Clifford E. Kashtan
Hereditary disorders of the glomerulus are categorized on the basis of the demonstrated or predicted function(s) of the affected proteins. These are somewhat arbitrary categorizations that likely simplify the cell-cell and cell-matrix interactions that produce disease phenotypes, as listed in Chapter 472, Table 472-1.
GLOMERULAR BASEMENT MEMBRANE DISORDERS
FAMILIAL HEMATURIAS: ALPORT SYNDROME AND THIN BASEMENT MEMBRANE NEPHROPATHY
Between 30% and 50% of children with persistent hematuria have an inherited disorder of glomerular basement membranes (GBM). Accurate diagnosis of familial hematuria is crucial for predicting prognosis and providing accurate reproductive counseling.
Most children and adolescents with familial glomerular hematuria have either Alport syndrome (AS) or thin basement membrane nephropathy (TBMN). All patients with AS, and about 50% of those with TBMN, have mutations in genes that code for type IV collagen proteins, the major collagenous constituents of basement membranes. About 80% of AS patients have X-linked disease due to mutations in COL4A5, the gene encoding the a5 chain of type IV collagen (a5[IV]). Autosomal recessive AS accounts for about 15% of patients and arises from mutations in both alleles of COL4A3 or COL4A4, which encode the a3(IV) and a4(IV) chains, respectively. About 5% of AS patients have autosomal dominant disease, due to heterozygous COL4A3 or COL4A4 mutations. However, most people with heterozygous mutations of COL4A3 or COL4A4 have TBMN, a nonprogressive form of familial hematuria.
Persistent microscopic hematuria is the hallmark of AS, occurring in 100% of X-linked AS males, 95% of X-linked AS females, and all patients with autosomal recessive AS. Episodic gross hematuria is common. The onset of hematuria in X-linked AS males occurs during infancy. Since only 10% to 15% of children with X-linked AS have de novo mutations, most children with X-linked AS have a parent with hematuria. However, normal parental urinalyses do not exclude a diagnosis of X-linked AS. Each parent of a child with autosomal recessive AS is a heterozygous carrier of a mutation in COL4A3 or COL4A4. Since about 50% of these carriers are symptomatic, hematuria may be found in both parents, one parent, or neither parent.
Microscopic hematuria is also the cardinal clinical finding in children with TBMN, who may have episodic gross hematuria, often in association with acute infection. TBMN is a dominant disorder, so hematuria is frequently found in a parent.
As TBMN is typically nonprogressive, a family history of kidney failure in a child with hematuria suggests a diagnosis of AS. A family history of deafness should also raise suspicion for AS. Sensorineural deafness develops in 80% of X-linked AS males and most patients with autosomal recessive AS. The onset of measurable hearing deficits typically occurs in late childhood. The hearing defect is bilateral and initially involves high-frequency wavelengths, gradually extending into conversational speech wavelengths over time. About 40% of X-linked AS males exhibit ocular anomalies, including maculopathy, anterior lenticonus, posterior polymorphous dystrophy, and recurrent corneal erosions. The maculopathy and anterior lenticonus also occur in autosomal recessive AS patients. Because TBMN is a renal-limited disorder, the presence of extrarenal abnormalities like deafness or ocular lesions in someone with hematuria makes a diagnosis of TBMN unlikely. The absence of such findings does not rule out AS, especially in the young patient.
Rarely, X-linked AS is associated with smooth muscle tumors (leiomyomata) of the esophagus; the tracheobronchial tree; and, in females, the external genitalia. The AS-diffuse leiomyomatosis complex is a contiguous gene syndrome resulting from deletions involving the adjacent COL4A5 and COL4A6 genes on the X chromosome.
Kidney function is usually well preserved during the first decade of life in X-linked AS males. Overt proteinuria frequently appears during late childhood or early adolescence, followed by development of hypertension and renal insufficiency. About 50% of X-linked AS males reach end-stage renal disease (ESRD) by age 25 and 90% by age 40. The probability of ESRD in X-linked AS females is 15% by age 45 and 30% by age 60. Subjects with autosomal recessive AS follow a course similar to X-linked AS males. In contrast, the great majority of people with TBMN maintain normal urine protein excretion and kidney function throughout life.
AS and TBMN may be indistinguishable by routine light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM) in children. While X-linked AS males will eventually exhibit LM abnormalities, females may have normal-appearing kidneys by LM, as do individuals with TBMN. In children with familial hematuria, the presence of mesangial proliferation or focal segmental glomerulosclerosis on LM suggests a diagnosis of AS.
By EM, individuals with TBMN display diffuse glomerular basement membranes (GBM) thinning. Since GBM thinning is also the earliest abnormality in AS patients, TBMN and AS may be indistinguishable by EM in young children. While GBM thinning is a static abnormality in TBMN, in AS the GBM undergoes progressive thickening associated with fragmentation of the lamina densa into multiple lamellae. In X-linked AS males, these changes typically first appear during childhood, and the extent of GBM displaying these alterations increases with age. In X-linked AS females, the extent of GBM thickening ranges from focal to diffuse, and the impact of aging on GBM thickening is variable.
Immunostaining of kidney biopsy specimens using monospecific antibodies shows diagnostic abnormalities in expression of a3(IV), a4(IV), and a5(IV) chains in most X-linked and autosomal recessive AS patients. Abnormal expression of the a5(IV) chain in epidermal basement membranes occurs frequently in patients with X-linked AS, allowing diagnosis by skin biopsy. Type IV collagen expression is normal in patients with TBMN. Molecular analysis of the COL4A5 gene for diagnosis of X-linked Alport syndrome (XLAS) is commercially available in the United States and Europe.
Patients who receive a diagnosis of TBMN do not require treatment but do need regular monitoring to identify the small number who will develop proteinuria, hypertension, or renal insufficiency due to superimposed focal segmental glomerulosclerosis and those who have received an inaccurate diagnosis of TBMN. There is no proven treatment for AS other than renal transplantation, although studies in transgenic mice have suggested several possible approaches, including angiotensin II antagonism and stem cell transplantation. Transplant outcomes in AS are generally excellent, although a small percentage of patients develop severe crescentic glomerulonephritis of the allograft mediated by antibodies to type IV collagen a5 or a3 chains.1,2
Pierson syndrome is a recessive disorder consisting of congenital nephrotic syndrome associated with ocular abnormalities (buphthalmos, micro-coria, cataracts) and hypotonia. Pierson syndrome arises from mutations in the LAMB2 gene, which encodes the laminin b2 chain.3
DISORDERS OF THE SLIT DIAPHRAGM
CONGENITAL NEPHROTIC SYNDROME, FINNISH TYPE (CNF)
CNF is the predominant cause of massive proteinuria in the first month of life. Proteinuria begins in utero, manifested by elevated amniotic fluid a-fetoprotein levels and postnatal edema. Untreated, the disease frequently results in early death due to malnutrition, overwhelming infection, and thrombosis. With appropriate therapy, affected children can survive infancy and can undergo renal transplantation, with excellent patient and graft survival rates.
Pathophysiology and Genetics
CNF is a recessive disorder resulting from homozygous or compound heterozygous mutations in the NPHS1 gene on chromosome 19, which encodes the podocyte slit diaphragm protein nephrin. Nephrin is a cell-surface protein with a single transmembrane domain and eight extracellular Ig-like domains that are specifically expressed at the slit diaphragms between podocyte foot processes. Nephrin molecules projecting from adjacent foot processes appear to interact to define pores in the slit diaphragm. Nephrin knockout mice develop massive proteinuria associated with absence of podocyte foot processes and slit diaphragms.
Infants with CNF typically present within the first month of life with edema, hypoalbuminemia, and proteinuria. Placental enlargement is common. Glomerular filtration rate (GFR) is typically normal for at least the first 6 months of life.
Early histological findings include mesangial hypercellularity and matrix expansion, dilatation of Bowman’s spaces and renal tubules, and podocyte foot process effacement. Later biopsy may show glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Molecular analysis of NPHS1 and NPHS2 is commercially available, making renal biopsy unnecessary for diagnosis in most infants with congenital nephrotic syndrome.
With appropriate therapy, infants with CNF should grow enough to undergo renal transplantation. Management is complex, involving aggressive nutritional support, thyroid supplementation, prompt recognition and treatment of bacterial infection, and early identification and therapy of thrombotic events. Once the child reaches 7 to 8 kg in weight, bilateral nephrectomies are performed, followed by 6 to 8 weeks of hemodialysis to allow optimal nutrition and normalization of plasma proteins in preparation for renal transplantation.4-6
AUTOSOMAL RECESSIVE STEROID-RESISTANT NEPHROTIC SYNDROME (FAMILIAL SRNS)
Genetic studies of families exhibiting recessive transmission of childhood-onset nephrotic syndrome characterized by steroid resistance, rapid progression to ESRD, and absence of recurrence after transplantation led to the identification of the NPHS2 locus and its protein product, podocin.
Pathophysiology and Genetics
NPHS2 is located on chromosome 1 and encodes podocin, a member of the band-7 protein family predicted to comprise two intracellular domains and an interposed intramembranous domain that results in a “hairpin” tertiary structure. Podocin is expressed exclusively in the kidney and localizes to podocyte foot process plasma membranes in association with slit diaphragms. Transgenic mice lacking NPHS2 fail to form slit diaphragms and develop proteinuria, azotemia, and glomerulosclerosis. A variety of mutation types, distributed throughout the gene, have been identified in NPHS2. Protein-truncating mutations may be associated with earlier onset disease.
The mean age of onset of nephrotic syndrome in patients with familial SRNS due to NPHS2 mutations is 3 to 6 years. Mean age at ESRD occurs at 8 to 10 years, although patients as old as 27 years have developed ESRD.
Renal biopsies typically demonstrate focal segmental glomerulosclerosis, with or without mesangial expansion and immunoprotein deposition.
Steroid resistance is a diagnostic feature of familial SRNS and is characteristic of patients with homozygous or compound heterozygous NPHS2 mutations. Cytotoxic agents and calcineurin inhibitors are usually ineffective. Kidney transplantation is the preferred therapy. Recurrence of proteinuria after transplant has been reported, but with lesser frequency and severity than in patients with idiopathic focal segmental glomerulosclerosis (FSGS).
DISORDERS OF THE CYTOSKELETON
AUTOSOMAL DOMINANT FOCAL SEGMENTAL GLOMERULOSCLEROSIS
To date, three loci (FSGS1, FSGS2, and FSGS3) encoding proteins expressed in podocytes have been implicated in families exhibiting dominant transmission of FSGS. Mutations in a-actinin-4, the protein product of FSGS1, are associated with onset of proteinuria in adolescence or adulthood and variable progression to ESRD. The FSGS2 locus encodes TRPC6 (transient receptor potential cation channel 6), a nonselective cation channel involved in plasma membrane calcium flux. Proteinuria is typically identified in adulthood. Heterozygous mutations in CD2AP (CD2-associated protein) have been reported in a few adult patients with FSGS (FSGS3).7,8
MYH9 DISORDERS: EPSTEIN AND FECHTNER SYNDROMES
Epstein and Fechtner syndromes are autosomal dominant disorders that share some features with Alport syndrome, including hematuria, progression to ESRD, and sensorineural deafness, but patients also exhibit thrombocytopenia and giant platelets. Fechtner patients exhibit granulocyte cytoplasmic inclusions (Döhle-like bodies). These conditions—along with two other genetic conditions featuring giant platelets, Sebastian syndrome and May-Hegglin anomaly—and nonsyndromic hereditary deafness DFNA17 result from heterozygous mutations in the gene MYH9, which encodes nonmuscle myosin heavy chain IIA (NMMHC-IIA). NMMHC-IIA is expressed in podocytes.9,10
DISORDERS OF GENE REGULATION
DENYS-DRASH SYNDROME (DDS) AND DIFFUSE MESANGIAL SCLEROSIS
DDS comprises the triad of XY gonadal dys-genesis with ambiguous genitalia, Wilms tumor, and diffuse mesangial sclerosis (DMS). Children with DDS may exhibit DMS and genital abnormalities without Wilms tumor, or they may exhibit DMS and Wilms tumor without genital abnormalities. DMS can also occur as an isolated condition.
Pathophysiology and Genetics
DDS and some cases of isolated DMS arise from heterozygous mutations in WT1, a 10-exon gene that encodes the transcription factor WT1, or Wilms tumor suppressor.
WT1 mRNA is expressed during nephrogenesis in the condensed mesenchyme, renal vesicle, and podocytes. Podocytes of adult kidneys express WT1 mRNA at low levels. WT1 mRNA expression patterns suggest that it may mediate the differentiation of nephrogenic mesenchyme to glomerular epithelium and help maintain the epithelial phenotype of the podocyte. Loss of WT1 function is predicted to allow uncontrolled growth of metanephric blastema cells, resulting in Wilms tumor and aberrant podocyte differentiation. WT1 mRNA is also expressed in primordial tissue of the gonadal ridge, the ovarian follicular granulosa cells, and the Sertoli cells; normal maturation of the gonads may also depend upon the functional integrity of WT1.
Most DDS patients have a mutation in exon 9 of the WT1 gene affecting the third zinc finger. Persistence of nephrogenic rests (undifferentiated mesenchyme) in DDS kidneys likely results from the germ-line WT1 mutation. A Wilms tumor will then result if a somatic mutation (“second hit”) inactivates the normal WT1 allele within a nephrogenic rest. In contrast to Wilms tumor, DMS and gonadal dysgenesis in DDS do not occur by a recessive mechanism, since DDS patients are heterozygous for their WT1 mutations. DDS mutations behave in a dominant-negative fashion (ie, the mutant protein interferes with the function of the product of the wild-type allele).
In 46XY DDS patients, genital abnormalities range from hypospadias with cryptorchidism to clitoral enlargement with labial fusion. External genitalia usually appear normal in 46XX patients. Anomalies of the internal reproductive organs, including atrophy of the vagina and uterus, streak ovaries, or dysgenetic testes, may occur with either karyotype. The abnormal gonads of 46XY patients may evolve into gonadoblastoma. DDS patients are more likely to have bilateral Wilms tumor and are younger when their tumors are identified than children with sporadic Wilms tumor.
Proteinuria appears during infancy and is frequently of nephrotic range. Hematuria and hypertension are common. Most patients progress to ESRD by 3 years of age.
The glomerular changes of Denys-Drash syndrome (DDS)-associated diffuse mesangial sclerosis (DMS) depend on the cortical depth of the glomerulus (ie, its degree of maturation) and the timing of sampling. The pathognomonic lesion is observed in middle cortical glomeruli, which show mesangial expansion with obliteration of capillaries, producing a solidified mass covered by a corona of hyper-trophied podocytes.
DDS should be suspected in children with proteinuria associated with Wilms tumor or with ambiguous genitalia and should be confirmed by renal biopsy and karyotyping. The presence of DMS on kidney biopsy should prompt suspicion of DDS. Evaluation of DDS patients includes screening for WT1 mutations where available; imaging the internal reproductive organs; and, at some point, examining the gonadal histology.
Because of the high risk of Wilms tumor, any remaining renal tissue should be removed once end-stage renal disease (ESRD) occurs (some will have had previous unilateral nephrectomy for Wilms tumor). Once the diagnosis of DDS has been made, some clinicians favor prophylactic bilateral nephrectomies or removal of the remaining kidney after excision of a unilateral Wilms, and then proceeding to transplant. Others prefer to monitor such patients for development of Wilms tumor in any remaining renal tissue by frequent ultrasound examination, moving to nephrectomy and transplant when ESRD supervenes. Gonadal tissue should be excised in 46XY DDS patients because of the risk of gonadoblastoma. Gonadectomy is not necessary in those with an XX karyotype.
Frasier syndrome is another WT1-associated disorder characterized by male pseudohermaphroditism and renal failure. Patients have normal female external genitalia but a 46XY karyotype and often go unrecognized until evaluated for primary amenorrhea. Proteinuria appears during childhood, progressing to nephrotic syndrome and chronic renal failure during adolescence. Renal pathology consists of focal segmental glomerulosclerosis. Gonadoblastoma is a frequent complication, but the risk of Wilms tumor appears to be low. Mutations in the donor splice site in intron 9 have been reported in patients with Frasier syndrome.11-13
NAIL-PATELLA SYNDROME (NPS)
NPS is an autosomal dominant disorder consisting of hypoplasia or absence of the patellae, dystrophic nails, dysplasia of the elbows, and iliac horns. About 50% of NPS patients exhibit renal disease, including hematuria, proteinuria, and hypertension. The risk of progression to ESRD is about 10%. While light and immunofluorescence microscopy show nonspecific changes, electron microscopy reveals multiple irregular lucencies in glomerular basement membranes (GBM), resulting in a moth-eaten appearance. Staining with phosphotungstic acid may reveal cross-banded collagen fibrils within these lucent areas; by immunostaining, these fibrils appear to represent type III collagen. Heterozygous mutations in the LIM homeodomain transcription factor gene LMX1B have been found in NPS patients. These mutations appear to result in haploinsufficiency of LMX1B protein.14,15
Glomerular dysfunction may be detected in patients who have various inherited storage diseases caused by accumulation of the storage material in glomerular cells, mesangium, or glomerular basement membranes. Fabry disease is an X-linked disorder caused by deficiency of the lysosomal hydrolase enzyme a-galactosidase A (a-Gal A), resulting in accumulation of glycosphingolipid in various tissues, including the kidney. It is discussed in detail in Chapter 161.
The earliest renal manifestation is a concentrating defect. Proteinuria is first detected in young adulthood, and some patients exhibit hematuria. End-stage renal disease (ESRD) typically occurs in the third to sixth decade. Gb3 accumulation affects the majority of renal cells. Podocytes are most prominently affected and appear to contain multiple cytoplasmic vacuoles on light microscopy. The characteristic lesion of Fabry disease is seen on electron microscopy and consists of stacks or whorls of dense lysosomal inclusions. Diagnosis of the hemizygote patient can usually be made on clinical grounds. The diagnosis should be confirmed by demonstrating decreased to absent a-Gal A activity in serum, leukocytes, cultured skin fibroblasts, or biopsy samples. Molecular testing is also available, and studies of replacement therapy initiated in childhood are in progress.16,17
Lecithin-cholesterol acyltransferase (LCAT) deficiency prevents esterification of plasma cholesterol and thus interferes with reverse cholesterol transport from tissues to the liver. The accumulation of free cholesterol in renal cells results in proteinuria that frequently progresses to ESRD. Ultrastructural findings are distinctive, consisting of numerous, irregular lucencies in the mesangium and GBM that contain dense granular or membranelike structures.
Sialidosis results from deficiency of sialidase, which removes terminal sialic acid residues from sialyloligosaccharides released during glycoprotein degradation, leading to accumulation of sialic acid-rich material in various tissues, including the kidney. Renal involvement, manifested by proteinuria, occurs in type II, or dysmorphic-type, sialidosis. Light and electron microscopy of renal biopsy specimens shows massively swollen podocytes, due to the presence of innumerable thin-walled cytoplasmic vesicles.
Accumulation of storage material in podocytes has also been described in I-cell disease and in Hurler syndrome. Although renal disease is not unusual in older patients with glycogen storage disease type 1 (GSD1) due to glucose-6-phosphatase deficiency, it is not clear that the pathological changes in the kidney arise from glycogen storage. It has been proposed that proteinuria and glomerulosclerosis in patients with GSD1 result from hyperfiltration injury.