Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.     

Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C^high monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis.     

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0–3 points), intermediate risk (4–6 points), and high risk (7–9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.     

Non-lethal Right Liver Atrophy After TIPS Occlusion in A Cirrhotic Patient: Introducing The Hepatic Biembolization

Background

Transjugular intrahepatic portosystemic shunt (TIPS) is the standard procedure in the treatment of refractory ascites and variceal bleeding in the setting of portal hypertension. Secondary obstruction of the shunt is a classic but potentially lethal complication.

Methods

We present here the case of a cirrhotic patient that underwent a TIPS for refractory ascites, with early complete thrombosis without lethal complication.

Results

Obstruction of the TIPS led to thrombosis of both the right hepatic and the right portal veins with progressive total atrophy of the right liver and marked hypertrophy of the left liver. Despite initial poor liver function, biological hepatic markers improved slowly until complete recovery.

Conclusion

Hence, we suggest the concept of combined right portal and hepatic vein embolization as a new procedure to induce partial liver hypertrophy before major liver resection, even in cirrhotic patients.

     

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long‐term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4‐Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft‐mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3‐dioxigenase were observed only in CTLA4‐Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long‐term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation.     

Management of Urinary Symptoms Associated with Fibroids

Uterine fibroids are the most common benign tumours in women of reproductive age. Fibroids are linked with a variety of lower urinary tract symptoms (LUTS). Direct pressure on the bladder, but also vascular, neurogenic and hormonal changes have been proposed as underlying pathophysiological mechanisms. There is conflicting evidence in the literature regarding the association between LUTS and fibroid volume and position. Conservative management with bladder retraining, supervised pelvic floor muscle training with or without drug therapy might be used as first line. In the presence of persistent symptoms, conventional urodynamics or ideally videourodynamics might be considered before more invasive treatment. Counselling of patients prior to uterine artery embolisation, myomectomy or hysterectomy could be challenging, as it is difficult to estimate the effect of fibroid reduction or removal on LUTS.     

Le paludisme dans l’Archipel des Comores : état des lieux en 2015 après quinze années de lutte

The four volcanic islands of the Comoros archipelago are an area of intense, stable and permanent malaria transmission, almost exclusively with Plasmodium falciparum. Our purpose is to describe the current situation on malaria in Mayotte and Comoros in 2015, after the implementation of various strategies of control during the past 15 years. In 2015, Mayotte is in the phase of elimination of malaria. In the three islands forming the Union of Comoros, the transmission is much lower in the islands of Anjouan (incidence of 0.02‰) and Moheli (incidence of 0.14‰), ranking the two islands in pre-elimination phase. Grande Comore (incidence of 3.68‰) remains in the control phase with not enough time to assess what the mass treatment campaign long-term effects might be. These strategies could be applied in other islands with endemic malaria and with limited population.