RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD): a review on the clinical manifestations and therapeutic options.

BACKGROUND: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated Autosomal Dominant Kidney Hypomagnesemia with Cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mTORC1 pathway. This disruption hinders the the nuclear translocation and transcriptional activity of the transcription factor EB (TFEB) a crucial regulator of lysosomal and autophagic function. SUMMARY: All identified RRAGD variants compromise kidney function, leading to hypomagnesemia and hypokalemia of various severity. The renal phenotype for most of the variants (i.e. S76L, I221K, P119R, P119L), typically manifests in the second decade of life occasionally preceded by childhood symptoms of dilated cardiomyopathy. In contrast, the P88L variant is associated to dilated cardiomyopathy manifesting in adulthood. To date, the T97P variant has not been linked to cardiac involvement. The most severe manifestations of ADKH-RRAGD, particularly concerning electrolyte imbalance and heart dysfunction requiring transplantation in childhood appear to be associated with the S76L, I221K, P119R variants. KEY MESSAGES: This review aims to provide an overview of the clinical presentation for ADKH-RRAGD, aiming to enhance o awareness, promote early diagnosis and facilitate proper treatment. It also reports on the limited experience in patient management with diuretics, magnesium and potassium supplements, metformin, or calcineurin- and SGLT2-inhibitors.

[Non-pharmacological prevention of chronic kidney disease]. / Prévention non médicamenteuse de la maladie rénale chronique.

Preventing chronic kidney disease (CKD) is a major public health objective. CKD leads to significant cardiovascular morbidity and mortality, with a negative impact on quality of life and significant societal repercussions. Several drugs are effective in preventing and curbing CKD, including blockers of the renin/angiotensin/aldosterone system and inhibitors of the SGLT2 co-transporter. New molecules are currently in clinical trials focusing on the nephro-protection, such as non-steroidal mineralocorticoid receptor antagonists and GPL-1 receptor agonists. In addition to this drug arsenal, CKD prevention also relies on non-pharmacological optimization of hygienic-dietary measures, including smoking avoidance, physical activity and dietetics. The aim of this article is to detail this non-medicinal approach to the prevention and slow down of CKD.

La prévention de la maladie rénale chronique (MRC) est un objectif majeur de santé publique. La MRC engendre, en effet, une morbi-mortalité cardiovasculaire importante, avec un impact négatif sur la qualité de vie et des répercussions sociétales non négligeables. Plusieurs piliers médicamenteux sont efficaces dans la prévention et la freination de la MRC, tels que les bloqueurs du système rénine/angiotensine/aldostérone et les inhibiteurs du co-transporteur SGLT2. De nouvelles molécules sont en cours d'essais cliniques visant la néphro-protection, comme les antagonistes non stéroïdiens du récepteur aux minéralocorticoïdes et les agonistes du récepteur au GPL-1. Outre cet arsenal médicamenteux, la prévention de la MRC repose également sur une optimisation non pharmacologique des mesures hygiéno-diététiques, comprenant l'éviction tabagique, l'activité physique et la diététique. L'objectif de cet article est de détailler cette approche non médicamenteuse dans la prévention et la freination de la MRC.

[Prevention of preeclampsia and its complications]. / Prévention de la prééclampsie et de ses complications.

Preeclampsia is a pregnancy-specific condition characterized by gestational hypertension associated with proteinuria or organ dysfunction after 20 weeks of gestation. It complicates 2 to 8 % of pregnancies worldwide and represents the leading cause of maternal and fetal mortality in developed countries. The only definitive treatment remains termination of pregnancy and delivery of the placenta. Prompt assessment of maternal and fetal status should be held in search of severity criteria and adequate management of this condition according to gestational age. Foremost concerns for pregnant patients are impending eclampsia or placental abruption, while fetal complications arise from placental insufficiency and risks associated with premature pregnancy termination. The sole efficient prophylaxis of preeclampsia in current state of evidence is aspirin at a dosage of 160 mg per day in high risk patients. Preeclampsia is now recognized as a high-risk factor for cardiovascular, renal, and neurological diseases and should therefore be considered as an opportunity for screening and prevention.

La prééclampsie (PE) est un syndrome unique à la grossesse défini par une hypertension artérielle gravidique, associée à une protéinurie ou une atteinte d'organe après 20 semaines d'aménorrhée. Elle complique 2 à 8 % des grossesses à l'échelle mondiale, et représente la première cause de mortalité maternelle et fœtale dans les pays industrialisés. Le seul traitement curatif demeure l'arrêt de la grossesse et la délivrance du placenta. Cette pathologie justifie une évaluation rapide de l'état maternel et fœtal, afin de juger des critères de sévérité et d'orienter la prise en charge selon le terme de la grossesse. La menace maternelle est dominée par le risque de survenue d'une éclampsie ou d'un hématome rétroplacentaire alors que les complications fœtales découlent de l'insuffisance placentaire et des risques inhérents à un arrêt prématuré de grossesse. Le seul traitement préventif actuellement validé en prévention secondaire chez les patientes à haut risque est l'aspirine à une dose de 160 mg par jour. La PE est désormais reconnue comme un facteur de risque cardiovasculaire, rénal et neurologique, et doit être considérée, de ce fait, comme une opportunité de dépistage et de prévention.

[Prevention of contrast-induced nephropathy]. / Prévention de la néphropathie aux produits de contraste iodés.

Contrast-induced nephropathy (CIN) is a renal complication occurring after the administration of iodinated contrast agents routinely used in medical imaging. CIN causes acute renal failure of varying severity. The pathophysiology of CIN is probably multifactorial: it involves (i) renal vasoconstriction inducing tissue hypoxia, and (ii) a possible direct toxicity of iodine derivatives leading to tubular inflammation and necrosis. Several risk factors are associated with CIN, some related to the procedure itself, others to the patient's co-morbid profile. In particular, the pre-existence of chronic renal failure, dehydration, congestive heart failure, diabetes or hypotension has been associated with an increased risk of CIN, as summarized in the Mehran score. Prevention of CIN relies essentially on adequate i.v. hydration before and after the procedure, and on the administration of the lowest possible volumes of contrast. In patients at high risk of CIN, the use of metformin and non-steroidal anti-inflammatory drugs is contraindicated at the time of contrast medium i.v. injection. In these patients, renal function assessment after 3-7 days post imaging is required.

La néphropathie aux produits de contraste iodés (NPCI) est une complication rénale survenant après l'administration de certains agents de contraste utilisés en imagerie médicale. La NPCI cause une insuffisance rénale aiguë de gravité variable. La physiopathologie de la NPCI est probablement multifactorielle : elle implique (i) une vasoconstriction rénale induisant une hypoxie tissulaire et (ii) une possible toxicité directe des dérivés iodés entraînant inflammation et nécrose tubulaire. Plusieurs facteurs de risque sont associés à la NPCI, liés tantôt à la procédure elle-même, tantôt aux comorbidités du patient. La préexistence d'une insuffisance rénale chronique, d'une déshydratation, d'une insuffisance cardiaque congestive, d'un diabète ou d'une hypotension artérielle a, notamment, été associée à un risque accru de NPCI, tel que résumé dans le score de Mehran. La prévention de la NPCI repose essentiellement sur une hydratation i.v. adéquate avant et après la procédure, ainsi que sur l'administration de volumes de contraste aussi faibles que possible. Chez les patients à haut risque de NPCI, l'utilisation de metformine et/ou d'anti-inflammatoires non stéroïdiens concomitante à l'injection de PCI est formellement contre-indiquée, et la vérification de la fonction rénale à J3-J7 après l'examen radiologique est requise.

[Diagnostic approach to rhabdomyolysis]. / Vignette diagnostique de l'étudiant. Approche diagnostique de la rhabdomyolyse.

Rhabdomyolysis is a clinical syndrome related to the damage of skeletal muscle. The symptomatology is often poor, but it classically includes muscle weakness, myalgia and red-brown urine. The causes may be multiple but are most frequently traumatic : the so-called "crush syndrome". The diagnosis is based on the increase in serum creatine kinase, which is sometimes associated with myoglobinuria. Rhabdomyolysis may cause severe complications, such as ionic disorders or acute kidney injury which can lead to the death of the patient.

La rhabdomyolyse est un syndrome clinique lié à la destruction du muscle squelettique. La symptomatologie est souvent pauvre et associe classiquement une faiblesse musculaire, des myalgies et des urines noirâtres. Les causes peuvent être multiples, mais sont le plus fréquemment traumatiques et regroupées sous le terme anglophone de «crush syndrome¼. Le diagnostic repose sur la majoration sérique de la créatine kinase, à laquelle s'associe parfois une myoglobinurie. Rarement bénigne, la rhabdomyolyse peut engendrer des complications sévères, telles que des troubles ioniques ou une insuffisance rénale pouvant mener au décès du patient.

[Multifocal tuberculosis despite immunocompetence]. / Tuberculose multifocale en dépit d'une immunocompétence.

Tuberculosis is one of the deadliest infectious disease. Its annual incidence was 10 million cases in 2019. We report the case of a 40 years old immunocompetent patient presenting with two large subcutaneous masses in his back. The diagnosis work-up will reveal multifocal tuberculosis with pulmmonary, vertebral, muscular and lymph node lesions. This case is unusual due to its presentation in an immunocompetent patient. Several laboratories have conducted experiments to isolate characteristics of the host that would allow the infection to spread despite the absence of an immunosuppressive medical condition. We also analyze the role of the PET scanner in the initial assessment and its interest in the monitoring of extra-pulmonary disease under anti-tuberculosis treatment. Multifocal tuberculosis cases are no longer the preserve of the immunocompromised and can be found in our industrialized countries. We must enonciate this diagnosis in front of unusual presentations. The delay in consultation, but also the delay of treatment, allows more widespread infections.

La tuberculose est une des maladies infectieuses les plus mortelles. Son incidence annuelle était de 10 millions de cas en 2019. Nous rapportons le cas d'un patient immunocompétent de 40 ans qui se présente avec deux volumineuses masses sous-cutanées au niveau du dos. La mise au point révélera une tuberculose multifocale avec une atteinte pulmonaire, vertébrale, ganglionnaire et des collections abcédées musculaires plurifocales. Ce cas est atypique de par sa présentation chez un patient immunocompétent. Plusieurs laboratoires ont essayé d'isoler des caractéristiques de l'hôte qui permettraient à l'infection une extension disséminée malgré l'absence de condition médicale immunodépressive. Nous analysons également le rôle du PET scanner dans le bilan initial et son intérêt dans le suivi des foyers extra-pulmonaires sous traitement anti-tuberculeux. Les cas de tuberculose multifocale ne sont plus l'apanage des patients immunodéprimés et peuvent se rencontrer dans les pays industrialisés. Le diagnostic doit pouvoir être évoqué devant des présentations atypiques. Le retard du diagnostic et de la prise en charge thérapeutique favorise des infections plus étendues.

[Renal manifestations of syphilis]. / Manifestations rénales de la syphilis.

Syphilis is an acquired or congenital systemic pathology, currently on the rise in Europe. The clinical manifestations of syphilis are not very specific and variable over time. In this case report, we describe two renal presentations of syphilis in patients followed in a Pre-Exposure Prophylaxis (PrEP) program for the prevention of HIV infection. The specificity of the renal involvement of syphilis, the diagnostic and the therapeutic management will be discussed in this article.

La syphilis est une pathologie systémique acquise ou congénitale, actuellement en recrudescence en Europe. Les manifestations cliniques de la syphilis sont souvent peu spécifiques et variables au cours du temps. Nous décrivons ici deux présentations rénales de la syphilis survenues chez des patients suivis dans un programme de Pre-Exposure Prophylaxis (PrEP) de prévention contre l'infection VIH. La spécificité de l'atteinte rénale de la syphilis, la mise au point diagnostique et la prise en charge thérapeutique seront discutées dans cet article.

[Pneumococcal vaccination among at-risk groups with comorbidities : guidelines from the "Belgian Superior Health Council" and reimbursement criteria]. / Vaccination antipneumococcique dans les groupes à risque avec comorbidités : recommandations du Conseil Supérieur de la Santé et critères de remboursement.

Streptococcus pneumoniae infections cause community-acquired pneumonia and invasive pneumococcal disease such as sepsis and acute meningitis. In the adult population, the risk of severe infections, which can be lethal, is particularly high among people aged above 65 years and subgroups with comorbidities. Pneumococcal vaccines underwent progressive improvement and a new conjugated vaccine targeting 20 serotypes (PCV20) is now available. The Belgian Superior Health Council has recently reiterated the importance of vaccinating at-risk individuals against S. pneumoniae and now recommends vaccination with PCV20 (Apexxnar®) as the preferred primary vaccination regimen in all at-risk adults. The present article reminds the risk of severe pneumococcal infections among patients with comorbidities, by targeting five of them, chronic respiratory diseases, heart failure, chronic kidney disease, diabetes mellitus and cirrhosis. It emphasizes the too low rate of pneumococcal vaccination in these at-risk subgroups and summarizes the last guidelines of the Belgian Superior Health Council in favor of pneumococcal vaccination in at-risk patients with comorbidities. Finally, it describes the Belgian reimbursement criteria recently granted to people aged 65-85 years with comorbidities.

Les infections par le Streptococcus pneumoniae sont responsables de pneumonies communautaires et de maladies invasives à pneumocoques telles que sepsis et méningites aiguës. Dans la population adulte, le risque d'infections graves, potentiellement léthales, est particulièrement élevé chez les personnes âgées de plus de 65 ans et parmi des sous-groupes avec comorbidités. Les vaccins antipneumococciques ont été progressivement améliorés et un nouveau vaccin conjugué ciblant 20 sérotypes (PCV20) est désormais disponible. Le Conseil Supérieur de la Santé (CSS) belge a rappelé, en 2022, l'importance de vacciner contre S. pneumoniae les personnes à risque et privilégie le PCV20 (Apexxnar®) pour la primo-vaccination chez les personnes adultes dans tous les groupes à risque. Cet article rappelle le risque d'infections pneumococciques graves chez les patients avec comorbidités, en ciblant plus particulièrement quatre d'entre elles, les maladies respiratoires chroniques, l'insuffisance cardiaque, la maladie rénale chronique, le diabète sucré et la cirrhose. Il insiste sur le trop faible taux de vaccination antipneumococcique dans ces populations à risque et résume les dernières recommandations du CSS en faveur de la vaccination antipneumococcique des groupes à risque en fonction de la présence de comorbidités. Enfin, il fait état des conditions de remboursement récemment accordées à la vaccination antipneumococcique dans les groupes à risque chez les personnes âgées de 65 à 85 ans.

[Delayed graft function : an ongoing clinical challenge]. / Reprise retardée de fonction du greffon après transplantation rénale : un challenge clinique toujours d'actualité.

Delayed Graft Function (DGF) is defined as the need for dialysis during the first week after transplantation. DGF is frequent and mostly derived from the ischemia/reperfusion cascade to which the graft is subjected throughout the transplantation process. A graft biopsy is recommended after 7 days of DGF to exclude an episode of acute rejection. Note that DGF per se is associated with an increased risk of acute graft rejection, as well as with a shorter long-term graft survival. Several strategies are being studied to mitigate the ischaemic damage, thereby improving graft quality. Among these, cellular therapy using mesenchymal stromal cells (MSC) is promising, in particular via the administration of MSC in the machine perfusion during the preservation of the graft. We will discuss here the different definitions of DGF and the main predictive factors of DGF, as well as the impact on the graft outcomes. The current strategies to prevent DGF will be briefly reviewed.

La reprise retardée de fonction du greffon rénal (DGF en anglais pour Delayed Graft Function), définie notamment par la nécessité de dialyse durant la 1ère semaine après transplantation, reste un événement fréquent. La DGF résulte principalement des phénomènes d'ischémie/reperfusion auxquels le greffon est soumis tout au long du processus de transplantation. Néanmoins, une biopsie du greffon est préconisée après 7 jours de DGF afin d'exclure une cause non ischémique telle qu'un rejet aigu. La DGF est per se associée à un risque accru de rejet du greffon, ainsi qu'à une moins bonne survie du greffon rénal au long cours. Plusieurs stratégies sont étudiées afin d'atténuer les dommages ischémiques et améliorer la qualité du greffon. Parmi celles-ci, la thérapie cellulaire par cellules stromales mésenchymateuses est prometteuse, notamment via l'administration de celles-ci dans la machine de perfusion lors de la préservation du greffon. Nous aborderons les différentes définitions de la DGF ainsi que ses principaux facteurs prédictifs, l'impact sur le devenir du greffon et, brièvement, les stratégies actuelles dans le cadre de la prévention de la DGF.

Kidney-targeted irradiation triggers renal ischemic preconditioning in mice.

Renal ischemia-reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5 Gy) was done in male 8- to 12-wk-old C57bl/6 mice using a small animal radiation therapy device. Left renal I/R was performed by clamping the renal pedicles for 30 min, with simultaneous right nephrectomy, at 7, 14, and 28 days postirradiation. The renal reperfusion lasted 48 h. Following I/R, blood urea nitrogen (BUN) and serum creatinine (SCr) levels were lower in preirradiated mice compared with controls; so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in preirradiated mice. The numbers of proliferating cell nuclear antigen (PCNA)-, cluster of differentiation molecule 11b (CD11b)-, and cell surface glycoprotein F4/80-positive cells in the renal parenchyma post-I/R were reduced in preirradiated versus control groups. Such IPC was significantly observed as early as day 14 postirradiation. RNA sequencing showed an upregulation of angiogenesis- and stress response-related signaling pathways in irradiated nonischemic kidneys on day 28. Qualitative RT-PCR confirmed the increased expression of vascular endothelial growth factor (VEGF), activin receptor-like kinase 5 (ALK5), heme oxygenase-1 (HO1), platelet endothelial cell adhesion molecule-1 (PECAM1), NADPH oxidase 2 (NOX2), and heat shock proteins 70 and 27 (HSP70 and HSP27, respectively) in irradiated kidneys compared with controls. In addition, irradiated kidneys showed an increased CD31-positive vascular area compared with controls. A 14-day gavage of irradiated mice with the antiangiogenic drug sunitinib before I/R abrogated the irradiation-induced IPC at both functional and structural levels. Our observations suggest that kidney-centered irradiation activates proangiogenic pathways and induces IPC, with preserved renal function and attenuated inflammation post-I/R.NEW & NOTEWORTHY This study based on a mouse model of renal ischemia-reperfusion (I/R) aimed to 1) test whether and how irradiation strictly centered on the kidney protects against the I/R injury and 2) determine the shortest efficient delay of kidney irradiation to achieve such nephroprotection. Kidney irradiation increased the vascular surface in the renal parenchyma and conferred resistance against renal I/R damage, which highlights novel putative strategies in the field of ischemic acute kidney injury.

Infusion of Allogeneic Mesenchymal Stromal Cells After Liver Transplantation: A 5-Year Follow-Up.

Various properties of mesenchymal stromal cells (MSCs) might be particularly of interest after liver transplantation (LT). In this article, we report the long-term results of a prospective, controlled, and first-in-human phase 1 study evaluating the safety of a single MSC infusion after LT. A total of 10 LT recipients treated with standard immunosuppression received 1.5 to 3 × 106 /kg third-party unrelated MSCs on postoperative day 3 and were prospectively compared with a control group of 10 LT recipients. Primary endpoints were set to prospectively detect potentially delayed adverse effects of MSC infusion, particularly the occurrence of infections and cancers. Secondary endpoints of liver graft and patient survival, graft rejection and function, occurrence of bile duct complications, and development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) against liver or MSC donors were studied. The median follow-up was 85 months. There was no difference in overall rates of infection or cancer at 5 years of follow-up between the 2 groups. There was also no difference in secondary endpoints. The prevalence of de novo liver DSAs related to HLA mismatches was twice as high in the MSC group compared with the control group. All of the de novo class II HLA antibodies against MSCs were linked to a shared HLA mismatch between the liver and MSCs. This study confirms the safety of a single MSC infusion after LT. The potential benefits of MSC injections in the context of organ transplantation have yet to be demonstrated by larger prospective studies. The development of anti-HLA antibodies against an MSC donor should be further evaluated, especially in cases of shared HLA mismatches between graft and MSC donors, despite the fact that no deleterious effect has been detected.

Estimating urine albumin to creatinine ratio from protein to creatinine ratio using same day measurement: validation of equations.

OBJECTIVES: Severity of chronic kidney disease is defined by glomerular filtration rate (GFR) and albuminuria (ACR) by the KDIGO and are related to cardiovascular outcomes and end-stage-kidney-failure. However, proteinuria (PCR) is more often available than ACR in records. Recently, equations were developed to estimate ACR from PCR. We investigated their performances in our population. METHODS: In the academic medical hospital of Liège, we retrospectively analysed same day measurement of ACR and PCR and staged them according to the KDIGO A1-A2-A3 categories. Analyser Roche Cobas (R) gathered 2,633 urinalysis (May 2018-May 2019) and analyser Abbott Alinity (A) 2,386 urinalysis (May 2019-March 2020). We compared the KDIGO staging of mACR and eACR obtained from Weaver's and Sumida's equations. RESULTS: Median age was 63 [52;71]/64 [53;72] years old, 43/42% were female; 78/74% had diabetes; proportion of mACR-A1 was 65.6%/64.2%, A2 was 25.5%/25.5% and A3 was 8.8%/10.3% (Method R/A, respectively). Both equations gave similar distribution of KDIGO staging of eACR. Overall agreements were higher than 88% regardless of the analyser or of the equation. Performances in between equations were equivalent according to the multi-level AUC (multinomial logistic regression model). CONCLUSIONS: Good concordance was observed between mACR and eACR regardless of the equation or of the analyser. No patient with an A3-measured ACR was estimated within the KDIGO A1 category. Though ACR should be measured when clinically needed, it may be reasonably estimated from the PCR through these equations, for epidemiologic retrospective studies or research purposes.

Is autosomal dominant polycystic kidney disease an early sweet disease?

The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD. Moreover, defective glucose metabolism and metabolic reprogramming have been reported in distinct ADPKD models highlighting these pathways as potential therapeutic targets in ADPKD. Several "metabolic" approaches are currently under evaluation in adults, including ketogenic diet, food restriction, and metformin therapy. No data are available on the impact of these approaches in childhood thus far. Yet, according to World Health Organization (WHO), we are currently facing a childhood obesity crisis with an increased prevalence of overweight/obesity in the pediatric population associated with a cardio-metabolic risk profile. The present review summarizes the knowledge about the role of glucose metabolism in the pathophysiology of ADPKD and underscores the possible harm of overweight and obesity in ADPKD especially in terms of long-term cardiovascular outcomes and renal prognosis.

mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy.

BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

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.

The use of a visual 4-point scoring scale improves the yield of 18F-FDG PET-CT imaging in the diagnosis of renal and hepatic cyst infection in patients with autosomal dominant polycystic kidney disease.

PURPOSE: [18F]FDG PET/CT (PET/CT) proved useful in the diagnosis of renal and hepatic cyst infection (CyI) in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the definition of CyI by PET/CT is unclear. Here, we characterize the [18F]FDG uptake in CyI in order to infer a visual 4-point diagnostic scale. METHODS: All ADPKD patients hospitalized between 2007 and 2019 for suspected CyI and who underwent an [18F]FDG PET/CT scan were listed. CyI was defined by 5 concomitant criteria: fever ≥ 38 °C; abdominal pain; peak plasma CRP ≥ 70 mg/L; no other cause of inflammation; and favorable outcomes after antibiotics for ≥ 21 days. First, all PET/CT images were visually interpreted. Next, the [18F]FDG uptake around the suspected CyI was scored using a semiquantitative 4-point scale in comparison to blood and liver activities. RESULTS: Sixty [18F]FDG PET/CT scans were performed for suspected CyI in 38 ADPKD patients. Twenty-nine episodes met the gold-standard criteria for CyI. The visual assessment of PET/CT images reached a sensitivity of 73.1% and a specificity of 70.6%. Using the 4-point scale, an [18F]FDG score ≥ 3 (i.e., cyst uptake > liver) improved the specificity to 85.3%. CONCLUSION: [18F]FDG PET-CT is helpful in CyI diagnosis in ADPKD, and the use of a 4-point scoring of [18F]FDG uptake improves its diagnostic yield, with positive and negative predictive values of 78.3 and 78.4%, respectively. External validation is required.

[18F]FDG PET/CT imaging disproves renal allograft acute rejection in kidney transplant recipients with acute kidney dysfunction: a validation cohort.

PURPOSE: [18F]FDG PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. METHODS: We prospectively performed 86 [18F]FDG PET/CT in 79 adult KTRs who underwent per-cause transplant biopsy for suspected AR. Biopsy-proven polyoma BK nephropathies (n = 7) were excluded. PET/CT was performed 192 ± 18 min after administration of 254.4 ± 30.4 MBq of [18F]FDG. The SUVmean was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey's studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate "AR" from non-pathological ("normal" + "borderline") conditions. RESULTS: The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m2. Biopsies were categorized in 4 groups: "normal" (n = 54), "borderline" (n = 9), "AR" (n = 14), or "others" (n = 2). The median [min; max] mSUVmean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12], and 1.84 [1.57; 2.12] in "normal," "borderline," "AR," and "others" groups, respectively. ANOVA demonstrated a significant difference of mSUVmean among groups (F = 13.25, p < 0.0001). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively. CONCLUSION: [18F]FDG PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.

Mechanisms involved in AMPK-mediated deposition of tight junction components to the plasma membrane.

AMP-activated protein kinase (AMPK) activation promotes early stages of epithelial junction assembly. AMPK activation in MDCK renal epithelial cells facilitates localization of the junction-associated proteins aPKCζ and Par3 to the plasma membrane and promotes conversion of Cdc42, a key regulator of epithelial polarization and junction assembly, to its active GTP bound state. Furthermore, Par3 is an important regulator of AMPK-mediated aPKCζ localization. Both aPKCζ and Par3 serve as intermediates in AMPK-mediated junction assembly, with inhibition of aPKCζ activity or Par3 knockdown disrupting AMPK's ability to facilitate zonula occludens (ZO-1) localization. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the tight-junction protein zonula occludens-1. Afadin is phosphorylated at two critical sites, S228 (residing within an aPKCζ consensus site) and S1102 (residing within an AMPK consensus site), that are differentially regulated during junction assembly and that exert different effects on the process. Expression of phospho-defective mutants (S228A and S1102A) perturbed ZO-1 localization to the plasma membrane during AMPK-induced junction assembly. Expression of S228A increased the ZO-1/afadin interaction, while S1102A reduced this interaction during extracellular calcium-induced junction assembly. Inhibition of aPKCζ activity also increased the ZO-1/afadin interaction. Taken together, these data suggest that aPKCζ phosphorylation of afadin terminates the ZO-1/afadin interaction and thus permits the later stages of junction assembly.

Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-ß-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

Diagnostic yield of 18 F-FDG PET/CT imaging and urinary CXCL9/creatinine levels in kidney allograft subclinical rejection.

Subclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient." SCR detection relies on surveillance biopsy. Noninvasive approaches may help avoid biopsy-associated complications. From November 2015 to January 2018, we prospectively performed positron emission tomography/computed tomography (PET/CT) after injection of F18 -fluorodeoxyglucose (18 F-FDG) in adult kidney transplant recipients with surveillance biopsy at ~3 months posttransplantation. The Banff-2017 classification was used. The ratio of the mean standard uptake value (mSUVR) between kidney cortex and psoas muscle was measured. Urinary levels of CXCL-9 were concomitantly quantified. Our 92-patient cohort was categorized upon histology: normal (n = 70), borderline (n = 16), and SCR (n = 6). No clinical or biological difference was observed between groups. The mSUVR reached 1.87 ± 0.55, 1.94 ± 0.35, and 2.41 ± 0.54 in normal, borderline, and SCR groups, respectively. A significant difference in mSUVR was found among groups. Furthermore, mSUVR was significantly higher in the SCR vs normal group. The area under the receiver operating characteristic curve (AUC) was 0.79, with 83% sensitivity using an mSUVR threshold of 2.4. The AUC of urinary CXCL-9/creatinine ratios comparatively reached 0.79. The mSUVR positively correlated with ti and acute composite Banff scores. 18 F-FDG-PET/CT helps noninvasively exclude SCR, with a negative predictive value of 98%. External validations are required.