**4. Summary**

The pathogenesis and progression of CKD result from numerous physical and molecular changes that create a complex intracellular environment. Physical changes due to hypertrophy and hydrostatic forces may cause injury to cells and lead to an inability of the cells to manage small intracellular changes. Increased oxidative stress, ER stress, DNA modifications, mitochondrial dysfunction, and many other cellular and molecular changes lead to dysregulation of intracellular processes, cellular injury, and eventual cell death. Exposure to environmental toxicants such as heavy metals may lead to additional cellular injury and enhance the progression of CKD. Because of the complexity of the CKD, eliminating one path of pathogenesis may enhance pathogenesis via a different route. Stopping the progression of CKD will likely require a combination of multiple therapies, but each component of combination therapy will likely cause its own negative effects. The only reasonable and attainable goal may be slowing down the progression of this disease.

**Author Contributions:** Conceptualization, C.C.B.; investigation, M.M., L.N., A.A.D., J.P.C., E.H.P., P.L., A.J.V.C., J.D. and C.C.B.; writing—original draft preparation, M.M., L.N., A.A.D., J.P.C., E.H.P., P.L., A.J.V.C., J.D. and C.C.B.; writing—review and editing, M.M., L.N., A.A.D., J.P.C., E.H.P., P.L., A.J.V.C., J.D. and C.C.B.; funding acquisition, C.C.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by NIH ES030867.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
