Asymptomatic circulating T-cell clone cause renal polymorphic inflammatory fibrosis.

BACKGROUND: Renal complications of non-Hodgkin lymphoma encompass a wide spectrum of monoclonal Ig-related pathologies. Clonal circulating T cells can also be associated with non-renal autoimmune disorders induced by overproduction of specific patterns of cytokines or unbalanced lymphocytes sub-populations. METHODS: Immunophenotyping of circulating T cells and TCR gene restriction analysis using Biomed-2 protocol. NF-κB staining and mRNA quantification of inflammatory genes in HK-2 epithelial renal cells exposed to supernatants of peripheral blood mononuclear cells with clonal T-cell population. RESULTS: Here, we could identify a persistent clonal T-cell population, only characterized by in-depth immunophenotyping of circulating lymphocytes and using multiplex PCR analysis of TCR gene rearrangements, in two patients with polymorphic inflammatory renal fibrosis of unknown origin. Using an in vitro approach, we could demonstrate that peripheral blood mononuclear cells including the clonal population can trigger a phenotype switch of epithelial renal cells from a quiescent state to a pro-inflammatory state characterized by NF-κB nuclear translocation and overexpression of inflammatory cytokine or chemokine. CONCLUSION: These preliminary data suggest that circulating T-cell clones may directly activate epithelial renal cells or promote a T-/B-cell population with autoimmune reactive properties against kidney cells, which, in the absence of overt renal lymphoma infiltration, lead to the subsequent inflammatory renal fibrotic phenotype.

Rituximab-cyclophosphamide-dexamethasone is highly effective in patients with monoclonal Ig deposit-related glomerulopathy and indolent non-Hodgkin lymphomas.

Indolent non-hodgkin lymphomas (iNHL) are a rare cause of monoclonal immunoglobulin deposits-related glomerulopathy (mIgGN). In patients with iNHL-related mIgGN, whether treatment should include either single or a combination of drug(s) to target the malignant clone and renal inflammation remains elusive. In this retrospective study, we report a cohort of 14 patients with iNHL-related mIgGN (cryoglobulinemic glomerulonephritis [n = 5], membranous nephropathy [n = 3], membranoproliferative glomerulonephritis [n = 3], AL or AL/AH amyloidosis [n = 2], and Light Chain Deposits Disease [n = 1]) and who received a treatment combining rituximab, cyclophosphamide, and dexamethasone (RCD). After a mean follow-up of 18 ± 4 months, nine patients (63%) had complete haematological response. Renal response was observed in 12 of the 14 patients (86%; complete response: n = 9; partial: n = 3). Estimated glomerular filtration rate increased from 47 ± 7 to 63 ± 8 mL/min/1.73 m(2) , and proteinuria decreased from 6.5 ± 0.7 to 1.4 ± 0.8 g/24 hr at one year. Following hematological relapse, renal relapse occurred in two patients suggesting sustained clonal eradication offers the best renal protection. Tolerance of RCD was good and the most frequent adverse event was pneumonia (3/14, 21%). RCD is a promising regimen for patients with iNHL and mIgGN, irrespective of glomerular pathologic pattern. Whether steroids can be avoided or minimized remains to be addressed.

Abcc6 deficiency prevents rhabdomyolysis-induced acute kidney injury.

Rhabdomyolysis is a risk factor for acute kidney injury, transition towards chronic kidney disease, and death. The role of calcium phosphate deposits in the mechanisms of rhabdomyolysis-induced acute kidney injury (RAKI) is still unclear. Better insight of the role calcium in RAKI could lead to new therapeutic avenues. Here, we show in a mice model of RAKI that calcium phosphate deposits were frequent in the kidney (hydroxyapatite) and partly correlated with the severity of the kidney injury. However, the intensity of deposits was highly heterogeneous between mice. Treatment with sodium chloride, sodium bicarbonate or inorganic pyrophosphate (PPi; an inhibitor of the calcium phosphate crystallization), or combinations thereof, did not improve kidney outcomes and hydroxyapatite deposition during RAKI. Unexpectedly, Abcc6 knockout mice (ko), characterized by PPi deficiency, developed less severe RAKI despite similar rhabdomyolysis severity, and had similar hydroxyapatite deposition suggesting alternative mechanisms. This improved kidney outcome at day 2 translated to a trend in improved glomerular filtration rate at month 2 in Abcc6-/-mice and to significantly less interstitial fibrosis. In addition, whereas the pattern of infiltrating cells at day 2 was similar between wt and ko mice, kidneys of Abcc6-/- mice were characterized by more CD19+ B-cells, less CD3+ T-cells and a lower R1/R2 macrophage ratio at month 2. In summary, kidney calcium phosphate deposits are frequent in RAKI but hydration with sodium bicarbonate or sodium chloride does not modify the kidney outcome. Blocking ABCC6 emerges as a new option to prevent RAKI and subsequent transition toward kidney fibrosis.

Ibrutinib does not prevent kidney fibrosis following acute and chronic injury.

Recent studies suggested that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, developed for the treatment of chronic lymphocytic leukemia, may prevent NLRP3 inflammasome activation in macrophages, IL-1ß secretion and subsequent development of inflammation and organ fibrosis. The role of NLRP3 has been underlined in the various causes of acute kidney injury (AKI), a pathology characterized by high morbimortality and risk of transition toward chronic kidney disease (CKD). We therefore hypothesized that the BTK-inhibitor ibrutinib could be a candidate drug for AKI treatment. Here, we observed in both an AKI model (glycerol-induced rhabdomyolysis) and a model of rapidly progressive kidney fibrosis (unilateral ureteral obstruction), that ibrutinib did not prevent inflammatory cell recruitment in the kidney and fibrosis. Moreover, ibrutinib pre-exposure led to high mortality rate owing to severer rhabdomyolysis and AKI. In vitro, ibrutinib potentiated or had no effect on the secretion of IL-1ß by monocytes exposed to uromodulin or myoglobin, two danger-associated molecule patterns proteins involved in the AKI to CKD transition. According to these results, ibrutinib should not be considered a candidate drug for patients developing AKI.