Proteinuria-take a closer look!

Abstract

Proteinuria is a hallmark of kidney disease. Therefore, measurement of urine protein content plays a central role in any diagnostic work-up for kidney disease. In many cases, proteinuria analysis is restricted to the measurement of total protein content knowing that very high levels of proteinuria (nephrotic proteinuria) are characteristic of glomerular disease. Still, proteinuria can also be a manifestation of impaired tubular protein reabsorption or even be physiological. This review will discuss the physiology of renal protein handling and give guidance on a more sophisticated analysis of proteinuria differentiating albumin, low-molecular weight proteins and immunoglobulins. These non-invasive tests are available in most routine clinical laboratories and may guide the clinician in the diagnostic process before ordering far more expensive (molecular genetic testing) and/or invasive (kidney biopsy) diagnostics.

Keywords: Acute kidney injury; Glomerular disease; Low molecular weight proteins; Proteinuria; Selectivity; Tubulointerstitial disease.

Fig. 1

Estimated glomerular sieving coefficients for 12 plasma proteins versus molecular weight. Abbreviations: ß2m, ß2-microglobulin; RBP, retinol-binding protein; α1m, α1-microglobulin; TSH, thyroid-stimulating hormone; ß2GI, ß2-glycoprotein-I; ZAG, zinc-α2-globulin; α1AG, α1-acid glycoprotein; DBP, vitamin D-binding protein; TTR, transthyretin; ALB, albumin; TRF, transferrin; IgG, immunoglobulin G. From Norden et al. [15], reproduced with permission

Fig. 2

Absorption and intra-cellular handling of LMW proteins in the proximal tubule. Megalin is present on the cell surface in high abundance. When low-molecular-weight proteins bind to megalin, this “cargo” is internalized into the early endosome. The endosome is acidified by the action of H⁺ATPase in concert with chloride channel 5 (CLCN5). At low pH, the cargo dissociates from megalin and passes through the late endosome and on to the lysosome where it is degraded. Megalin returns from the early endosome back to the surface of the cell, where it is available for internalization of more cargo. From Guggino [16], reproduced with permission

Fig. 3

Simultaneous changes of the urinary cystatin C-creatinine ratio and the protein-creatinine ratio. Paired measurement of patients during the active phase (A) and in remission of minimal change nephropathy (B). Data presented as mean ± SD. From Herget-Rosenthal et al. [18], reproduced with permission

Fig. 4

Albumin concentration along the nephron. Data calculated from a rat fractional micropuncture study. Arrows indicate the percentage of ultrafiltrated albumin which is reabsorbed in the respective nephron segment. From Tojo et al. [17], reproduced with permission

Fig. 5

Histological diagnosis and urine albumin/protein ratio. A urine albumin/creatinine ratio (uAPR) value of 0.4 (dotted line) demonstrates a clear distinction between tubulointerstitial disorders and glomerular disorders. uPEI, urine protein electrophoresis and immunofixation; ATN, acute tubular necrosis; DN, diabetic nephropathy; Fib, fibrillary glomerulonephritis; FGS, focal segmental glomerulosclerosis; HT, hypertensive nephrosclerosis; IgA, IgA nephropathy; LC, light chain deposition disease; LN, lupus nephritis; MC, minimal change disease; MCGN, mesangiocapillary glomerulonephritis; MPGN, mesangioproliferative glomerulonephritis; MN, membranous nephropathy; MyCN, myeloma cast nephropathy; NGN, necrotizing glomerulonephritis; NGNC, necrotizing glomerulonephritis with crescents; TIN, tubulointerstitial nephritis; TMA, thrombotic microangiopathy. From Smith et al. [71], reproduced with permission