficiency according to haemoglobin concentration and chronic kidney disease stage, the proportion of centres that perform routine evaluation of iron status and the number of patients receiving iron supplementation. RESULTS: A total of 1211 patients with non-dialysis chronic kidney disease were included in the analysis. The overall prevalence of iron deficiency was 47.1%. The rates of absolute iron deficiency and functional iron deficiency and anaemia were 13.4% and 17.1%, respectively. Among the 25 participating centres, 12 reported routine assessment of iron status in non-dialysis chronic kidney disease patients. CONCLUSION: In this observational study, a high prevalence of iron deficiency was observed among non-dialysis chronic kidney disease patients. Less than half of participating centres reported routine assessment of iron status.

Diagnosis and risk factors for intracranial aneurysms in autosomal polycystic kidney disease: a cross-sectional study from the Genkyst cohort.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is associated with an increased risk for developing intracranial aneurysms (IAs). We aimed to evaluate the frequency of diagnosis of IAs in the cross-sectional, population-based, Genkyst cohort, to describe ADPKD-associated IAs and to analyse the risk factors associated with the occurrence of IAs in ADPKD patients. METHODS: A cross-sectional study was performed in 26 nephrology centres from the western part of France. All patients underwent genetic testing for PKD1/PKD2 and other cystogenes. RESULTS: Among the 2449 Genkyst participants, 114 (4.65%) had a previous diagnosis of ruptured or unruptured IAs at inclusion, and ∼47% of them had a positive familial history for IAs. Most aneurysms were small and saccular and located in the anterior circulation; 26.3% of the patients had multiple IAs. The cumulative probabilities of a previous diagnosis of IAs were 3.9%, 6.2% and 8.1% at 50, 60 and 70 years, respectively. While this risk appeared to be similar in male and female individuals <50 years, after that age, the risk continued to increase more markedly in female patients, reaching 10.8% versus 5.4% at 70 years. The diagnosis rate of IAs was >2-fold higher in PKD1 compared with PKD2, with no influence of PKD1 mutation type or location. In multivariate analysis, female sex, hypertension <35 years, smoking and PKD1 genotype were associated with an increased risk for diagnosis of IAs. CONCLUSIONS: This study presents epidemiological data reflecting real-life clinical practice. The increased risk for IAs in postmenopausal women suggests a possible protective role of oestrogen.

Flank pain has a significant adverse impact on quality of life in ADPKD: the CYSTic-QoL study.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of kidney failure worldwide. However, its impact on quality-of-life has not been systematically explored. Methods: The CYSTic-QoL study was an observational study designed to study quality-of-life in adult European ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A total of 465 patients were recruited from six expert European centres with baseline data recorded, including health-related quality-of-life (HRQoL), incorporating a Kidney Disease QoL short form questionnaire (KDQoL-SF, version 1.3), magnetic resonance imaging (MRI) for total kidney volume (TKV) measurements and DNA for genotyping. The cohort was stratified by baseline eGFR, TKV or genotype and correlated with HRQoL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the RAND organization. For 36-item short form values, mean centre scores were normalized to their native populations. Results: The mean age of participants was 43 years and 55% were female, with a mean eGFR of 77 mL/min/1.73 m2 and height-adjusted TKV (ht-TKV) of 849 mL/min; 66% had PKD1 pathogenic variants. ADPKD patients uniformly reported decreased general health and less energy, with the majority also experiencing poorer physical, mental or emotional health and limitations in social functioning. A total of 32.5% of participants experienced flank pain, which was significantly and negatively correlated with the majority of KDQoL-SF subscales by multivariate analysis. Higher ht-TKV and lower eGFR were negatively associated with decreased energy and poorer physical health, respectively, although not with flank pain. Conclusion: ADPKD patients suffer from significantly decreased QoL in multiple domains, exacerbated particularly by chronic pain.

Abdominal multi-organ segmentation with cascaded convolutional and adversarial deep networks.

Abdominal anatomy segmentation is crucial for numerous applications from computer-assisted diagnosis to image-guided surgery. In this context, we address fully-automated multi-organ segmentation from abdominal CT and MR images using deep learning. The proposed model extends standard conditional generative adversarial networks. Additionally to the discriminator which enforces the model to create realistic organ delineations, it embeds cascaded partially pre-trained convolutional encoder-decoders as generator. Encoder fine-tuning from a large amount of non-medical images alleviates data scarcity limitations. The network is trained end-to-end to benefit from simultaneous multi-level segmentation refinements using auto-context. Employed for healthy liver, kidneys and spleen segmentation, our pipeline provides promising results by outperforming state-of-the-art encoder-decoder schemes. Followed for the Combined Healthy Abdominal Organ Segmentation (CHAOS) challenge organized in conjunction with the IEEE International Symposium on Biomedical Imaging 2019, it gave us the first rank for three competition categories: liver CT, liver MR and multi-organ MR segmentation. Combining cascaded convolutional and adversarial networks strengthens the ability of deep learning pipelines to automatically delineate multiple abdominal organs, with good generalization capability. The comprehensive evaluation provided suggests that better guidance could be achieved to help clinicians in abdominal image interpretation and clinical decision making.

Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease.

Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.

EPURE Transplant (Eplerenone in Patients Undergoing Renal Transplant) study: study protocol for a randomized controlled trial.

BACKGROUND: Despite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades. Ischemia/reperfusion injury (IRI) is one of the main pathophysiological mechanisms underlying delayed graft function, which is associated with poor long-term graft survival. Due to organ shortage, the proportion of grafts from expanded criteria donors (ECDs) is ever growing. These grafts may particularly benefit from IRI prevention. In preclinical models, mineralocorticoid receptor antagonists (MRAs) have been shown to efficiently prevent IRI. This study aims to assess the effect of MRA administration in the early phase of kidney transplantation (KT) among recipients of ECD grafts on mid-term graft function. METHODS/DESIGN: This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients on hemodialysis and undergoing a single or a dual KT from an ECD will be eligible for inclusion. We plan to randomize 132 patients. Included patients will be randomized (1:1) to receive either eplerenone 25 mg every 12 h during 4 days (the first dose being administered just prior to KT) or placebo. The primary outcome is graft function at 3 months, assessed by glomerular filtration rate (GFR, in mL/min/1.73m2) measured using iohexol clearance. Secondary outcomes include (1) proportion of patients with either dialysis dependency or a GFR < 30 mL/min/1.73m2 at 3 months, (2) proportion of patients with immediate, slow, or delayed graft function, (3) proteinuria at 3 months, (4) occurrence of hyperkalemia during the first week following KT, (5) length of hospital stay for the KT, and (6) occurrence of biopsy-proven acute rejection in the first 3 months following KT. Estimated GFR, graft, and patient survival will also be collected at 1, 3, and 10 years via the national database of organ recipients. DISCUSSION: Improvement of ECD grafts is a public health priority, since better ECD outcomes could eventually limit organ shortage. MRA administration in the early phase of KT may prevent IRI and subsequently improve mid-term graft function. The trial will also assess the safety of MRA administration in this population, primarily the absence of threatening hyperkalemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02490904 . Registered on 1 July 2015.

Novel long-range regulatory mechanisms controlling PKD2 gene expression.

BACKGROUND: Cis-regulatory elements control gene expression over large distances through the formation of chromatin loops, which allow contact between enhancers and gene promoters. Alterations in cis-acting regulatory systems could be linked to human genetic diseases. Here, we analyse the spatial organization of a large region spanning the polycystic kidney disease 2 (PKD2) gene, one of the genes responsible of autosomal dominant polycystic kidney disease (ADPKD). RESULTS: By using chromosome conformation capture carbon copy (5C) technology in primary human renal cyst epithelial cells, we identify novel contacts of the PKD2 promoter with chromatin regions, which display characteristics of regulatory elements. In parallel, by using functional analysis with a reporter assay, we demonstrate that three DNAse I hypersensitive sites regions are involved in the regulation of PKD2 gene expression. CONCLUSIONS: Finally, through alignment of CCCTC-binding factor (CTCF) sites, we suggest that these novel enhancer elements are brought to the PKD2 promoter by chromatin looping via the recruitment of CTCF.

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.

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.

Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8.

Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1α isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates.

PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis.

BACKGROUND: PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. STUDY DESIGN: Case series, January 2010 to March 2016. SETTINGS & PARTICIPANTS: Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. OUTCOMES: Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. RESULTS: The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. LIMITATIONS: Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. CONCLUSIONS: Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 (∼85% and ∼15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations. After screening, 7%-10% of ADPKD-affected and ∼50% of ADPLD-affected families were genetically unresolved (GUR), suggesting further genetic heterogeneity of both disorders. Whole-exome sequencing of six GUR ADPKD-affected families identified one with a missense mutation in GANAB, encoding glucosidase II subunit α (GIIα). Because PRKCSH encodes GIIß, GANAB is a strong ADPKD and ADPLD candidate gene. Sanger screening of 321 additional GUR families identified eight further likely mutations (six truncating), and a total of 20 affected individuals were identified in seven ADPKD- and two ADPLD-affected families. The phenotype was mild PKD and variable, including severe, PLD. Analysis of GANAB-null cells showed an absolute requirement of GIIα for maturation and surface and ciliary localization of the ADPKD proteins (PC1 and PC2), and reduced mature PC1 was seen in GANAB(+/-) cells. PC1 surface localization in GANAB(-/-) cells was rescued by wild-type, but not mutant, GIIα. Overall, we show that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.

Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice.

Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient.

A candidate gene approach of the calcineurin pathway to identify variants associated with clinical outcomes in renal transplantation.

AIM: To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. MATERIALS & METHODS: Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. RESULTS: Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor-recipient Cytomegalovirus mismatch was the only variable associated with serious infection. CONCLUSION: This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10-year postrandomization follow-up study.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).

Anti-alpha-actinin antibodies are part of the anti-cell membrane antibody spectrum that characterize patients with lupus nephritis.

Anti-membrane autoantibodies (MbA) have been reported in sera from patients with lupus nephritis (LN) but the targets of the MbA remain to be explored, which is the aim of the current study. Sera were collected from 40 patients with LN determined by renal biopsy, and from 30 systemic lupus erythematosus (SLE) patients without clinical evidence of LN. Thirty autoimmune disease control patients (rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis), and 30 healthy controls were also included. Using flow cytometry, the presence of anti-MbA was explored revealing that IgG anti-MbA positivity was associated with LN (62.5% vs 13.3%) when compared to non-LN SLE patients, autoimmune disease patients (6.7%) and healthy controls (0%). Next, using purified plasma membrane fractions from human embryonic kidney (HEK) cells, the more prominent targets and their occurrence rates were located at 50 kDa, 60/65 kDa, 90 kDa, 110 kDa, 180 kDa and 220 kDa. Alpha-actinin (110 kDa) autoAb was characterized as a major target in LN patients positive for anti-MbA, and anti-MbA binding activity was reduced (36.9 ± 13.7%) in the presence of α-actinin. Laminin (200 kDa) was also characterized as a minor target, which was not the case for annexin A2 (36 kDa). Finally, anti-MbA IgG subclass analysis indicated a predominance of IgG2. In conclusion, IgG anti-MbA were detected at high levels in LN patients supporting a primary pathogenic role for anti-MbA and anti-MbA/α-actinin+ in LN that needs further research.

Genetics and pathogenesis of autosomal dominant polycystic kidney disease: 20 years on.

Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is characterized by the progressive development and expansion of bilateral fluid-filled cysts derived from the renal tubule epithelial cells. Although typically leading to end-stage renal disease in late middle age, ADPKD represents a continuum, from neonates with hugely enlarged cystic kidneys to cases with adequate kidney function into old age. Since the identification of the first causative gene (i.e., PKD1, encoding polycystin 1) 20 years ago, genetic studies have uncovered a large part of the key factors that underlie the phenotype variability. Here, we provide a comprehensive review of these significant advances as well as those related to disease pathogenesis models, including mutation analysis of PKD1 and PKD2 (encoding polycystin 2), current mutation detection rate, allelic heterogeneity, genotype and phenotype relationships (in terms of three different inheritance patterns: classical autosomal dominant inheritance, complex inheritance, and somatic and germline mosaicism), modifier genes, the role of second somatic mutation hit in renal cystogenesis, and findings from mouse models of polycystic kidney disease. Based upon a combined consideration of the current knowledge, we attempted to propose a unifying framework for explaining the phenotype variability in ADPKD.