Mechanism Underlying Selective Albuminuria in Minimal Change Nephrotic Syndrome

Abstract

As water and solutes are filtered through the slit membrane, it is an a priori concept that a slit membrane is an essential filtration barrier for proteins, including albumin. However, in cases of minimal change nephrotic syndrome, the number of slit membranes is reduced by the foot process effacement and tight junction-like cell adhesion. Furthermore, albumin endocytosis is enhanced in the podocytes under condition of minimal change disease, and albumin is selectively transported by the albumin receptor FcRn. Suppressing the endocytosis of albumin with anti-FcRn antibody decreases the urinary protein level. The expression of motor molecules, such as cytoplasmic dynein 1 and myosin IX, is increased in the podocytes under conditions of minimal change nephrotic syndrome, suggesting the enhanced transport of vesicles containing albumin. Podocyte vesicle transport may play an important role in the pathology of selective albuminuria in cases of nephrotic syndrome.

Figure 1

SDS-polyacrylamide gel electrophoresis in various renal diseases including Fanconi syndrome, minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), and IgA nephropathy (IgAN). MW: molecular weight marker; NS: nephrotic syndrome; CR: complete remission; THP: Tamm–Horsfall protein.

Figure 2

Morphological changes of the glomerular filtration barrier and selectivity of proteinuria. (a) A schematic illustration. (b) A micrograph of a glomerulus in a paraffin section obtained using a low-vacuum scanning electron microscope (LVSEM) in each group of proteinuria selectivity. (c) A micrograph of the glomerular capillary wall obtained using a transmission electron microscope (TEM) in each group of proteinuria selectivity. Selective albuminuria is usually found in patients with minimal change nephrotic syndrome, nonselective proteinuria without hematuria associated with podocyte detachment (yellow arrows) is found in patients with membranous nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy, and nonselective proteinuria with hematuria associated with GBM rupture/hole (red arrowheads) is found in patients with IgA nephropathy, ANCA-related glomerulonephritis, poststreptococcal acute glomerulonephritis, and membranoproliferative glomerulonephritis. P: podocyte; E: glomerular endothelium; C: glomerular capillary; M: mesangium; RBC: red blood cell. Scale bars indicate 2 μm on the LVSEM micrograph and 500 nm on the TEM micrograph.

Figure 3

Correlation between the percentage of the area along the capillary wall with foot process effacement and proteinuria in human patients with minimal change nephrotic syndrome with or without acute kidney injury (AKI) (a) and an animal model of minimal change nephrotic syndrome induced by a single or two injections of puromycin aminonucleoside (PAN, n = 5 in each) (b). Patients with MCNS with AKI (n = 13) showed significantly higher levels of serum creatinine and lower levels of serum albumin at biopsy than MCNS patients without AKI (n = 25).

Figure 4

A schematic illustration of glomerular podocyte effacement in minimal change nephrotic syndrome with or without acute kidney injury.

Figure 5

A micrograph of podocytes in a patient with minimal change nephrotic syndrome obtained using a transmission electron microscope (a). A micrograph of the podocyte surface in a patient with minimal change nephrotic syndrome obtained using a low-vacuum electron microscope with PAM staining section followed by 1% Ponceau S staining (b). P: podocyte; E: glomerular endothelium; C: glomerular capillary; M: mesangium; RBC: red blood cell; GBM: glomerular basement membrane; Bw: Bowman's capsule. Scale bars indicate 2 μm.

Figure 6

Putative mechanism of selective albuminuria in minimal change nephrotic syndrome.