This thesis presents the results of six year's work on
macromolecular clearance determinations.This work is placed in context by an introductory review
of literature relating to the physiology of protein excretion.
Early concepts of the mechanisms involved in proteinuria are
discussed. Among the studies reviewed are observations on
micropuncture of the glomeruli and proximal tubules, clearance
experiments, stop-flow analyses, histochemicai findings, and
electron microscopy studies, It is concluded from this review of
the literature that some protein is filtered at the glomeruli, but
that in health virtually all of this is reabsorbed by a process
which, for albumin and molecules larger than albumin, is non-selective, Reasons are given for the opinion that tubular
secretion of protein is unimportant.The immunodiffusion method used in protein clearance studies
is then described, along with the gel filtration technique used to
determine protein, dextran, and polyvinylpyrrolidone clearances.
The errors involved in these techniques are discussed.Results are presented for protein clearance studies carried
out in parallel by the two techniques. From an analysis of these
results it is concluded that in patients excreting over 1.OG of
protein daily, -K (the index of protein selectivity by the immuno-diffusion technique) is related to Δ (the index of selectivity by
the gel filtration technique) by the formula Δ = 0.73 (-K).Dextran and protein selectivity values are compared in normal
subjects, in proteinuria induced by plasma infusion, and in a
variety of disease states. In minimal lesion glomerulonephritis,
membranous glomerulonephritis and in induced proteinuria, dextran
and protein selectivity values are in substantial agreement. In
normal subjects under normal conditions, in proliferative glomerulonephritis, in postural proteinuria, and in acute ischaemic renal
failure, dextran selectivity values are consistently and considerably higher than protein selectivity values. These findings are
explained in terms of differences in the renal handling of protein
and dextran and in terras of differences in the mechanisms involved
in proteinuria in the various conditions described. From the
experiments on induced proteinuria it is concluded that the
filtration of protein at the normal glomerulus, like that of dextran,
is highly selective.The results of protein selectivity determinations in 207
patients with major proteinuria are presented and related to the
histological diagnoses. Selectivity values in minimal lesion
glomerulonephritis are consistently high, while in patients with
renal failure proteinuria is uniformly unselective.The relationship between protein selectivity and prognosis
is assessed in 197 patients. A very high selectivity (-K over
2.6) is associated with a very good prognosis (3 year survival
with functioning kidneys of 96%). A very low selectivity (-K less
than 1.4) is associated with a poor prognosis (3 year survival of
27%).The relationship between selectivity and responsiveness to
steroid therapy is assessed in 82 treated patients. In our
experience, a selectivity value of 2.0 or less is consistently
associated with unresponsiveness to steroid therapy• While prompt
abolition of proteinuria following steroid therapy is to be
expected only in patients with minimal lesion glomerulonephritis,
comparison of the outcome at 8 weeks in 30 treated proliferatives
with findings at 8 weeks in 26 untreated controls with similar
histology shows a significant reduction in proteinuria in response
to steroids in patients with proliferative histology and selective
proteinuria
