At least two cortical collecting duct (CCD) intercalated cell populations mediate HCO3- secretion and reabsorption. The present study examined the membrane location of intercalated cell Cl-/base exchange activity and the axial distribution of CCD intercalated cells. CCD were studied using in vitro microperfusion in CO2/HCO3(-)-containing solutions; intracellular pH was measured using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The A-type intercalated cell (A cell) and B-type intercalated cell (B cell) were identified functionally by the absence and presence of apical Cl-/HCO3- exchange activity, respectively. When a 0 mM Cl-, 0 mM HCO3- luminal solution was used, removal of Cl- from the peritubular solution caused intracellular alkalinization in all B cells. The alkalinization required neither extracellular Na+ nor changes in membrane potential. Peritubular 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) (10(-4) M) inhibited A cell but not B cell basolateral Cl-/base exchange activity. In comparison to studies performed with a 0 mM Cl- 0 mM HCO3- luminal solution, the use of a 0 mM Cl-, 25 mM HCO3- luminal solution inhibited both the identification and the magnitude of B cell basolateral Cl-/base exchange activity. When CCD from the inner and outer cortex were separately studied, only 7% of outer CCD intercalated cells were A cells, whereas 93% were B cells. In contrast, in the inner CCD, 58% of intercalated cells were A cells and 42% were B cells. Under stop-flow conditions, outer CCD alkalinized the luminal fluid, whereas inner CCD acidified the luminal fluid. These results indicate that all CCD intercalated cells possess basolateral Cl-/base exchange activity; however, A cell and B cell basolateral Cl-/base exchange activity differs, at least in terms of sensitivity to DIDS. Furthermore, there is axial heterogeneity in both intercalated cell type and function.
Objectives
The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyze the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICI) rechallenge.
Methods
We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analyzed in both groups. The modalities and outcomes of ICI rechallenge were reviewed.
Results
Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤ 3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤ 0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favorable evolution, including one irM-related death, and required heavy immunosuppression. ICI were safely reintroduced in 9 patients presenting a moderate (n = 6) or a severe (n = 3) irM.
Conclusion
Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favor of a safe reintroduction of ICI following symptom resolution and CK normalization in moderate and severe forms of irM.
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