Brain dysfunction in tubular and tubulointerstitial kidney diseases

Abstract

Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research.

Keywords: brain; chronic kidney disease; cognitive function; electrolyte; tubulointerstitial.

Figure 1:

Neuronal metabolic activity with cytochrome oxidase histochemistry in different brain areas in sagittal sections. (A) Graphic representation of the different brain areas analyzed. (B) Representative graphed data of the comparison of cytochrome oxidase activity [optical density (OD)] between the different brain areas in Dicer/flox^–/–; AQP2/Cre^+/– mice, an experimental model of NDI type II and Dicer/flox^–/–; AQP2/Cre^+/+ mice, as a littermates control. The data shown are mean ± standard deviation from at least three independent experiments. *P < 0.05 compared with controls (unpublished data; detailed protocols in Supplementary material).

Figure 2:

Proposed mechanisms for behavioral modifications in CDI and NDI. (A) Schematic representation of brain VP and peripheral VP systems. Peripheral VP is released by hypothalamic nuclei in the bloodstream and regulates urine (and plasma) concentration by acting on V1aR in the kidney distal tubules. The brain VP system is composed of the periventricular hypothalamic nucleus, which projects to the neurohypophysis and the preoptic nucleus and bed nucleus of stria terminalis, with fibers sent to various brain regions. Central VP acts through V1bR. Behavioral changes may be caused by this brain VP system or by changes in plasma osmolarity. (B) In familial CDI, both central and peripheral VP are suppressed. Therefore behavioral alterations may be due to an altered brain VP system, although an indirect effect of plasma osmolarity is still plausible. (C) In genetic NDI, only V1aR is lacking, whereas V1bR and brain VP remain intact. Indeed, memory is preserved, whereas a loss of attention has been described, which may derive from altered plasma osmolarity. (D) We have tested this hypothesis in animals with intact V1aR, VP and V1bR, in the presence of a distal tubule dysfunction (Figure 1). The resulting alterations in brain metabolic activity could be ascribed only to a change in plasma osmolarity.

Figure 3:

Brain expression pattern of genes involved in tubular and tubulointerstitial diseases (100% means that the gene is ubiquitously expressed in the brain). Data from the Allen Brain Atlas database.