Why is proteinuria an ominous biomarker of progressive kidney disease?

Progressive tubule injury and interstitial fibrosis frequently accompany glomerulopathies associated with proteinuria. Clinical experience indicates that higher levels of proteinuria prior to, as well as after initiation of treatment predict more rapid decline in renal function and more pronounced tubulointerstitial injury. It has been proposed that filtration of potentially tubulotoxic plasma proteins is responsible for the observed correlations between proteinuria and progression (i.e., proteinuria is a cause and not only a consequence of progressive renal injury). Numerous attempts have been made to identify the species of putative tubulotoxic proteins in this progressive injury process, but much uncertainty persists. These uncertainties stem from nonphysiologic exposure of apical cell surfaces to proteins in vitro, the extremely high concentrations of various proteins tested in vitro, and the nonuniformity of end points measured. Furthermore, there is often a lack of correlation between in vitro and in vivo findings, and a lack of uniformity of results even for seemingly similar in vitro experiments. Less controversy is evident in the potential pathways whereby injured tubules evoke a tubulointerstitial inflammatory and fibrotic response, with many in vivo models serving to incriminate excessive cytokine and chemokine production, infiltration of various inflammatory cells, and the balance between apoptosis and cell proliferation. Despite many years of concerted efforts, we believe it is still unclear whether proteinuria is a cause (and if so, which species of protein), or only a consequence of progressive renal injury. Nevertheless, pending the resolution of these uncertainties by more decisive and unambiguous experimentation, the strongly predictive inverse relationship between level of proteinuria and long-term renal survival currently justifies aggressive antiproteinuric treatment strategies, with a goal of reducing protein excretion rate to the lowest level possible without the induction of symptoms or undue risk.