Abstract: SA-PO699
Lithium Nephrotoxicity Is Associated with Dysmorphic Proximal Tubule Cell Lysosomes
Session Information
- Pathology and Lab Medicine: Clinical
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1602 Pathology and Lab Medicine: Clinical
Authors
- Nast, Cynthia C., Cedars-Sinai Medical Center, Los Angeles, California, United States
- Vervaet, Benjamin Arthur, University of Antwerp, Antwerp, Belgium
- Schreurs, Gerd, University of Antwerp, Antwerp, Belgium
- Jayasumana, Channa, Faculty of Medicine, Anuradhapura, Sri Lanka
- Servais, Aude, Necker University Hospital, Paris, France
- De Broe, Marc E., University of Antwerp, Antwerp, Belgium
Background
Long term lithium (L) use is associated with tubulointerstitial fibrosis, renal dysfunction and ESRD in select patients. The mechanisms resulting in parenchymal fibrosis are not well understood. We have described proximal tubular cell (PTC) dysmorphic lysosomes (DLs) in calcineurin inhibitor (CNI) toxicity and chronic interstitial nephritis in agricultural communities (CINAC), suggesting this is a marker of tubulotoxic exposure. Similar lysosomes were identified in cases of chronic interstitial nephritis due to lithium toxicity (LT) used as controls for our CINAC studies, prompting further assessment of this finding.
Methods
9 kidney biopsies from patients with clinical LT were reviewed, Ki67 staining was performed and clinical data were obtained from the medical records.
Results
Patient data are in the Table. 7 patients discontinued L for 0.15 to 31 years prior to biopsy. All biopsies showed tubulointerstitial fibrosis and tubular microcysts diagnostic of LT. 7 biopsies had PTCs with cytoplasmic large DLs containing electron dense aggregates, identical to patients with CINAC and CNI toxicity. Ki67 staining showed no to few positive proximal and distal tubular cells in 8 biopsies, demonstrating reduction in tubular cell proliferation and repair. The 1 patient with moderate numbers of Ki67 positive tubular cells had scattered PTC DLs and had discontinued L 14 years before biopsy, possibly indicating evolving tubular cell repair. The patient off L for 31 years had no DLs or Ki67, suggesting completed recovery from LT.
Conclusion
PTC DLs are a marker of tubulotoxic exposure to L and are associated with a reduction in PTC regenerative capacity. In the setting of LT, PTCs are senescent and the DLs may persist for up to 14 years after drug discontinuation. As tubular cell mitotic arrest has been associated with tubulointerstitial fibrosis, further evaluation of the relationships between DL development, DL cargo, and loss of PTC proliferative capacity may help elucidate mechanisms of L-induced tubulointerstitial fibrosis, which currently are poorly understood.
Clinical and Biopsy Data
| PT dysmorphic lysosomes | Age | Gender | Time on L | L stopped before biopsy | Cr (mg/dL) | Tubulointerstitial fibrosis |
| Yes (n=7) | 46+/-18 | 2M:5F | 7->25 yrs | 0-14 yrs | 1.8+/-0.1 | 35+/-15% |
| No (n=2) | 67+/-25 | 2M | 15->25 yrs | 0-31 yrs | 2.8+/-0.8 | 27.5+/-10.5% |