Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.

Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury.

Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is  recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus,  renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced.

The effects of modified versus unmodified wheat gluten administration in patients with celiac disease.

Celiac disease (CD) treatment requires a gluten-free diet (GFD), although alternative approaches have been proposed. Modification of gliadin peptides using microbial transglutaminase (mTG) inhibits their ability to induce immune response in vitro. Our aim was to evaluate the safety of mTG-modified wheat flour ingestion in CD patients. Twenty-one CD patients in remission were randomized to receive mTG-modified (n=11) or unmodified (n=10) wheat flour rusks, in double-blind fashion. Monthly, patients completed a symptom questionnaire. Serum anti-tTG, EMA and creatinine levels were monitored. At baseline and after 90days, serum anti-actin antibodies (AAA) were measured and upper endoscopy was performed. Data were analyzed by non-parametric tests. 7/11 patients eating modified rusks and 7/10 patients receiving unmodified rusks completed the study. At baseline, all patients showed negative serum anti-tTG and EMA results. At the end, 2/7 (28.6%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented positive serum anti-tTG and EMA results. Creatinine results were unmodified. Moreover, 1/7 (14.3%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented villous atrophy. In patients who received unmodified rusks, the AAA levels increased significantly and duodenal anti-tTG levels appeared higher than those measured in patients who ate modified rusks. Abdominal swelling, bloating and nausea were more severe in patients ingesting unmodified rusks than those taking modified rusks. Our results may support larger clinical trials to confirm the enzymatic treatment of wheat flour as an alternative to GFD. Clinicaltrials.gov registration no: NCT02472119.

Identification of a serum transglutaminase threshold value for the noninvasive diagnosis of symptomatic adult celiac disease patients: a retrospective study.

BACKGROUND: A celiac disease (CD) diagnosis is based on duodenal histology, with the exception of children showing anti-tissue transglutaminase (anti-tTG) serum levels exceeding ten times the cut-off. Our aim was to reproduce this simplified approach in adults, identifying an anti-tTG threshold value useful to diagnose CD without endoscopic procedures. METHODS: A total of 671 adult CD patients were subjected to blood sampling to determine anti-tTG serum levels, as well as to endoscopy with biopsy to perform duodenal histology. The anti-tTG serum levels/cut-off ratio was compared with the degree of duodenal lesions. RESULTS: Anti-tTG serum levels/cut-off ratio determined in patients with type IIIc was significantly higher than that measured in patients with type IIIb (p < 0.001), IIIa (p < 0.001), II (p < 0.05) and 0 (p < 0.001) of Marsh-Oberhuber histological classification. A significant correlation (r = 0.297, p < 0.0001) was found between the anti-tTG serum levels/cut-off ratio and the degree of duodenal lesions. The anti-tTG serum levels/cut-off ratio was classified as an accurate parameter (AUC = 0.715, p < 0.0001), with the best diagnostic performance obtained considering the threshold value >3.6 (sensitivity = 76.8 %, PPV = 97.2 %). CONCLUSIONS: The anti-tTG serum levels/cut-off ratio correlates with the degree of duodenal lesions and, if used with the threshold value >3.6, could avoid endoscopy with biopsy in about 75 % of seropositive adults waiting for CD diagnosis. However, since this procedure could also imply CD diagnosis in almost 3 % of seropositive patients with normal villous architecture, a consensus opinion is needed to suggest its use in the diagnosis of adult CD.

Podocyte Regeneration Driven by Renal Progenitors Determines Glomerular Disease Remission and Can Be Pharmacologically Enhanced.

Podocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes. When the same model was established in inducible transgenic mice where renal progenitors are tagged, the disease remitted if renal progenitors successfully differentiated into podocytes, while it persisted if differentiation was ineffective, resulting in glomerulosclerosis. Treatment with BIO, a GSK3s inhibitor, significantly increased disease remission by enhancing renal progenitor sensitivity to the differentiation effect of endogenous retinoic acid. These results establish renal progenitors as critical determinants of glomerular disease outcome and a pharmacological enhancement of their differentiation as a possible therapeutic strategy.