Permeability plasma factors in nephrotic syndrome: more than one factor, more than one inhibitor (original) (raw)

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Gian Marco Ghiggeri, Mary Artero, Michele Carraro, Francesco Perfumo, Permeability plasma factors in nephrotic syndrome: more than one factor, more than one inhibitor, Nephrology Dialysis Transplantation, Volume 16, Issue 5, May 2001, Pages 882–885, https://doi.org/10.1093/ndt/16.5.882
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Idiopathic FSGS: definition and classification

Idiopathic focal segmental glomerulosclerosis (FSGS) is a common clinical entity characterized by the nephrotic syndrome, unresponsiveness to steroids and frequent progression to end‐stage renal failure.

The basic pathological lesion of FSGS involves focal accumulation of extracellular matrix and lipids within glomeruli that is present also in other glomerular diseases leading to sclerosis. However, owing to the characteristic focal and segmental nature of the process, FSGS emerges as a well‐defined clinical entity in which local, mechanical or other undefined mechanisms may play a pathogenetic role. Most cases of FSGS are sporadic, but a few family pedigrees have been reported in which the disease is inherited in dominant or recessive forms. Recent advances in molecular genetics of familial forms indicate that FSGS results from mutations in podocyte cytoskeleton components such as podocin [1] and _α_‐actinin 4 [2] or structural proteins of the slit diaphragm [3] such as nephrin. Screening studies in non‐familial FSGS now indicate that mutations of podocin are a frequent finding in sporadic FSGS as well, at least in children, and further molecular analysis in adults is currently in progress [Caridi G et al., personal observation]. It is relevant that clinical features of sporadic molecular FSGS are comparable to non‐molecular forms. In the past, lack of separation between the two entities clearly produced artefacts in studies on permeability factors in FSGS. Currently, we are carefully distinguishing between true idiopathic and molecular FSGS forms, and the future classification of the different mechanisms which result in FSGS histology will depend on this dichotomy.

The role of humoral factors in glomerular albumin permeability in idiopathic FSGS

Several lines of evidence have suggested that a circulating humoral factor is involved in the pathogenesis of FSGS: (i) the frequent recurrence of proteinuria after renal transplantation [4]; (ii) the efficacy of ex vivo techniques such as plasmapheresis in reducing post‐transplant proteinuria [5,6]; and (iii) the results of the in vitro bioassay which detects permeability changes induced by FSGS serum on isolated glomeruli [7,8]. A fourth demonstration comes from the paper by Rea et al. [9] in a recent issue of NDT. These authors demonstrated that the main clinical feature of FSGS, i.e. proteinuria, disappeared within 1 year after transplantation in two recipients of kidneys from a patient with FSGS. Although the available data cannot allow any definitive conclusions, and beyond any ethical and legal considerations, the good outcome of grafted FSGS kidneys is further strong evidence for the humoral genesis of FSGS.

The bioassay for the determination of permeability activity in FSGS serum developed by Savin et al. [7] detects changes in volume of isolated glomeruli which are exposed to different oncotic pressures in the presence or absence of permeability‐enhancing substances. The bioassay defines a parameter, Palb, whose values are predictive for the recurrence of the disease after renal transplantation [8,10], whereas the evidence for a clearcut differentiation of patients with FSGS from those with other types of nephrotic syndrome on the basis of Palb is not overwhelming.

The identification of the plasma factor which determines increased Palb would provide a solid basis for the humoral pathogenesis of FSGS. In a first attempt, Dantal and colleagues [11] suggested that the putative permeability factor may be bound to an immunoglobulin if it is not, in fact, an immunoglobulin itself. Sharma et al. [12] described a candidate compound with a molecular weight of 30–50 kDa, probably not a protease. Recently, Trachtman et al. [13] found that enriched supernatants from FSGS plasma eluates inhibited inducible nitric oxide synthase. In our hands, the search has been more complex; more than one factor which maintains permeability activity after isolation has been purified from FSGS sera. In the future, specific antibodies should be developed for each factor to achieve a clear and definite differentiation between FSGS and normal sera on the basis of a quantitative approach.

Cellular origin of permeability factors

One of the collateral aspects pertinent to the nature of the permeability activity is the cellular origin of the responsible factors. In 1974 Shalhoub [14] theorized that a disordered clone of T lymphocytes present in both minimal change disease and FSGS, secreted a circulating substance with toxic effects on the glomerular barrier. In an elegant experiment Koyama et al. [15] formed hybridomas from T cells from four patients with minimal change disease and three control subjects. The hybridomas of the patients, but not of the controls, produced a substance that induced proteinuria in rats. In a more recent attempt to demonstrate the involvement of T cell clonality, Frank and colleagues [16] found a dominant clone of CD8+T in patients suffering from nephrotic syndrome with frequent relapse and hypothesized that the ‘nephrotic’ factor might be produced by the dominant T cells. The major problem with these studies is the lack of reproducibility and specificity regarding the clinical entity of FSGS.

Physiologic inhibitors of increased glomerular permeability

The most recent development in the field is that blocking or inhibiting substances to the permeability factor may be found in normal serum, which are absent in patients with FSGS. Savin et al. [17] showed that normal serum abrogated the permeability activity of FSGS serum when pre‐incubated with glomeruli. We have successfully purified five components of normal serum which inhibit FSGS permeability activity [18] and have characterized them as apolipoproteins (apo) of the HDL complex. Among others, apo E2, apo E4 and apo J were found to exert a definite and independent inhibitory effect. The effective plasma level of each inhibitory component in FSGS is currently unknown and future studies will address this point. We can only speculate that loss of inhibitory substances may have a direct and pathogenetic impact in the permeability pathway in FSGS. For example, simple experiments with FSGS serum cross‐matched with homologous urine in the isolated glomeruli assay demonstrated that nephrotic but not normal urine blocked the original permeability activity [Caridi et al., submitted]. These observations suggest that an imbalance between permeability factors and their inhibitors determined by increased production and/or by urinary loss may be a central event in the natural history of FSGS.

Loss of inhibitors and specificity of permeability activity: the case of molecular FSGS

The possibility that urinary loss of inhibitors has a direct impact on permeability activity raises questions on the specificity of the mechanism of permeabilty factors in the pathogenesis of FSGS. A corollary dilemma is whether increased production of permeability factors and loss of inhibitors influence Palb to the same extent. The first point can be addressed by determining Palb in other proteinuric states which are comparable to FSGS with respect to clinical impact and selectivity of proteinuria. Molecular FSGS due to mutations of podocin is the model which may definitively resolve the problem since proteinuria in this case is not related to humoral factors, while the clinical picture reproduces idiopathic FSGS. We have measured Palb in five patients carrying homozygous or composite heterozygous mutations of podocin and found in all cases a Palb higher than 0.7 [Caridi et al., submitted]. Once again Palb was normalized by co‐incubation with urine. Thus, high Palb values occur in clinical conditions in which proteinuria is the result of a molecular alteration of podocyte cytoskeleton and inhibitors are lost in urine due to the glomerular barrier defect. This observation clearly suggests that high Palb is not specific for idiopathic FSGS and that the urinary loss of inhibitors may very well mimic other conditions characterized by high production of permeability factors.

Future aspects and conclusions

Towards a new classification and selective therapeutic approaches

The new developments in the area of molecular genetics of FSGS and the new acquisitions with respect to humoral permeability factors and their inhibitors may have a clinical impact, leading to a modified classification of the disease. Steroid unresponsive nephrotic syndrome could be subdivided into molecular forms due to mutations of podocin and _α_‐actinin 4, and into idiopathic forms. The latter group includes malignant forms characterized by a rapid evolution towards renal failure and rapid recurrence after renal transplantation, in which case a humoral factor may be responsible for the disease and Palb is truly elevated. Nephrotic syndrome with a better clinical outcome, often sensitive to non‐steroidal treatment such as cyclosporin, but still showing high Palb values, may constitute a parallel group. Palb is absolutely or relatively increased in these cases as well as in the molecular forms because of urinary loss of inhibitors. The differentiation of FSGS on the basis of the presence of permeability factors, their natural inhibitors and molecular differences has practical implications. First of all, aggressive immunosuppression should be avoided in molecular FSGS, while it is probably the most adequate approach in the other forms which respond to major immunosuppression and cyclosporin. Characterization of plasma factors may lead to new pharmacological strategies aimed at blocking the permeability‐increasing activity. Finally, repletion of blood stores with natural inhibitors should be the most immediate goal for new therapeutic approaches to this disease.

Note added in proof

Recently Kemper, Wolf and Müller‐Wiefel demonstrated transmission of the glomerular permiability factor from a mother affected by FSGS to her child during gestation (N Engl J Med 2001; 344: 386–387). After birth, proteinuria in the child decreased and then disappeared, suggesting a strong correlation with some factors transmitted from the mother.

Correspondence and offprint requests to: Gian Marco Ghiggeri MD, Unità di Nefrologia, Istituto G. Gaslini, Largo Gaslini 5, I‐16148 Genoa, Italy.

We are indebted to Professor R. Gusmano for her continuous interest and suggestions. The Fondo Malattie Renali del Bambino provided financial support.

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European Renal Association-European Dialysis and Transplant Association

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