FSGS is also characterized by nephrotic range proteinuria, often in the setting of a nephrotic syn- drome. In contrast to MCD, the proteinuria is mostly refractive to steroid treatment, and comes with a progressive decline in renal function that eventually may necessitate transplantation. The histopathology of FSGS is characterized by scarring of some of the glomeruli (focal), in a way that involves only limited parts of a glomerulus (segmental). The lesions that are seen in FSGS are diverse, and recently a classification has been made to describe the different forms of FSGS (260). In this classification, five patterns of FSGS are distinguished on the basis of their morphologic features, namely the collapsing, tip lesion, cellular, perihilar, and not otherwise specified variants of FSGS. Diagnosis of one of the variants requires exclusion of the previous variants in the order listed here. These different variants of FSGS may coexist in a single renal specimen (38), and it is unclear whether the classification on morphologic basis relates to different pathophysiologic mechanisms. The first studies that evaluate the clinical implications of the classification do show differences between the variants; for example, the collapsing variant is associated with a popu- lation that differs in demographics from that of the other variants, and clearly carries a worse prognosis (261).
FSGS should not be regarded as a disease in itself, but rather as the stereotypic histomorphologi- cal representation of different specific diseases. These include hereditary diseases, obesity, hyper- tension, viral infection, medication, and mechanical stress. A substantial percentage of cases of FSGS, however, are of unknown origin, the so-called primary or idiopathic forms of FSGS. In diseases that lead to FSGS, the secondary forms of FSGS and hereditary syndromes, podocyte injury has been shown to be a central step in development of FSGS and the associated proteinuria (262). In hereditary cases, the mutated genes often code for proteins with a more or less specific expression in podocytes, as discussed before. In animal models, direct damage to podocytes, for example through the injection of puromycin aminonucleoside, leads to proteinuria and subse- quently development of FSGS. Medication like cyclosporine and pamidronate may damage the
41 causes of proteinuria in various kidney diseases > focal segmental glomerulosclerosis (fsgs) podocyte; the latter gives rise to a collapsing variant of FSGS with high proteinuria (263). Podo- cytes have been shown to be a target of infection by HIV (264), which may lead to HIV-associated nephropathy, a disease characterized by rapid decline in renal function, high proteinuria, and FSGS of the collapsing type (265). FSGS can be seen in hypertensive patients. In these cases, the mechanical stress put on podocytes through the increased intraglomerular pressure may lead to damage of podocytes. Indeed, cultured podocytes have been found to be stress-responsive (266). Protein overload also leads to the development of FSGS (267,268). Consequently, not only damage to the podocyte, but also other mechanisms that cause increased passage of proteins through the glomerular filtration barrier may, via podocyte injury, lead to FSGS.
Despite this progress in the elucidation of the secondary FSGS, the etiology of the primary forms of FSGS remains elusive. Much research has been done to identify a putative humoral permeabil- ity factor. Such a factor would explain the high rate of FSGS recurrence in patients that receive a renal transplant because of FSGS. Also, a permeability factor would explain the transmission of a proteinuric condition from mother to her unborn child (269). Several groups, most notably that of Savin and coworkers, identified characteristics of this permeability factor, but the ultimate structure and origin remain unknown (262,270). Others have supposed that not the presence of a permeability factor, but the absence of crucial plasma factors lead to the development of proteinuria and FSGS. The hypotheses about the pathophysiologic mechanisms again incorpo- rate the podocyte as a crucial target. Coward et al tested the influence of plasma of normal and nephrotic patients on the distribution and signaling of slit diaphragm proteins in cultured podocytes, and found that the effect of nephrotic plasma could be abrogated by adding normal plasma (271). Wei et al found that the plasma concentration of soluble urokinase receptor (uPAR) is elevated in serum of patients with recurrent FSGS (Wei et al, J Am Soc Nephrol 2008(19):103A). In mouse models, uPAR signaling in podocytes has been shown to cause foot process effacement and proteinuria (272), but mechanistical evidence for a pathogenic role of soluble uPAR in human FSGS is lacking.
Irrespective of the cause of proteinuria, podocyte injury is a crucial step in the further develop- ment of FSGS. Using combined observations from different animal models, Kriz (273) has de- scribed a sequence of events that explains the development of FSGS: podocyte injury leads to loss of podocytes, which results in denuded parts of the GBM and hypertrophy of the remaining podocytes. This will increase the possibilities for the formation of adhesions of the podocytes or the GBM to the parietal epithelial cells. Once such an adhesion has been formed, this leads to an encroachment of the parietal cells on the capillaries, and to ‘misdirected filtration’, the delivery of glomerular filtrate to the space between Bowman’s capsule and the overlying parietal epithelial cells.
chapter 1 > causes and consequences of proteinuria 42
Despite the initial pivotal role of the podocyte, the further development of the FSGS lesions does involve other glomerular cell types. Kihara et al and Nagata et al suggested that in the collapsing and cellular variants of FSGS, the proliferating cells are of parietal origin (274,275). In a series of studies, Smeets et al and Dijkmans et al have recently brought more evidence for the involvement of parietal epithelial cells in the development of collapsing FSGS in animal models (35), human idiopathic FSGS (38), as well as HIV and pamidronate associated collapsing FSGS (39).
Taken together, the pathogenetic mechanisms in secondary FSGS all converge on podocyte dam- age as a central initiating step of development of proteinuria. In primary causes of FSGS, the initial pathogenetic mechanisms of proteinuria remain unclear, although a contribution of the podocyte is to be expected, and certainly this cell is at play in the later development of FSGS.