Renal Disease Caused by Inborn Errors of Metabolism, Storage Diseases, and Hemoglobinopathies

Renal Disease Caused by Inborn Errors of Metabolism, Storage Diseases, and Hemoglobinopathies

Laura S. Finn

This chapter covers familial metabolic defects in the kidney, along with more systemic metabolic and hematologic disorders that affect the kidney secondarily. Renal involvement in the first group includes several lysosomal storage diseases caused by deficiencies of lysosomal enzymes in renal tissues as, for example, in

Fabry disease. However, not all lysosomal storage diseases primarily affect the kidney; renal involvement in Gaucher disease, for example, results from the entrapment in the kidney of circulating macrophages engorged with glucosyl ceramide. Clearly, secondary renal involvement follows the hyperlipidemia of familial lecithin-cholesterol acyltransferase (LCAT) deficiency, hyperoxaluria of hepatic peroxisomal alanine-glyoxylate aminotransferase deficiency, and the microcirculatory abnormality of hemoglobinopathies. The defect of tubular transport in inherited Fanconi syndrome is intrinsic to the proximal convoluted tubule, although an identical transport abnormality is much more commonly secondary to the renal accumulation of cystine, as the result of a generalized primary defect in lysosomal membrane transport. Therefore, simple categorization of these disorders into primary and secondary groups serves little purpose. The diseases are grouped into broad categories, with descriptions of the genetic basis, molecular and functional abnormalities, and the renal pathologic consequences.


Familial Lecithin-Cholesterol Acyltransferase Deficiency

Familial LCAT deficiency (FLD) is an uncommon autosomal recessive disorder resulting from a heritable defect in the esterification of plasma cholesterol. Increased plasma concentrations of unesterified cholesterol, triglycerides, and phosphatidylcholine result in lipid deposition in tissues. The enzyme LCAT is carried by high-density lipoprotein (HDL) with Apolipoprotein (Apo) AI as a cofactor, and it catalyzes the esterification of free cholesterol bound to lipoproteins. Mutations in the LCAT gene, localized to chromosome 16q21-q22, cause classic familial LCAT deficiency (FLD) and fish eye disease (FED). More than 60 mutations have been described, all of which result in greatly reduced concentrations of high-density lipoprotein (HDL). The residual plasma HDL is characterized on electron microscopy by an accumulation of disk-shaped pre-β HDL that may form rouleaux. Other lipid phenotypes include morphologically abnormal low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles and the formation of free cholesterol and phospholipid-rich, triglyceridepoor vesicles known as lipoprotein X (LpX) (1).

Classic FLD is due to the inheritance of homozygous or complex heterozygous deletions that either abolish LCAT production or cause the synthesis of an LCAT enzyme with complete or nearly complete loss of both α-LCAT and β-LCAT activities. The disease, originally described in Norway, appears to be widely distributed. Clinical manifestations of FLD include corneal opacities, hemolytic anemia, accelerated peripheral atherosclerosis, and proteinuria with renal insufficiency. Lipid deposits also occur in the liver, spleen, and bone marrow, in which foam cells (sea-blue histiocytes) are present (2). In contrast to FLD, FED patients, whose lipid/lipoprotein profile overlaps with that seen in FLD, have reduced α-LCAT activity but preserved β-LCAT activity (1). In FED, there are no major clinical manifestations except corneal opacity. Heterozygous carriers may have a lipid/lipoprotein profile intermediate between carriers of two and zero copies of mutant alleles.

Renal involvement, the major cause of morbidity and mortality, commonly begins with proteinuria during childhood (3), and it culminates after several decades of renal insufficiency. The progression of renal disease is variable; some patients show severe proteinuria, and others experience little.

Hypertension may appear early in the course or as a late complication of renal insufficiency. Urinalysis usually shows mild hematuria, leukocyturia, and cylindruria. Renal insufficiency is not invariable (1); when present, it usually develops by the fourth decade.

Pathologic Changes

The glomeruli are the principal site of renal injury, undergoing mesangial expansion and a characteristic capillary wall thickening. Foamy lipid is most obvious in thickened capillary walls, which have a bubbly, vacuolated, or honeycomb appearance that is accentuated when stained with toluidine blue (Fig. 27.1). Silver-stained sections show craters in and vacuolization of the glomerular basement membrane (GBM), resembling late-stage membranous glomerulonephritis; double contours are often noted (4,5,6). Mesangial cellularity is normal to mildly increased, and the mesangium is often expanded, with the same vacuolated appearance as the capillary walls. Collections of endocapillary foam cells are an occasional feature. The mesangium also contains an acellular, eosinophilic matrix that accumulates in areas of segmental sclerosis and eventual global sclerosis (Fig. 27.2). Interstitial foam cells may be present, and lipid deposition has been noted in arterial walls. The tubules are generally normal until atrophy accompanies interstitial fibrosis. Immunofluorescence is usually negative for immunoglobulin and complement components, occasionally showing mild, nonspecific changes. The deposits have been shown by immunostaining to contain large amounts of ApoB and ApoE (7).

FIGURE 27.1 Glomerulus from a patient with LCAT deficiency. It shows mesangial and focal capillary wall thickening with prominent bubbly lipid interposed between what appear to be two layers of basement membrane (double contours). (Periodic acid-Schiff [PAS]; ×400.)

Electron microscopy has shown a mixture of glomerular epimembranous, intramembranous, subendothelial, and mesangial lipid deposits (Fig. 27.3). One study of sequential biopsy specimens showed early subepithelial and intramembranous deposition, followed by predominantly subendothelial
and mesangial deposits (8); these observations contrast with sequential assessment in a kidney allograft where deposits were initially identified in the mesangium (9). The lipid deposits are partly lucent and partly deeply osmiophilic, the latter including cross-striated curvilinear serpiginous fibrils, rounded lamellar densities, and granular densities (5,6). The former two are predominantly in epimembranous and intramembranous deposits, while granular densities are predominantly in subendothelial deposits. Densely osmiophilic basement membrane deposits have resembled the glomerular alterations of densedeposit disease and may increase basement membrane fragility because focal disruptions are identifiable (10). Mesangial deposits tend to be large and dense, comprising increased matrix and hyaline. Foam cells may be present in the mesangium, as shown by light microscopy; they rarely seem to be endocapillary. Arteriolar endothelial and medial cells may also contain lipid deposits (5). Tubular atrophy and interstitial fibrosis progress variably.

FIGURE 27.2 Glomerulus in LCAT deficiency showing thickened basement membranes and mesangial foam cells (bottom) entrapped within increased eosinophilic matrix. (Hematoxylin & eosin [H&E]; ×200.)

FIGURE 27.3 Electron microscopy in LCAT deficiency shows glomerular epimembranous, intramembranous, subendothelial, and mesangial accumulations of extracellular lipid material with membranous profiles and granules. (×9000.)

Mesangial lipid deposits recur rapidly in renal allografts (9), sometimes within weeks (Figs. 27.4 and 27.5). The deposits do not necessarily impair renal function, because long-term graft survival has been described (1,11). Renal transplantation has no effect on the systemic metabolic disorder.

The renal abnormality, although distinctive, is not entirely specific, because similar lipid deposits occur in kidneys of patients with chronic liver disease, Alagille syndrome, and cirrhosis of various etiologies, who also have elevated serum lipoprotein (12,13,14).


The cause of renal injury, despite lipid accumulation, has not been completely elucidated. A role for LpX has been supported by animal studies. In vitro experiments have shown up-regulation of monocyte chemoattractant protein-1 mRNA expression and protein levels and increased nuclear activities of nuclear factor κB in rat mesangial cells, suggesting that LpX may induce a proinflammatory response (15). In the LCAT knockout mouse, high-fat diets produced LpX accumulation, with the development of proteinuria and glomerulosclerosis in a subset (16). A more recent analysis circumvented the potentially confounding contribution of coexisting hyperlipidemia in the prior study by generating a novel murine model in which circulating lipoproteins were predominantly LpX. These mice spontaneously developed progressive glomerular lesions that had light and electron microscopic abnormalities similar to those seen in human LCAT deficiency (17). Infusion of recombinant LCAT into LCAT-KO mice rapidly increases HDL cholesterol and lowers cholesterol in fractions containing VLDL and LpX, providing some rationale for enzyme replacement therapy (18). The long-term effect on renal disease of (a) lipid-modifying therapy to change the lipid profile, including lowering LpX; (b) corticosteroid therapy to suppress an inflammatory response; or (c) blockade of the renin-angiotensin system to protect renal function via blood pressure control and reduction of proteinuria has not been adequately assessed in humans (19,20,21).

FIGURE 27.4 Glomerulus from renal allograft in a patient with LCAT deficiency, 7 weeks after transplantation, with recurrence of foamy mesangial cells. (PAS; ×400.)

Lipoprotein Glomerulopathy

Lipoprotein glomerulopathy (LPG) is a rare disorder associated with distention of glomerular capillaries by lipoprotein thrombi, proteinuria, and progression to renal failure (22). The majority of patients are of Asian ancestry, principally Japanese and Chinese, but occasional cases have been in patients with non-Asian backgrounds (23,24,25,26,27,28,29). The disease may present in childhood, and males outnumber females approximately three to two (23,30). Subjects have a characteristic biochemical finding of a twofold to threefold elevation of serum ApoE level, usually accompanied by hyperlipidemia with a predominance of triglycerides (30). Detailed analysis using electrophoresis or ultracentrifugation shows increased very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) fractions, which resembles type III hyperlipoproteinemia (HLP); however, hyperlipidemia is often milder than in familial type III HLP and not even recognized in some cases (23). Unlike type III HLP, systemic manifestations of hyperlipidemia, corneal arcus, cutaneous xanthomas, and atherosclerosis are very uncommon in LPG. The finding of ApoE2 heterozygosity by isoelectric focusing, rather than ApoE2 homozygosity, typical in type III HPL, also helps to differentiate the diseases.

FIGURE 27.5 Electron microscopy shows recurrence of mesangial and subendothelial lipid deposits in renal allograft at 7 weeks after renal transplantation in a patient with LCAT deficiency. (×10,400.)

Clinical onset is usually marked by proteinuria, and most develop steroid-resistant nephrotic syndrome. Hematuria is not typical. The disease may undergo spontaneous amelioration, but slow progression to renal failure has been observed in half of patients (23).

Pathologic Changes

The glomeruli are large and contain capillaries distended with lipoprotein thrombi (Fig. 27.6). The capillary ectasia is accompanied by mesangiolysis. Capillary walls may be at first attenuated, but they often become thickened, with double contour, as in other types of mesangiolysis. The thrombi are weakly periodic acid-Schiff (PAS) positive, silver methenamine negative, and pale blue with Masson trichrome, in contrast to the typical fuchsinophilia of fibrin thrombi, with which they might be confused. The lack of congophilia excludes amyloid. The material has a moderately vacuolated and laminated structure under high magnification and is also strongly positive with oil red O and variably sudanophilic in frozen section. Increasing mesangial cellularity and matrix, segmental sclerosis, and hyalinosis progress to global sclerosis (Fig. 27.7). Tubulointerstitial changes are secondary, although interstitial foam cells may appear early in the course. LPG can coexist with other glomerular diseases.

Immunofluorescence shows that the glomerular thrombi contain β-lipoprotein, ApoB, and ApoE. Immunoglobulin M, C1q, and fibrinogen often surround the thrombi. Electron microscopy shows the thrombi to be finely, almost concentrically lamellated, with numerous small lipid vacuoles (Fig. 27.8). In milder cases, lipid deposits may localize to the mesangium and then extend into the subendothelial space. Endothelial hypertrophy may be present in unobstructed capillary segments. Mesangial hypercellularity is associated with segmental interposition and double contours of the GBMs. Effacement of foot processes tends to correlate with proteinuria.


Apolipoprotein E plays a major role in lipid and lipoprotein metabolism by functioning as the ligand for receptor-mediated catabolism of chylomicrons, VLDLs, and some HDLs. The

ApoE gene, located on chromosome 19q13.2, has three common alleles—ε2, ε3, and ε4—which code the three main isoforms: E2, E3, and E4. Six common polymorphisms are ApoE2/2, ApoE3/3, ApoE4/4, ApoE3/2, ApoE4/2, and ApoE4/3; ApoE3 is the most common with the ε3 allele accounting for 70% to 80% of the gene pool in Caucasians. ApoE and its polymorphisms are also instrumental in the pathogenesis of renal disease; they influence the development and progression
of diabetic nephropathy, the incidence, severity, and response to therapy of various other nephropathies, and the serum lipid profile and the risk of atherosclerosis in end-stage renal disease (ESRD) (30). Novel missense mutations and deletions in the ApoE gene are thought to be pathogenic in LPG, and their existence was proven by sequencing after observing discordant results between restriction fragment genotyping and ApoE phenotyping via isoelectric focusing. A growing number of mutant isoforms—ApoE Sendai, Kyoto, Tokyo/Maebashi, Tsukuba, Chicago, Okayama, Guangzhou, Hong Kong, Modena, and Las Vegas (each genotype named after the index patient’s city of origin) and ApoE1 and ApoE5—have
been associated with LPG (31), and the development of LPG in ApoE Sendai-infected mice suggests an etiologic role for these atypical isoforms (32,33). Some of the mutations can alter the tertiary structure of the variant apolipoprotein, thereby affecting interactions with receptors and cell surfaces that may induce abnormal intraglomerular lipid trafficking (34,35). Multiple family members may carry the same ApoE mutation in a heterozygous form, but not all family members with mutant isoforms develop LPG. This observation implies that LPG is a dominantly inherited disease with incomplete penetrance and that other genetic or environmental factors participate in its pathogenesis. For example, alterations in lipoprotein metabolism may be detrimental. The Fc receptor γ on macrophages and mesangial cells is involved in the recognition and clearance of LDL. The development of LPG in Fc receptor γ-deficient mice suggests that a reduction in LDL clearance may induce lipoprotein deposition (36). As lesions are localized to the glomeruli, the role of intrinsic mesangial cells seems paramount. The exact mechanism of the renal disease, however, remains to be defined, but variant ApoE appears to be a prerequisite. With one exception, all patients described thus far were found to be heterozygous for ApoE gene mutations (37).

Although a similar glomerular lesion has been described in two siblings homozygous for nonmutated ApoE2 (38) and a nonmutated E2/E3 heterozygote with varying degrees of hyperlipidemia (39), the characteristic layered intraglomerular deposits, considered essential for the diagnosis of LPG (23), were not identified by electron microscopic study; these cases have been considered “LPG-like disease.”

FIGURE 27.6 The glomerulus from a patient with lipoprotein glomerulopathy. The capillaries are distended by pale lipoprotein thrombi that have a vague laminated appearance. Dilation of the capillary is associated with mesangiolysis. (PAS-silver methenamine; ×200.)

FIGURE 27.7 Capillaries in the glomerulus with lipoprotein glomerulopathy are distended with lipoprotein thrombi. The lobule at the bottom has increased mesangial cellularity and matrix. There are multiple adhesions to Bowman capsule, which will progress with sclerosis and hyalinosis. (PAS; ×100.)

FIGURE 27.8 Electron micrograph shows the glomerular capillary lumina to be filled with partially lamellated, finely vacuolated lipoprotein thrombi. The mesangium is thickened by cell processes and increased matrix. The capillary wall is also thickened, with mesangial interposition and duplication of the glomerular basement membrane (arrowheads). (×1900.)


Traditional therapies for nephrotic syndrome, such as corticosteroids and immunosuppressive agents, and various alternative treatments, such as anticoagulants and plasmapheresis, have been ineffective. Intensive lipid-lowering therapy, including niceritrol and fibrates, has induced resolution of symptoms and disappearance of glomerular lipoprotein thrombi (40,41,42,43,44). Clinical and histologic improvements have also been achieved by protein A immunoadsorption (45). However, the longterm efficacy of either treatment approach has not been established.

Recurrence of the lesion in renal allografts has also been described; stabilization of graft function and reduction of proteinuria were achieved with renin-angiotensin system blockade in several cases (46,47).

Type III Hyperlipoproteinemia (Familial Dysbetalipoproteinemia)

Type III HLP with characteristic xanthomas develops in approximately 10% of patients who are homozygous for ApoE2/2, where it is associated with combined and often severe mixed hyperlipidemia caused by the accumulation of β-VLDL, which leads to accelerated atherosclerosis. The ε2 allele is found in approximately 8% of the population (30), and ApoE2 homozygosity occurs with a frequency of about 1% in Caucasian populations. That only a minority of ApoE2 homozygotes develop type III HLP implies a multifactorial disorder, and recent studies found an increased incidence of rare ApoC3 and ApoA5 alleles in those expressing an abnormal lipid profile (48). Uncommonly, these patients develop glomerular lipidosis, manifested as proteinuria. Renal biopsies have shown large numbers of foam cells in the glomerular mesangium and distending glomerular capillaries (Fig. 27.9). Interstitial foam cells have been noted. Lipid vacuoles focally admixed with lamellated electron-dense material and occasional cholesterol clefts have been detected by electron microscopy in the cytoplasm of glomerular intracapillary foam cells, as well as in mesangial, endothelial, and tubular epithelial cells. Podocyte foot processes may be effaced. Renal lipid deposits have cleared with plasmapheresis and lipid-lowering agents. Similar renal pathology including glomerular foam cells was recently described in a patient whose lipid profile was compatible with type III HLP, but whose genotype was ApoE2/3 and in whom a novel ApoA5 mutation was discovered (49). “Lipoprotein glomerulopathy-like” disease has also been described in a few patients with type III HLP (38).

FIGURE 27.9 Glomerulus from a child with type III hyperlipoproteinemia that shows groups of foam cells in the mesangium and distending the capillary lumens. (Masson trichrome; ×400.)


Several dozen diseases are caused by the pathologic accumulation of naturally occurring molecules inside lysosomes. Taxonomic classification is based on the stored material, which allows organization but does not necessarily reflect a common clinical manifestation. Many lysosomal storage diseases present in infancy or early childhood, although milder adult variants are known. Diagnosis is ascertained by combining the clinical phenotype with biochemical parameters, pathology, and genetic confirmation whenever possible. Fabry disease is the classic example of a lysosomal disorder with primary kidney impairment, and, in a few settings, the diagnosis is made by kidney biopsy. Most lysosomal storage diseases, however, demonstrate only morphologic involvement without clinical renal manifestations; it is unlikely that a renal biopsy in those disorders will lead to the unsuspected diagnosis. More often, these become evident by disturbances of the central nervous and skeletal systems, hepatosplenomegaly, and/or dysmorphic features. In rare cases, clinical renal disease has been described, for example, nephrotic syndrome in children with Hurler syndrome and proximal tubular dysfunction in I-cell disease (50). Several observations about the kidney and lysosomal storage disease are worth noting. Renal involvement in
Gaucher disease, the most common lysosomal storage disease, only becomes symptomatic after splenectomy, a therapeutic procedure in type 1 nonneuropathic disease that is performed less often in the era of enzyme replacement (51,52,53). Its characteristic “wrinkled paper” appearance allows the diagnosis of Gaucher disease by light microscopy, whereas the pathology of the majority of lysosomal disorders is not distinct. Rather, storage cells are typified by clear and sometimes foamy cytoplasm, the consequence of storage material dissolving with processing (54). Special histochemical staining, especially on frozen sections where water and alcohol-soluble substances are preserved, may help to characterize the stored material, but is frequently nonspecific. Electron microscopy can usually define the disorder further. In most instances, the diagnosis will already be known from the history, laboratory data, and enzyme analysis.

The lysosomal storage diseases that primarily involve the kidney or cause symptoms are briefly discussed below, whereas those that only secondarily involve the kidney appear in Table 27.1. Representative features of I-cell disease and neuronal ceroid lipofuscinosis are illustrated in Figures 27.10, 27.11, 27.12, 27.13, 27.14. Cystinosis, a lysosomal membrane transport defect, is discussed in the section with Fanconi syndrome.

Fabry Disease (Angiokeratoma Corporis Diffusum Universale)

This condition, described by both Fabry and Anderson in 1898, is a rare metabolic disorder arising from a deficiency of a lysosomal exoglycohydrolase, ceramide trihexosidase, commonly referred to as α-galactosidase A (55). The enzyme catalyzes the cleavage of glycosphingolipids, especially globotriaosylceramide, which is present in most cell membranes. Deficient enzyme activity results in the systemic accumulation of neutral glycosphingolipids with terminal α-linked galactosyl moieties, primarily globotriaosylceramide (Gb3), in plasma and particularly lysosomes of vascular endothelia of the kidneys, heart, brain, and skin.

The disease is uncommon, although it is the second most prevalent inherited lysosomal storage disorder after Gaucher disease. Recent estimates of the frequency range from 1 in 40,000 to 1 in 117,000 births; however, Fabry disease may be more prevalent because of a lack of recognition in patients with isolated renal or cardiac involvement. The prevalence of previously undiagnosed Fabry disease in dialysis patients, with subsequent DNA confirmation, was shown to be 0.33% in men and 0.10% in women undergoing dialysis. Approximately 3% to 4% of patients with left ventricular hypertrophy or cardiomyopathy are discovered to have Fabry disease, and newborn screening programs with subsequent mutational analysis found an incidence of 1 in 3100 to 4700 male infants (56,57). More than 500 mutations of the α-galactosidase gene at Xq22.1 have been described, and most are family specific (55,58). About 5% of the cases are sporadic. Mutations leading to complete loss of gene product are associated with classic forms of the disease, whereas those resulting in amino acid substitutions might occasionally link to a mild phenotype or late manifestation; however, genotype-phenotype correlations are low. The X-linked disease is completely expressed in hemizygous males, but clinical presentation is quite variable, even within families. Most heterozygous females, contrary to historical accounts, are affected. Highly variable levels of enzyme activity in females and the broader range of clinical symptoms can only partly be accounted for by X inactivation (59). Although renal biopsy may be diagnostic, and EM is a reliable approach to identify the intracellular myeloid bodies, they are not pathognomonic as similar structures are present in silicon nephropathy and pseudolipidosis induced by amiodarone, chloroquine, and hydroxychloroquine (60,61,62,63). An aid to diagnosis may be immunofluorescence with a monoclonal anticeramide trihexoside; this technique has been effectively employed in routinely processed paraffin-embedded tissue (64). Affected males with classic and variant phenotypes are reliably diagnosed by the demonstration of deficient enzyme activity in plasma, leukocytes, cultured cells, or dried blood spots (65). By contrast, female carriers can exhibit normal α-galactosidase A levels, such that exclusion of a carrier status can only be done by mutational analysis of the α-galactosidase A gene. High-throughput PCR-based technologies, such as high-resolution melting analysis, may be cost-effective for newborn screening in females (66). Prenatal diagnosis is possible by amniocentesis, but preferred methods include enzyme and molecular testing on fresh fetal tissue obtained by chorionic villus sampling (67). Diagnosis by molecular probes is typically limited to patients with a positive family history and known mutation; DNA sequencing has proven to be the most reliable strategy for mutation detection. Routine mutational analysis, however, may miss deletions and duplications, which are better detected using quantitative and real-time PCR, multiplex probe amplification and hybridizations, and array comparative genome hybridization (65). New screening tools, based on measurement of urinary Gb3 isoforms via electrospray ionization mass spectrometry, as well as identification of unique proteomic biomarker profiles using capillary electrophoresis coupled to mass spectrometry, may prove relevant for screening females and monitoring response to enzyme replacement therapy (68,69).

Manifestations in hemizygous males may begin in early childhood although storage material has been observed in the prenatal period (70). The earliest and often disabling symptom is acroparesthesia. Gastrointestinal symptoms, nausea, abdominal pain, and diarrhea, commonly appear in childhood and persist into adulthood. Strokes and transient ischemic attacks are not uncommon. Cardiac disease is a well-recognized complication, classically, hypertrophic cardiomyopathy that may initially manifest as arrhythmias in childhood. The skin lesions—angiokeratomas—cluster on the lower trunk and thighs as reddish purple dark spots or papules with dilation of superficial capillaries and variable hyperkeratosis. They typically develop during adolescence and increase with age but are rarely problematic. They remain a valuable clue to the diagnosis because they are seen in only a few rare conditions. Anhidrosis or hypohidrosis and corneal opacities are seen in most patients (71). In addition to the classical phenotype, there are milder variants with residual α-galactosidase A activity that lack the characteristic features. “Cardiac” and “renal” variants present with late-onset manifestations primarily limited to the heart and kidney, respectively (55). Males generally experience onset of symptoms earlier than females, with a median age of 6 years versus 9 years in females.

Progressive nephropathy is a major feature, and ESRD can occur during adolescence (72). Clinical evolution to renal insufficiency and hypertension is variable over several decades and correlates with residual α-galactosidase activity (73). Glomerular pathology may exist, despite the presence of an apparently

normal estimated glomerular filtration rate (GFR), without manifestation of overt proteinuria or even microalbuminuria (74,75,76). As clinical parameters lack sensitivity, kidney biopsy has been employed by some to assess baseline injury (74,76). Proteinuria seems to be the most important predictor for renal progression, especially for men, in whom advanced nephropathy is more prevalent and generally occurs earlier (77,78). Most females have slowly progressive kidney disease; however, the subset (15% to 20%) that develops ESRD does so at approximately the same age as men (79). Loss of urine-concentrating ability leads to polyuria and polydipsia, and altered tubular functions have also been identified, such as impaired glucose and potassium reabsorption, to a greater degree than can be accounted for by reduced GFR (80). The urine sediment contains lipid globules showing Maltese crosses on polarization and desquamated cells containing myeloid bodies (81).

TABLE 27.1 Renal involvement by lysosomal storage disorders (without significant functional impairment)


Stored Material

Enzyme Defect

Storage Location

Light Microscopy

Electron Microscopy



Gaucher disease

Glycosyl ceramide


MC, MI; rare, BM

Gaucher macrophage with “wrinkled” cytoplasm

50-nm tubular bilayers

Renal involvement follows splenectomy.

Niemann-Pick (types A and B)



P, E, MI, PT, DT

Small, uniform cytoplasmic vacuoles

Myelin-like lamellae

Involved in >50% of cases; red birefringence with polarization

Metachromatic leukodystrophy

Galactocerebroside sulfate

Arylsulfatase A

H, DT, CT, rare PT

15- to 20-µm cytoplasmic spheroids

6- to 8-nm “stacked disks”; honeycomb pattern opposite plane

Kidney is the major site of pathology in the fetus; green birefringence with polarization

Neuronal ceroid lipofuscinosis

Ceroid (lipofuscin); subunit c of mitochondrial ATP synthase, saposins A and D

Palmitoyl-protein thioesterase 1; tripeptidyl peptidase 1

E, DT, PT, P

Tan, waxy lipid globules

Granular osmiophilic bodies, curvilinear profiles, fingerprints, rectilinear complexes

Yellow-green autofluorescence


Ganglioside (GM1)


P, H, M

Clear cytoplasmic vacuoles

Finely granular material with some lipid lamellae

Sandhoff disease

Ganglioside (GM2) and other sphingolipids

Hexosaminidase-α and hexosaminidase-β


Clear cytoplasmic vacuoles

Finely granular material with some lipid lamellae



Sialyl oligosaccharides

N-acetylglucosamine-phosphotransferase deficiency

P, rare PT, fibroblasts

Ballooning of cells with clear cytoplasmic vacuoles


Light microscopy resembles GM1; defect in multiple enzyme transport


Hurler disease (I)

Heparan sulfate, dermatan sulfate


P, rare PT

Clear cytoplasmic vacuoles

Sparse fibrillogranular

Reported with nephrotic syndrome



Fucosyl oligos



Clear cytoplasmic vacuoles

Sparse fibrillogranular and lamellar


Mannosyl oligos

α-Mannosidase, β-mannosidase


Clear cytoplasmic vacuoles

Sparse fibrillogranular





Clear cytoplasmic vacuoles

Sparse fibrillogranular

PAS, periodic acid-Schiff; SB, Sudan black; AB, Alcian blue; P, podocyte; E, glomerular capillary endothelium; M, mesangial cells; BM, basement membrane; PT, proximal tubular cells; DT, distal tubular cells; H, loop of Henle cells; CT, collecting tubular cells; A, arterial endothelium; MI, interstitial macrophage; MC, circulating and entrapped macrophage; oligos, oligosaccharides.

FIGURE 27.10 Glomerulus in I-cell disease has profoundly enlarged, finely vacuolated podocytes. (H&E; ×400.)

FIGURE 27.11 The vacuolated podocytes in I-cell disease contain abundant glycolipids and acidic glycosaminoglycans. (Hale colloidal iron; ×400.)

FIGURE 27.12 Electron micrograph of a podocyte in I-cell disease shows that the vacuoles contain a few membranous and lamellated inclusions. The material in the largely “empty” vacuoles may have been dissolved during processing. (×9215.)

FIGURE 27.13 Glomerulus from a 13-year-old boy with neuronal ceroid lipofuscinosis. The child had severe cerebral atrophy and neurologic impairment but normal renal function. The visceral podocytes are distended with granular ceroid material. (H&E; ×200.)

Pathologic Changes

Gross descriptions of the kidney in Fabry disease are limited, but the kidneys may be enlarged by the accumulation of storage material. Glomeruli may look white on direct examination using stereomicroscopy (74,82). Renal cortical or parapelvic cysts have been demonstrated by ultrasound, magnetic resonance imaging, and computed tomographic imaging in up to 50% of patients studied, which includes classically affected hemizygous males, female carriers, and cardiac variants. The prevalence of the cysts increases with age, but their presence does not correlate with residual enzyme activity, mutation type, proteinuria, or kidney function (83,84). The nature and pathogenesis of the cysts remain undetermined.

FIGURE 27.14 Electron microscopy of storage material in neuronal ceroid lipofuscinosis showing characteristic granular osmiophilic bodies (A) and fingerprint (B) and curvilinear (C) profiles. (×31,500.)

FIGURE 27.15 The glomerular podocytes are swollen and finely vacuolated in a patient with Fabry disease. Epithelial cells of distal tubules are also vacuolated. (Mallory trichrome; ×200.)

Light microscopic changes are remarkable and can easily yield a diagnosis. The glomerular tuft contains strikingly enlarged and vacuolated glomerular cells, especially podocytes (Fig. 27.15). Similar changes are present to a lesser degree in endothelial and mesangial cells and occasionally in the parietal epithelial cells lining Bowman capsule. They appear empty in paraffin sections because the accumulated glycosides are removed during clearing and paraffin embedding of the tissue. The material is preserved by prior osmification and is easily demonstrated in semithin sections of tissue embedded in epoxy resin (Fig. 27.16). The material in frozen sections, whether fresh
or formalin fixed, is birefringent, autofluorescent, sudanophilic, and positive to oil red O and PAS. It may also be demonstrated in frozen sections by lectin binding (85). A similar vacuolated appearance, variable in quantity but sometimes considerable, is present in tubular epithelial cells, particularly of the distal tubules and the loop of Henle (Figs. 27.15 and 27.17). Small arteries and arterioles show vacuolation of the endothelial cells and finely vacuolated areas in the smooth muscle (Fig. 27.18). Interstitial foam cells can be seen. Progression of the disease leads to mildly increased mesangial matrix and cellularity with segmental glomerular sclerosis (Fig. 27.19), capillary wall thickening, tubular atrophy, interstitial fibrosis, and arterial and arteriolar sclerosis. Immunofluorescence is negative or nonspecific. Storage of myeloid bodies has been shown also in the liver and spleen (86). Hemizygotes have more severe lipid storage than do heterozygotes (75,87,88).

FIGURE 27.16 The intracellular lipid inclusions in Fabry disease are preserved in osmicated, epoxy-embedded tissue. The enlarged podocytes and tubular epithelial cells contain lamellated inclusion bodies (same patient as in Fig. 27.15). (Methylene blue; ×250.)

FIGURE 27.17 Fine, foamy vacuolation of tubular cells from a patient with Fabry disease. (PAS; ×400.)

Electron microscopy shows enlarged secondary lysosomes filled with osmiophilic, granular to lamellated membrane structures that have an onion skin-like appearance or parallel dense layers (zebra bodies) (Fig. 27.20) (87,88). The inclusions are present especially in podocytes, parietal epithelium, distal tubular epithelium, and vascular myocytes, although a few inclusions may be present in virtually all renal cells (89). Generally, inclusions within mesangial cells are smallest and those in podocytes the largest. Quantitative stereologic EM methods have documented progressive accumulation of Gb3 inclusions in podocytes with age, but not in endothelial or mesangial cells. This observation may reflect different rates of production or cell turnover (75). The periodicity of the lamellated structures, when measured in plastic thin sections, varies between 3.5 and 5.0 nm but is estimated at 14 to 15 nm when studied by freeze-fracture electron microscopy (90,91).
Recently described are unique subendothelial deposits associated with basement membrane duplication and composed of membrane-like material arranged in geographic layers (88).

Foot process width and the extent of foot process effacement with microvillous transformation correlate with the degree of proteinuria (75,85).

FIGURE 27.18 Renal artery in end-stage Fabry disease has moderate intimal fibroplasia, cleared endothelial cells (top), and empty spaces in the media (bottom). (PAS; ×400.)

FIGURE 27.19 Glomerulus in Fabry disease shows thickened capillary walls and partial solidification. Fine vacuolation is still evident in a few podocytes (arrows) over an intact portion of the tuft. (PAS; ×400.)

FIGURE 27.20 Electron micrograph of glomerulus in Fabry disease shows lamellated lipid inclusions (“myeloid bodies”) in podocytes. A few mesangial inclusions are also present (arrowheads, just above the center). (×3000.)


Endothelial lipid deposits may be pathogenic in renal disease, as they are absent in the Fabry knockout mouse model that does not develop renal failure (92). Interestingly, deposits are also unapparent in renal endothelial cells from Fabry cardiac variants (93). A putative role for endothelial dysfunction comes from mouse models that demonstrate a prothrombotic and proatherogenic age-dependent phenotype and abnormal vascular reactivity (94,95,96). Lyso-Gb3 (deacylated Gb3), a bioactive lipid metabolite found at elevated concentrations in Fabry disease, has been shown to increase the expression of TGF-β and CD74 in cultured human podocytes, potentially mediating injury (97). Tubular dysfunction may result from aberrant proteolytic processing and reduced and ectopic expression of uromodulin (UMOD) in epithelial cells with Gb3 storage (98). In addition, cells lacking α-galactosidase A show reduced viability and increased membranous Gb3 expression that could disrupt cellular signaling (99). Renal manifestations may therefore result from a combination of vascular insufficiency, podocyte toxicity, and tubular damage (85).

Nephrosialidosis and Variants


Sialidosis is an autosomal recessive disorder caused by mutations in the NEU1 gene on chromosome 6p21, affecting the degradation of glycoprotein. The resulting deficiency of α-neuraminidase activity leads to the accumulation of several sialyl oligosaccharides and glycoproteins, which are excreted in the urine and are useful in diagnosis. Another recently discovered function of α-neuraminidase is to negatively regulate lysosomal exocytosis, a basic physiologic process in many cell types. Therefore, mutations in NEU1 also exacerbate lysosomal exocytosis that may underlie other phenotypic abnormalities of the disorder (113). Over 40 mutations have been described. The residual catalytic enzyme activity and its subcellular localization (endoplasmic reticulum/Golgi vs. lysosome) appear to influence the clinical severity, with phenotypic heterogeneity even within families. Type 1 sialidosis, the milder form, usually presents in the second decade with visual impairment, generalized myoclonus, ataxia, and epilepsy. Sialidosis type 2 (mucolipidosis I) is divided into three subgroups based on the age of symptom onset: congenital (in utero), infantile (0 to 12 months), and juvenile (approximately 2 to 20 years). Type 2 is distinguished from type 1 by its earlier onset and mucopolysaccharide-like phenotype with abnormal facies, dysostosis multiplex, hepatosplenomegaly, and psychomotor retardation (114). The congenital form is associated with hydrops fetalis and stillbirth or neonatal ascites and early death (115). Infantile sialidosis severely affecting the kidney and causing symptomatic renal disease has been termed nephrosialidosis. Macular cherry-red spots, myoclonus, and delayed neurodevelopment soon become manifest. Proteinuria, developing in infancy, progresses to nephrotic syndrome and to early renal insufficiency (116).


Galactosialidosis is closely related to sialidosis and results from a combined deficiency of neuraminidase and β-galactosidase, owing to a defect in another lysosomal protein, the protective protein cathepsin A, with which they are complexed (113,114). Patients have coarse facies, cherry-red spots, skeletal anomalies, and foam cells in the bone marrow. A juvenile/adult form is characterized by myoclonus, ataxia, and neurologic deterioration and is found predominantly in consanguineous Japanese families, whereas the late infantile form has hepatosplenomegaly, growth retardation, and cardiac valvular disease (116,117). In addition to hydrops, visceromegaly, and skeletal dysplasia, the kidneys are affected in the early infantile form of galactosialidosis, with histopathologic features and progression to renal insufficiency matching that of nephrosialidosis (118).

Free Sialic Acid Storage Disorders (Salla and Infantile Sialic Acid Storage Diseases)

Sialic acid storage disorders are characterized by the lysosomal accumulation of free sialic acid as a result of defects in sialin, encoded by SLC17A5, a carrier-mediated lysosomal membrane transport protein (119). The disorder is divided into two phenotypes: the milder Salla disease, nearly unique to the Finnish population, which shows reduced but residual function; and the severe infantile sialic acid storage disease, which is associated with complete loss of sialin activity (120). Patients store in their tissues and excrete in their urine approximately 10 to 100 times the normal amounts of sialic acid. The infantile form can be detected in utero with hydrops fetalis or present at birth with hepatosplenomegaly, failure to thrive, severe mental and motor retardation, coarse facies, and dysostosis multiplex; those with Salla disease are normal at birth but develop psychomotor delay and ataxia during infancy (121). The renal features are similar histopathologically to those of nephrosialidosis and may be associated with steroid-resistant nephrotic syndrome (122).

Pathologic Changes in Nephrosialidosis and Variants

The glomerular podocytes are enlarged by abundant foamy and vesicular cytoplasm (Fig. 27.21) (117,122). Similar histopathologic abnormalities in the podocytes occur in asymptomatic sialidosis. The vesicles in paraffin sections are clear,
although they stain lightly with colloidal iron, indicating partial preservation of the material during processing. PAS staining shows only a fine granularity. Tubular cells, especially in proximal tubules, and interstitial cells are also vacuolated. Cytoplasmic vacuoles have also been found in endothelial cells of renal vessels (123).

FIGURE 27.21 The glomerulus in nephrosialidosis contains vacuolated podocytes that fill Bowman space. The adjacent interstitium and tubules contain vacuolated storage cells. (H&E; ×200.)

Immunofluorescence may show small, nonspecific glomerular deposits of IgM and C3, reflecting hyalinosis. In sialidosis, some podocyte vacuoles in frozen sections bind concanavalin A and wheat germ agglutinin, demonstrating mannose and sialic acid residues within the stored oligosaccharides.

Electron microscopy shows the vacuoles to be membrane bound and almost empty (Fig. 27.22). Some vacuoles contain granules and membranous profiles of electron-dense material. Similar vacuoles are present in tubules and occasionally in mesangial cells, endothelial cells, or parietal epithelial cells (123). Podocyte changes relate to proteinuria, and renal insufficiency is associated with glomerular collapse and sclerosis.

No specific treatment exists for this rare group of lysosomal storage disorders. A few attempts at bone marrow transplantation have met with limited success, and renal transplantation does not preclude development of systemic abnormalities (124,125).


Cobalamin C Deficiency

Cobalamin C (CblC) is required for conversion of dietary vitamin B12 to its reduced and methylated forms, which function as coenzymes. Deficiency of cblC is a panethnic disease and the most common inborn error of cobalamin metabolism, with an estimated incidence of 1:100,000 based on expanded newborn screening (126). Cobalamin C defects lead to impaired activities of methylmalonyl-CoA mutase and methionine synthase, resulting in methylmalonic aciduria and homocystinuria. The disorder is inherited as an autosomal recessive trait, and the severity of presentation can vary considerably. CblC-deficient patients typically present in the newborn period with failure to thrive, neurologic and ophthalmologic abnormalities, and hematologic disturbances, especially megaloblastic anemia. Cardiopulmonary and gastrointestinal involvement is not uncommon. Hemolytic uremic syndrome (HUS) is characteristic, and proteinuria may be apparent. Late-onset disease is rarer and milder and can appear at any time from early childhood to adulthood, presenting as neurologic deterioration without systemic symptoms (127,128). Renal damage may be the sole manifestation of late-onset disease (129,130).
CblC defect can be difficult to diagnose on a clinical basis due to its heterogeneous manifestation but is established by finding the combination of methylmalonic aciduria, homocystinuria, and increased propionylcarnitine with normal serum vitamin B12 and transcobalamin II concentrations.

FIGURE 27.22 Electron microscopy of a glomerulus in nephrosialidosis shows vacuolated podocytes and mesangial cells. The vacuoles are partially filled with electron-dense bodies and also contain lucent and finely granular material. (×10,400.) (Courtesy of Drs. C. E. Kashtan and Z. Posalaky.)

FIGURE 27.23 Mildly hypercellular glomerulus from a 5-year-old boy with cobalamin C deficiency. Chronic microangiopathic changes include thickened and duplicated basement membranes without capillary thrombi. (PAS-silver methenamine; ×400.)

Renal pathology in this group of patients has most typically been that of thrombotic microangiopathy (129,131). The glomeruli have shown mesangial expansion with mild mesangial and endothelial proliferation, endothelial swelling, capillary dilation, and basement membrane double contours (Fig. 27.23). Intracapillary fibrin or platelet thrombi can be seen. Foot process effacement, endothelial cell detachment, and expansion of the subendothelial space by granular, fibrillary material have been noted by electron microscopy (Fig. 27.24). Immunofluorescence is typically negative or nonspecific, but the peripheral glomerular membrane and primarily mesangial C3, C1q, and IgM were found in a single case, which also had widespread electron-dense deposits (131).

FIGURE 27.24 Electron microscopy in cobalamin C deficiency showing narrowing of the capillary lumen by subendothelial granular and fibrillar material and focal mesangial cell interposition. Foot process fusion is only focal. (×2500.)

Nearly 60 causal mutations have been identified in the recently discovered responsible gene designated MMACHC, which maps to chromosome region 1p34.1 (132,133). The protein is involved in binding cobalamin, decyanating cyanocobalamin, and dealkylating alkylcobalamins (134). Presumed mechanisms for the renal pathology include hyperhomocysteine- and hypomethionine-induced vascular damage and methylmalonate-induced proximal tubular injury (128). Successful management requires large amounts of hydroxocobalamin and betaine. Many patients die from severe hemolytic anemia, and in those without HUS, there is often improvement of hematologic, biochemical, visceral, and growth parameters although neurologic and visual complications persist (128).


Methylmalonic Acidemia

Isolated methylmalonic acidemia is an autosomal recessive disorder of branched-chain amino acid metabolism that has a varied presentation, but neonatal onset is typified by recurrent vomiting, lethargy, dehydration, failure to thrive, hypotonia, and metabolic ketoacidosis that, if untreated, results in multiorgan failure or death. It is caused by a deficiency of the enzyme methylmalonyl-CoA mutase (MCM) due to mutations in the MUT gene located on the short arm of chromosome 6 in which approximately 200 mutations have been identified (135). Defects in cobalamin metabolism (cblA, cblB, cblD variant 2) and a deficiency of methylmalonyl-CoA epimerase also yield methylmalonic acidemia (135). Children with complete MCM deficiency are cobalamin nonresponsive and typically develop renal tubular dysfunction that often progresses to ESRD by late childhood or early adolescence; partial enzyme activity correlates with lower urinary methylmalonic acid concentration, which might predict occurrence of renal failure (136,137). Assessment of nonvolatile organic acid patterns, acylcarnitine profiles, and complementation analysis are useful for diagnosis (135). Treatment is centered on dietary control and carnitine supplementation, with emergency support during times of illness.

Chronic organ damage ensues despite improved outcome of the acute metabolic crisis. Impaired renal function occurs in the majority of patients, and kidney pathology has shown tubulointerstitial nephritis with interstitial fibrosis, tubular atrophy, and interstitial mononuclear cell infiltrates (138). Mitochondrial dysfunction has been demonstrated in the MCM-deficient kidney and human proximal tubule cell models and might be implicated in renal perturbation (139,140). Chronic renal failure usually develops in the first or second decade and can be treated with dialysis. Liver transplantation provides enzyme to effectively avoid systemic metabolic derangement, but renal transplantation is required for replacement of localized kidney enzyme; neither prevents the neurologic complications that develop in some patients. The effectiveness of combined kidney and liver transplantation as a therapeutic option remains to be proven (141,142).


Glycogen Storage Disease

The glycogen storage diseases are genetic defects that result in the storage of abnormal amounts and/or abnormal forms of glycogen. Some affect several tissues, whereas others may affect only one, most commonly the liver or muscle because of their abundant quantities of glycogen.

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. It includes two major subtypes: GSD-Ia (von Gierke disease), caused by a deficiency of glucose-6-phosphatase alpha (G6Pase-α), which accounts for about 80% of cases; and GSD-Ib, caused by a deficiency in the glucose-6-phosphate transporter (G6PT) (143,144). Glucose-6 transporter translocates glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, where G6Pase-α hydrolyses it into glucose and phosphate; together, these enzymes maintain glucose homeostasis, and their deficiency results in an accumulation of glycogen, as conversion of glucose-6-phosphate to glucose in both glycogenolysis and gluconeogenesis is impaired. Glucose-6-phosphatase-α is expressed in high levels in the gluconeogenetic liver and kidney, whereas G6PT is ubiquitous.

Patients with GSD-I commonly become symptomatic in early infancy, presenting with hepatorenomegaly and hyperlactacidemia. They are hypoglycemic, with large abdomens and rounded faces, and some present with seizures. Hyperlipidemia, paralleling that in type IV hyperlipidemia, causes xanthomas; hyperuricemia may cause symptoms of gout in older children. The diagnosis, based on clinical and biochemical findings, is confirmed by measurement of G6Pase-α activity in fresh liver biopsy samples. More recent recommendations for diagnosis combine clinical and biochemical abnormalities with mutational analysis, the latter of which can also be used for carrier testing of at-risk families and prenatal diagnosis (144).

Renal enlargement begins early, and functional impairment is a late complication. Effective renal plasma flow (RPF) and glomerular filtration are increased at first, followed by microalbuminuria with subsequent proteinuria and hypertension. Microalbuminuria and proteinuria have been detected in children less than school age (145). The degree of hyperfiltration correlates with renal size. Patients have an incomplete form of distal tubular acidosis, and they are prone to hypercalciuria with development of nephrocalcinosis and stone disease, which can be demonstrated within the first year of life (146). Hyperuricemia, if untreated, can lead to gout. A form of Fanconi syndrome, originally thought to be associated with GSD-I, is now attributed to Fanconi-Bickel syndrome (see section later in this chapter).

Pathologic Changes

Renal enlargement and glomerular hyperperfusion are associated with twofold to threefold glomerular hypertrophy. The glomeruli may be mildly hypercellular, and they contain large amounts of mesangial lipid. Tubules are lined with large vacuolated cells engorged with glycogen (147) (Fig. 27.25). Frozen tissue or alcohol maintains glycogen to the best advantage, but it is partly preserved with routine formalin processing. Enlarged cells have rarefied or cleared cytoplasm that will stain with PAS and lose their pink blush after treatment with diastase. Progressive renal damage leads to focal segmental and, eventually, complete glomerular sclerosis (Fig. 27.26), the latter with arteriolar sclerosis, tubular atrophy, and interstitial fibrosis. Immunofluorescence is often positive for immunoglobulin and complement components; it may be positive for ApoAI.

FIGURE 27.25 A glomerulus in a patient with GSD-I is hypertrophied and has mildly increased numbers of prominent mesangial cells. Adjacent tubules show intense vacuolation of epithelial cells. (PAS; ×100.)

Electron microscopy shows twofold thickening of the GBM, sometimes diffusely. Lamellation and irregular contour, reminiscent of the abnormality in Alport syndrome, occur in areas of severe thickening (Fig. 27.27) (148). Glycogen granules are present among the basement membrane lamellae and focally within mesangial, epithelial, and endothelial cells. Widening of foot processes relates to proteinuria. Mesangial widening and segmental sclerosis are also present. The glomerular abnormality partially resembles that of diabetic nephropathy. Glycogen is present both diffusely and in membrane-bound vesicles in tubular epithelial cells. It is recognized ultrastructurally as aggregates of dense osmiophilic particles, typically small (150 to 200 Å) and monoparticulate but occasionally forming rosettes.

FIGURE 27.26 Nephrectomy kidney from a child with GSD-I shows an enlarged glomerulus and extensive global glomerulosclerosis. Atrophic tubules are associated with interstitial inflammation, fibrosis, and thickened arteries. (PAS; ×50.)

FIGURE 27.27 Electron microscopy shows the glomerular basement membrane in GSD-I to be frequently lamellated, incorporating irregular lucencies and fine granules. (×12,000.) (Courtesy of Dr. R. Verani.)


Peroxisomes are single membrane-bound organelles that are found in nearly all cells and participate in β- and α-oxidation of fatty acids; the synthesis of bile acids, cholesterol, and plasmalogens; as well as amino acid and purine metabolism. Disorders are grouped as those that affect single peroxisomal enzymes and as biogenesis disorders (assembly deficiencies) in which the organelle fails to form normally, resulting in defects that involve multiple peroxisomal functions (158). Defects in peroxisomes cause multiorgan disease that often involves the nervous system. Those discussed here include renal abnormalities.

Zellweger Syndrome

Of the peroxisome biogenesis disorders, Zellweger syndrome (ZS) (cerebrohepatorenal syndrome) is the most severe and caused by various mutations in at least 13 different PEX genes that encode peroxins, proteins involved in different stages of peroxisomal protein import, and/or the biogenesis of peroxisomes. Peroxisomal enzymes, synthesized in the cytosol, fail to be incorporated into peroxisomes, resulting in a complete deficiency of functional peroxisomes and all peroxisomal functions (159). PEX1 mutations are most common in ZS, and those that induce premature stop codons correlate with the most severe phenotype and shortest survival (160). Peroxisomes are markedly reduced and sometimes absent in the kidney, liver, and other organs (161). Infants are affected at birth and show severe hypotonia, feeding disability, brain and hepatic dysfunction, periarticular calcifications, and characteristic facies. Elevated very long-chain fatty acids in blood and tissues are diagnostic, but confirmation of “ZS spectrum” patients may require complementation analysis or PEX gene testing (162,163).

More than 90% of patients have renal cortical cysts, often of glomerular origin, that may develop in utero and vary from microscopic dimensions to several centimeters in size (Figs. 27.28 and 27.29) (158,164). Most patients die within the 1st year of life. Although the renal cysts are usually asymptomatic and renal function is usually normal, occasional instances of albuminuria, aminoaciduria, and mild azotemia have been described. A high incidence of hyperoxaluria, occasionally associated with urolithiasis and nephrocalcinosis, has been observed (165).

FIGURE 27.28 Autopsy kidney from an infant with Zellweger syndrome shows prominent fetal lobulation and numerous small, thin-walled cysts in the peripheral cortex and subcapsular area.

FIGURE 27.29 Microcysts of both tubular and glomerular origin are evident in the cortex of a Zellweger kidney without significant functional implication. (H&E; ×100.)

The hypotonia, hepatic dysfunction, facial dysmorphism, and renal cysts of Zellweger could be confused with the entity of glutaric aciduria type 2 (multiple acyl-CoA dehydrogenase deficiency), a mitochondrial electron transfer disorder, but a characteristic organic acid pattern in the urine establishes the latter diagnosis. Renal anomalies in glutaric aciduria type 2 may be dramatic and include extensive cortical and medullary cyst formation, sometimes with dysplastic changes (166).

Adult Refsum Disease

Adult (classic) Refsum disease (heredopathia atactica polyneuritiformis), a rare autosomal recessive disorder, results from an abnormal accumulation of phytanic acid owing to a defect in phytanoyl-CoA hydroxylase (PhyH). Most patients harbor mutations in the PHYH gene, although in a subset, mutations have been found in PEX7, which encodes the peroxisomal targeting signal receptor that is required for the import of PhyH into peroxisomes (167). Heterozygotes, with approximately 50% enzyme activity, do not accumulate phytanic acid.

Phytanic acid is a 20-carbon, branched-chain fatty acid derived from phytol, a component of chlorophyll. The human source of phytol and phytanic acid is entirely dietary, from dairy products and animal fats. Phytanic acid is stored in plasma and tissues, mostly adipose tissue, liver, kidney, muscle, and nerve, predominantly in triglycerides, and to a lesser extent in phospholipids and cholesterol esters (168). Phytanic acid may cause cellular toxicity by mitochondrial inhibition (169,170).

Clinical symptoms usually present in late childhood as anosmia and night blindness, caused by retinitis pigmentosa. Peripheral neuropathy, cerebellar ataxia, nerve deafness, cardiac arrhythmias, and ichthyosis often occur in the following decades (171). About 35% of patients have bone abnormalities, especially in the hands and feet, that are present at birth but typically are not recognized until other disease manifestations
become evident. High concentrations of protein are present in the spinal fluid. Full expression of the disease occurs during the fourth or fifth decade, but it can manifest in childhood.

Renal involvement is demonstrated by proteinuria, mild renal insufficiency, glycosuria, and lipiduria. Elevated plasma phytanic acid esters are demonstrated by gas chromatography, but these elevations are not specific to Refsum disease since they are seen in peroxisome biogenesis disorders; molecular genetic testing is clinically available. The condition is treated by dietary restriction and lipid apheresis (172).

Pathologic Changes

Renal tubular epithelial cells, both proximal and distal, are filled with fine sudanophilic vacuoles. Glomeruli are initially minimally affected, with only mild podocyte vacuolization. Glomerular sclerosis and interstitial fibrosis correlate with renal insufficiency. Electron microscopy shows perinuclear cytoplasmic vacuoles and membrane-bound vesicles in glomerular and tubular epithelial cells. Lancet-shaped inclusions of microtubular material are present within cells of the distal tubules and loop of Henle (173); they are visible in semithin plastic sections.

The inclusions resemble mitochondrial paracrystalline structures, but they are not membrane bound. They contain quadrangular microtubular arrays, shown in cross-section to have geometric patterns (Fig. 27.30) (174). Their origin and composition are unknown, although they may be lipid organized into lamellae.

FIGURE 27.30 The tubular epithelial cells in adult Refsum disease contain crystalloid inclusions, with geometric structures. (×77,000.) (Courtesy of Dr. B. Panner.)

Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a rare autosomal recessive calcium oxalate kidney stone disease with three recognized molecular causes (175). In type 1 (PH1), which is the most common, continuing renal deposition of calcium oxalate leads to nephrocalcinosis, recurrent nephrolithiasis, and chronic renal insufficiency. The disease is caused by a deficiency of the vitamin B6-dependent liver-specific peroxisomal alanine-glyoxylate aminotransferase (AGT), which transaminates glyoxylate to glycine. Glyoxylate thus accumulates and is instead oxidized to oxalate and reduced to glycolate. Oxalate is not metabolized further and is eliminated from the body in the urine.

Crystallization occurs from highly concentrated solutions, causing urolithiasis or nephrocalcinosis with renal tubulointerstitial damage and progressive renal functional impairment. Primary hyperoxaluria type 1 is characterized by hyperoxaluria and hyperglycolic aciduria. Renal colic and hematuria, secondary to urolithiasis, often commence in childhood, although there is marked heterogeneity in the onset and severity, even within families. Five clinical presentations have been
recognized: (a) infantile oxalosis with early nephrocalcinosis and kidney failure; (b) childhood recurrent urolithiasis and rapidly progressive renal failure; (c) late onset with only occasional stone passage in adulthood; (d) post-kidney transplantation recurrence; and (d) presymptomatic discovery with family screening (176). Approximately 10% of patients have severe disease, with early infantile onset manifesting as failure to thrive, severe metabolic acidosis, anemia, and rapid progression to renal failure, whereas another 10% may not become symptomatic until the fourth or fifth decades (177). Progressive parenchymal deposition of calcium oxalate impairs renal function, which ultimately leads to systemic oxalosis. Complications include severe deforming osteopathy, arthropathy, cardiomyopathy, retinopathy, neuropathy, and pancytopenia. The kidneys are often small and may feel gritty on cut section (Fig. 27.31). Small, polyhedral or rhomboid, usually transparent, doubly refractile crystals are recognized histologically and accumulate in tubules, where they compress and destroy epithelium. The crystals can extend into the interstitium and induce fibrosis (Fig. 27.32). End-stage kidneys show extensive glomerulosclerosis and widespread interstitial fibrosis that encases abundant crystals (Fig. 27.33). Stone analysis demonstrates virtually pure (>95%) calcium oxalate monohydrate (whewellite) and a whitish or pale-yellow surface with a loose, unorganized center comprised of spherical, variably sized crystal aggregates, approximately 50 µm in diameter, that resemble balls of wool (178).

FIGURE 27.31 Autopsy kidney of 5-year-old boy with primary hyperoxaluria who presented at 5 months with seizures and failure to thrive. The kidneys were one third the expected weight and had a gritty consistency caused by yellow-tan oxalate crystals. A 0.3-cm calculus occupies a calyx. (Courtesy of J. Siebert, Ph.D., Seattle Children’s Hospital, University of Washington.)

FIGURE 27.32 Renal tubules in primary hyperoxaluria are filled with rhomboid and polyhedral refractile oxalate crystals. A glomerulus is collapsed and segmentally sclerotic (same kidney as Fig. 27.31). (H&E, partial polarization; ×200.)

PH should be suspected in any child with a renal stone, any adult with recurrent stone disease, and anyone with oxalate crystals in tissues or body fluids or with nephrocalcinosis and decreased GFR. Renal ultrasound may disclose stones and possibly medullary or diffuse nephrocalcinosis. Markedly elevated
levels of urinary oxalate usually indicate PH in the absence of any likely causes of secondary hyperoxaluria, either increased intake (excessive star fruit and peanut ingestion), increased absorption (“enteric hyperoxaluria” related to orlistat therapy or gastrointestinal disease or surgery), or increased production (ascorbic acid or ethylene glycol ingestion). Histologic demonstration of calcium oxalate deposition in the kidney has been used for diagnosis, but it is not specific for primary disease; determining the AGT activity in a liver biopsy sample has been considered the gold standard for diagnosis. Molecular genetics has now reached a level of sensitivity and specificity that makes it useful for definitive testing and is also considered the preferred method for prenatal testing (179). More than 150 mutations have been identified in the AGXT gene, which resides on chromosome 2q37.3 (180,181). Mutations result in accelerated proteolysis, peroxisome-to-mitochondrion targeting defects, intraperoxisomal AGT aggregation, absence of AGT catalytic activity, and absence of both catalytic activity and immunoreactivity. The clinical heterogeneity may relate to great variability in enzymatic activity among patients but is clearly influenced by potential modifier genes, environmental factors, and genetic background, as the genotype-phenotype correlation is limited. However, some mutations that result in AGT mistargeting appear to be associated with responsiveness to pyridoxine treatment (181,182,183,184,185,186).

FIGURE 27.33 The end-stage kidney in primary hyperoxaluria has interstitial fibrosis and inflammation that separate crystal-filled tubules. This unique case had marked embryonal hyperplasia characterized by nodular proliferations of small basophilic tubules peppering the cortex; the patient was not dialyzed. Osseous metaplasia is present adjacent to the glomerulus. (H&E; ×250.)

Type 2 hyperoxaluria (PH2) is caused by defective cytosolic glyoxylate/hydroxypyruvate reductase (GRHPR) due to mutations in the GRHPR gene located on chromosome 9, in which at least 15 mutations have been identified (175,187,188). Type 2 PH is rare and can be distinguished from PH1 by finding elevated glycolate and L-glycerate in addition to high oxalate levels. Clinical manifestations are less severe and consist primarily of urolithiasis, although ESRD has been documented (175,189,190). Liver enzyme analysis confirms the diagnosis. PH3 is caused by mutations in the HOGA1 gene located on chromosome 10q24. The encoded enzyme, 4-hydroxy-2-oxoglutarate aldolase, catalyzes the synthesis of mitochondrial glyoxylate and is found primarily in the liver and kidney. Patients primarily suffer from urinary stones, but urinary oxalate concentration overlaps with PH1 and PH2. The age of onset is similar, but occasional adult presentation may imply a milder disease (191,192).

Generous fluid intake and drugs that increase the urinary solubility product are important therapeutic measures (193). Pyridoxine (vitamin B6), which affects AGT expression or activity, lowers urinary oxalate in only about one third of patients (193). Pyridoxamine, by scavenging carbonyl intermediates in the glyoxylate pathway, inhibits oxalate biosynthesis, has been shown to decrease crystal formation in hyperoxaluric animal models, and may offer therapeutic hope for the treatment of PH (194). Combined liver/kidney transplantation, which results in enzyme replacement, has achieved better outcomes than the disappointing early results from isolated kidney transplantation, in which oxalate deposits constantly recurred in the graft (179,195,196,197). Preemptive liver transplantation may be considered in some settings (198).


Functional tubular abnormalities take the form of both specific defects in solute resorption and generalized disorders of proximal tubular transport. Most specific transport defects are heritable and are not associated with structural abnormalities.

Fanconi syndrome is a heterogeneous disorder of proximal tubular transport, by definition comprising aminoaciduria, glucosuria, and phosphaturia. Children develop hypophosphatemic, vitamin D-resistant rickets; adults develop osteomalacia. The disorder commonly includes proximal tubular acidosis, impaired urine concentration, and impaired resorption of potassium, urate, and citrate. Fanconi syndrome occurs as a primary idiopathic disease (Lignac-de Toni-Debré-Fanconi syndrome), a heritable tubular defect, or a secondary manifestation of a recognized heritable metabolic disease.

Acquired Fanconi syndrome is the result of a variety of toxic and immunologic renal tubular injuries. The renal manifestations are largely the same in all forms. So-called incomplete Fanconi syndromes with, for example, only renal glycosuria and aminoaciduria may be caused by the same basic tubular disturbances as occur in the complete syndrome.

Fanconi syndrome seems to be the final common manifestation of assorted cellular perturbations that interfere with tubular epithelial function by affecting solute uptake and/or excretion via interference with receptor-mediated endocytosis or passage along the endocytic apparatus (199). Diverse etiologies can affect the delicate balance that maintains tubular function; these include (a) altered energy production, for example, mitochondrial dysfunction that inhibits Na+, K+−ATPase and thereby impedes Na+−dependent transport; (b) abnormal apical or basolateral membrane transport molecules, for example, mutations in SLC6A19 or GLUT2; and (c) interference with membrane trafficking and recycling, for example, CLCN5 mutations that interrupt the activities of megalin and cubilin. As new discoveries are made, the so-called idiopathic Fanconi syndrome may cease to exist.

Inherited Fanconi Syndrome

Idiopathic Fanconi Syndrome

Primary Fanconi syndrome, a diagnosis of exclusion, occurs in both adults and children as familial traits that appear to be predominantly autosomal dominant (200). Sporadic cases without identifiable nephrotoxicity are not necessarily genetic. Although a defined genetic defect is currently unknown, this form of the syndrome can only be diagnosed when no underlying metabolic disease exists and all possible acquired causes have been excluded. The demonstrated absence or partial loss of proximal tubular brush border is common to all forms of Fanconi syndrome. The occurrence of heavy glycogen deposition (Armanni-Ebstein lesion), similar to that in diabetes mellitus, has been described in the pars recta of some patients with Fanconi syndrome (201); this phenomenon is rarely seen in current practice. Clinical manifestations in children include failure to thrive, growth retardation, polydipsia, polyuria, rickets, and unexplained fever. Adults have weakness and bone pain, with polydipsia and polyuria.


Cystinosis, a rare autosomal recessively inherited lysosomal transport disorder, is the most common identifiable cause of Fanconi syndrome in children. It has an estimated incidence of 1 in 100,000 to 200,000 live births, although higher incidences are reported in some regions of France, Germany, Quebec, and the United Kingdom (202). More than 90 mutations have been
identified in the responsible gene, CTNS, which resides on chromosome 17p13 and encodes cystinosin, a ubiquitous lysosomal transmembrane protein that facilitates efflux of cystine from the lysosome (203). It differs thereby from other lysosomal storage diseases, which are caused by deficiencies in lysosomal acid hydrolases. Recently identified is a second cystinosin isoform, cystinosin-LKG, that results from alternative splicing and localizes to lysosomes and other cellular compartments including the plasma membrane, endoplasmic reticulum, and small, nonlysosomal cytoplasmic vesicles (204). All mutations currently described alter the sequence of both isoforms; however, the function of cystinosin-LKG remains unknown.


Cystinosis is clinically classified into three forms. Infantile cystinosis is nephropathic, with early onset of Fanconi syndrome and progression to ESRD usually within the first decade of life. Less severe variants probably form a continuum, but two distinct subtypes include (a) intermediate cystinosis (“juvenile” or “late onset”), which causes a mild nephropathy with slow progression of renal impairment, without Fanconi syndrome; and (b) ocular or nonnephropathic cystinosis (“benign” or “adult”), which is characterized by ocular findings without renal involvement.

Free cystine, from lysosomal protein hydrolysis, increases in cells to concentrations between 10 and 1000 times normal. Cystine accumulation and crystal formation vary considerably among tissues and may be related to different rates of protein degradation and cell turnover. The diagnosis can be made either by demonstrating increased concentrations of cystine in peripheral leukocytes and other cells or by demonstrating cystine crystals in the cornea by slit-lamp examination and in bone marrow macrophages, conjunctiva, intestinal mucosa, and kidney by polarization microscopy. In contrast to cystinuria, urinary cystine levels are not elevated. Diagnosis of fetal disease can be made by measurement of cystine in amniotic fluid, amniocytes, or chorionic villi. Molecular analysis of the CTNS gene provides confirmation and can be used for prenatal assessment (205).

Children with infantile nephropathic cystinosis develop polyuria, polydipsia, dehydration, and febrile episodes within the first year of life. Features of Bartter syndrome and nephrogenic diabetes insipidus have preceded the development of Fanconi syndrome in occasional patients (206,207). Proximal tubular dysfunction, with aminoaciduria, glycosuria, phosphaturia, and renal tubular acidosis, leads to vitamin D-refractory rickets and growth retardation. Patients may develop muscle weakness as a consequence of myopathy. Glomerular impairment leads to end-stage renal failure by 10 years of age. With renal replacement therapy, widespread end-organ damage may develop from cystine deposition in the eyes, liver, endocrine glands, and muscular and central nervous systems, resulting in late complications of diabetes mellitus, male infertility, hypothyroidism, and coronary artery disease (208,209,210). Photophobia and abnormal retinal pigmentation are not uncommon and typically the only manifestation in the nonnephronic/adult form. Caucasian children have noticeably less skin and hair pigmentation than their unaffected siblings as a consequence of defective melanin synthesis; the skin and hair of patients from darkly pigmented ethnic groups appear normally pigmented. The juvenile form is uncommon, generally presenting after 10 years of age with renal disease ranging from mild proximal tubulopathy to apparent nephrotic syndrome. The renal disease usually progresses more slowly than the infantile form, with ESRD developing in the second or third decade (202,211), although the deterioration rate can differ tremendously among family members (212).

FIGURE 27.34 Renal cortex from an 8-year-old boy with cystinosis showing considerable atrophy of the tubules, interstitial fibrosis, and glomerular solidification. (H&E; ×200.)


The ultimate histopathologic abnormality in all forms of Fanconi syndrome is tubular atrophy with interstitial fibrosis, variable inflammation, and progressive glomerular sclerosis (Fig. 27.34). Morphologic complications include the occasional development of nephrocalcinosis. The tubular atrophy has been shown by microdissection to be particularly pronounced in the first part of the proximal tubule, in which a shortened and narrow postglomerular segment has been described as the “swan-neck deformity” (Fig. 27.35) (213). This abnormality likely reflects progressive apoptotic cell death and a moderately severe degree of secondary tubular atrophy; it is neither specific to Fanconi syndrome nor an explanation of its functional derangements but may lead to an increased incidence of atubular glomeruli (214). Among the earlier tubular changes, loss of brush border accompanies cell shortening, and the generalized absence of brush border mentioned in the description of idiopathic Fanconi syndrome may well be a secondary phenomenon. Other secondary changes include cellular vacuolization and basement membrane calcification, the latter perhaps a consequence of renal insufficiency and secondary hyperparathyroidism.

Cystinosis is distinguished by the deposition of cystine crystals, predominantly in the interstitium (Fig. 27.36). Large extracellular collections of crystals lie among the tubules in the cortical labyrinth. The crystals, easily dissolved from the tissues in aqueous solutions during tissue processing, are preserved in alcoholic solutions. They have a hexagonal, rhombohedral, or polymorphous configuration; are birefringent; and, even when sparse, are demonstrable by polarization microscopy in frozen sections. A few crystals may be present in tubular and glomerular epithelial cells, and clefts are identified by electron microscopy in podocytes and mesangial cells (Fig. 27.37) (215,216).

FIGURE 27.35 “Swan-neck” appearance of a dissected proximal convoluted tubule. The thinned early part of the proximal convoluted segment is apparent (glomerulus at top). (Courtesy of Dr. E. M. Darmady.)

FIGURE 27.36 Alcohol-fixed kidney section from a child with cystinosis showing interstitial deposition of rectangular refractile cystine crystals. A rare crystal is also evident in the glomerulus. (H&E, partial polarization; ×100.)

Early and distinctive abnormalities in cystinosis are multinucleated podocytes (Fig. 27.38) and, occasionally, tubular and parietal epithelial cells, a finding not unique to cystinosis but helpful in diagnosis (216,217). Similar cells occur in noncystinotic Fanconi syndrome and few other conditions.

Glomerular podocytes in cystinosis are sometimes opaque on light microscopic examination of semithin sections of osmicated, plastic-embedded tissue; transmission electron microscopy confirms the observation, showing the dark cells to be filled with electron-dense granular material (215). Dark cells
are present rarely in tubules and occasionally in the interstitium. The phenomenon is probably caused by a reaction between osmium and intracellular cystine; electron-probe analysis shows that the dark cells contain sulfide, a constituent of cystine. Recently, it was suggested that they represent autophagic vesicles, which are increased in cystinosis (218).

FIGURE 27.37 Electron micrograph shows an epithelial cell from a glomerular tuft that contains rectangular and spindle-shaped clear areas, presumably once occupied by cystine. (×4000.)

FIGURE 27.38 Glomeruli from a child with cystinosis showing multinucleated visceral epithelial cells. (H&E; ×160.)

Intermediate, or juvenile, cystinosis causes predominantly glomerular disease, with mesangial hypercellularity, increased matrix, capillary wall thickening, and segmental and global glomerular sclerosis; multinucleated podocytes may be unapparent (212). Crystal deposition may only be detected by electron microscopy, which also demonstrates podocyte foot process effacement.

Dent Disease

Dysfunction of renal proximal tubules with low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and rickets characterizes Dent disease. Renal function may begin to decline in the teenage years, and renal failure eventually develops in about two thirds of patients, but the progression is varied (228). Proximal tubular dysfunction is variable but may become evident in the neonatal period. Isolated nephrotic syndrome, notably without hypoalbuminemia, has been reported (229,230). Hypercalciuria, the hallmark of Dent disease, can be detected in the first year of life, but stone formation may not be present in pediatric patients. Some patients complain of night blindness secondary to increased loss of retinol-binding protein in the urine and retinol deficiency, which is responsive to vitamin A supplements (231,232). Hypophosphatemic rickets is not universal but can be one of the first clinical presentations. The disease is generally found in males, but milder features of low molecular weight proteinuria and hypercalciuria are evident in 50% to 75% of female carriers with end-stage renal failure occurring rarely (233). Different clinical features predominated in the original descriptions, but it is now recognized that Dent disease and its “variants”—X-linked recessive hypophosphatemic rickets and X-linked recessive nephrolithiasis—are a single disorder caused by inactivating mutations in the CLCN5 gene, located on chromosome Xp11.22; nearly 150 mutations have been reported with no apparent genotype-phenotype correlation (234). Interestingly, mutations in OCRL1, the gene responsible for Lowe syndrome (see following), have been identified in approximately 15% of patients with a classic Dent disease phenotype (the so-called Dent-2 disease) who lacked mutations in CLCN5 (233,235,236). Additional genes likely harbor mutations, as normal CLCN5 and OCRL1 have been found in 25% to 35% of patients with clinically indistinguishable Dent disease. No mutations have been identified in the CLC5-endocytic pathway-associated proteins, CLC4 and CFL1, in the endosomal associated sodium-proton exchanger, SLC9A6 or TMEM27, a proximal tubular protein (233,237).

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Jun 21, 2016 | Posted by in UROLOGY | Comments Off on Renal Disease Caused by Inborn Errors of Metabolism, Storage Diseases, and Hemoglobinopathies

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