Brenner and Rector's The Kidney, 8th ed.

CHAPTER 26. Renal and Systemic Manifestations of Glomerular Disease

Sharon Anderson   Radko Komers   Barry M. Brenner

  

 

Proteinuria, 820

  

 

Mechanisms of Proteinuria, 820

  

 

Glomerular Permselectivity, 821

  

 

Clinical Consequences of Proteinuria, 824

  

 

Hypoalbuminemia, 824

  

 

Pathogenesis of Hypoalbuminemia, 824

  

 

Regulation of Albumin Metabolism in Nephrotic Syndrome, 825

  

 

Consequences of Hypoalbuminemia, 826

  

 

Hyperlipidemia, 829

  

 

Lipid Abnormalities in Nephrotic Syndrome, 829

  

 

Pathogenesis of Nephrotic Hyperlipidemia, 829

  

 

Clinical Consequences of Nephrotic Hyperlipidemia, 831

  

 

Therapy for Nephrotic Hyperlipidemia, 832

  

 

Hypertension, 832

  

 

Hematologic Abnormalities, 832

  

 

Hypercoagulable State and Renal Vein Thrombosis, 832

  

 

Pathogenesis of Hypercoagulability, 833

  

 

Hormonal and Other Systemic Manifestations, 834

PROTEINURIA

Proteinuria characterizes most forms of glomerular injury and causes or contributes to all of the complications of the nephrotic syndrome. This section reviews the physiology and pathophysiology of glomerular proteinuria and the mechanisms by which proteinuria engenders systemic complications. Extensive discussion of the mechanisms of proteinuria may also be found in several reviews. [1] [2] [3] [4] [5] [6] [7]

Mechanisms of Proteinuria

Prerenal, Glomerular, and Tubular Proteinuria

The amount of protein excreted in the urine is a function of three factors: the amount of protein presented to the glomerulus (the filtered load); the permeability of the glomerular capillary wall (GCW); and the efficiency of proximal tubule reabsorption of filtered proteins. The major clinically relevant proteinuric syndromes, and the only ones that may lead to massive proteinuria, result from alterations in glomerular permeability to normally filtered proteins. Defense against proteinuria is dependent upon the structure and function of the GCW, characteristics of the protein molecule being presented to the glomerular barrier, and hemodynamic factors.

The Anatomic Barrier to Proteinuria: The Glomerular Capillary Wall

The classic view of the anatomic barrier to the filtration of protein has been extensively reviewed[1] and is briefly summarized here. As detailed later, recent years have seen a major advance in our insight into this process through the discovery of nephrin and associated studies of the molecular nature of the slit diaphragm.

The glomerular capillary barrier consists of multiple layers: the fenestrated endothelial cell surface layer (glycocalyx); the glomerular basement membrane (GBM); and the epithelial podocytes and intercalated slit diaphragms. Early studies concluded that the GBM was the component of the GCW that restricted passage of proteins.[8] Subsequent studies were consistent with this “single-barrier” hypothesis,[1] until studies with peroxidative tracers found that the slit diaphragm was an effective barrier to filtration.[9] Later studies led to the “double-barrier” hypothesis: that the GBM restricts the passage of larger macromolecules, whereas slit diaphragms regulate the passage of smaller ones.[10] However, this hypothesis failed to explain the findings that some relatively large tracers were restricted just beneath the slit diaphragm and some were completely restricted at the level of the inner layers of the GBM, so the potential contribution of charge needed to be addressed. Rennke and co-workers[11] used several ferritin fractions of similar size with varying isoelectric points (pIs). A stepwise increase in the pI of ferritin resulted in a proportionate increase in its permeation into the GBM, with the more negatively charged particles penetrating furthest. Thus, these studies pointed to the existence of an intrinsic electrical charge in the GBM that was imparted by fixed anionic sites.[11]

These anionic sites have been localized to the surfaces of endothelial and epithelial cells, as well as GBM interposed between these cells. [1] [12] The podocyte and its foot processes are covered with a surface coat of acidic glycoproteins (sialoproteins or glomerular polyanions) that are highly negatively charged. Stainable polyanion has been identified to be podocalyxin, a sialoprotein that carries most of the glomerular sialic acid.[13] The epithelial slit diaphragm also consists, in part, of glycosialoproteins,[14] as does the endothelial cell coat.

The biochemical composition of the GBM has been extensively studied. [1] [15] The GBM consists of a nonpolar collagen-like component and a more polar noncollagen fraction of asparagine-linked polysaccharide units. Glomerular epithelial cells are capable of synthesizing all major GBM components. Integral components of the GBM include type IV collagen, laminin, entactin/nidogen, and various proteoglycans, including chondroitin sulfate proteoglycan and heparan sulfate proteoglycan (HS-PG). Of the latter, HS-PG has been shown to be particularly important in imparting charge selectivity to the GBM. [1] [16] Normally, polyanions (particular HS-PG) act as “anticlogging” agents to prevent the adsorption of plasma protein so that ultrafiltration may proceed.[16] Many studies have indicated the importance of anionic sites and HS-PG specifically in the defense against proteinuria. [17] [18] However, as discussed later, newer evidence points away from a predominant role of the GBM in filtration barrier function.

The role of glomerular cells in the defense against proteinuria has recently taken center stage, in view of innovative technologies and improvements in understanding of the molecular basis of the GCW. Daniels and colleagues [19] [20] used confocal microscopy to examine diffusion of fluorescent macromolecules across individual glomerular capillaries in intact glomeruli. Studies in this system showed that protein (dextran) clearance in intact glomeruli is much less than that for the GBM alone; most of the selectivity of the GCW resides in the cells rather than in the GBM.[20] In further support of this concept, removal of perlecan, the principal proteoglycan of the GBM, does not produce proteinuria.[21]

Observations of changes in the structure of podocytes in various clinical proteinuric diseases prompted speculation that defects in that cell might be responsible for increased GCW permeability. In vivo studies have provided further confirmation of the importance of podocytes[22] and slit diaphragms [2] [3] [23] in the restrictive properties of the GCW. In 1998, Kestilä and associates[24] identified the gene mutation in congenital nephrotic syndrome of the Finnish type (CNF, NPHSI), which is characterized by congenital proteinuria and absence of the slit diaphragm. The disease gene was shown to encode the protein nephrin in the slit diaphragm. [25] [26] Experimentally, nephrin-deficient mice were shown to develop massive proteinuria at birth, resulting in neonatal mortal-ity.[26] Clinically, nephrin deficiency has been identified in a number of proteinuric renal diseases, including diabetic nephropathy.[27]

The structure and function of the slit diaphragm is an area of active investigation. Although the actual structure is not yet fully understood, there are a number of interacting components. [3] [6] A hypothetical model of the slit diaphragm is depicted in Figure 26-1 .[6] According to this model, the slit diaphragm components nephrin and Neph1 likely interact with each other and form the backbone of the slit diaphragm. The function of other included proteins, such as P-cadherin and FAT, are unresolved. Nephrin and Neph1 interact with the intracellular adapter molecules podocin, CD2AP and Zona Occludens-1 (ZO-1), which connect the slit diaphragm to the actin cytoskeleton of foot process. The adapter molecules also enhance the signaling function of nephrin and Neph1. Regulation of these molecules and their interactions is under active investigation. [3] [6] Interestingly, it has recently been reported that angiotensin II induces reorganization of F-actin fibers and redistribution of ZO-1 that is physically associated with actin in murine podocytes and that the F-actin stabilizer jasplakinolide prevented both ZO-1 redistribution and albumin leakage.[28]

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FIGURE 26-1  Hypothetical model of the podocyte slit diaphragm. See text for discussion.  (Reproduced from Jalanko H: Pathogenesis of proteinuria: Lessons learned from nephrin and podocin. Pediatr Nephrol 18:487–491, 2003, with permission.)

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Several other candidate genes have been identified as potentially being associated with nephrotic syndromes; further details are available in Chapter 39 and several recent reviews. [3] [4] [5] [6]

Whereas most attention has centered on the role of the podocyte, the role of the endothelial cell and its surface coat, the glycocalyx, is beginning to receive some attention.[5] The glycocalyx consists of highly negatively charged proteoglycans and glycosaminoglycans reinforced with plasma proteins such as orosomucoid (a protein produced by endothelial cells).[29] Synthesis of proteoglycans and glycosaminoglycans is down-regulated when endothelial cells are exposed to puromycin, a proteinuric toxin.[30] In an extrarenal system (the peritoneum), transvascular protein transport is markedly increased in mice lacking endothelial caveolae,[31] suggesting another mechanism by which the endothelial layer retards protein filtration.

Proximal Tubule Protein Reabsorption

“Tubular proteinuria” results from impairment in the normal proximal tubular degradation of filtered proteins. In the normal kidney, significant amounts of albumin are filtered, but the amount reaching the final urine is less than 30 mg/day. The degradation of filtered proteins occurs through lysosomal or endosomal activity; protein degradation consists of lysosomal protein uptake from the tubular fluid and subsequent exocytosis of peptide products back into the urine. It now appears that reabsorption of albumin is receptor-mediated (see reviews [32] [33] [34] [35]). Luminal endocytosis is initiated by ligand binding to receptors localized in the clathrin-coated pits, followed by internalization, segregation of ligands and receptors in early and late endosomes, and directing of ligands to lysosomes for degradation, whereas the receptors are directed back to the apical plasma membrane via dense apical tubules.[7] Pathways of albumin handling in the kidney are schematized in Figure 26-2 .[35] The initial recognition step by receptor-mediated endocytosis involves at least two proteins, megalin and cubilin, that appear to operate cooperatively.[32] Their importance is demonstrated in studies in mouse knockout models. In animals lacking CLC-5,[36] megalin,[37] or cubulin[38] proteinuria increases markedly.

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FIGURE 26-2  Pathways of albumin degradation in the proximal tubule. Albumin is filtered in the glomeruli (1) and reabsorbed by the proximal tubule cells by receptor-mediated endocytosis (2a). Internalization by endocytosis is followed by transport into lysosomes for degradation. Classically, this is considered to result in the formation of free amino acids released into the circulation (2b); however, it has been recently suggested that significant amounts of albumin fragments are excreted in the urine, possibly resulting from tubular degradation of filtered albumin (2c). Some intact albumin may escape tubular reabsorption (3), the amount being greater as the glomerular filtration fraction of albumin increases or tubular function is compromised. The upper right shows a schematic representation of the intracellular pathways following endocytic uptake of albumin and possible associated substances. Following binding to the receptors, cubilin or megalin, the receptor-albumin complex is directed into coated pits for endocytosis, a process that may also involve amnionless (AMN). The complex dissociates following vesicular acidification, most likely also leading to the release of any bound substances. Albumin is transferred to the lysosomal compartment for degradation. Some albumin may be degraded within a late endocytic compartment and recycled as fragments to be released at the luminal surface. Alternatively, albumin fragments may be recycled from the lysosomal compartment by a yet unknown route. Receptors recycle through dense apical tubules, whereas released substances carried by albumin may be released into the cytosol or transported across the tubular cell. An alternative high-capacity retrieval pathway for nondegraded albumin located immediately distal to glomerular basement membrane has been proposed (4), but yet not characterized. Misdirected filtration of albumin into the interstitium resulting from pathologic, glomerular changes has been proposed as a pathway for progression of renal disease (5).  (From Birn H, Christensen EI: Renal albumin absorption in physiology and pathology. Kidney Int 69:440–449, 2006.)

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Glomerular Permselectivity

Proteinuria has been further characterized by studies of permselectivity, the extent to which the GCW discriminates among molecules of different size, charge, and configuration. Classically, measurement of the Bowman space-to-plasma concentration ratio (the “sieving coefficient,” θ) for various proteins has been determined by direct sampling via micropuncture techniques.[2] These studies indicate that small substances appear in the glomerular filtrate in concentrations similar to those in plasma, whereas the serum albumin is filtered to a much lesser extent (<0.1% that of inulin). The most extensively used method to quantify glomerular capillary permselectivity involves measurement of the fractional clearance of test macromolecules. If, like inulin, the test macromolecule is not reabsorbed or secreted, its fractional clearance will exactly equal its Bowman space-to-plasma concentration ratio, θ.[2]Proteins are not ideal test markers because of variations in size, charge, and shape, as well as tubule reabsorption of filtered protein. These difficulties may be circumvented with the use of a variety of exogenous nonprotein polymers, and much of the available permselectivity data relate to the use of dextran.[1] However, Ficoll has been evaluated and appears to be superior. [2] [39]

Permselectivity Based on Molecular Size

The use of neutral dextran to analyze glomerular size selectivity is illustrated in the middle curve of Figure 26-3 . [40] [41] [42] A value of 1.0 on the ordinate denotes a dextran clearance equal to that of inulin (e.g., no measurable resistance to the filtration of dextran). Measurable restriction to filtration of neutral dextran does not occur until the effective radius exceeds about 20 Å. As dextran size increases, fractional dextran clearance (θd) decreases progressively.

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FIGURE 26-3  Filtrate-to-plasma concentration ratio (θ) as a function of molecular size for tritiated dextran sulfate (DS), neutral dextran (D), and diethylaminoethyl dextran (DEAE). Data points are means ± SE measured in the normal Munich-Wistar rat. [51] [52] All three solid curves were calculated theoretically by using the membrane parameters Kf = 4.8 nL/(min · mm Hg), rp = 47 Å, and Cm = 165 mEq/L.  (From Deen WM, Satvat B, Jamieson JM: Theoretical model for glomerular filtration of charged solutes. Am J Physiol 238:F126, 1980.)

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Theoretical Interpretation of Size Selectivity

Isoporous Models.

The most useful theoretical descriptions of macromolecular transport are based on the concept of hindered movement of solutes through water-filled pores. Dextran filtration data such as those in Figure 26-3 are predicted by models that envision transport as taking place through numerous, identical cylindrical pores with a radius of approximately 55 Å. Fluxes are hindered both by a partitioning phenomenon in which the macromolecule is partially excluded by virtue of its shape, size, or charge and by a hydrodynamic effect related to the nearby presence of the pore wall.[2] For relatively high fluid flow rates through the pore and for large solutes that diffuse poorly, solute movement is primarily via convection. For lower fluid flow rates or small solutes that diffuse rapidly, solute movement is governed primarily by diffusion. The rate of filtration of a solute depends on two independent glomerular membrane properties: Kf, the glomerular capillary ultrafiltration coefficient, and rp, the apparent glomerular pore radius. A more complete discussion of the theories of partitioning and hindered particle motion has been recently reviewed.[2]

Application of this theoretical model to the data in Figure 26-3 results in calculated values of rp that are relatively independent of molecular size. Presumably, all molecules “see” the same pores, so the finding that the “best-fit” value of rp is independent of molecular size confirms that the theory successfully correlates most of the available data. Values of θ calculated with the use of the theory for neutral dextran are shown by the middle solid curve in Figure 26-3. In this case, a pore radius of 47 Å provides an excellent fit to the data presented, except for molecular radii smaller than 24 Å, for which the isoporous theory appears to underestimate dextran transport.

An additional parameter that may be derived from values of Kf and rp is the ratio of total pore area to pore length. For pores of a given radius and length, this parameter is a measure of “pore density,” the apparent number of pores per unit area of the GCW. Further calculations suggest that some 10% of the glomerular capillary surface area is perforated by pores.

Heteroporous Models.

Theoretical calculations indicate that the normal GCW behaves much as an isoporous filter with a pore radius of about 50 to 55 Å.[42] However, in some human diseases, experimental data are incompatible with the isoporous theory. In these proteinuric patients, θd was enhanced for the largest dextrans (>45 Å), but it was often decreased for the smallest dextrans.[43] These findings suggested that the selective increase in filtration of large dextrans could be explained by a second population of pores, fewer in number but with larger radii. Accordingly, Deen and co-workers[43] formulated a heteroporous model of glomerular size selectivity designed to account for the experimental observations. Data in nephrotic humans more closely fit a model of solute transport through a heteroporous membrane with a subpopulation of large pores. This model assumes that most of the GCW is perforated by cylindrical pores of radius ro and that a smaller portion of the GCW is permeated by large, nondiscriminatory “shunt” pathways that do not exhibit size selectivity. The portion of the GCW permeated by shunt pores is denoted ωo, a parameter that quantitates the magnitude of the size selectivity defect. The fractional area of the membrane occupied by this shunt pathway, though small, increases with each successive grade of barrier injury. This subpopulation of large pores is presumed to allow passage of immunoglobulin G (IgG) and probably most of the filtered albumin. Therefore, nonselective heavy proteinuria appears to result from loss of barrier size selectivity, which renders the glomerular membrane more porous to large plasma proteins.[43]

Lognormal Models.

In some cases, better results are obtained with a model assuming lognormal distribution of pore radii. Remuzzi and colleagues[44] used this model to define an index of the size of the largest pores in the GCW. By definition, 5% of the glomerular filtrate passes through pores with radii greater than r* (5%) and 1% passes through pores with radii greater than r* (1%).

Dextran, which has been used to obtain most of the available permselectivity data, appears to overestimate the true θ. Oliver and colleagues[39] proposed that Ficoll is a better probe of glomerular pore size; the use of Ficoll is now being extended to studies in rats, humans, and in vitro models. [19] [45] [46] For Ficoll, a lognormal plus shunt pathway model was found to be the most effective.[39]

Interestingly, it has been reported that cultured podocytes are capable of establishing a size-selective barrier, regulated by specific signaling pathways,[47] opening up a new pathway for study of the function of the glomerular barrier.

Permselectivity Based on Molecular Charge

The charge-selective characteristics of the GCW have traditionally been evaluated with negatively charged markers such as dextran sulfate (DS). In a normal kidney, fractional DS clearance is lower than that for neutral dextran at any given molecular radius, whereas positively charged molecules pass through more freely (see Fig. 26-3 ).[48] However, the use of DS as an appropriate marker to assess charge selectivity has been challenged by observations that it is not as inert a tracer as once believed and that earlier studies probably overestimated the effects of charge.[2] For example, Guasch and co-workers[49] found that DS binds with plasma proteins. Furthermore, cellular uptake and intracellular desulfation of DS may affect the interpretation of fractional clearance data.[50] A detailed discussion of controversies in this field may be found in recent reviews. [2] [5] Though not believed to invalidate the concept of charge selectivity, these observations indicate a need for further study in this area.

Permselectivity Based on Molecular Configuration

To compare sieving of molecules with different conformations, the effects of molecular shape or configuration must be taken into account. Bohrer and colleagues[51] compared the fractional clearance of neutral dextran with that of Ficoll, an uncharged cross-linked copolymer of sucrose and epichlorohydrin. At any given effective radius, the flexible coil dextran was filtered more readily than Ficoll, a nearly rigid sphere; the superior accuracy of Ficoll was subsequently confirmed.[39] More recently, available studies indicate that the shape and deformability of a protein are important and that polyscaccharides may exhibit more physiologically appropriate shape characteristics.[52]Overall, these studies suggest that protein configuration also plays a role in filtration, although size and charge appear to be more important. [2] [52]

Influence of Hemodynamic Factors on Filtration of Macromolecules

Hemodynamic factors influence the filtration of macromolecules (see review[53]). Often, θ varies inversely with the single-nephron glomerular filtration rate (SNGFR).[42] Thus, filtration of macromolecules is influenced not only by the intrinsic membrane properties of the GCW but also by other determinants of SNGFR: QA, the glomerular capillary plasma flow rate; ▵P, the glomerular transcapillary hydraulic pressure difference; and CA, the afferent arteriolar plasma protein concentration. The absolute single-nephron clearance of a macromolecule is given by the product θ × SNGFR.[42] Absolute clearance usually increases as QA is elevated, but less than in proportion to SNGFR; hence, θ decreases. Absolute macromolecular clearance rates also increase as ▵P rises. For neutral and anionic macromolecules, this increase is less than the increase in SNGFR, and as a result, θ decreases. For highly anionic molecules, this trend reverses at sufficiently high ▵P, and θ may increase. The opposite behavior is observed for positively charged molecules, with θ increasing with rising ▵P. The theoretical effects of CA on θ are similar to those for inverse changes in ▵P because CA and ▵P exert opposing effects on SNGFR. The actual effects of changes in CA are likely to be more complicated because of parallel changes in Kf.[54] Hemodynamic factors may also influence rates of volume flux through the shunt pathway. Not surprisingly, interventions that alter glomerular hemodynamics also influence permselectivity, as has been best described using blockers of the renin-angiotensin system (RAS). For example, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs), which routinely reduce ▵P and proteinuria, have been shown to reduce the clearance of neutral dextrans of all sizes. [45] [55]

Clinical Consequences of Proteinuria

Loss of albumin and other proteins into urine is the hallmark of nephrotic syndrome and a proximate or contributing cause to virtually all the systemic complications of this disorder. As depicted in Figure 26-4 [56] and detailed later, increased filtration of plasma proteins contributes to hypoalbuminemia and its complications, to hyperlipidemia, to alterations in coagulation factors, and to alterations in cellular immunity, hormonal status, and mineral and electrolyte metabolism (see reviews [56] [57] [58] [59] [60] [61]).

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FIGURE 26-4  Pathophysiology of nephrotic syndrome. All abnormalities originate from increased glomerular permeability to plasma proteins; hypoalbuminemia initiates the major manifestations.  (From Bernard DB: Extrarenal complications of the nephrotic syndrome. Kidney Int 33:1184, 1988.)

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HYPOALBUMINEMIA

Pathogenesis of Hypoalbuminemia

Nephrotic hypoalbuminemia results from multiple abnormalities in albumin homeostasis and is only partially explained by urinary albumin loss. Normal albumin metabolism is schematized in the upper panel of Figure 26-5 .[59] The liver normally synthesizes 12 to 14 g/day of albumin, 90% of which is catabolized in extrarenal sites, primarily the vascular endothelium.[62] About 10% of the albumin synthesized daily is catabolized in the kidney, mainly by proximal tubule reabsorption of filtered albumin.[63] About 150 g of albumin (or 30%–50% of the total exchangeable pool) is located intravascularly, with the remainder in interstitial fluid, mostly skin and muscle.[64] The fractional catabolic rate, or the percentage of the plasma pool that is catabolized daily, is about 6% to 10%. [62] [65] Thus, nephrotic hypoalbuminemia could result from some combination of urinary loss, decreased or insufficiently increased hepatic albumin synthesis, increased albumin catabolism, or altered albumin distribution.[66]

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FIGURE 26-5  Daily albumin turnover in normal individuals (A) and in patients with nephrotic syndrome (B).  (Reproduced from Bernard DB: Metabolic complications in nephrotic syndrome: Pathophysiology and complications. In Brenner BM, Stein JH [eds]: The Nephrotic Syndrome, vol. 9. New York, Churchill Livingstone, 1982.)

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Extracorporeal Losses.

The magnitude of hypoalbuminemia tends to increase with increasing proteinuria, but the relationship is inconsistent. Urinary losses alone should not lead to hypoalbuminemia because the liver can easily augment albumin synthesis and thus compensate for such losses. Evidence for enhanced intestinal albumin loss, or in-creased albumin catabolism, in the nephrotic syndrome is not strong.[66] As discussed later, renal albumin catabolism is in-creased, thereby contributing to the greater tendency to hypoalbuminemia.

Hepatic Albumin Synthesis.

Hepatic albumin synthesis is not impaired and, in fact, may be significantly increased in the nephrotic syndrome. [67] [68] In nephrotic rats, hepatic release of albumin is enhanced, and the relative synthetic rate of albumin is markedly increased, with a comparable increase in albumin mRNA. [69] [70] Oncotic pressure may play a role in albumin synthesis, as albumin gene expression varies inversely with oncotic pressure in experimental models.[71] That a transcriptional process is mainly responsible is suggested by findings that both steady-state levels and transcription rates of albumin mRNA are increased in the livers of nephrotic rats.[72] However, the increase in hepatic albumin synthesis is inadequate for the degree of hypoalbuminemia; thus, the albumin synthetic response rate is relatively impaired.

Albumin Catabolism.

In some hypoalbuminemic states, albumin catabolic rates are reduced.[73] In contrast, the possibility that hypoalbuminemia might be exacerbated by a maladaptive increase in albumin catabolism was suggested by Katz and associates,[74] who speculated that the increased urinary albumin load might up-regulate tubular albumin catabolism. In that case, most filtered albumin would be catabolized, and thus urinary albumin would represent only a small fraction of the filtered load. In confirmation of this notion, tubule albumin reabsorptive rates increase in nephrotic rats, though variably.[75] Additional support for the concept comes from evidence of a dual transport system for albumin uptake in the isolated perfused rabbit proximal tubule. This model exhibits both a low-capacity system that becomes saturated once the protein load exceeds physiologic levels and a high-capacity, low-affinity system that permits tubule albumin reabsorptive rates to rise as the filtered load increases.[76] Thus, an increase in the fractional catabolic rate may occur in the nephrotic syndrome. Regardless of whether fractional catabolism is normal or increased, total body albumin stores are markedly decreased. The net result is that absolute catabolic rates are normal or decreased.[66] Nutritional considerations affect this process. In nephrotic rats, absolute catabolic rates are decreased in rats fed adequate dietary protein but increased in rats receiving a low-protein diet.[77] Although decreased catabolism may serve to preserve total albumin stores, it is obviously insufficient to maintain albumin homeostasis.

Albumin Distribution.

In nephrotic syndrome, the extravascular albumin pool is even more depleted than the intravascular pool.[78] Mobilization of extravascular albumin represents an early response to acute albumin loss, but this compensatory mechanism is clearly inadequate in the setting of continuing albumin loss, as in nephrotic syndrome.

Regulation of Albumin Metabolism in Nephrotic Syndrome

Several factors contribute to regulation of albumin metabolism and dysregulation in nephrotic syndrome.[66] The most widely studied factors regulating albumin synthesis are serum oncotic pressure and nutritional status. Albumin synthetic rates do not correspond to either serum albumin concentration or oncotic pressure in nephrotic patients.[67] It has been postulated that the hepatic albumin synthetic rate is more directly determined by changes in the hepatic extravascular interstitial albumin pool than by plasma characteristics and that this hepatic pool is not depleted in nephrotic syndrome and thus albumin synthesis is not stimulated.[79] More recently, it has been suggested that some serum factor or factors in hypo-oncotic states may stimulate albumin synthesis. In support of this hypothesis, incubation of rat hepatocytes with serum from nephrotic rats led to increased albumin and transferrin synthesis, even when oncotic pressure in the medium was normalized.[80]

Dietary factors also play a role. Albumin synthesis and serum albumin are not correlated in nephrotic rats fed a low-protein diet, but in the presence of high protein intake, albumin synthetic rates vary inversely with serum albumin.[72] Increasing dietary protein intake in nephrotic rats results in increased hepatic albumin mRNA content, as well as increased transcription, whereas decreased dietary protein intake limits hepatic albumin synthesis. [72] [81]However, increasing dietary protein intake does not increase serum albumin or body albumin pools in nephrotic animals [77] [81] or patients.[67] Feeding a high-protein diet stimulates hepatic albumin synthesis in nephrotic rats, but does not correct hypoalbuminemia, however, because dietary protein supplementation also increases urinary protein loss. [77] [81] This unfortunate consequence of a high-protein diet also occurs in nephrotic patients; those eating a high-protein diet exhibit higher albumin synthetic rates, but also increased albuminuria, which results in no change in serum albumin levels.[67]

Factors contributing to enhanced proteinuria in the setting of a high-protein diet may include increased renal blood flow and glomerular filtration rate (GFR), with enhanced fractional renal clearance of albumin.[82] However, the net result is that, despite enhanced albumin synthesis, increased urinary losses predominate, so the serum albumin concentration and body albumin pools are further reduced.[82] Experimentally, blockade of the RAS in the setting of a high-protein diet allows increased hepatic synthesis but limits proteinuria, thereby allowing some amelioration of the hypoalbuminemia.[83] In nephrotic patients, both dietary protein restriction and ACEIs reduce proteinuria; however, protein restriction also reduces hepatic albumin synthesis, whereas albumin synthetic rates are maintained with angiotensin-converting enzyme (ACE) inhibition.[84]

Many hormones are needed for albumin synthesis,[66] but their relevance to nephrotic hypoalbuminemia is not well understood. Albumin synthesis is suppressed in the presence of inflammation,[85] and it is possible that elevated levels of lymphokines such as tumor necrosis factor[86] interfere with albumin synthesis in nephrotic syndrome.

In summary, nephrotic hypoalbuminemia is characterized by large urinary albumin losses and a marked reduction in the total exchangeable albumin pool. Mechanisms tending to counteract these forces are mobilization of extravascular pools, increases in albumin synthesis, and decreases in albumin catabolism. However, these compensatory mechanisms are insufficient to correct the hypoalbuminemia. Comparisons between normal and nephrotic albumin homeostasis are schematized in the bottom panel of Figure 26-5 .[59] Normally, hepatic synthesis equals catabolism, with a yield of 1 to 2 g, which undergoes glomerular filtration and proximal tubular catabolism. In the nephrotic state, hepatic synthesis may be slightly increased, but the plasma albumin pool is smaller because catabolism is proportionally enhanced. Larger amounts are presented to the glomerulus, thereby resulting in both increased urinary loss and enhanced tubule catabolism.

Consequences of Hypoalbuminemia

Edema Formation and Blood Volume Homeostasis

Mechanisms of edema formation in the nephrotic syndrome are complex and have been recently reviewed. [87] [88] [89] [90] Nephrotic edema does not result solely from hypoalbuminemia. The balance of Starling forces at the arteriolar end of the capillary favors net filtration of fluid into the interstitium. However, ongoing fluid transudation (edema accumulation) is normally limited by at least three protective mechanisms. First, lymphatics expand and proliferate so that increased lymphatic flow provides protection. Second, transudation of protein-free filtration into the interstitium reduces interstitial oncotic pressure, thus decreasing the oncotic pressure gradient and slowing ultrafiltration. Third, fluid flux tends to increase interstitial hydrostatic pressure, thereby reducing the transcapillary pressure gradient and further slowing filtration. Furthermore, the compliance characteristics of the interstitium resist fluid accumulation.[91] Thus, the appearance of edema in glomerulonephritis implies substantial disrup-tion of the normal defenses against edema formation[88]; the role of primary sodium retention in this setting is discussed later.

Relationship of Edema Formation to Reduced Plasma Oncotic Pressure.

Hypoalbuminemia lowers the colloid oncotic pressure of blood, thereby favoring movement of water from the vascular to the interstitial space. However, continued edema formation would require disruption of normal defenses against edema, and evidence for such derangement is not clearly found. Patients studied during relapse and remission show almost equivalent changes in interstitial and plasma colloid osmotic pressure.[92] The reduction in interstitial oncotic pressure results in part from acceleration of lymphatic flow, which in turn returns interstitial protein to the intravascular space.[88] It has been suggested that this “wash-down” phenomenon is triggered by a slight increase in interstitial volume and hydraulic pressure induced by the initial loss of fluid into the interstitium. Body albumin pools are thus redistributed so that a greater fraction is located in the intravascular space.[78] These events thus serve to maintain blood volume and defend against edema formation.

Another mechanism related to nephrotic edema is the finding that capillary filtration capacity is higher in nephrotic patients. [90] [93] Capillary hydraulic conductivity is determined by intercellular macromolecular complexes between endothelial cells, for example, tight junctions made of occludins, claudins, and ZO proteins, and adherens junctions made of cadherin, actinin, and catenins. These junctional complexes are closely related to the actin cytoskeleton. [94] [95] Such a mechanism may increase capillary conductivity in nephrotic patients, under the influence of circulating permeability factors such as tumor necrosis factor-a. [86] [96]

Taken together, it appears that substantial disruption of the renal mechanisms responsible for extracellular fluid homeostasis, rather than the level of hypoalbuminemia per se, is the primary determinant of the severity of edema formation. In assessing the relative contribution of hypoalbuminemia to edema formation, it is necessary to take into consideration the prevailing intravascular volume as well.

Relationship of Edema Formation to the Prevailing Intravascular Volume.

One postulated scenario linking hypoalbuminemia to edema formation relates to the “underfill mechanism,” as depicted in Figure 26-6 .[97] According to this scenario, reductions in serum albumin and plasma oncotic pressure lead to edema formation, but also to hypovolemia. The reduced plasma volume (PV) then triggers compensatory mechanisms (e.g., nonosmotic vasopressin release, the RAS, and the sympathetic nervous system) that stimulate renal Na+and water retention. The latter serve to restore intravascular volume but also exacerbate hypoalbuminemia, so edema formation continues. However, some experimental observations are at odds with this hypothesis. [88] [98] [99]Moreover, the presence of hypovolemia is questionable; there has been inability to document hypovolemia by direct measurements, inability to consistently find changes in hormonal modulators compatible with hypovolemia, and failure of predicted changes to occur after remission or diuretic therapy. In nephrotic patients, PV and blood volume are not usually reduced; in fact, they are generally normal or even expanded. [100] [101] [102] Available studies note a range of PV in nephrotic patients, and methodologic issues may interfere with the interpretation of these studies. [97] [102] [103] Nonetheless, it should be possible to indirectly estimate blood volume by measurement of vasoactive hormones that are volume-responsive. Such functional evidence of hypovolemia is not consistently found in nephrotic syndrome. [59] [97] [98] [99] [101] [102] Plasma renin activity (PRA) and aldosterone levels tend to be low and do not always correlate well with changes in PV. [102] [104] Similarly, plasma levels of norepinephrine, arginine vasopressin (AVP), and atrial natriuretic peptide (ANP) tend to be normal or inconsistently changed. [105] [106] Moreover, PV expansion by infusion of hyperoncotic plasma[107] or salt-poor albumin[108] and head-out water immersion[109] does not regularly result in diuresis or natriuresis. Nevertheless, some studies have found evidence consistent with hypovolemia and a natriuretic response to these maneuvers. [97] [104] [107]

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FIGURE 26-6  The “underfill” mechanism of edema formation. Hypovolemia (resulting from hypoalbuminemia and decreased plasma oncotic pressure) is viewed as the key event promoting Na+ and water retention by the kidney.  (From Perico N, Remuzzi G: Edema of the nephrotic syndrome: The role of the atrial peptide system. Am J Kidney Dis 22:355, 1993.)

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Evidence from patients undergoing remission from nephrotic syndrome is also unclear. In responsive patients, steroid therapy leads to diuresis and natriuresis before any change in serum albumin. PRA and aldosterone levels are initially high and fall during natriuresis. After resolution of edema, PRA and aldosterone again rise to high levels, whereas plasma albumin and blood volume remain low; however, Na+ retention does not occur, and Na+ balance is maintained.[104] Taken together, these observations suggest a wide spectrum in prevailing PVs. These data have important therapeutic implications. The data suggest that edema is not necessary for maintenance of blood volume and, as a corollary, that vigorous treatment of edema with diuretics does not cause failure to maintain blood volume.[110]

Role of Intrarenal Mechanisms.

Most of the evidence implicates a primary intrarenal defect in the pathogenesis of nephrotic edema. This hypothesis, termed the “overfill theory,” is schematized in Figure 26-7 .[97] According to this hypothesis, a primary increase in renal Na+ retention leads to extracellular fluid volume expansion, altered Starling forces, and edema formation. Evidence in support of this mechanism comes from observations that Na+ retention occurs only in the ipsilateral kidney of rats with unilateral glomerulonephritis.[111] Moreover, the reduction in GFR that is often present would further limit Na+ excretion and contribute to renal sodium retention.

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FIGURE 26-7  The “overfill” mechanism of edema formation. The abnormal renal Na+ retention is viewed as the primary event that through the increased plasma volume leads to alteration of the Starling forces at the local tissue level.  (From Perico N, Remuzzi G: Edema of the nephrotic syndrome: The role of the atrial peptide system. Am J Kidney Dis 22:355, 1993.)

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Micropuncture and other studies have localized the primary Na+ handling abnormality to the distal nephron.[111] Regarding mechanisms, considerable attention has focused on the role of ANP. Clinical[112] and experimental[113]studies have noted renal ANP resistance (i.e., blunted or absent natriuretic responses to ANP) in the nephrotic syndrome. ANP resistance is confined to the ipsilateral kidney in unilateral glomerulonephritis,[113] thus suggesting a role for this hormone in primary renal Na+ retention. Some evidence relates this finding of ANP resistance to heightened efferent sympathetic nervous activity.[114] At the level of the tubular cell, evidence suggests that the problem is accelerated breakdown of normally produced cyclic guanosine monophosphate. [115] [116] [117]

Recently, insight has been gained into the molecular mechanisms of renal sodium avidity. The hydrolytic and transport activities of sodium-potassium-adenosine triphosphatase (Na+,K+-ATPase) are increased in the cortical collecting duct in nephrotic rats. The proportional increases in Na+,K+-ATPase activity, cell surface expression, and total cellular content are associated with increased amounts of α- and β-subunit mRNA.[118] In principal cells from nephrotic rats, the epithelial sodium channel (ENaC) activity is increased in the absence of transcriptional induction of the mRNA encoding any of the ENaC subunits.[119] Though clearly invoked in some studies of the nephrotic syndrome, [119] [120] ENaC activation and targeting may be secondary to hyperaldosteronism. [119] [121] Overall, Na+ retention in the cortical collecting duct appears to be due, at least in part, to coordinated overactivity of the Na+,K+-ATPase and ENaC sodium transporters.[118] Finally, a role for the proximal tubule has been invoked with the observation that Na+ retention may also be associated with a shift of the cortical Na+/H+ exchanger NHE3 from an inactive to an active pool.[122] Indeed, it has recently been reported that NHE3 is activated in nephrotic rats,[122] and that NH3 is activated in vitro by albumin.[123]

A novel hypothesis regarding the interrelationship of sodium retention, interstitial inflammation, and nephrotic edema has recently been advanced by Rodríguez-Iturbe and co-workers.[124] The authors hypothesize that interstitial inflammation of the kidney induces primary sodium retention ( Fig. 26-8 ). The generation of interstitial vasoconstrictors, driven by the inflammatory cell infiltrate, leads to reduction in Kf and SNGFR. As a consequence, there is a net increase in tubular Na+ reabsorption leading to primary sodium retention (“overfill”). The decrease in plasma oncotic pressure favors fluid extravasation from the intravascular compartment, thereby buffering changes in PV induced by sodium retention. If hypoalbuminemia is severe or the inflammatory infiltrate is absent, the reduction in plasma oncotic pressure may lead to “underfill” and secondary compensatory sodium retention. In support of this hypothesis are experimental observations that administration of mycophenolate mofetil prevents salt-sensitive hypertension after inflammation produced by infusion of angiotensin II[125]; the hypothesis has not yet been rigorously tested clinically.

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FIGURE 26-8  Pathophysiology of edema in the nephrotic syndrome. Proteinuria induces tubulointerstitial inflammation, with stimulation of vasoconstrictive mediators (angiotensin II, AII) and inhibition of vasodilatory mediators (e.g., nitric oxide [NO]). In the glomeruli, proteinuria causes a reduction in glomerular capillary untrafiltration coefficient (Kf) and single nephron glomerular filtration rate (SNGFR). Consequently, there is a net increase in tubular Na+ reabsorption leading to primary Na+ retention (“overfill”) and increased capillary hydrostatic pressure (Pc). The decreased plasma oncotic pressure (Pcop) favors fluid movement outward, thereby buffering changes in PV induced by Na+ retention. If hypoalbuminemia is severe and inflammation is minimal, the reduction in Pcop may cause “underfill” and secondary Na+ retention.  (From Rodríguez-Iturbe B, Herrera-Acosta J, Johnson RJ: Interstitial inflammation, sodium retention, and the pathogenesis of nephrotic edema: A unifying hypothesis. Kidney Int 62:1379–1384, 2002, with permission.)

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Though less well studied, the mechanisms underlying abnormalities in water handling in experimental nephrotic syndrome have begun to be explored. These studies have noted reduced renal medullary water channel expression,[126]impaired aquaporin and urea transporter expression,[127] and decreased abundance of thick ascending limb Na+ transporters.[128]

Alterations in Renal Function

The Starling equation would predict that hypoalbuminemia and thus reduced plasma colloid oncotic pressure would reduce the forces opposing ultrafiltration, thereby increasing glomerular filtration. However, clinical[129] and experimental[130] studies indicate that such is not the case and that values of GFR are in fact reduced in conditions of reduced plasma protein levels. Baylis and colleagues[54] reported that the failure of SNGFR to rise resulted from a concomitant reduction in Kf. Reduced values of SNGFR, primarily caused by a reduction in Kf, have subsequently been observed in some,[130] but not all,[131] experimental nephrotic models; these differences in SNGFR derive, in part, from the presence or absence of compensatory elevations in ▵P. These observations suggest that serum albumin per se may not directly affect Kf, or that other factors may mitigate the effects of hypoalbuminemia on Kf. Innovative methods for estimating values of SNGFR and its determinants in humans also suggest that a reduction in Kf commonly accompanies clinical glomerulonephritis as well. For example, this pattern has been observed in patients with minimal change disease[132] and membranous nephropathy.[133]

Alterations in Drug Pharmacokinetics

Kidney disease induces changes in all aspects of drug handling, including changes in bioavailability, the volume of distribution, renal drug metabolism, and renal excretion of drug and/or its metabolites.[134] Guidelines for modification of drug dosage in kidney disease are readily available [134] [135] [136] [137] and are detailed in Chapter 57 . The nephrotic syndrome poses special problems in drug handling. Hypoalbuminemia limits sites available for protein binding, thus increasing the amount of circulating free drug and potentially increasing first-pass hepatic drug removal. In addition, binding of organic bases and especially acids and bases is altered in hypoalbuminemia. In nephrotic patients, reduced protein binding results both from hypoalbuminemia and from a decrease in albumin's affinity for drugs. Accordingly, the unbound fraction of acidic drugs, including salicylate and phenytoin, may be markedly increased.[137] The clinical consequences of altered protein binding may be difficult to predict: Decreased binding allows for a higher concentration of free drug, but this effect may be counteracted by a larger volume of distribution and/or faster metabolism. Furthermore, protein binding may enhance tubule drug secretion; the lesser protein binding in nephrotic syndrome may result in delayed renal excretion of some drugs.[134] Edema and ascites may increase the apparent volume of distribution of drugs that are highly water soluble or protein bound, thereby resulting in inadequate plasma levels, an effect particularly prominent with aminoglycoside antibiotics.[134]

The actions of diuretics are substantially altered in kidney disease and nephrotic syndrome, thereby contributing to the observed resistance to these drugs in these conditions. [138] [139] [140] The unbound fraction of furosemide increases markedly in severely hypoalbuminemic patients.[141] Nephrotic patients with a normal GFR deliver normal amounts of loop diuretics into the urine, but drug delivery is decreased in the setting of renal insufficiency.[142]When proteinuria is present, a substantial amount of furosemide may bind to urinary proteins, thereby reducing the amount of active, unbound drug in urine.[143] Tubule albumin blunts the inhibitory effects of furosemide on fractional loop Cl- reabsorption,[144] whereas agents that block albumin-furosemide binding in the proximal tubule, such as warfarin and sulfisoxazole, partially restore diuretic responsiveness in experimental animals.[145]However, a careful study found that sulfisoxazole was ineffective in nephrotic patients.[146] Nephrotic patients also exhibit abnormal pharmacodynamic responses to furosemide,[143] so that the renal response to the drug is diminished even when adequate amounts of unbound, active drug reach the active site. Furthermore, animal studies indicate that furosemide is less potent in inhibiting Cl- reabsorption in the loop in nephrotic rats.[147] Thus, both the pharmacodynamics and the pharmacokinetics of loop diuretics are altered in nephrotic syndrome. Single intravenous doses of 80 to 120 mg may be required to attain therapeutic levels of furosemide in urine, but doses above this range are unlikely to achieve any added therapeutic response.[138]

Studies in analbuminemic rats indicated that injection of furosemide bound to albumin resulted in natriuresis, with normalization of the plasma disappearance rate and increased urinary excretion of furosemide.[148] Thus, binding to plasma albumin appeared to be necessary for efficient delivery of drug into urine. These investigators then examined hypoalbuminemic patients with furosemide resistance and found that injecting furosemide as an admixture with equimolar albumin produced a diuresis, whereas giving either alone was without effect. Whether natriuresis occurred was not specifically mentioned. However, the available literature overall is conflicting as to the efficacy of combining albumin and furosemide in nephrotic patients.[149] Because administration of large amounts of albumin alone is both ineffective and expensive, this therapeutic combination will require clear validation before its routine use can be recommended. Other interventions, such as use of ultrafiltration[150] or combining furosemide with indapamide,[151] have been reported but also require further validation.

Therapy for glomerular disease or nephrotic syndrome may also be associated with drug interactions. For example, corticosteroids may inhibit hepatic microsomal enzymes, thereby altering the metabolism of other drugs. Clinically important drug interactions may be seen with other immunosuppressive drugs, including cyclosporine and azathioprine, as well as with diuretics and antihypertensive agents.[137]

Alterations in Platelet Function

Hypoalbuminemia may contribute to abnormal platelet function in nephrotic patients because conversion of arachidonic acid to metabolites that aggregate platelets is regulated by albumin.[152] In the presence of hypoalbuminemia, arachidonic acid may be metabolized to platelet-aggregating substances such as endoperoxides and thromboxane A2.[153] In support of this notion, the degree of platelet dysfunction tends to correlate with the severity of hypoalbuminemia and proteinuria.[154] Platelets from nephrotic patients are refractory to adenylate cyclase stimulation by prostaglandin E1, further enhancing the tendency toward increased platelet aggregation.[155] However, a firm correlation between the plasma albumin concentration and platelet aggregability is not well established clinically.[155]

HYPERLIPIDEMIA

Hyperlipidemia is a frequent complication of nephrotic syndrome. Marked dysregulation of lipid metabolism occurs, with both quantitative and qualitative abnormalities in plasma lipids and lipoproteins. Although hyperlipidemia may be found in any kidney disease, it is most striking in nephrotic syndrome, in which such changes occur even when the GFR remains normal. The major lipid abnormalities are listed in Table 26-1 and described later.


TABLE 26-1   -- Mechanisms in the Pathophysiology of Lipid Abnormalities in Nephrotic Syndrome

  

 

Alterations in low-density lipoprotein and cholesterol metabolism

  

 

Increased LDL generation

  

 

Increased apo B synthesis

  

 

Increased CETP activity

  

 

Increased cholesterol synthesis

  

 

Increased HMG-CoA reductase activity

  

 

Decreased cholesterol 7α-hydroxylase

  

 

Up-regulation of hepatic ACAT

  

 

Defects in LDL clearance

  

 

Reduction in hepatic LDL expression

  

 

Reductions in apo B catabolism

  

 

Alterations in very low density lipoprotein metabolism

  

 

Impaired VLDL clearance

  

 

Reduced LPL and hepatic lipase activity

  

 

Reduced VLDL receptor

  

 

Impaired enrichment with apo E and apo C

  

 

Increased hepatic production of fatty acids and triglycerides

  

 

Elevated enzymatic activity of acyl-CoA carboxylase and fatty acid synthase

  

 

Increased hepatic DGAT activity

  

 

Alterations in high-density lipoprotein

  

 

Diminished LCAT activity

  

 

Apo A-I enrichment of HDL[*]

  

 

Reduced expression of HDL (SR-B1) receptor

Increased Lp(a) synthesis

 

ACAT, acetyl coenzyme A:cholesterol actytransferase; acyl-CoA, acyl coen-zyme A; apo A-I, apolipoprotein A-I; apo B, apolipoprotein B; apo C, apolipoprotein C; apo E, apolipoprotein E; CETP, cholesterol ester transferase protein; DGAT, diacylglycerol acyltransferase; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); LPL, lipoprotein lipase; VLDL, very low density lipoprotein.

 

*

Observed in rats. Unlike experimental models, fractional catabolism of apo A-I in nephrotic patients is increased because of the increase in CETP, which is absent in rats. CETP mediates conversion of the larger HDL2 to the smaller HDL3, which has less affinity for apo A-I, and thus indirectly facilitates clearance of apo A-I.

 

Lipid Abnormalities in Nephrotic Syndrome

The nephrotic syndrome is characterized by abnormalities in virtually every aspect of lipid and lipoprotein metabolism. [156] [157] [158] Increased levels of the apolipoprotein B (apo B)–containing lipoproteins, very low density (VLDL), intermediate-density (IDL), and low-density (LDL) lipoproteins result in hypercholesterolemia, sometimes with hypertriglyceridemia. Cholesterol and phospholipid levels rise early in the disease course, whereas triglyceride (TG) elevations are more commonly found with more severe disease. Total high-density lipoprotein (HDL) levels are usually normal, but in severely proteinuric patients, HDL may be lost in the urine, with resultant reduced levels. [156] [157] [158] Subtype analysis demonstrates an abnormal distribution with significant reductions in the protective subtype HDL2. [159] [160] Plasma concentrations of lipoprotein (a) (Lp[a]) are also elevated in nephrotic syndrome. [161] [162] [163] In addition, nephrotic patients show qualitative abnormalities in lipoprotein composition. The cholesterol-to-TG ratio is elevated in all classes of lipoproteins, which also tend to be enriched with cholesterol ester.[164] The highly atherogenic small LDL-III fraction is elevated as well.[165] The apolipoprotein content is also abnormal, with reduced apo C and E despite elevations in apo B, C-II, and E and an increased ratio of apo C-III to apo C-II. [158] [166] [167] Taken together, these abnormalities result in an increased atherogenic profile.[168]

Pathogenesis of Nephrotic Hyperlipidemia

Nephrotic hyperlipidemia results from both overproduction and impaired catabolism or composition of serum lipids and lipoproteins. A major issue is whether the lipid abnormalities in nephrotic syndrome arise as a consequence of hypoalbuminemia or proteinuria. In general, the severity of hyperlipidemia tends to correlate with the severity of hypoalbuminemia. In addition, remission of nephrotic syndrome is usually associated with a decrease in serum cholesterol as the albumin level rises, whereas albumin infusion acutely raises serum albumin and lowers serum cholesterol levels. [59] [159] [169] Because hepatic synthetic rates of albumin and lipoproteins react to similar stimuli and follow the same synthetic pathways, it has been hypothesized that increased lipoprotein synthesis was simply a side effect of increased albumin synthesis. However, although albumin synthesis is increased, no clear correlation has been found between hyperlipidemia and the rate of albumin synthesis in nephrotic patients. Kaysen and associates[170] showed that serum cholesterol levels in nephrotic patients were dependent only on the renal clearance of albumin and were totally independent of albumin synthetic rates, but that serum TG levels showed some dependence on albumin synthesis. Similarly, serum lipid levels in nephrotic rats correlated with proteinuria and not with albumin synthetic rates.[171] An alternative stimulus may be the reduction in plasma oncotic pressure. Infusion of either albumin or dextran into nephrotic patients and animals reduces serum lipid levels, thus suggesting that low plasma oncotic pressure may stimulate hepatic lipoprotein synthesis. [170] [172] [173] These findings correspond to in vitro observations demonstrating modulation of lipoprotein synthesis in hepatocytes cultured in media containing variable amounts of albumin.[69]

It is now apparent that reductions in plasma albumin levels or oncotic pressure, as well as the direct consequences of proteinuria, contribute to lipid alterations in nephrotic syndrome. As discussed later, these major factors operate on various levels of the lipid metabolic pathways. Metabolism of lipoproteins is closely linked. For purposes of this review, defects in the metabolism of individual fractions are discussed separately, with the understanding that one mechanism may alter the levels and composition of multiple lipoproteins.

Alterations in Low-Density Lipoprotein and Cholesterol Metabolism

Increases in LDL and total cholesterol in nephrotic syndrome are attributable to both increased synthesis and impaired catabolism. It has been shown that some nephrotic patients have increased absolute synthetic rates of apo B-100, the principal apoprotein constituent of LDL. Importantly, increased LDL apo B synthesis does not correlate with the synthetic rate of albumin.[174] Moreover, significant reductions in apo B catabolism have also been demonstrated.[175] [176] Another line of evidence has suggested that plasma levels and the activity of cholesterol ester transfer protein (CETP) are enhanced in nephrotic syndrome.[177] This protein, which is present in humans but not in rats, mediates the transfer of esterified cholesterol from HDL to VLDL remnants to yield LDL.

Hepatic cholesterol synthesis is increased in experimental nephrotic syndrome. Complex studies by Vaziri and co-workers [178] [179] have identified enzymatic defects in the liver of nephrotic rats that can collectively enhance hepatic cholesterol synthesis. These studies have shown increased hepatic activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for biosynthesis, in nephrotic rats. These changes are typical for the induction phase of proteinuria and are followed by a gradual decline to baseline levels.[178] This may explain why some other studies failed to find increases in this enzyme in nephrotic models.[180] In contrast to HMG-CoA reductase, hepatic expression of cholesterol 7a-hydroxylase, the rate-limiting enzyme responsible for conversion of cholesterol to bile acids, is reduced in nephrotic rats. [179] [181]

More recently, the same group described marked up-regulation of hepatic acetyl coenzyme A:cholesterol acyltransferase (ACAT) in nephrotic rats.[182] This multifunctional enzyme is involved in the catalysis of intracellular cholesterol esterification and is responsible for lowering intracellular free cholesterol. By lowering hepatic free cholesterol, ACAT up-regulation may be responsible for the aforementioned defects in HMG-CoA reductase and 7a-hydroxylase activity and the enhanced cholesterol synthesis. Furthermore, enhanced ACAT activity leads to intracellular accumulation of cholesterol ester. Increases in hepatic cholesterol concentrations could contribute to hyperlipidemia both by increasing VLDL production and by down-regulating expression of LDL receptors, as discussed later.[180] In the vascular system, this phenomenon leads to foam cell formation and atherosclerosis.[183]Indeed, recent evidence has further suggested that ACAT plays a crucial role in complex alterations of lipid metabolism in nephrotic syndrome, at least experimentally.[180] Treatment of rats with puromycin nephrosis with an ACAT inhibitor resulted in reductions in plasma cholesterol and TGs, normalized the total cholesterol-to-HDL ratio, and lowered hepatic ACAT. This was accompanied by near normalization of plasma LCAT, hepatic SRB-1, and the LDL receptor (see later) and significant amelioration of proteinuria and hypoalbuminemia.[180]

Results of studies in humans are less clear. Turnover studies using radiolabeled glycerol and mevalonate have suggested increases in cholesterol synthesis.[164] In contrast, the serum lathosterol-to-cholesterol ratio, an index of cholesterol synthesis, is not elevated and does not change in response to antiproteinuric treatment.[184] Whether increased cholesterogenesis actually occurs in human nephrotic syndrome requires further clarification.

In addition to the defects discussed earlier, acquired defects in LDL clearance could also be responsible for LDL elevation in the nephrotic syndrome. Some earlier clinical studies have suggested reduced receptor-mediated LDL clearance with associated increases in LDL catabolism via alternative pathways. [176] [177] Supporting this hypothesis, Vaziri and co-workers [179] [185] described marked reduction in hepatic LDL receptor protein expression in nephrotic rats. These changes were present despite normal LDL receptor mRNA, suggesting inefficient LDL receptor translation or enhanced protein turnover in these rats. The authors hypothesized that, in addition to reduced LDL clearance, an acquired hepatic LDL receptor defect could contribute to low hepatocellular cholesterol levels and consequent dysregulation of hepatic HMG-CoA reductase and 7a-hydroxylase, as discussed previously.[186] Another defect in nephrotic syndrome is the finding of marked up-regulation of hepatic LDL receptor-related protein expression, which is partly reversed with statin administration.[187]

Alterations in Very Low Density Lipoprotein Metabolism

The increased VLDL levels in nephrotic syndrome occur predominantly as a result of impaired VLDL clearance. Early studies demonstrated defective chylomicron clearance in nephrotic rats,[171] a phenomenon that correlated with proteinuria rather than with hypoalbuminemia. In addition, plasma TG levels are higher in nephrotic than in analbuminemic rats despite similar increases in hepatic TG production.[188] Defective VLDL clearance has also been documented in nephrotic patients.[174]

As a major determinant of chylomicron and VLDL clearance, the functional integrity of lipoprotein lipase (LPL) has been a logical focus for study in this area. Reduced LPL activity in nephrotic patients was proposed by Garber and colleagues.[189] Earlier reports suggested that decreased LPL activity may relate to the increased levels of circulating free fatty acids that result from hypoalbuminemia and the lowered protein-binding capacity of plasma. The increased free fatty acid level contributes by providing the lipid substrate for increased hepatic lipoprotein synthesis and by leading to decreased activity of LPL. [190] [191]

LPL is attached to the endothelium by ionic bonding to a negatively charged matrix of glycosaminoglycans such as heparan sulfate.[190] This endothelium-bound LPL is an active, metabolically important pool, which is reduced in nephrotic rats. [171] [191] Urinary excretion is markedly increased in nephrotic patients,[192] and circulating levels of heparan sulfate are reduced in nephrotic plasma and contribute to the decrease in LPL activity. In support of this concept, studies in nephrotic rats show that the markedly delayed plasma disappearance of radiolabeled chylomicrons may be completely normalized by injection of minute amounts of purified urinary heparan sulfate.[193] The heparan sulfate deficiency may also result from deficient hepatic synthesis of glycosaminoglycans. Nephrotic syndrome is characterized by excessive urinary losses of orosomucoid, a plasma glycoprotein synthesized by the liver. Urinary losses may lead to an increase in hepatic synthesis with a resultant excessive drain of key sugar intermediates from liver parenchymal cells, thus limiting the substrates available for heparan sulfate synthesis.[1] Because the endothelial pool of LPL in Nagase analbuminuric rats is reduced to the same extent as in nephrotic rats but TG levels are much higher in the latter model, it has been hypothesized that, in addition to defects in endothelial LPL, other important determinants of VLDL levels are present in nephrotic syndrome.

Indeed, more recent studies have revealed abnormalities in other determinants of VLDL clearance. In several models of nephrotic syndrome, Liang and Vaziri [194] [195] demonstrated that elevated serum TG levels are in part attributable to reduced VLDL receptor and LPL expression. Reductions in VLDL receptor protein and mRNA were inversely related to plasma VLDL and TG concentrations. The same group implicated secondary hyperparathyroidism in the reduced LPL and hepatic lipase activity of proteinuric rats with progressive renal failure and suggested that, because of depletion of hepatic LPL in nephrotic rats, there is no liver compensation for the LPL defect.[196] Furthermore, defective receptor-mediated clearance and a metabolic defect in recognition and removal by the liver owing to hepatic lipase deficiency may underlie the elevated remnant particles in nephrotic syndrome.[197]

VLDL isolated from nephrotic rats hydrolyzes at a different rate in vitro than it does in control animals.[198] Shearer and associates[199] perfused hearts from normal, analbuminemic, and nephrotic rats with chylomicrons and found identical clearance of these particles in analbuminemic and nephrotic rats that was correctable with albumin. In contrast, binding of VLDL from nephrotic rats to cultured rat aortic endothelial cells was reduced as compared with binding in analbuminemic rats. These observations suggest that altered structure or composition of TG-rich lipoproteins must play a role in altered VLDL clearance. In both studies, the defects in lipolysis in nephrotic rats were corrected by normal HDL, thus suggesting that a component within HDL played a role in the genesis of these alterations. To facilitate VLDL receptor-mediated and LPL-mediated clearance, HDL supplies VLDL with most of the apo E and apo C. Alterations in these molecules in nephrotic syndrome have been described; apo E is reduced in the HDL of nephrotic rats and in the VLDL of nephrotic patients.[167] Apo C has been found to be markedly reduced per unit of VLDL in nephrotic patients [166] [167] despite normal or even increased plasma levels. Reductions in VLDL apo C and apo E correlate with particle size.[167] The significance of alterations in apo E content in VLDL has more recently been further emphasized.[200] The authors have demonstrated normal binding of nascent VLDL from livers from nephrotic rats to endothelial cells. However, prior incubation of nascent VLDL with nephrotic HDL reduced binding in association with lower apo E content. The defect was corrected by reintroduction of apo E and suggests failure of nephrotic HDL to enrich VLDL with apo E. Thus, in addition to reduced LPL activity, VLDL clearance in nephrotic syndrome is delayed because of altered composition.

VLDL synthesis has been also evaluated. Increased hepatic production of fatty acids and TGs has been demonstrated in various nephrotic models. [188] [201] Increased hepatic production of fatty acids in nephrotic rats has been shown to be caused by elevated enzymatic activity of acyl-CoA carboxylase and fatty acid synthase, the key enzymes in fatty acid biosynthesis.

More recently, the possible role of acyl CoA:diacylglycerol acyltransferase (DGAT) has been studied in this context. DGAT is a microsomal enzyme that joins acyl CoA to 1,2-diacylglycerol to form TG. Nephrotic rats demonstrated up-regulation of hepatic DGAT-1 expression and activity, which could contribute to the associated hypertriglyceridemia by enhancing TG synthesis.[202] Although the reduced clearance of VLDL seems to play the principal role in hypertriglyceridemia, slightly increase or even normal TG synthesis in the face of reduced VLDL clearance, documented previously, could also contribute.

Alterations in High-Density Lipoprotein

Nephrotic syndrome is associated with specific abnormalities in enzymatic functions required for effective function of HDL. Diminished activity of the enzyme lecithin-cholesterol acyltransferase (LCAT) appears to contribute to the lipoprotein abnormalities in nephrotic syndrome. [203] [204] LCAT is involved in catalyzing the esterification of cholesterol and its incorporation into HDL particles, as well as the conversion of HDL3 to HDL2. Low LCAT levels would impair this HDL maturation, in turn reducing the transfer of apo C-II to VLDL and thus inhibiting the catabolism of TG-rich lipoproteins.[164] Nephrotic patients have a distribution in HDL isoforms that corresponds to the LCAT defect; the higher-molecular-weight HDL2 is reduced and replaced by an increase in the lower-molecular-weight HDL3. The LCAT deficiency in nephrotic rats is due to urinary losses.[204] However, hypoalbuminemia may also play a role by increasing levels of free (unbound) lysolecithin, an inhibitor of LCAT.[205]

Increased hepatic production and elevated plasma CETP levels may contribute to HDL abnormalities in nephrotic patients.[178] As a mediator of transfer of esterified cholesterol from HDL to VLDL, elevated CETP levels might contribute to cholesterol enrichment of TG-rich lipoproteins, as well as the observed reductions in HDL2. [178] [206]

Elevated HDL in nephrotic rats is associated with apo A-I enrichment of HDL particles. [207] [208] This abnormality has been linked to hypoalbuminemia and reduced oncotic pressure, and the accumulation of apo A-I-rich HDL is due to increased hepatic synthesis and reduced catabolism of HDL and apo A-I. [207] [208] In addition, recent studies indicate that HDL is structurally altered by levels of albuminuria, associated with changes in concentrations of apo A-IV, apo E, apo A-II, apo C-II, and apo C-III.[209] Importantly, the relevance of these observations for human studies is unknown. Unlike experimental models, fractional catabolism of apo A-I in nephrotic patients is increased because of the increase in CETP that is absent in rats. CETP mediates conversion of the larger HDL2 to the smaller HDL3, which has less affinity for apo A-I, and thus indirectly facilitates clearance of apo A-I.[210]

Finally, the altered plasma HDL levels and composition in nephrotic rats are at least partly attributable to reduced protein expression of SR-B1.[211] This molecule has been identified as an HDL receptor responsible for the clearance of these particles. This situation closely resembles the defect in the LDL receptor in nephrotic rats, described previously. [175] [185] Combined LDL and HDL receptor deficiency has been proposed as a crucial factor for development of hypercholesterolemia in the nephrotic syndrome.[186]

Lipoprotein (a)

Lp(a) is increased in nephrotic patients. [162] [163] [184] In view of the atherogenic potential of Lp(a), these findings are important. The principal mechanism leading to elevations in Lp(a) seems to be increased synthesis.[162] Lp(a) is related to apo B synthesis in nephrotic humans. As demonstrated by Noto and co-workers,[163] Lp(a) levels in nephrotic children inversely correlate with apo(a) isoform size and plasma albumin levels, but not with proteinuria.

Clinical Consequences of Nephrotic Hyperlipidemia

Many of the lipid abnormalities in nephrotic syndrome are significant risk factors for atherosclerotic cardiovascular (CV) disease in the general population, including increases in total cholesterol, LDL- and VLDL-cholesterol, apo B, and Lp(a) and reductions in HDL2 cholesterol. Furthermore, additional risk factors, such as hypertension, endothelial dysfunction, and hypercoagulability, may also contribute to the risk of atherosclerotic CV disease. A small study found elevated plasma homocysteine levels in nephrotic patients as well.[212] Nonetheless, evidence that CV risk is indeed increased in these patients remains controversial, and prospective long-term data are not available. Studies attempting to define CV risk in nephrotic patients have been flawed by inclusion of patients with minimal change disease, which typically remits; diabetes, which is inherently atherogenic; or failure to control for the presence of other risk factors. Indeed, the risk of CV disease in adults with a history of relapsing nephrotic syndrome during childhood is similar to that of the general population.[213] This observation agrees with early studies, which included relatively young patients, contained small numbers, and were retrospective in design, but also did not uniformly find an increased risk of CV events. [214] [215] [216] However, in a retrospective analysis of 142 currently nephrotic patients without diabetes, Ordonez and colleagues[217] found that, after correction for hypertension and smoking, the relative risk of myocardial infarction was increased 5.5-fold and that of coronary death was increased 2.8-fold in comparison to non-nephrotic controls. In addition, Falaschi and colleagues[218] evaluated the carotid intima-media wall thickness (IMT) in young patients with lupus as a marker of early atherosclerosis and CV risk. Patients with nephrotic-range proteinuria had a significantly higher IMT than did those without. The IMT did not correlate with the lupus activity score or other possible risk factors except for proteinuria, thus suggesting a higher risk of early atherosclerosis even in this young age group.[218]

Recent studies have focused on alterations in endothelial function associated with nephrotic syndrome. These complex changes with multifactorial etiology may be a common denominator of the clinical consequences of nephrotic syndrome, such as atherosclerosis, hypertension, and hypercoagulability. Nephrotic patients may exhibit impaired endothelium-dependent relaxation [219] [220] and decreased total plasma antioxidant potential.[221] Hyperlipidemia itself is also a risk factor for impaired endothelial function. Indeed, treatment with HMG-CoA reductase inhibitors resulting in significant reductions in hypercholesterolemia has been associated with substantial improvement in endothelium-dependent vasodilation in patients with nephrotic syndrome.[222] Altered lysophosphatidylcholine metabolism, linked to both hyperlipidemia and hypoalbuminemia, is another factor responsible for the endothelial dysfunction in nephrotic syndrome.[223]

Hyperlipidemia probably contributes to other adverse consequences of nephrotic syndrome. The increased platelet aggregation tends to correlate with the magnitude of hyperlipidemia.[153] Hyperlipidemia may also contribute to the increased susceptibility of nephrotic patients to infection inasmuch as serum from nephrotic patients inhibits lymphocyte proliferation in response to specific and nonspecific antigen stimulation.[224] In addition to increasing the risk for CV disease, Lp(a), which may act to inhibit plasminogen, could contribute to hypercoagulability. Finally, the role of hyperlipidemia as a risk factor for progression of chronic kidney disease is discussed in detail in Chapters 47and 48 .

Therapy for Nephrotic Hyperlipidemia

In view of the magnitude of the CV risk in this population, further studies are needed to establish the need for aggressive hypolipidemic therapy.[168] Attempts to modify the lipoprotein profile may be worthwhile in patients with unremitting nephrotic syndrome, particularly if other CV risk factors are present. The principles of therapy are similar to those in other populations and include alterations in diet, the use of pharmacologic agents, and attention to other CV risk factors. Although few studies have systematically looked at the impact of standard dietary therapy in proteinuric patients, a moderate reduction in dietary cholesterol intake appears to be relatively ineffective.[225]Studies of vegetarian soy diets that are low in protein and rich in monounsaturated and polyunsaturated fatty acids have demonstrated improvements in serum cholesterol, LDL, and apo B in patients with proteinuria.[226]Supplementation of this diet with fish oil was of no additional benefit,[227] although it may provide some beneficial effect on TG levels. [164] [226] Fibric acid derivatives have a more prominent effect on TG metabolism than on cholesterol. In one study of 11 patients treated with gemfibrozil, TG levels fell and HDL levels rose, with little change in total cholesterol or LDL-cholesterol levels.[228] Controlled prospective studies have indicated that colestipol and probucol may also have modest hypolipidemic effects. [229] [230]

The preferred agents in nephrotic patients are HMG-CoA reductase inhibitors, which induce the greatest and most consistent hypolipidemic effect.[230] Experimentally, statins have been shown to ameliorate hepatic LDL receptor and HDL receptor deficiencies and to lower plasma total cholesterol, LDL, and the total cholesterol-to-HDL-cholesterol ratio.[231] Clinically, these drugs reduce total cholesterol, LDL, apo B-100, and TG, and increase HDL. [232] [233] [234] [235] Lp(a) levels may also be reduced by statins. [234] [235] but the literature regarding Lp(a) is inconsistent. In the largest reported study, Olbricht and associates[236] conducted a prospective, randomized, placebo-controlled trial of 102 patients with glomerulonephritis and at least 3 g of proteinuria per day. With simvastatin, mean changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol, and serum TG were -39%, -47%, +1%, and -30%; serum Lp(a) was not affected. Another study demonstrated a possible benefit of combinations of statins with fibrates.[237] Other than lipid lowering, the beneficial effects of statins could be associated with their pleiotropic, non-lipid-lowering effects and may include a reduction in platelet aggregation and procoagulant factors, inhibition of mesangial cell proliferation and matrix accumulation, and anti-inflammatory effects.[238] Use of ezetemibe in nephrotic hyperlipidemia has not yet been reported.

In addition to standard hypolipidemic therapies, interventions that reduce proteinuria may also indirectly improve serum lipid profiles. Several studies of ACEI or ARB therapy have demonstrated improvement in lipid profiles, including reductions in Lp(a). [239] [240] [241] Finally, several reports have indicated beneficial effects of lipoprotein apheresis on severely hyperlipidemic nephrotic patients, [242] [243] although evidence of long-term outcomes from this intervention are currently lacking.

HYPERTENSION

Hypertension frequently accompanies glomerular diseases. Hypertension in the absence of renal insufficiency is more likely to be present in primary glomerular diseases than in diseases of tubulointerstitial origin. The relationship between hypertension and glomerular disease has been the subject of many reviews [244] [245] and is discussed in detail in Chapters 43 and 47 . In nephrotic syndrome, hypertensive patients also appear to fall in the group with plasma volume expansion,[102] with blood pressures falling after remission or diuretic therapy.[246] Though not well studied, urinary loss of an antihypertensive substance is a possibility.

HEMATOLOGIC ABNORMALITIES (see also Chapter 49 )

Hypercoagulable State and Renal Vein Thrombosis

The nephrotic syndrome is frequently a hypercoagulable state, with increased risk of thromboembolic complications. The most common manifestation in adults is the development of renal vein thrombosis, most frequently associated with membranous glomerulonephritis. Prospective studies of the incidence of renal vein thrombosis in patients with membranous nephropathy indicated an average incidence of about 12%, with individual studies finding a range of 5% to 62%. [153] [247] [248] The incidence is lower in other forms of glomerulonephritis, for unknown reasons.

The incidence of thrombotic complications at other sites ranges from 8% to 44%, with an average of about 20%. [247] [248] [249] Of such complications, pulmonary embolism is the most frequent and serious. In a study of 204 children and 116 adults with nephrotic syndrome, children exhibited a lower incidence of events than adults did. However, the complications tended to be more severe in children, almost half of whom exhibited arterial thrombosis.[250] As mentioned earlier, the relative risk of coronary thrombotic events is increased in these patients,[217] and hypercoagulability could well contribute.

Pathogenesis of Hypercoagulability

The numerous abnormalities in the coagulation and hemostasis systems in the nephrotic syndrome have been extensively reviewed [56] [57] [153] [247] [251] and are briefly summarized here. These abnormalities include altered levels and activity of factors in the intrinsic and extrinsic coagulation cascades, levels of antithrombotic and fibrinolytic components of plasma, platelet counts and platelet function, blood viscosity, and other factors. A pathogenetic mechanism for these abnormalities is depicted in Figure 26-9 ,[153] and reported abnormalities are summarized in Table 26-2 . As reviewed by Llach,[153] abnormalities of coagulation in the nephrotic syndrome may relate to each of the five major functional classes of coagulation components: (1) zymogens (factors II, V, VII, IX, X, XI, and XII), which are activated to enzymes, and cofactors (factors V and VIII), which accelerate the conversion of zymogens; (2) fibrinogen; (3) the fibrinolytic system; (4) clotting inhibitors; and (5) components of platelet reaction and thrombogenesis.

000457

000519

FIGURE 26-9  Schematic representation of pathogenetic factors leading to hypercoagulability, thromboembolic phenomena, and renal vein thrombosis in nephrotic syndrome.  (From Llach F: Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int 28:429, 1985.)

000519

 

 


TABLE 26-2   -- Coagulation Abnormalities in Nephrotic Syndrome

  

 

Alterations in zymogens and cofactors

  

 

Deficiency in factors IX, XI, and XII

  

 

Increased levels of factor II and combined factors VII and X

  

 

Increased levels of factors V and VIII

  

 

Increased plasma fibrinogen levels

  

 

Alterations in the fibrinolytic system

  

 

Deficiency of plasma plasminogen

  

 

Low antiplasmin activity (α1-antitrypsin)

  

 

Increased antiplasmin activity (α2-macroglobulin fraction)

  

 

Increased α1-antiplasmin

  

 

Alterations in coagulation inhibitors

  

 

Deficiency of antithrombin III

  

 

Deficiency of protein S

  

 

Deficiency of protein C (possible)

  

 

Alterations in platelet function

  

 

Enhanced platelet aggregability

  

 

Increased levels of β-thromboglobulin

Data modified from Llach F: Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int 28:429, 1985.

 

 


Alterations in Zymogens and Cofactors

Most studies have noted deficiencies in levels of factors IX, XI, and XII, [251] [252] which are likely to relate to urinary loss of these low-molecular-weight proteins. Deficient factor XII levels are particularly important because this factor regulates coagulation activity as well as the fibrinolytic and kinin-kallikrein pathways.[253] Increased levels of factor II and combined factors VII and X have also been noted.[254] These zymogen abnormalities usually normalize with clinical remission of nephrotic syndrome.[252] The nephrotic syndrome is also characterized by increased levels of the cofactors V and VIII, which may correlate inversely with the serum albumin level. [254] [255] [256]The serum elevations appear to result from increased hepatic synthesis, perhaps in response to the decreased oncotic pressure and/or hypoalbuminemia. These abnormalities in zymogens and cofactors have not been clearly associated with thrombotic complications.[153]

Alterations in Fibrinogen Levels and the Fibrinolytic System

The nephrotic syndrome is associated with elevated plasma fibrinogen levels, [250] [254] [255] [256] [257] likely resulting from increased hepatic synthesis and normal catabolic rates.[258] Fibrinogen levels correlate directly with urinary protein and serum cholesterol levels and inversely with serum albumin levels. [254] [255] [256] [257] Fibrinogen is an important determinant of plasma viscosity, and the increased levels may be important in the hypercoagulability of nephrotic syndrome. Indeed, by inducing fibrin deposition, hyperfibrinogenemia may be a major factor determining thrombotic risk.[258]

The data on fibrinolytic abnormalities in nephrotic syndrome are conflicting. Several studies noted deficient plasma levels of plasminogen, with the decrease correlating with the magnitude of hypoalbuminemia and proteinuria. [259] [260] Other reported abnormalities include low antiplasmin activity (α1-antitrypsin)[255] and increased antiplasmin activity (α2-macroglobulin fraction, which is the primary plasmin inhibitor and may be the most reliable marker of renal vein thrombosis).[261]

Alterations in Coagulation Inhibitors

Nephrotic patients exhibit increased urinary losses and decreased plasma levels of antithrombin III (AT III), the most important inhibitor of coagulation and thrombin. [250] [262] Deficient serum levels of AT III are sometimes,[262]though not always[263] present and correlated with thromboembolic phenomena in nephrotic patients. AT III deficiency is reversible with steroid therapy.[264]

Abnormalities in other coagulation inhibitors, including protein C and protein S, may also occur; congenital deficiencies of each are associated with recurrent venous thrombosis. [265] [266] Both are found in the urine of nephrotic patients. [267] [268] Levels of total protein S and protein C antigens are elevated, but the activity of protein S is reduced because of a significant reduction in free (active) protein S levels, a consequence of elevated urinary losses.[268]Protein C anticoagulant activity is elevated, although a marked reduction in specific activity has been noted.[268] Nephrotic patients may exhibit elevations in serum thrombin activatable fibrinolysis inhibitor (TAFI), as well as a deficiency in protein Z, two additional factors that may predispose to thrombosis.[269] A reduction in tissue factor pathway inhibitor (TFPI) has been postulated, but one study found that proteinuria was in fact associated with increased TFPI levels, so the thrombotic tendencies cannot be readily ascribed to TFPI deficiency.[270] Another study noted that many markers of endothelial cell injury (thrombomodulin, intracellular adhesion molecule-1, vascular cell adhesion molecule, TAFI, and vascular endothelial growth factor levels, but not protein Z) were elevated in nephrotic patients, but did not correlate with levels of proteinuria or serum albumin in general.[269] Finally, one study examined the incidence of genetic mutations in factor V Leiden. In 35 patients with nephrotic syndrome, 10 developed thrombotic events. Of these, 2 were heterozygous for a factor V gene mutation, 1 with thrombosis and 1 without.[271]

Alterations in Platelet Function

Platelet counts in nephrotic patients tend to be normal or elevated. [254] [255] Platelet aggregability may be increased. [263] [272] Potential contributions of hyperlipidemia and hypoalbuminemia to this abnormality were discussed earlier. Nephrotic patients may also exhibit elevations in β-thromboglobulin, a specific protein released by platelets on aggregation. [273] [274]

In summary, numerous coagulation abnormalities are found in nephrotic syndrome. Furthermore, nephrotic syndrome may be characterized by increased blood viscosity,[274] as a result of both hyperlipidemia and increased fibrinogen. Steroid therapy may also exacerbate hypercoagulability in nephrotic patients.[275]

The specific role of each of these abnormalities in the pathogenesis of thromboembolic complications remains incompletely defined.[153] An increased tendency toward thrombotic events has been correlated with increased α2-antiplasmin levels,[261] and the presence of factor XII and prekallikrein in subepithelial deposits has been noted in patients with membranous glomerulonephritis.[276] However, a prospective study of nephrotic adults monitored for an average of 21 months found significant increases in factor I, factor VIIIc, factor VIIIr:Ag, α1-antitrypsin, and α2-macroglobulin, as well as platelet hyperaggregability, in the group as a whole, but no correlation between these abnormalities and thromboembolic events. Low levels of AT III and severe hypoalbuminemia were of no predictive value for thromboembolic events.[263]

HORMONAL AND OTHER SYSTEMIC MANIFESTATIONS

Other systemic manifestations of glomerular disease, which are covered in detail elsewhere in this volume, include enhanced susceptibility to infection, [59] [277] possibly as a result of urinary loss of components of the alternate complement pathway, including factor B, and loss of IgG.[277] IgG synthesis may also be impaired.[278]

Deficiencies of trace metals such as copper, zinc, and iron may occur. [279] [280] Urinary losses of thyroxine-binding globulin, triiodothyronine, and thyroxine have been noted, although patients remain clinically euthyroid.[281]Urinary levels of corticosteroid-binding globulin[282] and insulin-like growth factor type I[283] are elevated, although the clinical consequences are unclear. Abnormalities in Ca2+ and vitamin D metabolism, such as hypocalcemia, hypocalciuria, and low serum levels of vitamin D, also characterize the nephrotic syndrome. [59] [284] [285] It is not clear that clinically significant hypovitaminosis D occurs in the majority of nephrotic patients,[57] but one study found an increased incidence of isolated osteomalacia and bone resorption in association with defective mineralization in patients with sustained nephrotic syndrome.[286] Urinary levels of erythropoietin are increased, and plasma levels fail to rise despite anemia[287]; erythropoietin deficiency can occur and cause anemia even in the setting of normal kidney function.[288,]289 Transferrin synthesis is increased, but not sufficiently to replace urinary losses. [289] [290] Finally, extrarenal protein loss in the presence of inadequate protein intake may be associated with negative nitrogen balance and protein malnutrition.[66]

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