Toward Understanding Renal Fanconi Syndrome: Step by Step Advances through Experimental Models

Abstract

Renal Fanconi syndrome (FS) is a generalized dysfunction of proximal tubular epithelial cells leading to the urinary leak of essential metabolites like phosphate, uric acid, glucose, amino acids and low molecular weight proteins. From inherited forms involving mutations on apparently unrelated genes to acquired forms induced by drugs, heavy metals or monoclonal immunoglobulin (Ig) light chains (LC), heterogeneous causalities of FS have complicated the understanding of this pathology for a long time. Experimental models of FS have allowed researchers to face the challenge and have helped unravel the main mechanisms disturbing proximal tubule reabsorption. Administration of cadmium to animals first demonstrated an inhibition of Na/K/ATPase activity, highlighting how a single toxic component could induce the general sodium-linked transport defect observed in FS. Today, genetically modified mice allow the development of reliable and reproducible experimental models for inherited or acquired forms of FS. One of the most exciting advances offered by these models is the unexpected major role of endocytosis in the function of the proximal tubule revealed by megalin and ClC-5 knockout mice. Using gene-targeted insertion, a transgenic mouse for LC-associated FS, the most frequent adult form of FS, has also been recently developed and represents a major step in the development of models of this pathology. Beyond deciphering molecular and cellular events at the origin of FS, these models also represent essential tools for the development of therapeutic strategies.

Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

“…[53][54][55][56][57] An animal model for this variant has shown that the primary structure of the light chains is directly responsible for the pathologic findings observed, and a transgenic model has been created where the disease has been reversed with experimental manipulations. 57,[59][60][61] An incomplete form of this condition has also been reported, 62 emphasizing once more the importance of the physicochemical characteristics of the light chains in producing pathologic processes. Light chains from most of these cases (j type) exhibit a specific amino acid substitution at position 30, which provides resistance to catabolism, [59][60][61] promoting the formation of cytoplasmic inclusions.…”

“…57,[59][60][61] An incomplete form of this condition has also been reported, 62 emphasizing once more the importance of the physicochemical characteristics of the light chains in producing pathologic processes. Light chains from most of these cases (j type) exhibit a specific amino acid substitution at position 30, which provides resistance to catabolism, [59][60][61] promoting the formation of cytoplasmic inclusions.…”

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

“…8,9 Monoclonal gammopathy is a main cause of RFS in adults .50 years of age. 10 PT dysfunction and RFS may also result from congenital disorders, such as Dent disease and cystinosis, with defective receptor-mediated endocytosis as a common feature. [11][12][13] There is a remarkable heterogeneity in the capacity of free LCs to induce renal tubular damage.…”

Transient Fanconi syndrome in two preterm infants with hydronephrosis and urinary tract infection

“…In proximal cells, the electrochemical gradient generated by the basolateral Na + -K + -ATPase facilitates the activity of sodium dependent co-transporters expressed at the apical side, allowing the reabsorption of glucose, phosphate, and others [1]. To maintain the electrochemical gradient, proximal cells have high metabolic rates and are rich in mitochondria.…”

“…They also have endocytic receptors such as megalin and cubilin that are critical for the reabsorption of filtered proteins [2]. Thus, the mechanism of FS can be categorized as the inhibition of (1) Na + -K + -ATPase activity [1], (2) mitochondrial activity, and (3) receptor-mediated endocytosis.…”