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.