The Nephrotic Syndrome and Minimal Change Disease



The Nephrotic Syndrome and Minimal Change Disease


Jean L. Olson



The kidney is an efficient ultrafilter, and urinary protein loss is only 80 to 150 mg per day in the normal adult: 60% of the excreted protein is filtered by the glomeruli, with the remaining portion, chiefly Tamm-Horsfall protein, derived from tubular secretion (1). The nephrotic syndrome (NS) comprises heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia. Nephrotic-range proteinuria is defined as ≥3.5 g/d/1.73 m2 surface area. Pathologic proteinuria is the defining feature and the most readily quantitated sign of the NS, and heavy proteinuria represents a profound departure from homeostasis.

The NS is associated with a spectrum of primary and secondary glomerular diseases. It is important to make a distinction among the various causes of NS, because these diverse glomerular lesions have different clinical courses, treatments, and prognoses. Furthermore, investigators are now beginning to understand the molecular basis for many of these diseases leading to more specific therapeutic strategies. This chapter is concerned primarily with minimal change disease (MCD) and its variants although other causes of NS are mentioned, and the basic pathogenetic mechanisms of the NS are reviewed. Briefer mention is made of other glomerular diseases that cause the NS, with references to discussions of them in other chapters of this book.


FILTRATION OF MACROMOLECULES

Because the major characteristic of the NS is heavy proteinuria, it would be helpful at this point to review our understanding of the filtration of macromolecules.


Brief Review of Anatomy

The anatomy of the glomerular capillary wall is discussed in detail in Chapter 1, and only the salient points are emphasized here. Traditionally, the glomerular filter has been considered to be composed of three components: the endothelial layer of the glomerular capillary, the glomerular basement membrane (GBM), and the podocytes with their interdigitating foot processes and slit diaphragms. More recently, two additional components, namely, the glycocalyx of the endothelial cells and the subpodocyte space (SPS), have been found to contribute to
glomerular permselectivity (2,3). Starting on the luminal side and proceeding outward, the glomerular capillary wall consists of the following structures. First, there is a fenestrated endothelial cell layer with a negatively charged glycocalyx coat. The glycocalyx is composed of proteoglycans with a core of perlecan, syndecan, and versican and covalently bonded side chains of glycosaminoglycans such as heparan sulfate (3). Various serum proteins may become adsorbed to this surface. The endothelial fenestrations occupy between 20% and 50% of the endothelial surface and are maintained by vascular endothelial growth factor (VEGF) secreted by the podocytes (3,4). The basement membrane can be resolved into three layers: the lamina rara interna, the lamina densa, and the lamina rara externa. The GBM is composed of type IV collagen (with a triple helix of α3, α4, and α5 chains) forming a three-dimensional framework that serves as a lattice for the remaining components (2,5). Laminin that is bound to the collagen by entactin and nidogen anchors both endothelial and epithelial cells via the α3β1-integrin (2,6,7) and contributes additional structural support to the collagen. The negative charge of the GBM is imparted by the heparan sulfate proteoglycans, primarily perlecan and agrin (2,7,8).

The podocyte or visceral epithelial cell is recognized as a major player in glomerular filtration. The foot processes—which interdigitate—are attached to the outer aspect of the GBM by both laminin and fibronectin (5). The dystroglycan complex links α3β1-integrin to the actin cytoskeleton in the foot processes, and its proper glycosylation is important in maintaining the foot processes (9). Additional proteins involved in the development and maintenance of the foot processes include podocalyxin, podoplanin, glomerular epithelial protein 1 (GLEPP-1), and glucocorticoid-induced transcript 1 (7,10,11). MicroRNAs also play a role in podocyte function (12). Synaptopodin and actin are important in podocyte motility, and megalin plays a role in endocytosis at the base of the foot processes (7). Chloride intracellular protein 5 may act as an adapter between the actin cytoskeleton and the plasma membrane of the podocyte (13). Filtration slits are located between adjacent foot processes and are bridged by the slit diaphragm. Since the description of nephrin in 1998 (14), more than 15 different gene products have been localized to or near the slit diaphragm (2,15,16). These proteins also help maintain the shape of the foot processes, are important in signaling pathways, and function in regulation of cytoskeleton, polarized sorting and endocytosis, cell differentiation, suppression of differentiation, mechanotransduction, and podocyte viability (15). The exact shape and size of the pores in the slit diaphragm are not known. The original description posited a zipper-like structure (17). A more recent study suggests the possibility of a heteroporous structure (18). The anatomy of the podocyte and the slit diaphragm is more fully described in Chapter 1. Three-dimensional reconstruction has demonstrated the presence of a flow-restrictive SPS (3). This is discussed below in the section on the effect of hemodynamic factors.


Factors Involved in Glomerular Filtration

Numerous factors control the filtration of macromolecules, and they are best considered under the following headings: the various properties of the molecules themselves, the principal ones being size, charge, and shape; the properties of the capillary wall; and hemodynamic factors, chief of which are the glomerular plasma flow rate and transcapillary hydraulic pressure difference.


Properties of Molecules

Fractional clearance studies have determined how size affects the ability of molecules to cross the glomerular filter. When tritiated neutral dextrans were used to test glomerular permeability in the rat, their fractional clearance was 1 (no measurable restriction of filtration) when the effective hydrodynamic radius, ae, was ≤20 Å; but with increasing ae values, the fractional clearance decreased progressively until it approached 0 with radii greater than approximately 40 Å (19,20). Numerous studies over the years have confirmed that for neutral solutes, the sieving coefficient decreases with increasing molecular size (21). Charge also plays a role in controlling the transglomerular passage of macromolecules as suggested by the observation of Michael et al. (22) that there was a reduction in negative charge in the glomerular capillaries associated with proteinuria in rats with aminonucleoside nephrosis and in humans with MCD. Since these initial observations were made, fractional clearance studies using different sizes of neutral dextran and comparing their fractional clearances with those of negatively charged dextran sulfate of similar size and cationic dextran molecules supported the importance of electrostatic charge (23,24). However, others have argued that there is no charge selectivity and that negatively charged molecules of small size such as albumin may pass freely through the glomerulus to be reabsorbed by tubules (25). A raging controversy developed that is discussed below in the context of the properties of the capillary wall. Shape of the molecule undergoing filtration is another important determinant of filtration (26,27).


Properties of the Capillary Wall

The various elements of the glomerular capillary wall act together in series to control the filtration of macromolecules forming both size and charge barriers. The barrier is dynamic with cross talk between the epithelial and endothelial cells (28,29). The size-selective barrier resides in all layers of the glomerular filtration barrier. Originally, the GBM was thought to be the principal size-selective barrier (7), but this is no longer the prevailing opinion (29). Nonetheless, the occurrence of proteinuria associated with mutations in laminin (a protein found only in GBM) supports a contribution of the GBM to the size selectivity of the barrier (29). The role of the filtration slit diaphragm, first described by Rodewald and Karnovsky (17), was confirmed by Kestila et al. (14) following their discovery of nephrin mutations in congenital nephrotic syndrome (CNS) of the Finnish type in association with a loss of the slit diaphragms. More recent work shows a heteroporous structure in the slit diaphragms with variation in the size of the pores under pathologic conditions (18). Edwards et al. found that the sieving curve was highly dependent on changes in filtration slit width and not in changes in the GBM (30). They concluded that size selectivity is most sensitive to the size of the slit diaphragm and the hindrance coefficient of the GBM (30). Most recently, a role for the endothelial surface layer has also been described for size restriction (31). This layer is composed of glycocalyx composed of proteoglycans bound to the cell membrane and an endothelial cell coat attached to the glycocalyx. This cell coat consists of proteoglycans, glycosaminoglycans, glycoproteins, and various plasma proteins such as
albumin and orosomucoid (31). Deen (32) using mathematical modeling suggested that the endothelial and epithelial cell layers are most important for size selectivity.

Originally, it was believed that the charge barrier resided chiefly in the anionic sites of the GBM (33). It is now generally accepted that the charge barrier also resides in the endothelial and/or epithelial cells (7,21,28,29). Jeansson and Haraldsson (34) gave hyaluronidase and heparitinase III to mice and measured glomerular selectivity in both in vivo and isolated perfused kidneys. They found evidence for both size and charge selectivity using a heterogeneous charged fiber model. Treatment with hyaluronidase increased albumin permeability fourfold without changing the selectivity of similar sized neutral molecules. Additional evidence for the presence of both size and charge barriers was obtained from a study of adriamycin-induced NS in the mouse. The investigators demonstrated increased clearance of larger Ficolls in treated mice as compared to control mice (35). Furthermore, loss of charge selectivity was also established by comparison of the clearance of neutral as compared to anionic albumin (35). These changes were associated with a thinning of the glycocalyx of the endothelial cells and down-regulation of synthesis of the heparan sulfate proteoglycans (35). However, it has also been suggested that no charge barrier exists. Some investigators believe that albumin passes through the capillary wall but is then returned to the plasma by a proximal tubular albumin retrieval pathway in which megalin, a low-affinity albumin-binding receptor, directs albumin to lysosomes or via transcytosis to the basolateral membrane and cubilin, a higher-affinity albumin receptor, directs albumin to lysosomes (25). These authors suggest that proteinuria is due to inhibition of this retrieval pathway rather than increased glomerular permeability. This group using in vivo two-photon microscopy demonstrated that the glomerular sieving coefficient for albumin was higher than expected to a degree that supported lack of a charge barrier (36). This raised a storm of controversy with contentious articles and editorials. Several other investigators using the same two-photon technique demonstrated a glomerular sieving coefficient for albumin that was close to or at the expected value (37,38) supporting the presence of a charge-selective barrier. Most recently, Sandoval et al. (39) have shown that the glomerular sieving coefficient may vary in different strains of rats and under different conditions. Thus, the controversy is not yet entirely resolved and requires further consideration as our understanding evolves (40). Nonetheless, most investigators agree that a charge-selective barrier is present in the glomerulus. Additional evidence for the presence of a glomerular charge barrier is supported by the association of proteinuria with glomerular injury particularly the accumulating evidence of mutations to various elements of the glomerular filter and the occurrence of proteinuria (28).


Hemodynamic and Other Biophysical Factors

Hemodynamic factors, including blood flow, convection, diffusion, transcapillary hydraulic pressure difference, and intra-glomerular pressure, have been shown to play an important role in the passage of macromolecules across the glomerulus (19). Fractional clearance of a solute depends on the relative transport of water and the molecule in question. The latter takes place by both convection and diffusion for intermediate-sized macromolecules (an ae value between approximately 20 and 34 Å). For small and large macromolecules, convection is the predominant mode of solute transport. An increase in the glomerular filtration rate (GFR) results in comparable increments in water flux and solute transport by convection so that no change in fractional clearance occurs when diffusion is not a factor. However, in the case of intermediate-sized molecules, an increase in GFR produces a decrease in diffusion and, therefore, a reduction of fractional clearance. Afferent arteriolar plasma protein concentration may also affect these factors. These findings, predicted on theoretical grounds (20), were confirmed using dextran under conditions of different glomerular plasma flow rates, one of the determinants of the GFR. Other evidence that glomerular hemodynamics may affect glomerular permeability is provided by the observation that angiotensin-converting enzyme (ACE) inhibition reduces proteinuria. Another structural feature that may affect water or macromolecular flux through the glomerulus is the SPS first demonstrated in three-dimensional reconstruction of the glomerulus (41). This space is bounded by the podocyte cell body and the filtration barrier. Filtrate leaves the SPS and enters the urinary space through small exit pores between cell bodies, which produces a high-resistance space that may be controlled by the podocyte (3,41,42).

A recent contribution from Hausmann et al. (43) suggests the possibility that extracellular potential differences could be a determinant of glomerular filtration. They studied the Necturus maculosus (common mudpuppy), which has sufficiently large glomeruli to undertake such a study, and found a potential difference of 0.09 mV at a perfusion pressure of 20 cm H2O that could be eliminated by perfusion with a cation such as protamine. They explained this phenomenon as a streaming potential. This concept was further elucidated in an accompanying editorial in which a dilute ionic solution passes through a negatively charged filter, the positive ions will distribute in a uniform fashion (44). However, application of flow under pressure will cause the positive ions to flow through the filter where some will stick to the nonplasma side. Some of the negative ions will be reflected resulting in a streaming potential difference. Another editorial in the same issue suggests caution in the interpretation of these results (45).




Mechanisms of Proteinuria and the Effacement of Foot Processes

In general, proteinuria may result when there is addition of protein to tubular fluid (Tamm-Horsfall protein), altered tubular reabsorption, or altered glomerular permeability. We discuss only the last in this section and specifically address mechanisms that apply to those glomerular diseases that primarily have the NS as the initial manifestation.

Numerous experimental models have been used to study possible mechanisms of proteinuria. The model of puromycin aminonucleoside nephrosis (PAN) has been used extensively over the years. This model shares many features of human MCD, and it is produced in rats by administering puromycin aminonucleoside (PA), either in a single injection or in several injections. A considerable proteinuria ensues that is due to increased glomerular permeability. Studies of the glomerular lesion using transmission and scanning electron microscopy (47,48) have revealed a replacement of foot processes by continuous sheets of flattened cytoplasm, epithelial vacuoles, a reduction in the number of epithelial slits with formation of occluding junctions, and focal areas where the epithelium has detached from the outside of the basement membranes (Fig. 5.1). Other experimental models of proteinuric diseases as well as in human disease associated with proteinuria have similar changes.

The association between glomerular foot process effacement (FPE) and proteinuria is well known, but the mechanism of this effacement is complex and dynamic. In fact, podocyte motility is a term that is now used to reflect this dynamic view of the filtration barrier and changes in podocyte conformation (49). Maintenance of foot processes may be deranged by alteration in negative charge of the apical domain of the podocyte, alterations in slit diaphragm, or interference with GBM-podocyte interaction (50,51). All three of these are functionally linked by the actin cytoskeleton (52). The association between loss of negative charge from the podocyte and FPE has been known for some time. Seiler et al. (53) showed that neutralization of glomerular polyanion by infusion of protamine, a polycation, produced the same flattening of epithelium, which was reversible by perfusion of polyanions. Loss of polyanion has also been demonstrated in PAN (48) and following administration of anti-podoplanin antibody to rats (54). Podoplanin is a mucin-like substance expressed on the surface of rat podocytes that contributes to the negative charge. Its removal by specific antibody results in massive proteinuria and FPE (54). Additional evidence for a role for changes in the negative charge of the glomerular barrier was demonstrated by the recognition that angiopoietin-like protein 4 is up-regulated in the podocyte in MCD and is associated with both a loss of charge in the GBM and FPE mediated at least in part by a decrease in sialylation (55,56). This alteration is discussed in greater detail in the section on Pathogenesis of MCD.






FIGURE 5.1 Electron micrograph of glomerular capillary (C) in a nephrotic rat that was subjected to aminonucleoside 5 days earlier. There is spread of epithelial cytoplasm and focal loss of covering on the outside of the GBM (asterisks). U, urinary space (×6000). (From Ryan GB, Karnovsky MJ. An ultrastructural study of the mechanisms of proteinuria in aminonucleoside nephrosis. Kidney Int 1975;8:219, with permission.)

The disruption of the components of the slit diaphragm in association with proteinuria and FPE has been demonstrated in CNS of the Finnish type (57) as well as in knockout models for nephrin and CD2AP (58,59). FPE is always seen in these models accompanied by loss of the slit diaphragms. The proteins of the slit diaphragm are connected to the actin cytoskeleton by adapter proteins. Using the PAN model, Ito et al. (60) demonstrated that activation of the mammalian target of rapamycin complex 1 preceded the occurrence of endoplasmic reticulum stress and the unfolded protein response that resulted in cytoplasmic location of nephrin and disruption of the filtration slit diaphragm.

Attachment of the foot processes to the GBM is mediated by laminin, dystroglycan, and α3β1-integrin (61). Noakes et al. (62) examined a mouse model with a null mutation for laminin-β2. The mice developed massive proteinuria associated with FPE and died by 1 month of age. Others have examined the role of abnormalities in dystroglycan in detachment of the podocyte from the GBM. The dystroglycan complex mediates adhesion at the basal cell membrane of the foot process by connecting matrix protein of the GBM and the actin network of
the podocyte. Vogtlander et al. (63) noted that reactive oxygen species can cause deglycosylation of dystroglycan that may be associated with FPE. Reductions in dystroglycan have been seen in both MCD and focal segmental glomerulosclerosis (FSGS) (61,64).

As stated above, the three membrane domains on the podocyte are linked by the actin cytoskeleton, which has become a central focus in the concept of changing podocyte phenotype from stationary identified by the presence of intact foot processes to motile as associated with FPE. Prominent actin filaments are frequently seen in the effaced foot processes in human disease. Changes in the actin cytoskeleton have also been noted in PAN (48) as well as in an autosomal dominant form of FSGS that has mutations in α-actinin (65).

The regulation of the actin cytoskeleton is complex and is not yet completely understood. Nephrin in the slit diaphragm interacts with the actin cytoskeleton via various adapter proteins, notably CD2AP, Nck, and Crk (52,66). B7-1 (CD80) is a transmembrane molecule regularly found on B cells and antigen-presenting cells that may also be expressed on podocytes (67). It is up-regulated by lipopolysaccharide (LPS), and such up-regulation was associated with actin reorganization in podocytes as well as a loss of slit diaphragms in vitro (67). Cathepsin L-mediated proteolysis particularly of dynamin and synaptopodin, important in maintaining podocyte stability, has been demonstrated to play a critical role in changing podocyte phenotype to motility (52,68). Activation of RhoA, a member of the family of small GTPases, is associated with actin polymerization, but its inhibition also resulted in actin polymerization, suggesting that RhoA must be tightly regulated (49,69).

Several investigators have found that the onset of heavy proteinuria coincides with epithelial detachment (70). Furthermore, ultrastructural tracer techniques have shown penetration of anionic ferritin into the urinary space at these detachment sites (48). Use of the technique of multiphoton fluorescence imaging in vivo in the PAN model confirmed areas of increased glomerular permeability near damaged podocytes as well as real-time shedding of podocytes (37). FPE is a reversible change, but if it progresses to foot process detachment, then irreversible injury may result (52).


Effects of Proteinuria on the Tubules and Interstitium

For many years, the question of damaging effects of proteinuria on the tubules and interstitium has been raised. The fact that patients with steroid-dependent MCD could suffer from nephrotic-range proteinuria for years and not show such injury spoke against the idea. However, mounting evidence suggests that at least nonselective proteinuria may result in such injury. Albumin, various vitamins, and other substances in tubular fluid are normally nearly completely reabsorbed by the tubular epithelium by receptor-mediated endocytosis (71). Uptake of albumin requires cubilin with endocytosis of the albumin-cubilin complex and transport to the lysosome necessitating the presence of megalin (72). It has been proposed that the various substances may directly cause tubular toxicity, that growth factors and other substances may cause up-regulation of cytokines/chemokines, or that complement may be activated (73,74,75,76). Theilig et al. (77) induced crescentic glomerulonephritis (GN) in transgenic megalindeficient mice. The lack of expression of megalin was mosaic so that megalin-deficient tubules could be compared to those that expressed megalin. This comparison showed endocytosis and an up-regulation of TGFβ in the megalin-positive cells, while those deficient in megalin demonstrated apoptosis. However, neither group of tubules showed surrounding interstitial fibrosis. Kriz (77,78) believes that this experiment supports his contention that it is severe glomerular damage that is associated with downstream tubulointerstitial injury rather than tubular reabsorption of leaked proteins. Further experiments are necessary to dissect these possibilities.


PATHOPHYSIOLOGY AND COMPLICATIONS OF THE NEPHROTIC SYNDROME

The primary defect in the NS is loss of protein in the urine. Earley and Forland (79) calculated that complete failure to reabsorb filtered protein could account for proteinuria in humans of ≤0.5 to 2.5 g/24 hours at a GFR of 100 L/24 hours. It is now considered that proteinuria in excess of 2 to 2.5 g/24 hours indicates that at least some of the increased urinary protein has been derived from enhanced glomerular permeability. The nature of the protein lost in the urine may provide some information regarding the severity of the glomerular injury. Highly selective proteinuria—in which case only the smallest molecules are filtered in excess—indicates less injury to the glomerulus. Most glomerular diseases are manifest by poorly selective proteinuria.


Pathophysiology of the Nephrotic Syndrome

In addition to excessive loss of protein in the urine, the hallmarks of the NS include depression of certain serum proteins, edema formation, and a rise in serum lipids. Loss of protein in the urine is the basic defect, and the fall in serum protein, production of edema fluid, and hyperlipidemia stem from it (Fig. 5.2). Hypoalbuminemia in the NS is due to the combination of increased urinary loss and increased catabolism of albumin, chiefly in the kidney (80). The liver reacts to the low serum albumin levels by increasing albumin synthesis, but in the NS, the response is inadequate (80). The hypoalbuminemia then leads to both hyperlipidemia and edema formation.

Hyperlipidemia in the NS stems from several different mechanisms. A higher level of low-density lipoprotein (LDL) cholesterol is the principal alteration in the lipid profile, with increases chiefly in very low-density lipoproteins (VLDL) and apolipoproteins B, C-II, and C-III (81,82,83). The increase in apolipoprotein B is probably related to both hypoalbuminemia and changes in colloid oncotic pressure. The increase in LDL and VLDL is due to decreased catabolism secondary to decreased binding of lipoprotein lipase to endothelial cells (82,84), to reduced clearance of VLDL, and to a decrease in the VLDL receptor. In addition, lecithin cholesterol acyltransferase is lost in the urine so that there is limited uptake of surplus cholesterol (83). High-density lipoprotein (HDL) cholesterol shows little change so that the LDL/HDL is increased. However, the function of HDL in reverse cholesterol/lipid transport by the liver is impaired in NS due to deficiency of lecithin cholesterol acyltransferase, decreased docking receptor
for HDL in the liver, and increase in the hepatic HDL endocytic receptor (81). Triglycerides increase due to decreased clearance secondary to decrease in a number of lipases and up-regulation of hepatic diacylglyceride acyltransferase, the rate-limiting step in triglyceride synthesis (81). The increased synthesis of fibrinogen, transferrin, albumin, and apoA-1 is regulated transcriptionally (82).






FIGURE 5.2 Pathophysiology of the nephrotic syndrome and its major complications.

Edema formation is the symptom of the NS that usually brings the patient to clinical attention. Our understanding of the mechanism of edema formation in the NS has expanded.

In the classic mechanism, known as the underfill hypothesis, hypovolemia is the primary stimulus driving the kidney to retain sodium and water and eventually resulting in edema formation as the result of the Starling forces (Fig. 5.3) (85). However, most patients with NS are either normovolemic or hypervolemic. In an alternate theory, the overfill hypothesis, sodium retention by the kidney is primary. Sodium retention leads to increased blood volume and results in increased blood pressure. These changes then lead to alterations in the Starling forces, which result in edema. Recent investigations have demonstrated that the primary cause of sodium retention in the NS is hyperactivity of the epithelial sodium channel (ENaC) in the cortical collecting duct (86,87,88). The ENaC is activated by proteolysis of its γ subunit by plasmin, which has been found in the urine of nephrotic patients (87,88,89). Other possible contributors to sodium retention in this setting include increased renal efferent sympathetic activity, atrial natriuretic peptide (ANP), or increased Na+-K+ ATPase activity (86,88). It is no longer believed that the renin-angiotensin system plays the major role. Thus, hypoalbuminemia is only one potential contributor to edema formation. Rostoker et al.

(90) showed abnormal capillary permeability in patients with NS that resolved with steroid therapy. Current thinking still holds that increased capillary permeability and/or increased capillary-interstitial oncotic pressure gradient may participate in edema formation (86).






FIGURE 5.3 Mechanisms of edema formation in the nephrotic syndrome. Left: The classic view of edema formation, in which a low blood volume (underfill) serves as the signal for secondary renal sodium retention. Right: The mechanism of edema formation in most patients with the nephrotic syndrome who have normal or slightly elevated blood volumes (overfill). The blunted response to atrial natriuretic peptide observed in patients with the nephrotic syndrome may be the stimulus for primary renal sodium retention that plays a central role in edema formation.



Complications of the Nephrotic Syndrome

Hypercoagulability leading to thrombosis, increased susceptibility to infection, and cardiovascular disease are the principal nonrenal complications of the NS. Other complications are related to urinary losses of critical elements and include malnutrition, hormonal syndromes, and trace metal and vitamin deficiencies (see Fig. 5.2) (91).


Hypercoagulability and Renal Vein Thrombosis

Thromboembolic episodes occur in 20% to 42% of adults and in 1% to 9.2% of children with NS (92) and constitute the most life threatening of the complications of the NS. Deep venous thrombosis, renal vein thrombosis (RVT), and pulmonary embolism are the most common forms, but there are reports of arterial thrombosis and coronary thrombosis. Arterial thrombosis accounts for a higher percentage of thrombotic complications in children than in adults and results in a high rate of limb loss/death (93). In one study, the incidence of RVT in patients with NS was 35%, while the overall incidence of thrombotic complications outside the kidneys was 20% (94).

The pathogenesis of hypercoagulability in NS is multifaceted, stemming from an imbalance between coagulation and fibrinolysis (92). First, one must consider the presence of a genetic predisposition such as antithrombin deficiency that would increase the likelihood of thrombus formation (92). Many procoagulant factors are increased secondary to the lower serum albumin to which they are usually bound. These include fibrinogen; factors V, VII, and VIII; and von Willebrand factor (7,92,95). Increased fibrinogen leads to increased platelet aggregation and β-thromboglobulin. On the other hand, some anticoagulant substances are lost in the urine, including factors XI and XII, plasminogen, and antithrombin III (ATIII) (7,92,95). The loss of ATIII is thought to be particularly important as patients with NS who have such a deficiency have a 50% to 70% risk for thromboembolism (93). The fibrinolytic system is tilted toward decreased fibrinolysis with decreased plasminogen and plasminogen activator (92). It has been shown that the fibrin clot structure in NS may be less porous so that the thrombi are more resistant to fibrinolysis (92). Furthermore, prothrombotic microparticles, formed from various blood cells, may be increased in NS (92).

In children, the risk for thromboembolism is greater in those patients with CNS or with secondary forms of NS (92). In adults, the risk of RVT is higher in patients with membranous GN with 37% as compared to 24% for other forms of glomerular disease (92). Presentation of RVT varies with age. In young adults, it presents with flank pain and microscopic hematuria, whereas in older adults, presentation is characterized by a chronic syndrome. Furthermore, extrarenal thrombosis is also more common in older adults (92). Other clinical signs include acute renal enlargement, hematuria, oliguria, and acute renal failure (ARF) (96). Thromboembolic events occur early in the course of NS, usually within the first 6 months after diagnosis (97).


Infection

Infections were a major cause of mortality in patients with NS in the era before antibiotics (98), and bacterial infections remain a significant cause of morbidity. The prevalence of infections ranges from 8% to 38% in children (99), and one adult series reports a prevalence of 19%. Types of infections include sepsis, peritonitis, cellulitis, pneumonia, urinary tract infection (UTI), and meningitis (100,101,102). In 340 French children hospitalized with NS, severe bacterial infection was diagnosed 48 times (14%) in 32 patients. One half of the patients had spontaneous peritonitis, most often as the result of Streptococcus pneumoniae infection (99). The frequency of different types of infection varies by geographic location. A recent study from China found that 19% of admissions to a hospital for NS were also attended by infection (102). Pneumonia was most common followed by UTI, sepsis, peritonitis, and cellulitis. Age also affected the type of infection with children under 10 years suffering from pneumonia, while those older than 10 years had UTI most commonly (102). Infections with S. pneumoniae are sufficiently common that it is recommended that children with NS should be vaccinated against capsular antigens (100).

Comparisons of patients with NS with and without infections have cited risk factors for infection that include elevated levels of serum cholesterol (95), a serum IgG concentration of less than 600 mg/dL, a serum creatinine level of more than 2.0 (103), and increased fragility of the skin as a portal of entry (7). The heightened susceptibility to infection in patients with NS is usually attributed to hypogammaglobulinemia owing to urinary losses of immunoglobulin, increased catabolism, and a reduced rate of synthesis (7,95,100,101). Cellular immunity is also abnormal in the NS (95,100,101). These defects include a reduction in the numbers of circulating T lymphocytes and a depressed blastogenic response to mitogens (95). An increased incidence of infection results from these abnormalities in immunity and from inhibition of leukocyte chemotaxis (95). It has also been suggested that zinc deficiency resulting from urinary losses may contribute to an abnormal immune response in patients with NS (95). Loss of serum complement and opsonizing factors also contribute to the increased frequency of infection (95).


Atherosclerosis

Hypercholesterolemia and hyperlipidemia are almost always present in patients with NS, and these biochemical abnormalities may contribute to the progression of glomerular disease (104). Hyperlipidemia in patients with NS may also cause systemic atherosclerosis. The lipid profile seen in patients with NS is characterized by hypercholesterolemia, elevated plasma LDLs and lipoprotein (a), hypertriglyceridemia, and alterations in HDL metabolism (81,105). The increases in cholesterol and LDL are due to increased synthesis of both moieties and decreased catabolism of cholesterol (83,105). Hypertriglyceridemia is due to decreased clearance of VLDLs and chylomicrons and due to the up-regulation of hepatic diacylglyceride acyltransferase (81,106). The changes in HDL metabolism are described in the section above on pathophysiology of hyperlipidemia. Increased lipoproteins and oxidized lipoproteins have also been described in children with NS (107). Recent evidence suggests that increased oxidative stress, a known risk factor for atherosclerosis, in NS may be due at least in part to decreased paraoxonase-1 activity in patients with NS (108). Paraoxonase-1 prevents oxidation of serum lipoproteins and reduces risk of atherosclerosis.

Ordonez et al. (109) compared the risk of coronary heart disease in 142 nondiabetic adults (older than 15 years old) with
NS (proteinuria more than 3.5 g per day) and nonproteinuric control subjects matched for age and sex. Neither the subjects nor the controls had a preexisting coronary heart disease. The authors estimated that the risk of myocardial infarction (MI) is between five- and sixfold higher for the patients with NS than for the controls and that all coronary heart disease events (MI, angina pectoris, and coronary insufficiency) and deaths from coronary heart disease are two- to threefold higher in these patients. Exclusion of 17 patients with MCD from the analysis did not substantially alter the results. The increase in MIs may be related to increased LDL, resulting in decreased nitric oxide-mediated vasodilation (110). Another possible mechanism of increased MIs is related to loss of lysophosphatidylcholine resulting in decreased deformability of erythrocytes and increased platelet adhesion (110). Given the apparent risk of catastrophic complications, patients with prolonged NS and hyperlipidemia should be considered for pharmacologic or dietary treatment aimed at lowering the plasma lipid levels (109).


CAUSES AND CONDITIONS ASSOCIATED WITH THE NEPHROTIC SYNDROME

Clinical and pathologic observations have associated many different diseases with the NS, and the frequency and the consistency of the clinical association usually establish the validity of the relationship. Occasionally, there may be a direct relationship between a glomerular lesion and an etiologic agent. For example, finding of tumoral or microbial antigens in the immune deposits of membranous GN strongly supports an etiologic relationship between the agent and the underlying glomerular condition (reviewed in Chapter 7). The more common causes of the NS are listed in Table 5.1. When associations are only occasional, caution should prevail before making cause-and-effect assumptions from anecdotal experiences.


Frequency of Glomerular Diseases Causing Nephrotic Syndrome

The NS has been associated with myriad clinical disorders, but there are only a few forms of glomerular pathologic lesions that are responsible for most cases of the NS. One of the most important contributions of the renal biopsy has been to identify these different glomerular diseases. Table 5.2 summarizes the series that studied mainly adults, while Table 5.3 comprises series of children only. It is apparent from these tables that certain diseases are common causes of the NS.

Table 5.2 shows the relative incidence of the major histologic diagnoses among adults with the NS, taken from studies in which there was a clear distinction made between MCD and FSGS. Many variables affect the relative proportions of the diseases, such as the referral patterns and biopsy indications in different practice settings, and it is likely that these differences contributed to the patterns of disease in the different studies.

Series that come from referral centers are likely to contain patients with more serious or therapeutically difficult features. Such referral populations contain smaller numbers of patients with MCD and larger numbers of those with more serious conditions. This is brought out clearly by the study of White et al. (118). In a population of referred children, they found that MCD, FSGS, and membranoproliferative GN accounted for 64%, 11%, and 11%, respectively, of the cases of the NS. In contrast, a population of unselected patients yielded figures of 88%, 5%, and 1% for the same conditions (118). For these reasons, the prevalence of the less severe disease and, in the context of the NS, MCD will tend to be underestimated. MCD is further undercounted because standards of care do not require biopsy before initiating treatment in children with NS. Nevertheless, the frequency of FSGS relative to other causes of the NS is increasing in both adults (113) and children (119,120). The patients’ ages, geographic differences, and racial differences influence the prevalence of the diseases causing the NS, and they are discussed in turn.








TABLE 5.1 Major causes of NS































































Primary glomerular diseases presenting with nephrotic syndrome



Minimal change disease



Focal segmental glomerulosclerosis



Membranous glomerulonephritis



IgM nephropathy



C1q nephropathy



Fibrillary/immunotactoid glomerulopathy



Membranoproliferative glomerulonephritis



C3 glomerulonephritis



Dense deposit disease



Congenital nephrotic syndrome of Finnish type



Diffuse mesangial sclerosis


Primary glomerular diseases presenting with hematuria sometimes accompanied by NS



IgA nephropathy



Postinfectious glomerulonephritis


Systemic diseases



Diabetic nephropathy



Amyloidosis



Immunoglobulin deposition diseases



Henoch-Schönlein purpura



Lupus nephritis



Age Differences in Disease Prevalence

The distribution of glomerular lesions in children with NS differs from that in adults. Table 5.3 deals with a series made up of children only, and two thirds of these patients in the studies prior to 1990 have MCD. The incidence of MCD in children who had renal biopsies ranges between 34.1% and 52.7% (117,120,121). The incidence is higher in children less than 6 years of age relative to older children, 71.1% and 24.1%, respectively (120). The other relatively common lesions in children are FSGS and membranoproliferative GN. Membranous GN affects only small numbers of pediatric patients, except in Habib and Kleinknecht’s series (114). More recent series (117,121) show a lower percentage of patients with MCD, reflecting the current practice of not performing biopsies in young children with NS unless they are steroid unresponsive or resistant. Boyer et al. (121) examined 201 consecutive children who presented with idiopathic NS. Of those patients, 95 were steroid sensitive and were not biopsied. If one assumes that those patients had MCD, then the incidence of MCD
rises to 72%, which is closer to the figures from the 1970s (see Table 5.3). However, the percentage with FSGS is 24%, which is double the numbers for that entity from the earlier studies confirming the observations of others regarding an apparent increase in the incidence of FSGS (117,122).








TABLE 5.2 Incidence of glomerular lesions most commonly appearing in the form of nephrotic syndrome in adults




















































Cameron 1979 (111)


Tiebosch et al. 1987 (112)


Haas et al. 1976-1979 (113)


Haas et al. 1995-1997 (113)


Minimal change disease


25%


20.5%


23%


15%


Focal segmental glomerulosclerosis


9%


13.6%


15%


35%


Membranous GN


21%


31.8%


36%


33%


Membranoproliferative GN


14%


4.5%


6%


2%


Other proliferative GN


13%


20.5%


3%


9%


Other lesions


18%


9.1%


7%


4%


Total study population


500


44


199


233


The prevalence of the various glomerular lesions in older children and adults with NS is quite different from that in young children; significant proportions have membranous GN, MCD, FSGS, and various forms of proliferative GN, with significant contributions from systemic lupus erythematosus, diabetes mellitus, and amyloidosis (123,124,125). This morphologic diversity dictates a different clinical approach in adults with idiopathic NS in whom the morphologic diagnosis often cannot be deduced from the clinical history or the laboratory examination. The different forms of glomerular disease have very different therapeutic and prognostic implications, and lesion-specific therapy based upon a renal biopsy is the foundation for optimal treatment of these patients.

Studies of the NS in the elderly have found that membranous GN is the most common lesion in people between 65 and 79 years of age, with MCD as the most common lesion in the very elderly (Table 5.4) (126,127,128). Other lesions seen in biopsies in the elderly with NS include benign nephrosclerosis, diabetes, FSGS, IgA nephropathy, and amyloid. MPGN associated with hematologic neoplasms is also seen more frequently in the elderly (126). It is worth noting that in evaluating renal disease in the elderly, age-related changes may confuse the unwary (126). For example, the number of functioning glomeruli decreases by 30% to 50% in the seventh decade. In addition, there is a loss of capillaries within glomeruli accompanied by an increase in mesangial cell number, a decrease in epithelial cells, and a loss of filtering surface. Interstitial volume remains the same. Diverticula may form in distal tubules. Arteries spiral and become tortuous with the shrinking of the cortex (129). These morphologic changes are accompanied by physiologic alterations and a gradual loss of renal functional reserve. Furthermore, MCD may be superimposed on these changes so that it may be difficult to establish the diagnosis (127,128).








TABLE 5.3 Histologic diagnosis of nephrotic syndrome, exclusive of systemic disease, in children

























































Diagnosis


Habib and Kleinknecht (114)


International Study (115)


Chen et al. (116)


Gulati et al. (117)


Boyer et al. (121)


Minimal change disease


51.5%


76.4%


66.8%


34.2%


72%


Focal segmental glomerulosclerosis


11.6%


8.6%


11.6%


39.1%


24%


Membranous GN


9.1%


1.5%


2.1%


1.8%


2%


Membranoproliferative GN


9.4%


7.5%


1.7%


16.2%


2%


Diffuse mesangial sclerosis


1.5%


0%


0.4%


0.9%


Other lesions


16.9%


6%


17.4%


7.6%


Total


406


521


232


222


201



Geographic and Racial Differences in Disease Prevalence

The country of origin may also affect the proportions of the diseases causing the NS. For example, in Thailand, the incidence of common glomerular lesions in children is as follows: MCD, 16.5%; FSGS, 12%; mesangioproliferative GN (mostly IgM), 33%; membranoproliferative GN, 30.8%; and membranous GN, 7.7% (130). The high rate of membranoproliferative GN is attributed to a combination of infectious disease and malnutrition. In China, in a study of 1523 patients 14 years or older with NS, the frequency of these lesions was MCD 20.4%, FSGS 4.1%, mesangioproliferative GN (including IgA) 18.3%, membranoproliferative GN 10%, membranous GN 20.7%, amyloidosis 2.5%, lupus nephritis 16%, and other 8% (125). Additional differences were seen in a study using the Italian National Registry of Renal Biopsies. In that study, the frequency of these diseases in all ages was MCD 16.7%, FSGS 16.9%, mesangioproliferative GN (non-IgA) 5.3%, membranoproliferative GN 8.1%, membranous GN 44.1%, IgA nephropathy 8.1%, postinfectious GN 0.7%, and crescentic GN 1.4% (131).









TABLE 5.4 Comparison of frequency of common lesions producing nephrotic syndrome by age






































Elderly


Very elderly


Diagnosis


Children


Adults


65-79 y


80-91 y


Minimal change disease


58%


26%


20%


46%


Focal glomerulosclerosis


36%


39%


39%


36%


Membranous GN


6%


35%


41%


15%


Data from Nair R, Bell JM, Walker PD. Renal biopsy in patients aged 80 years and older. Am J Kidney Dis 2004;44:618.


Within a country, the frequency of lesions may be different among various races or ethnicity. For example, in South Africa, Bhimma et al. (132) studied the frequency of causes of NS in black, Indian, and mixed-race children. They found that the frequency differed as shown in Table 5.5. In addition, the course of the disease varied among the groups. For example, only 37.5% of the blacks with MCD were steroid sensitive compared to 96.2% of the Indian children (132).

Membranous GN is the most common cause of NS in European and North American adults, but observations suggest that this is not the case for African Americans. The most common cause of NS in African Americans is FSGS (113,133,134). In a series of 340 adult patients with idiopathic NS, Korbet et al. found that the incidence of FSGS was 57% among 121 African Americans compared with 23% among 123 Caucasians. Membranous GN remained the most common cause of NS in white adults (134).


MINIMAL CHANGE DISEASE


Terminology

After the introduction of the concept of nephrosis by Müller (135), the term lipoid nephrosis was coined by Munk (136) to describe the presence of fat bodies in the urine and fatty changes in the tubules seen at autopsy. The term lipoid nephrosis implies a degenerative appearance of the tubules as well as suggesting a possible role for abnormalities of lipid metabolism in the pathogenesis of the renal lesion, but in the era before the widespread application of percutaneous renal biopsy, it was applied to many different clinical situations and pathologic lesions linked primarily by the presence of the NS. Series of patients in whom lipoid nephrosis was defined clinically or without evidence from immunofluorescence and electron microscopy undoubtedly had other lesions. As lipoid nephrosis evolved to imply a specific glomerular lesion, many terms have been suggested in its place, including another obsolete term “nil disease.” Most authors now use the word minimal as part of the name of this lesion. Thus, such terms as minimal change NS, minimal lesion, and minimal change glomerulopathy are commonly seen. MCD is currently the most widely used and accepted term for this disease entity.








TABLE 5.5 Frequency of lesions associated with nephrotic syndrome in South African children according to race-ethnicity








































Diagnosis


Black


Indian


Mixed


Minimal change disease


13.5%


46.8%


21.7%


Focal segmental glomerulosclerosis


28.4%


20.6%


43.5%


Membranous (including hepatitis B)


39.8%


2.4%


26.1%


Membranoproliferative GN


5.1%


0%


3.1%


Mesangioproliferative GN


7.2%


2.4%


8.7%


Total subjects


263


263


20


Data from Bhimma R, Coovadia HM, Adhikari M. Nephrotic syndrome in South African children: changing perspectives over 20 years. Pediatr Nephrol 1997;11(4):429.



Clinical Presentation and Laboratory Findings


Clinical Presentation in Children

MCD is more common in boys than in girls; the ratio of boys to girls is approximately 2:1 (114,115,118). It is most commonly a condition of young children; with biopsy verification, the peak incidence was between 2 and 4 years (114,118). Almost 80% of histologically verified cases of MCD in the International Study of Kidney Diseases in Children (115) were found in children under the age of 6 years, with a median age of 3 years. However, MCD can occur at any age and is a common cause of NS in adults. It is more common among Caucasians, Asians, and Hispanics than among African Americans (137). The incidence is 2 to 16/100,000 per year in children under 16 years (137).

The clinical manifestations are similar to those seen in other forms of the idiopathic NS, and edema is the most common presenting sign (114). Microscopic hematuria was found in 36% of histologically confirmed cases in one study (114) and in 13% in another (118). Macroscopic hematuria was rare. Hypercholesterolemia is seen more frequently and is often elevated to very high levels. Blood pressure is usually normal at onset, and <20% of patients have hypertension (114,115,118). Transient depression of renal function has been recorded in 0.8% (138), 9.6% (114), and 19% (118) of children with MCD. In those cases in which the clearance is depressed initially, there is a return to normal with remission. The significance of decreased renal function in patients with MCD is discussed later (see “Acute Renal Failure in Minimal Change Disease”). Serum complement levels are not usually depressed (114,115,118). Proteinuria is almost always of the selective type (114,118). In fact, Adamson et al. (139) have suggested that the presence of higher levels of gamma globulins (greater
than 4.3%) on urine protein electrophoresis in conjunction with a normal GFR predicts an increased risk of FSGS.

MCD was defined in patients with NS, and there is a reluctance to make the diagnosis in patients with asymptomatic proteinuria. Hiraoka et al. (140) addressed the issue of “asymptomatic MCD” by reporting the cases of eight children with proteinuria discovered by chance on urinary screening. Two of the eight children underwent renal biopsy for coexistent hematuria, and the histopathologic diagnosis was MCD. None of the eight asymptomatic children relapsed for ≥1 year after completion of treatment, and only two experienced steroid-responsive relapses in greater than 6 years of follow-up. The authors concluded that among patients with steroid-responsive NS and a clinical diagnosis of MCD, those with mild manifestations without edema will have a favorable clinical course without relapse. Branten et al. (141) reported on a mother and two daughters with persistent proteinuria for 20 years in the mother but without any abnormality on biopsy including normal foot processes. These authors suggested the possibility that this represented a familial nephropathy different from MCD. On occasion, isolated FPE is found in patients with slightly elevated urine protein or no proteinuria. Because the relationship of isolated FPE to MCD is unknown and it is uncertain that the patients require treatment with steroids, I recommend that such patients be classified as having nondiagnostic glomerular changes. It is important to note that patients with MCD may have less than widespread FPE if the biopsy is performed when the patient is entering spontaneous remission or following treatment.


Clinical Presentation in Adults

MCD is a major cause of the NS in adults (see Table 5.2), but in contrast to the situation with children, it is not the most common glomerular pathologic manifestation (111,142,143,144,145,146). The clinical presentation is usually similar to that seen in children (142,144), although some studies report a higher incidence of hypertension, ARF (111,142,143,144,145,146), and nonselectivity of proteinuria (111), particularly in the elderly (128). The condition is identical to MCD of childhood so far as the appearances by light, immunofluorescence, and electron microscopy are concerned, except that obsolete glomeruli, focal tubular loss and atrophy, and thickening of arterioles and arteries are seen more often in adults. Children have more frequent relapses (137). Secondary cases of MCD are more common in adults, and in some 10% of cases, it is associated with a drug reaction or a lymphoproliferative disorder (142,144). A familial form of steroid-responsive NS, likely representing MCD, has been reported in a Bedouin kindred (147).

De novo MCD has been described (148,149,150). In one series of 67 patients with posttransplant NS, five had MCD (150). Fifteen cases have now been reported, and eight were in living-related donor kidneys (148,150). Many of these cases occurred within a few months following transplantation. None of the recipients had FSGS as a primary disease. Most remitted with appropriate therapy. It is critical to exclude other possible causes of NS prior to making this diagnosis.

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Jun 21, 2016 | Posted by in UROLOGY | Comments Off on The Nephrotic Syndrome and Minimal Change Disease
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