The renal inflammatory network of nephronophthisis.

Renal ciliopathies are the leading cause of inherited kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), mutations in the ciliary gene PKD1 lead to the induction of CCL2, which promotes macrophage infiltration in the kidney. Whether or not mutations in genes involved in other renal ciliopathies also lead to immune cells recruitment is controversial. Through the parallel analysis of patients' derived material and murine models, we investigated the inflammatory components of nephronophthisis (NPH), a rare renal ciliopathy affecting children and adults. Our results show that NPH mutations lead to kidney infiltration by neutrophils, macrophages and T cells. Contrary to ADPKD, this immune cell recruitment does not rely on the induction of CCL2 in mutated cells, which is dispensable for disease progression. Through an unbiased approach, we identified a set of inflammatory cytokines that are upregulated precociously and independently of CCL2 in murine models of NPH. The majority of these transcripts is also upregulated in NPH patient renal cells at a level exceeding those found in common non-immune chronic kidney diseases. This study reveals that inflammation is a central aspect in NPH and delineates a specific set of inflammatory mediators that likely regulates immune cell recruitment in response to NPH genes mutations.

Outcome of pretransplant melanoma after solid organ transplantation: an observational study.

The number of patients with a history of melanoma who are awaiting a solid organ transplantation (SOT) is increasing. Few recommendations exist on the timing to transplantation after melanoma diagnosis. The aim of this study was to assess the melanoma recurrence-free survival after pretransplant melanoma (PTM). We conducted a multicenter ambispective observational study. Organ transplant recipients (OTR) with a history of PTM and complete AJCC staging were included. Thirty-seven patients (predominantly men with a renal allograft) were included. Five melanomas were in situ, 21 stage IA, 4 stage IB, 5 stage II, and 2 stage IIIB. The median post-transplantation follow-up time was 4 years. Sixty-two percent of patients were followed up more than 2 years. Recurrence-free survival since melanoma reached 89.9%, but varied significantly according to AJCC staging (P = 0.0129). Three patients presented a recurrence. Despite the rather limited sample size and a wide range of follow-up, our findings concerning the recurrence-free survival appear reassuring for in situ and stage IA PTM; accordingly, we suggest that a waiting time to transplantation is not mandatory in patients with in situ or stage IA PTM, especially whenever SOT is urgently needed. Caution is, however, needed for patients with higher stage.

Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression. METHOD: To explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines. RESULTS: Our findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. CONCLUSIONS: STAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

Osmoregulation Performance and Kidney Transplant Outcome.

BACKGROUND: Kidney transplant recipients have an impaired ability to dilute urine but seldom develop baseline hyponatremia before ESRD. Although hyponatremia is a risk factor for adverse events in CKD and in kidney transplant recipients, it remains unclear whether subtler alterations in osmoregulation performance are associated with outcome. METHODS: We studied a single-center prospective cohort of 1258 kidney transplant recipients who underwent a water-loading test 3 months after transplant to determine osmoregulation performance. Measured GFR (mGFR) was performed at the same visit. A group of 164 healthy candidates for kidney donation served as controls. We further evaluated the association of osmoregulation performance with transplantation outcomes and subsequent kidney function. RESULTS: Unlike controls, most kidney transplant recipients failed to maintain plasma sodium during water loading (plasma sodium slope of -0.6±0.4 mmol/L per hour in transplant recipients versus -0.12±0.3 mmol/L per hour in controls; P<0.001). Steeper plasma sodium reduction during the test independently associated with the composite outcome of all-cause mortality and allograft loss (hazard ratio [HR], 1.73 per 1 mmol/L per hour decrease in plasma sodium; 95% confidence interval [95% CI], 1.23 to 2.45; P=0.002) and allograft loss alone (HR, 2.04 per 1 mmol/L per hour decrease in plasma sodium; 95% CI, 1.19 to 3.51; P=0.01). The association remained significant in a prespecified sensitivity analysis excluding patients with hyperglycemia. In addition, a steeper plasma sodium slope 3 months after transplantation independently correlated with lower mGFR at 12 months (ß=1.93; 95% CI, 0.46 to 3.41; P=0.01). CONCLUSIONS: Reduced osmoregulation performance occurs frequently in kidney transplant recipients and is an independent predictor of renal outcome.

Decoupling shear stress and pressure effects in the biomechanics of autosomal dominant polycystic kidney disease using a perfused kidney-on-chip.

Kidney tubular cells are submitted to two distinct mechanical forces generated by the urine flow: shear stress and hydrostatic pressure. In addition, the mechanical properties of the surrounding extracellular matrix modulate tubule deformation under constraints. These mechanical factors likely play a role in the pathophysiology of kidney diseases as exemplified by autosomal dominant polycystic kidney disease, in which pressure, flow and matrix stiffness have been proposed to modulate the cystic dilation of tubules with PKD1 mutations. The lack of in vitro systems recapitulating the mechanical environment of kidney tubules impedes our ability to dissect the role of these mechanical factors. Here we describe a perfused kidney-on-chip with tunable extracellular matrix mechanical properties and hydrodynamic constraints, that allows a decoupling of shear stress and flow. We used this system to dissect how these mechanical cues affect Pkd1 -/- tubule dilation. Our results show two distinct mechanisms leading to tubular dilation. For PCT cells (proximal tubule), overproliferation mechanically leads to tubular dilation, regardless of the mechanical context. For mIMCD-3 cells (collecting duct), tube dilation is associated with a squamous cell morphology but not with overproliferation and is highly sensitive to extracellular matrix properties and hydrodynamic constraints. Surprisingly, flow alone suppressed Pkd1 -/- mIMCD-3 tubule dilation observed in static conditions, while the addition of luminal pressure restored it. Our in vitro model emulating nephron geometrical and mechanical organization sheds light on the roles of mechanical constraints in ADPKD and demonstrates the importance of controlling intraluminal pressure in kidney tubule models.