Genetics and Chronic Kidney Disease

C H A P T E R

18 Genetics and Chronic Kidney Disease Barry I. Freedmana, Michelle P. Winnb and Steven J. Scheinmanc a

Department of Internal Medicine – Section on Nephrology, Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA, b Department of Internal Medicine – Division of Nephrology, Center for Human Genetics, Duke University Medical Center, Center for Human Genetics, Durham, North Carolina, USA, c The Commonwealth Medical College, Office of the President, Scranton, Pennsylvania, USA

INTRODUCTION The past decade has seen advances in the identification of genes associated with CKD and improved methodologies for detecting associated gene variants. Linkage analyses useful for detecting genomic regions co-inherited with a trait in families, genome-wide association studies (GWAS) and candidate gene association studies capable of detecting common variants in unrelated case and control samples, and admixture mapping (useful for detecting associated variants more common in one ancestral population of admixed groups) have all been performed in CKD. Major breakthroughs include the identification of a newly recognized spectrum of non-diabetic apolipoprotein L1-associated (APOL1) nephropathy, untangling of structural and signaling pathways involved in maintaining the delicate glomerular filtration barrier critical for preventing glomerulosclerosis, and identification of mutations producing rare interstitial kidney diseases. Nephropathy susceptibility genes have altered the classification of common complex kidney disease, offer new insights in pathogenesis, and provide hope for novel treatments.

NON-DIABETIC GLOMERULAR DISEASES LEADING TO CKD Approximately 50% of patients with advanced renal disease have non-diabetic forms of nephropathy.1 Disease etiologies were often unknown, as kidney biopsies are performed mainly in patients with nephrotic

P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00018-4

syndrome or heavy proteinuria. Those with isolated hematuria or low level proteinuria were deemed less likely to have a treatable lesion identified on biopsy, beyond the usual supportive measures of controlling blood pressure and lipids and use of RAAS blockade. Renal diagnoses in the absence of histology were most often ascribed to the effects of essential hypertension in those with low to absent proteinuria or to IgA nephropathy or familial hematuria in those with isolated hematuria. A paradigm shift occurred in 2010 with demonstration that the complex disorders idiopathic focal segmental glomerulosclerosis (FSGS), focal global glomerulosclerosis (FGGS) with interstitial scarring and vascular changes (previously labeled “hypertensionattributed nephrosclerosis”), and human immuno­ deficiency virus-associated nephropathy (HIVAN) were strongly associated with two coding variants in the apolipoprotein L1 (APOL1) gene on chromosome 22q13 in patients of African ancestry.2–4 Individuals inheriting two APOL1 nephropathy risk variants (G1: non-synonymous coding variant 342 G:384 M or G2: 6 bp deletion) have impressive 29-, 17-, and 7.3-fold increases in risk for HIVAN, FSGS, and non-diabetic (hypertension-attributed nephrosclerosis) ESRD, respectively. Odds ratios of this magnitude had not been seen before in complex disorders. Development of nephropathy in patients with sickle cell disease and progressive lupus nephritis (LN) were subsequently found to reside within the APOL1 disease spectrum (Table 18.1).5–7 The APOL1 discovery explained the marked familial aggregation of ESRD in African American families,

213

2015 Elsevier Inc. All rights reserved. © 2012

214

18.  Genetics and Chronic Kidney Disease

TABLE 18.1  Apolipoprotein L1-Associated Forms of Nephropathy in African Ancestry Populations Idiopathic focal segmental glomerulosclerosis (FSGS) Focal global glomerulosclerosis with interstitial fibrosis and vascular changes, historically termed hypertension-attributed nephrosclerosis or arteriolar nephrosclerosis HIV-associated nephropathy Sickle cell disease-associated nephropathy Lupus nephritis-associated glomerulopathy and associated lupus nephritis

often due to different etiologies of ESRD.8 More than 30% of incident African American patients with ESRD had close relatives already receiving RRT, excluding families with Mendelian disorders such as polycystic kidney disease.9 Far greater numbers had relatives with CKD not yet undergoing RRT. Familial clustering of ESRD is present, albeit weaker in European Americans.10 Importantly, aggregation of different types of CKD was often observed in African American families. This is in dramatic contrast to other population groups, where one type of kidney disease (such as IgA nephropathy or diabetic nephropathy) clusters in a family. Together, these findings supported the existence of an overarching kidney failure susceptibility gene in African American families, with multiple potential inciting events (such as the presence of antinuclear antibodies or HIV infection) that could trigger progressive kidney failure.11 The APOL1 gene encodes ApoL1, a secretory protein that associates with HDL-cholesterol in serum. Selection for APOL1 risk variants confers ability to kill Trypanosoma brucei rhodesiense, a parasite causing African sleeping sickness.2 This family of kidney disorders is of great public health and personal importance. Population ancestry differences in APOL1 allele frequency explain the excess risk of non-diabetic ESRD in African Americans, relative to European Americans, as well as the poorer graft survival of deceased donor kidneys transplanted from donors of African ancestry.12 The mechanisms whereby APOL1 gene variants lead to nephropathy remain unknown. The initial association detected between non-diabetic chronic kidney diseases and the adjacent non-muscle myosin heavy chain 9 gene (MYH9) is now felt to have resulted from linkage disequilibrium between APOL1 G1 and G2 risk variants and the MYH9 extended-1 risk haplotype.2,13,14 MYH9 is associated with progressive non-diabetic kidney disease in populations of European and Asian ancestry, albeit less strongly.15–17 It is unknown whether this observation results from true association or co-inheritance with nearby variants in the apolipoprotein L gene region. Recent evidence supports an epistatic effect

of MYH9 on genes underlying severe and progressive familial hematuria, including CFHR5 in European populations.18 APOL1 nephropathy variants are present in approximately 50% of African Americans, 12–13% of whom possess two variants and are at markedly increased risk for kidney disease.2 These frequencies are higher in people from West Africa.19 G1 and G2 risk variants are virtually absent in Asians and Europeans, suggesting relatively recent origin (approximately 10,000 years ago), after early humans departed the African continent. Importantly, all individuals possessing two APOL1 risk variants do not develop nephropathy. This suggests requisite “second hits” (likely gene–gene or gene–environment interactions) necessary for development of disease.20,21 APOL1-associated kidney disease appears relatively resistant to treatment with RAAS blockade or aggressively lowering blood pressure, although these therapies are often indicated in affected patients in order to reduce the risk of cardiovascular complications.22 HIV infection is a major environmental trigger for APOL1-associated kidney disease, with a population attributable risk of 70%. This means that 7 of 10 cases of HIVAN would not develop in the absence of the G1 and G2 APOL1 variants.23 The kidney serves as a reservoir for HIV replication and HIV infection produces the highest attack rates of nephropathy among genetically susceptible hosts. Half of patients with untreated HIV infection and two APOL1 nephropathy variants develop nephropathy. Aberrant replacement of partially differentiated podocytes develops in HIVAN, and renal histology reveals the most aggressive form of FSGS, the collapsing variant, in such patients. Individuals with these risk variants but without HIV infection develop other renal histologic patterns of FSGS, FGGS with interstitial fibrosis and vascular changes, while others develop non-specific FSGS variants. It has been proposed that different second hits likely determine final renal histopathology. Patients with FGGS appear to have the lowest levels of proteinuria and slowest rate of loss of kidney function, while those with non-specific FSGS variants appear to have intermediate degrees of proteinuria and rates of nephropathy progression.21 Based on this paradigm, there is reason for optimism. Rates of HIVAN have fallen dramatically1 with the introduction of highly active anti-retroviral therapy (HAART). This supports the concept that successful treatment of an environmental exposure can prevent kidney disease in those at high genetic risk. In this sense, HAART can be viewed as a novel treatment for kidney disease, while conventional therapies (such as blood pressure control and RAAS inhibitors) failed to reliably halt the progression of APOL1-associated nephropathy in cases with hypertension-attributed

IV. PATHOPHYSIOLOGY

215

Diabetes-Associated Chronic Kidney Disease

kidney disease (FGGS) in the National Institute of Health-sponsored African American Study of Kidney Disease and Hypertension (AASK).24,25 In contrast to HIVAN, the inciting cause(s) of hypertension-attributed nephropathy, perhaps better labeled as FGGS, remain unknown. As HIV infection is a modifiable risk factor for nephropathy, non-HIV viral infections were sought to identify other pathogens potentially influencing risk of kidney disease via interaction with APOL1. APOL1 genotypes and presence of urine JC polyoma virus (JCV) were assessed for their joint impact on parameters of kidney disease in first-degree relatives of African Americans with non-diabetic nephropathy.26 Adjusting for familial age at start of ESRD, sex and ancestry, an additive model testing for presence of urinary JCV genomic DNA and APOL1 genotype (recessive) were negatively associated with high cystatin C concentration (p = 0.006), albuminuria (p = 0.0002), and presence of nephropathy based on a low eGFR or albuminuria (p = 0.000017). Thus, African Americans at risk for kidney disease based on two APOL1 risk variants and with JC viruria had a lower prevalence of renal involvement. This suggests that JCV, like HIV, may interact with APOL1. Potential protective mechanisms include inhibition of urinary tract replication by other more nephropathic viruses or impact on gene expression profiles that alter nephropathy susceptibility. Further work is required to detect additional modifiable environmental factors modulating the risk of APOL1-associated nephropathy. Several genes interact with APOL1 (gene–gene interactions) altering the risk for non-diabetic ESRD, including NPHS2 (podocin), SDCCAG8 (serologically defined colon cancer antigen 8), and loci near the BMP4 (bone morphogenetic protein 4) genes.27 These findings will likely improve risk prediction. APOL1 now appears to impact CKD progression to ESRD more strongly than the initiation of nephropathy. This concept is based on the weaker association with mild renal phenotypes (albuminuria and slightly reduced GFR) compared to ESRD.22,28–30 The longitudinal AASK and Chronic Renal Insufficiency Cohort (CRIC) studies strongly support APOL1 predominantly as a factor in the progression of kidney disease.31 There will likely be benefits to screening potential kidney donors for risk variants in APOL1, as well as for the caveolin 1 (CAV1) and ATP-binding cassette, sub-family B (MDR/TAP), member 1 genes (ABCB1; also known as multi-drug resistance 1 encoding P-glycoprotein). Variants in these genes in kidney donors associate with the likelihood of prolonged allograft survival after transplantation.12,32,33 APOL1 variation in deceased kidney donors appears to have the most pronounced effect on outcomes.

Additional loci also contribute to the development and progression of non-diabetic kidney disease, including the chromogranin A gene (CHGA) involved in sympathetic nervous system activity and glutathione S-transferase gene (GSTM1).34,35

DIABETES-ASSOCIATED CHRONIC KIDNEY DISEASE Familial aggregation of diabetes-associated kidney disease (DKD) and related intermediate phenotypes have been widely reported, including in European, African, Asian, and South American populations. Albuminuria, kidney function (eGFR), mesangial fractional volume and other renal histologic findings, and diabetes-attributed ESRD aggregate in families.36 Certain populations face markedly higher risk for developing DKD than others. These findings suggested the presence of a major gene or genes underlying susceptibility for development of DKD.37,38 It has become apparent that genes regulating kidney function (GFR) likely differ from those associated with albuminuria in subjects with diabetes.39,40 Linkage analyses in severely affected families with DKD, genome-wide association studies, and admixture mapping analyses reveal that there are no DKD genes with effect sizes remotely approaching that of APOL1 in non-diabetic nephropathy. DKD is a polygenic disease and multiple variants contribute to risk. Few DKDassociated genes have replicated across study samples or between ethnic groups.41 This chapter focuses on DKD genes that have demonstrated consistent effects (Table 18.2). Finally, although many candidate gene association studies have been published in DKD, they often evaluated small numbers of cases and controls TABLE 18.2  Replicated Gene Associations in Diabetic Kidney Disease Chromosome

Gene Name and Symbol

9q21

4.1 protein ezrin, radixin, moesin domaincontaining 3 (FRMD3)

12q24

Acetyl CoA carboxylase β (ACACβ)

2q11

AF4/FMR2 family, member 3 (AFF3)

17q23

Angiotensin converting enzyme (ACE)

18q22

Carnosinase-1 (CNDP1)

11p15

Cysteinyl-tRNA synthase (CARS)

7p14

Engulfment and cell motility 1 (ELMO1)

7q22

Erythropoietin (EPO)

7q36

Nitric oxide synthase (NOS3)

16p12

Protein kinase C β-1 (PRKCβ1)

IV. PATHOPHYSIOLOGY

216

18.  Genetics and Chronic Kidney Disease

and typed few variants within genes of interest. As a result, candidate gene association results frequently do not replicate. Consistent evidence of association has emerged for the 4.1 protein ezrin, radixin, moesin domain-containing 3 (FRMD3), acetyl CoA carboxylase β (ACACB), protein kinase C β-1 (PRKCB1), erythropoietin (EPO), engulfment and cell motility 1 (ELMO1), cysteinyl-tRNA synthetase (CARS), angiotensin converting enzyme (ACE), nitric oxide synthase (NOS), and carnosinase 1 (CNDP1) genes in DKD. GWAS initially detected the association of FRMD3,42–45 ACACB,46,47 ELMO1,48–50 and CARS42 while candidate gene studies identified EPO,51 NOS,52–55 and PRKCB1.56 CNDP1 was detected based on a linkage analysis.57,58 Additional support for a role of NOS in DKD comes from animal (rodent) models of DKD.59 The functional role of these genes remains unclear, especially since many associated variants are non-coding (either intronic or intergenic). For FRMD3, a comparative promoter analysis demonstrated a common transcription factor binding site present among the most associated SNP near the promoter and bone morphogenetic protein gene (BMP) pathway members.45 This suggests that FRMD3 may mediate DKD via shared transcriptional regulation with BMPs. Understanding the mechanism whereby FRMD3 variants may lead to DKD is critical, as this gene associates with diabetic nephropathy in patients with type 1 and type 2 diabetes as well as subjects of European and African ancestry. Hence, variation in FRMD3 may explain the widely observed clustering of relatives with type 1 and type 2 DKD in single families. In a similar fashion, ELMO1 gene polymorphisms are associated with type 1 and type 2 DKD and have been detected in those of European, African, and Chinese ancestry. In a rodent model of nephropathy, Shimazaki et al.60 reported that ELMO1 was expressed in the renal cortex and glomeruli. In vitro studies revealed that cells overexpressing ELMO1 exhibited reduced adhesion to extracellular matrix and excessive production of fibronectin. Together, these findings suggest that DKD-associated ELMO1 variants could contribute to nephropathy via effects on matrix synthesis and altered cell adhesion properties. An intronic ACACB variant also reproducibly associates with proteinuria and DKD in Asian and European ancestry populations.46,47 ACACB encodes the enzyme regulating the rate limiting step in fatty acid oxidation. ACACB-derived malonyl-CoA inhibits mitochondrial fatty acid oxidation via allosterically binding to carnitine palmitoyltransferase (CPT1) and preventing transfer of fatty acids to the mitochondria for oxidation. Transfecting human proximal renal tubule cells with the DKD-associated ACACB intronic variant appeared to enhance enzyme activity. It is tempting to speculate that the ACACB minor allele associated with DKD

exerts its effects via cytosolic accumulation of free fatty acids which are toxic to the cell, as a result of ACACBmediated inhibition of CPT1 with reduced fatty acid oxidation. A GWAS for DKD in the GEnetics of Nephropathy: An International Effort (GENIE) consortium revealed significant evidence of association between diabetic ESRD and SNPs in the AFF3 gene and an intergenic region on 15q26 between RGMA and MCTP2.61 Although powerful genetic associations have not yet been identified in DKD, it is widely appreciated that many patients with presumed diabetic nephropathy lack kidney biopsies and other diseases may be present in such patients. This reality reduces the power to detect associations. Relative to European Americans, African Americans are more often affected by type 2 diabetes and proteinuric chronic kidney diseases such as FSGS. The majority of non-diabetic nephropathy in African Americans associates strongly with APOL1. This allowed for genetic dissection of APOL1-associated non-diabetic nephropathy from large cohorts of African ancestry cases with type 2 diabetes and advanced nephropathy.44,62 For example, a GWAS in African American type 2 diabetic ESRD observed suggestive associations with the ribosomal S12 gene (RPS12) and LIM domain kinase 2 (LIMK2)-SFi1 homologue, spindle-assembly associated gene region (SFI1) in DKD, but failed to identify FRMD3.63 However, stratified analyses accounting for APOL1 and MYH9 variants on chromosome 22q appeared to remove cases with type 2 diabetes who likely had non-diabetic forms of nephropathy (those with 2 APOL1 or MYH9 risk variants). In the remaining cases, presumably enriched for DKD, robust FRMD3 association was detectable.44 This demonstrates the importance of a clear phenotype in cases without a tissue diagnosis of DKD. Finally, as is true in all gene-hunting exercises, large numbers of cases with well-defined DKD (and diabetic controls who lack nephropathy) will be necessary for the identification of genes underlying DKD, particularly those with weaker effects.

KIDNEY DISEASE GENES IN IMMUNOGLOBULIN A NEPHROPATHY AND LUPUS NEPHRITIS IgA nephropathy (IgAN) is a common cause of chronic nephropathy worldwide.64 IgAN often presents with hematuria; however, severe cases typically develop progressive renal failure with proteinuria. This disorder results from the synthesis of IgA or IgG autoantibodies directed against abnormal IgA1 molecules.65 Circulating IgA1 in affected individuals contains a heavy chain hinge region that is deficient in galactose molecules in the O-glycans. The abnormal IgA1 leads

IV. PATHOPHYSIOLOGY

FSGS and Diffuse Mesangial Sclerosis

to recognition by the patient’s immune system, subsequent formation of antiglycan antibodies, and development of circulating immune complexes.66 Immune complexes ultimately lodge in the kidney where they can activate mesangial cells and lead to mesangial cell proliferation, production of excessive amounts of extracellular matrix components, and cytokine release. As a result of local cytokine exposure, podocytes may become injured and proteinuria ensues. This process appears to be impacted by different underlying genetic factors in affected patients. IgAN aggregates in families. Approximately 5% of cases are familial.67 Although familial and sporadic cases of IgAN demonstrate the same renal histopathologic changes, marked differences in risk are observed based on population ancestry. Asians face the highest risk for IgAN, followed by those of European ancestry. African ancestry populations are at lowest risk. IgAN requires a kidney biopsy for diagnosis. It was unclear whether insufficient access to healthcare accounted for population-based differences in risk. However, differential distributions of risk variants in major IgAN susceptibility genes appear to account for the different incidence rates based on population ancestry (Table 18.3).68 As in other autoimmune disorders, association between IgAN and human major histocompatibility complex (MHC) loci on chromosome 6 have been observed.69 This region is important in antibody generation. A GWAS also identified the complement factor H gene (CFH) on chromosome 1q32 as strongly disease associated.69 CFH gene polymorphisms reduce alternative complement pathway activation and related genes associate with immune complex nephropathies such as C3 glomerulopathy.70 The IgAN associated CFH SNP is in strong linkage disequilibrium with a common deletion involving the adjacent CFHR1 and CFHR3 genes. Novak et  al. speculated that the associated protection from IgAN seen with CFH reflects the combination of direct downregulation of the alternative complement pathway, coupled with reduced CFHR1 and CFHR3 activity.71 In addition a chromosome 22 locus that includes the HORMAD2, MTMR3, LIF, and OSM genes TABLE 18.3  Gene Associations in Immunoglobulin A (IgA) Nephropathy Chromosome

Gene Symbol

1q32

CFH, CFHR1, CFHR3

6p21

HLA-DQB1, HLA–DGA1, HLA-DRB1

6p21

HLA-DOB, PSMB8, PSMB9, TAP1, TAP2

6p21

HLA-DPB2, HLA-DPB1, HLA-DPA1

22q12

HORMAD2, MTMR3, LIF, OSM, GATSL3, SF3A1

Source: Reference68.

217

is associated.69 The chromosome 22 region further associates with serum total IgA concentration. Genetic risk scores (GRS) encompassing these five loci revealed a 10-fold decrease in risk for IgAN in individuals with five or more protective alleles, compared to those with none.69 A subsequent GWAS in Han Chinese replicated the aforementioned MHC loci and the chromosome 22 locus, as well as new loci on 17p23 (near TNFSF13 and associated with serum IgA concentration) and 8p23 (near the defensin gene cluster).72 An important ecologic report evaluated the seven major IgAN loci in geospatial analyses, including DNA samples from 85 world populations including Asia, Europe, and Africa.68 The GRS were lowest in Africa, rose dramatically through Europe and the highest GRS were seen in East Asians. The prevalence rates of disease paralleled the GRS in each region and reveal that the high rates of IgAN in Asians, relative to Africans, reflect a large component of genetic risk. Nephropathy in systemic lupus erythematosus (SLE), lupus nephritis (LN), is a common disease manifestation. Familial aggregation of severe LN is observed and populations of African and Hispanic ancestry are more often and more severely affected than Europeans.73 European ancestry appears to protect from LN.74 In contrast to IgAN, fewer replicated genes underlying LN susceptibility have been detected. Upcoming GWAS may soon identify novel loci for LN. APOL1 is associated with severe LN (collapsing variant) in populations of African ancestry.6,75 Such association is weak or absent in mild LN. This supports the notion of APOL1 as a nephropathy progression gene.76 It is tempting to speculate that immune response and autoimmunity genes lead to the initiation of LN, with additional environmental and inherited factors responsible for disease progression. To date, genes implicated in LN susceptibility include Fc gamma receptor (Fcγ), signal transducer and activator of transcription (STAT4), programmed cell death 1 (PDCD1), integrin, alpha M (complement component 3 receptor 3 subunit) (ITGAM), and tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4).77–82 Recent GWAS in SLE not directly focusing on LN may be detecting gene variants that associate with nephropathy (or impact both SLE and kidney disease).83 This can be addressed as LN sample sizes increase and stratified analyses are performed.

FSGS AND DIFFUSE MESANGIAL SCLEROSIS Genes that form and regulate the glomerular filtration barrier to albumin, including basement membrane components and podocytes, have been shown to be the

IV. PATHOPHYSIOLOGY

218

18.  Genetics and Chronic Kidney Disease

TABLE 18.4  Mendelian Forms of Steroid Resistant Nephritic Syndrome and FSGS CHILDHOOD (RENAL LIMITED) Nephrin (NPHS1) – congenital nephritic syndrome of the Finnish (AR) Podocin (NPHS2) – glomerulosclerosis (AR) Phospholipase C epsilon-1 (PLCε1) – diffuse mesangial sclerosis, uncommon (AR) CD-2 associated protein (CD2AP) – SRNS, rare (AR) Non-muscle myosin 1-E (MYO1E) – SRNS, rare (AR) CHILDHOOD (SYNDROMIC) Wilm’s tumor (WT1) – Denys–Drash and Frasier syndromes (AD) ADULT (RENAL LIMITED) Inverted formin-2 (INF2) – FSGS (AD) Transient receptor potential cation channel subfamily 6 (TRPC6) – FSGS (AD) Alpha-actinin 4 (ACTN4) – FSGS (AD) Abbreviations: AD, autosomal dominant; AR, autosomal recessive

cause of several primary and syndromic renal diseases (Table 18.4). These Mendelian disorders were the first to yield their secrets in linkage-based approaches of steroid-resistant nephrotic syndrome (SRNS), typically manifesting as non-specific glomerulosclerosis, FSGS, or diffuse mesangial sclerosis (DMS). It is simplest to approach genetics of SRNS as either primary (kidneylimited) or syndromal (with extra-renal manifestations). Clues to the likelihood of these disorders (and the associated need for genetic testing) lie in renal histology, age at onset, inheritance pattern (relative to sporadic cases), and occasionally the population ancestry of patients.84,85 Autosomal recessive (AR) inheritance should be suspected in familial cases where a single generation is affected, as well as in families with consanguineous marriages. X-linked disorders severely affect males. Autosomal dominant (AD) disorders impact multiple generations in a family. Half of the offspring of an affected parent will be affected since a single risk allele is sufficient to produce disease. It should be noted that the first case detected in a given family may appear to be sporadic, until proteinuria and kidney function measures are performed in close relatives and careful family histories are taken. Causative mutations are nearly always identifiable in congenital SRNS presenting with glomerulosclerosis at birth. AR mutations in the nephrin gene (NPHS1) are the cause in 95% of Finnish cases and the majority of cases worldwide.86 Early childhood SRNS presenting with glomerulosclerosis between the ages of several months and 5 years often relate to AR podocin gene (NPHS2) mutations (40% of familial and

6–17% of sporadic cases).87 Phospholipase C epsilon-1 gene (PLCε1) mutations are uncommon causes of AR DMS.88,89 CD2-associated protein (CD2AP) and nonmuscle myosin 1-E gene (MYO1E) variants are also rare causes of childhood AR SRNS.90–92 Wilm’s tumor-1 (WT1) mutations should be sought in childhood AD SRNS in females (and males with abnormal external genitalia). WT1 mutations are present in up to 16% of cases (see syndromic SRNS, below).93 In adults with AD FSGS, mutations in the inverted formin-2 (INF2), transient receptor potential cation channel subfamily 6 (TRPC6), and α-actinin 4 (ACTN4) genes are commonly detected, with respective frequencies up to 17%, 12%, and 3.5%.94–97 These often lead to proteinuria in the 20s and ESRD before age 50. In contrast, causative variants are rarely identified in adult cases of sporadic FSGS, with the exception of compound heterozygous NPHS2 mutations, including one R229Q variant.85 This variant is relatively more common in Western Europeans with frequencies of 5–10%. The R229Q variant is present in approximately 1–2.5% of African Americans. A single R229Q variant is not sufficient to produce kidney disease, but confers a carrier state for FSGS. If individuals inherit one causative NPHS2 gene variant plus an R229Q variant, they are at risk for FSGS (compound heterozygosity). Therefore, it is often appropriate to screen adults with sporadic FSGS for R229Q variants. If present, additional NPHS2 genetic testing should be performed to assist with genetic counseling and family planning. R229Q is less common outside of Western Europe. Syndromic forms of AD SRNS include the WT1associated Denys–Drash and Frasier syndromes.98 Denys–Drash syndrome is often apparent in childhood among phenotypic females (may be XY) or male pseudohermaphrodites. Screening for Wilm’s tumor is indicated and DMS with subsequent ESRD develops before the age of 5 years. Frasier syndrome is seen in male pseudohermaphrodites with FSGS developing between the age of 2–6 years and ESRD by age 30 years. Occasionally, Frasier syndrome may be identified in adult males with apparent sporadic FSGS. Screening for gonadoblastoma is indicated. AD mutations in the MYH9 produce Epstein, Sebastian, and Fechtner syndromes. Affected subjects have progressive glomerulosclerosis, macrothrombocytopenia and sensorineural hearing loss.99

GWAS FOR ESTIMATED GFR AND ALBUMINURIA IN GENERAL POPULATIONS Although relatively small numbers of subjects with advanced CKD have provided DNA for large-scale

IV. PATHOPHYSIOLOGY

Inherited Interstitial Nephropathies

genetic analysis, far larger numbers with preserved or mildly reduced kidney function have undergone GWAS in population-based testing. This allowed for detection of genes regulating kidney function and potentially renal disease. Initial studies have been performed mostly in European ancestry populations, with more recent studies in those of African and Asian ancestry. Severe renal disease is less common in European populations, compared to African, Asian and Native American populations, and familial aggregation of ESRD is less pronounced. Nonetheless, substantial knowledge has been gained in large GWAS where the contributors to regulation of eGFR have been studied. An initial GWAS for renal function traits detected several loci associated with eGFR (based on either S[Cr] or cystatin C concentrations) in four populationbased cohorts of European ancestry containing more than 40,000 individuals. Of these, more than 4300 had CKD.100 SNPs in the glycine amidinotransferase/spermatogenesis associated 5-like 1 gene region (GATMSPATA5L1) and cystatin gene superfamily (CST) were significantly associated with eGFR-creatinine and eGFR-cystatin C, respectively, apparently due to roles in the synthesis and metabolism of creatinine and cystatin C, not development of kidney disease. In contrast, the uromodulin (UMOD), shroom family member 3 (SHROOM3), and stanniocalcin 1 genes (STC1) were reproducibly associated with eGFR. UMOD was further associated with CKD (eGFR less than 60  mL/ min/1.73 m2). UMOD had been associated with familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease (MCKD) type 2 and uromodulinassociated kidney disease (UMAK). UMOD encodes the Tamm Horsfall glycoprotein. This GWAS supports the notion that common UMOD gene polymorphisms increase risk for decreased kidney function in general populations. The CKDGen consortium next performed a GWAS in 67,000 subjects of European ancestry. Of these, 5807 had established CKD. Replication was performed in nearly 23,000 additional individuals. Another 23 kidney disease or eGFR-associated loci were identified, including in (or near) LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC4A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2, and SLC7A9. With the UMOD, SHROOM3, and STC1 loci, 1.4% of the total variation in eGFRcreatinine in European ancestry populations could be explained by all 16 loci.101 An independent analysis in 23,812 population-based subjects from a large European consortium identified and confirmed several of these loci, including near ALMS1/NAT8, SCL7A9, SHROOM3 and UMOD.102 Pattaro et  al. expanded the CKDGen analysis to include 130,600 individuals of European ancestry to gain additional power.103 Six new loci in (or near)

219

MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80 were identified. The first four were associated with eGFR in African-ancestry populations demonstrating cross-ethnic validity. An Asian consortium detected association between S[Cr]-based eGFR and loci in or near the MHC on human chromosome 6, UNCX, MPPED2/DCDC5, and with CKD in MECOM, the MHC region, UMOD, UNCX, WDR72, MAF and GNAS.104 A novel strategy linking existing GWAS associations with eGFR and genes with functional evidence of nephropathy led to detection of genome-wide significant associations with markers near the FBXL20, INHBC, LRP2 (coding the megalin receptor), PLEKHA1, SLC3A2 and CLS7A6 genes. PLEKHA1 and FBXL20 revealed association with eGFR in African Americans, as well.105 Replicated eGFR-associations in African Americans were seen with SNPs in or near UMOD, ANXA9, GCKR, TFPD2, DAB2, VEFGA, ATXN2, SLC22A2, TMEM60, SLCA13, and BCAS3, also potentially implicating KCNQ1. Consistent results in African and European ancestry populations is reassuring and smaller haplotype blocks in those of African ancestry may facilitate detection of causal SNPs.106 Perhaps surprisingly, although several major eGFRassociated loci were found to be associated with development of CKD (e.g. UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1), only UMOD was nominally associated with ESRD.107 It is critical that genes regulating progression of chronic nephropathies to ESRD be identified. APOL1 appears to be one such gene in African ancestry populations. Further, SNPs associated with eGFR were generally not associated with urinary albumin excretion, supporting the notion of kidney function and albuminuria as independent phenotypes.108 Considering albuminuria independent from eGFR, the cubilin gene (CUBN) was strongly associated with urine albumin:creatinine ratio (ACR) in a GWAS.109 This may reflect effects on proximal tubule albumin reabsorption due to the relationship between cubilin and the megalin transporter. CUBN-associated albuminuria may not reflect CKD, but simply altered albumin transport in the nephron. Rare CUBN variants are associated with AR megaloblastic anemia and proteinuria (Imerslund-Grasbeck syndrome).

INHERITED INTERSTITIAL NEPHROPATHIES Autosomal Dominant Interstitial Renal Disease CKD inherited in a monogenic (Mendelian) fashion comprises an important minority of patients (Table 18.5). The largest groups are those with polycystic kidney disease (PKD). A distinct condition of

IV. PATHOPHYSIOLOGY

220

18.  Genetics and Chronic Kidney Disease

TABLE 18.5 Inherited Interstitial Nephropathies AUTOSOMAL DOMINANT Uromodulin (UMOD) Mucin 1 (MUC1) Renin (REN) AUTOSOMAL RECESSIVE (NEPHRONOPHTHISIS) Nephrocystin-1 (NPHP1) X-LINKED RECESSIVE Dent’s disease (CLCN5) Oculocerebral syndrome of Lowe (OCRL1)

tubulointerstitial nephritis inherited in AD fashion encompasses patients described under several disease names, including MCKD, FJHN, adult nephronophthisis, glomerulocystic kidney disease, and hereditary nephropathy with hyperuricemia and gout.110,111 The phenotypes for these entities overlap and they are all encompassed under the rubric of MCKD. This longstanding nomenclature is unfortunate since cysts may not be detectable in these conditions.112 Genetic linkage studies identified two loci for the MCKD phenotype, on chromosome 1 (MCKD1) and chromosome 16 (MCKD2).113,114 The MCKD2 locus is linked with UMOD encoding uromodulin (Tamm– Horsfall protein), which is mutated in families with MCKD, FJHN and glomerulocystic kidney disease.115,116 Uromodulin is the most abundant protein in normal human urine and the major component of urinary casts. Uromodulin is produced by the cells of the thick ascending limb. It has been proposed that uromodulin protects epithelial integrity in the loop of Henle and bladder, modulates inflammatory responses through binding of cytokines, protects from stone formation by inhibiting calcium oxalate crystal aggregation, and prevents urinary infections by preventing binding of E. coli to epithelial cells. The functions of uromodulin, however, are not known with confidence.117 Uromodulin accumulates in the endoplasmic reticulum of renal tubular cells in patients with UMOD mutations, with cytoplasmic accumulation of uromodulin in the thick ascending limb and distal tubule118 and reduction in urinary excretion119 consistent with a defect in processing the mutated protein. All known UMOD mutations alter its protein structure, many through substitution of cysteine residues in a cysteine-rich region in exons 4 and 5. Uromodulin is a glycosylated protein whose native structure is formed by polymerization of monomeric units. Its sequence is rich in highly conserved cysteine residues (7.5% of the amino acids) with the potential

for a high degree of cross-linkage.110,116 The majority of UMOD mutations are missense involving exon 4, with others in exons 3, 5, 7 and 8; most of them are substitutions of or by cysteine.111,116 Misfolding of the UMOD protein likely causes cellular accumulation. This phenomenon has been reproduced by transient transfection with mutated UMOD.120 Targeted ablation of UMOD in mice increases susceptibility to urinary infection and induces mild salt-wasting, but does not produce cellular aggregates of UMOD or abnormalities in renal histology.121,122 Aberrant protein processing due to misfolding explains the dominant-negative effect of heterozygous mutation. Particular mutations can be correlated with age of onset of ESRD.111 A GWAS meta-analysis for renal function in four geographically disparate cohorts detected strong association with rs12917707, a SNP close to UMOD.100 Another GWAS identified linkage between UMOD and CKD in Iceland.123 Coupled with physiological data from knockout mice, polymorphisms in UMOD likely contribute to CKD in the general population. The gene for MCKD1 had been localized on chromosome 1, but resisted identification for over a decade. It was recently reported that MUC1, encoding mucin 1, was mutated in six families with linkage to this region, and in more than a dozen additional families with the MCKD phenotype. In each case the mutation involved insertion of a single cytosine in the terminal portion of a canonical 60-mer repeat that produced a frameshift leading to the protein lacking several important domains.124 Mucin 1 is a transmembrane glycoprotein expressed broadly on epithelial cells including those of the distal convoluted tubule. Mucin 1 is thought to play a role in cell adhesion, recognition, and/or cytoprotection.125 As with UMOD, knockout of MUC1 yields mice with an essentially normal phenotype,126 consistent with the dominant inheritance of MCKD, which would not be expected were this a gene deficiency disease. Radiographic evidence of cysts is found in 34% of patients with documented UMOD mutations. Half of women and 75% of men with UMOD mutations have a history of gout.127 Clinical features of MCKD (whether UMOD-associated [MCKD2] or MUC1-associated [MCKD1]) overlap, and these entities cannot be distinguished solely on clinical grounds. The clinical hallmark of MCKD is renal insufficiency which may first manifest in childhood and progresses to ESRD in adulthood. The renal phenotype is not distinctive, with a bland urinary sediment and modest proteinuria consistent with tubulointerstitial disease. Urinary concentration is impaired, consistent with the degree of renal insufficiency. The findings of tubulointerstitial fibrosis and secondary glomerular sclerosis on renal biopsy are also non-specific. Cysts may be evident only if the specimen includes medullary tissue, and absence of cysts

IV. PATHOPHYSIOLOGY

Inherited Interstitial Nephropathies

does not argue against the diagnosis. Hyperuricemia is common and associated with a reduced fractional urate excretion. Presentation with renal insufficiency, nonnephrotic proteinuria, hyperuricemia, and gout should suggest the diagnosis of MCKD.112 Positional cloning identified the renin gene REN as mutated and segregating with disease in three families with AD progressive renal failure and a phenotype consistent with MCKD, including hyperuricemia.128 Additional features included mild hypoproliferative (erythropoietin-responsive) anemia in affected children, and mild hyperkalemia, both consistent with impaired renin effect. The mutations involved are either deletion or substitution of a single leucine residue in the signal sequence for renin, with evidence of activated endoplasmic reticulum stress on biopsy. The authors hypothesized this led to accelerated apoptosis in juxtaglomerular apparatus cells, with consequent impaired development and nephron loss. In families with FJHN, characterized by childhood hyperuricemia and gout, renal cysts, and progressive kidney failure, mutations in the hepatocyte nuclear factor-1 beta gene have also been identified.129

Autosomal Recessive Nephronophthisis Nephronophthisis (NPHP) is often placed in the same nosologic category as MCKD, but there are significant clinical and genetic differences between the two entities. NPHP is a tubulointerstitial nephritis with a bland sediment, modest proteinuria, and clinically significant polyuria resulting from a concentrating defect. However, unlike MCKD, it is inherited in AR fashion. Pathologically, NPHP is characterized by atrophic renal tubules with thickened basement membranes and, when evident, corticomedullary cysts. The disease progresses to end-stage much earlier than MCKD, typically by the end of adolescence. NPHP is the most common genetic cause of ESRD in children. There are several phenotypic variants of NPHP, distinguished by the age of onset and in some cases by extrarenal manifestations, particularly retinal disorders. To date, 15 genes have been found to be mutated in these phenotypic variants. Most encode protein components of the ciliary apparatus, unlike UMOD and MUC1, which encode cell surface proteins. Thus, NPHP is a ciliopathy like PKD.130 Three genes recently found to be mutated in NPHP and retinal degeneration are components of the DNA damage response pathway.131 The NPHP1 gene, encoding nephrocystin-1, is the most common NPHP-associated gene, accounting for 20–25% of cases. The others account for fewer than 3% of cases or isolated families. Over 50% of reported cases lack mutations in the reported genes, indicating that additional genes remain to be identified.130 The isolated

221

renal phenotype of NPHP is associated with mutations in about half of these genes, including NPHP1. NPHP with severe eye disease (including retinal degeneration, Leber’s congenital amaurosis, and coloboma) constitutes the Senior–Loken syndrome. NPHP with eye disease (particularly pigmentary retinopathy) and brain abnormalities including cerebellar ataxia and psychomotor retardation is known as the Joubert syndrome. NPHP with brain disorders and other extrarenal abnormalities including hepatic fibrosis constitute Meckel syndrome. Bardet–Biedl syndrome overlaps with Meckel syndrome and can variably include obesity, polydactyly and hypogonadism.132

Inherited Conditions of Renal Failure with Nephrocalcinosis Dent’s disease (DD) and the oculocerebrorenal syndrome of Lowe (LS) are X-linked recessive disorders with nearly identical renal phenotypes. These conditions, however, differ substantially in the disabling extrarenal features in LS that are absent in DD. Both conditions are characterized by proximal tubulopathy with low-molecular-weight proteinuria, non-nephrotic albuminuria, variable degrees of urinary losses of amino acids, glucose and phosphate, and progressive CKD. Clinically significant renal tubular acidosis with correctible growth slowing is a hallmark of LS, but RTA is absent in classic DD (Dent-1 disease). Hypercalciuria, renal stones, and nephrocalcinosis are common features of DD and have been reported in LS. It has been speculated that they are less prominent in LS because the progression of renal failure is typically more aggressive and onset of ESRD earlier, causing hypercalciuria to abate at an earlier age than in DD.133 Congenital cataracts, a hallmark feature of LS, and other eye disorders leading to blindness, and mental retardation, muscular hypotonia, and other neurologic disturbances, are often severely disabling.134 About 60% of cases of DD are associated with mutations in the CLCN5 gene, encoding a voltage-gated chloride transporter expressed in the proximal tubule, medullary thick ascending limb and α-intercalated cells of the collecting tubule. LS is consistently associated with OCRL1 mutations encoding a phosphatidylinositol-4,5-bisphosphate-5-phosphatase in the trans-Golgi network. Both proteins participate in pathways affecting trafficking of membrane proteins. Another 15% of patients with the clinical diagnosis of DD have mutations in the Lowe OCRL1 gene (Dent-2 disease) and some of these patients have mild extrarenal abnormalities.135,136 Thus, Dent-2 disease and LS are allelic phenotypic variants of OCRL1, with a spectrum of clinical severity ranging from the isolated renal phenotype of Dent-1 disease to the full oculocerebrorenal syndrome (LS).137

IV. PATHOPHYSIOLOGY

222

18.  Genetics and Chronic Kidney Disease

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive condition in which progressive renal failure, often evident in childhood, has been ascribed to nephrocalcinosis. Other clinically significant features of FHHNC include hypomagnesemia with inappropriate urinary losses, kidney stones, urinary tract infection, and in some cases ophthalmologic abnormalities such as severe myopia, macular colobomas, horizontal nystagmus, and chorioretinitis. Hyperuricemia can be present. Positional cloning led to the identification of paracellin-1 (claudin 16), on chromosome 3q as the mutated protein in FHHNC.138 Subsequently, another member of this family, claudin 19, was found to be mutated in patients with ocular abnormalities. These claudins are expressed at the tight junction between epithelial cells of the medullary thick ascending limb, and appear to be important in maintaining selectivity of paracellular cation transport, facilitating the reabsorptive transport of magnesium and calcium driven by the positive electrical potential in this segment of the nephron.139

APPROACH TO DIAGNOSIS AND THERAPY Renal abnormalities in these syndromes are not distinctive and they overlap. All feature non-nephrotic proteinuria, polyuria is common, cysts may be absent, and renal biopsy findings are often non-specific. The genes mutated in Dent’s disease and Lowe’s syndrome alter proximal tubular reabsorption. As such, evidence of Fanconi syndrome, most commonly loss of lowmolecular-weight proteins (β2-microglobulin, retinolbinding protein) would point to those diagnoses. Renal tubular acidosis would strongly support the diagnosis of LS, particularly in the presence of cataracts, hypotonia, or mental developmental abnormalities. The presence of cysts favors MCKD or nephronophthisis. With a history or family history of gout and in an older child, MCKD is most common. Age of onset and extrarenal findings are often most helpful in making a diagnosis and can be definitive. Clinical mutation analysis is now available, although in some cases limited, for some of these genes including UMOD, CLCN5, OCRL1, the more common of the NPHPH genes, and the claudins. Laboratories offering this service can be identified through the NCBI’s Genetic Testing Registry (http://www.ncbi.nlm.nih. gov/gtr/). No specific therapy exists for these tubulointerstitial nephropathies and treatment is conservative. As these disorders are not primarily glomerular or immunemediated, neither RAAS inhibition nor immunosuppression is indicated. When present, hypertension

should be treated, but these tubulointerstitial conditions often feature salt-wasting. The pathologic features do not recur in renal transplants since they are inherent to the host kidneys and not systemic.

SUMMARY The current era of personalized (or precision) medicine has altered our understanding of the pathogenesis of a variety of renal-limited and systemic disorders affecting the kidney. Additional discoveries are expected shortly, based upon whole exome sequencing and whole genome sequencing approaches. Identifying causative genes will allow improved understanding of the pathogenesis of disease and testing of rational therapies targeted to specific gene defects and disease pathways.

References 1. U.S. Renal Data System, USRDS 2012 Annual Data Report, Vol 1: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2012. 2. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et  al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010;329(5993):841–5. 3. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et  al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 2010;128(3):345–50. 4. Freedman BI, Kopp JB, Langefeld CD, Genovese G, Friedman DJ, Nelson GW, et al. The Apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. J Am Soc Nephrol 2010;21(9):1422–6. 5. Ashley-Koch AE, Okocha EC, Garrett ME, Garrett ME, Soldano K, De Castro LM, et  al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br J Haematol 2011;155(3):386–94. 6. Larsen CP, Beggs ML, Saeed M, Walker PD. Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 2013;24(5):722–5. 7. Freedman BI, Langefeld CD, Andringa KK, Croker JA, Williams AH, Garner NE, et  al. End-stage kidney disease in African Americans with lupus nephritis associates with APOL1. Arthritis Rheum 2014;66(2):390–6. 8. Freedman BI, Spray BJ, Tuttle AB, Buckalew Jr VM. The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis 1993;21(4):387–93. 9. Freedman BI, Volkova NV, Satko SG, Krisher J, Jurkovitz C, Soucie JM, et  al. Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol 2005;25(6):529–35. 10. Spray BJ, Atassi NG, Tuttle AB, Freedman BI. Familial risk, age at onset, and cause of end-stage renal disease in white Americans. J Am Soc Nephrol 1995;5(10):1806–10. 11. Freedman BI, Iskandar SS, Appel RG. The link between hypertension and nephrosclerosis. Am J Kidney Dis 1995;25(2):207–21.

IV. PATHOPHYSIOLOGY

223

REFERENCES

12. Reeves-Daniel AM, Depalma JA, Bleyer AJ, Rocco MV, Murea M, Adams PL, et al. The APOL1 gene and allograft survival after kidney transplantation. Am J Transplant 2011;11(5):1025–30. 13. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008;40(10):1175–84. 14. Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, et  al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008;40(10):1185–92. 15. O’Seaghdha CM, Parekh RS, Hwang SJ, Li M, Kottgen A, Coresh J, et al. The MYH9/APOL1 region and chronic kidney disease in European-Americans. Hum Mol Genet 2011;20(12):2450–6. 16. Cooke JN, Bostrom MA, Hicks PJ, Ng MC, Hellwege JN, Comeau ME, et al. Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans. Nephrol Dial Transplant 2012;27(4):1505–11. 17. Cheng W, Zhou X, Zhu L, Shi S, Lv J, Liu L, et al. Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese. Nephrol Dial Transplant 2011;26(8):2544–9. 18. Voskarides K, Demosthenous P, Papazachariou L, Arsali M, Athanasiou Y, Zavros M, et  al. Epistatic role of the MYH9/ APOL1 region on familial hematuria genes. PLoS One 2013;8(3):e57925. 19. Pollak MR, Genovese G, Friedman DJ. APOL1 and kidney disease. Curr Opin Nephrol Hypertens 2012;21(2):179–82. 20. Bostrom MA, Kao WH, Li M, Abboud HE, Adler SG, Iyengar SK, et  al. Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. Am J Kidney Dis 2012;59(2):210–21. 21. Freedman BI, Bowden DW, Rich SS. Genetic basis of kidney disease. In: Taal MW, editor. Brenner & rector's the kidney, chap 42. Philadelphia: Elsevier Saunders; 2012. p. 1554–69. 22. Lipkowitz MS, Freedman BI, Langefeld CD, Comeau ME, Bowden DW, Kao WH, et  al. Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney Int 2013;83(1):114–20. 23. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 2011;22(11):2129–37. 24. Lipkowitz MS, Freedman BI, Langefeld CD, Comeau ME, Bowden DW, Kao WHL, et  al. Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney Int 2013;83(1):114–20. 25. Appel LJ, Wright Jr. JT, Greene T, Agodoa LY, Astor BC, Bakris GL, et  al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010;363(10):918–29. 26. Divers J, Nunez M, High KP, Murea M, Rocco MV, Ma L, et al. JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy. Kidney Int 2013;84(6):1207–13. 27. Divers J, Palmer ND, Lu L, Langefeld CD, Rocco MV, Hicks PJ, et  al. Gene-gene interactions in APOL1-associated nephropathy. Neph Dial Transplant 2014;29(3):587–94. 28. Foster MC, Coresh J, Fornage M, Astor BC, Grams M, Franceschini N, et  al. APOL1 variants associate with increased risk of CKD among African Americans. J Am Soc Nephrol 2013;24(9):1484–91. 29. Friedman DJ, Kozlitina J, Genovese G, Jog P, Pollak MR. Population-based risk assessment of APOL1 on renal disease. J Am Soc Nephrol 2011;22(11):2098–105. 30. Freedman BI, Langefeld CD, Turner J, Nunez M, High KP, Spainhour M, et  al. Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American

31.

32.

33.

34.

35.

36.

37.

38. 39.

40.

41.

42.

43.

44.

45.

46.

47.

patients with non-diabetic end-stage renal disease. Kidney Int 2012;82(7):805–11. Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, et al. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013;369(23):2183–96. Moore J, McKnight AJ, Dohler B, Simmonds MJ, Courtney AE, Brand OJ, et  al. Donor ABCB1 variant associates with increased risk for kidney allograft failure. J Am Soc Nephrol 2012;23(11):1891–9. Moore J, McKnight AJ, Simmonds MJ, Courtney AE, Hanvesakul R, Brand OJ, et al. Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure. JAMA 2010;303(13):1282–7. Salem RM, Cadman PE, Chen Y, Rao F, Wen G, Hamilton BA, et al. Chromogranin A polymorphisms are associated with hypertensive renal disease. J Am Soc Nephrol 2008;19(3):600–14. Chang J, Ma JZ, Zeng Q, Cechova S, Gantz A, Nievergelt C, et al. Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK). Am J Physiol Renal Physiol 2013;304(4):F348–55. Murea M, Ma L, Freedman BI. Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Stud 2012;9(1):6–22. Hanson RL, Elston RC, Pettitt DJ, Bennett PH, Knowler WC. Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. Am J Hum Genet 1995;57(1):160–70. Krolewski AS. Genetics of diabetic nephropathy: evidence for major and minor gene effects. Kidney Int 1999;55(4):1582–96. Placha G, Canani LH, Warram JH, Krolewski AS. Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes. Adv Chronic Kidney Dis 2005;12(2):155–69. Langefeld CD, Beck SR, Bowden DW, Rich SS, Wagenknecht LE, Freedman BI. Heritability of GFR and albuminuria in Caucasians with type 2 diabetes mellitus. Am J Kidney Dis 2004;43(5): 796–800. Williams WW, Salem RM, McKnight AJ, Sandholm N, Forsblom C, Taylor A, et al. Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy. Diabetes 2012;61(8):2187–94. Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, et  al. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 2009;58(6):1403–10. Pezzolesi MG, Jeong J, Smiles AM, Skupien J, Mychaleckyj JC, Rich SS, et al. Family-based association analysis confirms the role of the chromosome 9q21.32 locus in the susceptibility of diabetic nephropathy. PLoS One 2013;8(3):e60301. Freedman BI, Langefeld CD, Lu L, Divers J, Comeau ME, Kopp JB, et  al. Differential effects of MYH9 and APOL1 risk variants on FRMD3 association with diabetic ESRD in African Americans. PLoS Genet 2011;7(6):e1002150. Martini S, Nair V, Patel SR, Eichinger F, Nelson RG, Weil EJ, et al. From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy. Diabetes 2013;62(7):2605–12. Maeda S, Kobayashi MA, Araki S, Babazono T, Freedman BI, Bostrom MA, et  al. A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes. PLoS Genet 2010;6(2):e1000842. Tang SC, Leung VT, Chan LY, Wong SS, Chu DW, Leung JC, et al. The acetyl-coenzyme a carboxylase beta (ACACB) gene is associated with nephropathy in Chinese patients with type 2 diabetes. Nephrol Dial Transplant 2010;25(12):3931–4.

IV. PATHOPHYSIOLOGY

224

18.  Genetics and Chronic Kidney Disease

48. Shimazaki A, Kawamura Y, Kanazawa A, Sekine A, Saito S, Tsunoda T, et al. Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 2005;54(4):1171–8. 49. Leak TS, Perlegas PS, Smith SG, Keene KL, Hicks PJ, Langefeld CD, et al. Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans. Ann Hum Genet 2009;73(2):152–9. 50. Pezzolesi MG, Katavetin P, Kure M, Poznik GD, Skupien J, Mychaleckyj JC, et  al. Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy. Diabetes 2009;58(11):2698–702. 51. Tong Z, Yang Z, Patel S, Chen H, Gibbs D, Yang X, et  al. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci USA 2008;105(19):6998–7003. 52. Noiri E, Satoh H, Taguchi J, Brodsky SV, Nakao A, Ogawa Y, et al. Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension 2002;40(4):535–40. 53. Suzuki H, Nagase S, Kikuchi S, Wang Y, Koyama A. Association of a missense Glu298Asp mutation of the endothelial nitric oxide synthase gene with end stage renal disease. Clin Chem 2000;46(11):1858–60. 54. Nagase S, Suzuki H, Wang Y, Kikuchi S, Hirayama A, Ueda A, et al. Association of ecNOS gene polymorphisms with end stage renal diseases. Mol Cell Biochem 2003;244(1-2):113–8. 55. Liu Y, Burdon KP, Langefeld CD, Beck SR, Wagenknecht LE, Rich SS, et  al. T-786C polymorphism of the endothelial nitric oxide synthase gene is associated with albuminuria in the diabetes heart study. J Am Soc Nephrol 2005;16(4):1085–90. 56. Ma RC, Tam CH, Wang Y, Luk AO, Hu C, Yang X, et al. Genetic variants of the protein kinase C-beta 1 gene and development of end-stage renal disease in patients with type 2 diabetes. JAMA 2010;304(8):881–9. 57. Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, Fischer C, et al. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 2005;54(8):2320–7. 58. Freedman BI, Hicks PJ, Sale MM, Pierson ED, Langefeld CD, Rich SS, et  al. A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol Dial Transplant 2007;22(4):1131–5. 59. Brosius III FC, Alpers CE, Bottinger EP, Breyer MD, Coffman TM, Gurley SB, et al. Mouse models of diabetic nephropathy. J Am Soc Nephrol 2009;20(12):2503–12. 60. Shimazaki A, Tanaka Y, Shinosaki T, Ikeda M, Watada H, Hirose T, et  al. ELMO1 increases expression of extracellular matrix proteins and inhibits cell adhesion to ECMs. Kidney Int 2006;70(10):1769–76. 61. Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, et  al. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet 2012;8(9):e1002921. 62. Gopalakrishnan I, Iskandar SS, Daeihagh P, Divers J, Langefeld CD, Bowden DW, et  al. Coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for MYH9 risk variants. Hum Pathol 2011;42(2):291–4. 63. McDonough CW, Palmer ND, Hicks PJ, Roh BH, An SS, Cooke JN, et al. A genome-wide association study for diabetic nephropathy genes in African Americans. Kidney Int 2011;79(5):563–72. 64. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med 2013;368(25):2402–14. 65. Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, et  al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol 2011;22(10):1795–803.

66. Lai KN. Pathogenesis of IgA nephropathy. Nat Rev Nephrol 2012;8(5):275–83. 67. Kiryluk K, Julian BA, Wyatt RJ, Scolari F, Zhang H, Novak J, et al. Genetic studies of IgA nephropathy: past, present, and future. Pediatr Nephrol 2010;25(11):2257–68. 68. Kiryluk K, Li Y, Sanna-Cherchi S, Rohanizadegan M, Suzuki H, Eitner F, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genet 2012;8(6):e1002765. 69. Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genomewide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 2011;43(4):321–7. 70. Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 2010;376(9743):794–801. 71. Novak J, Renfrow MB, Gharavi AG, Julian BA. Pathogenesis of immunoglobulin A nephropathy. Curr Opin Nephrol Hypertens 2013;22(3):287–94. 72. Yu XQ, Li M, Zhang H, Low HQ, Wei X, Wang JQ, et  al. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet 2012;44(2):178–82. 73. Freedman BI, Wilson CH, Spray BJ, Tuttle AB, Olorenshaw IM, Kammer GM. Familial clustering of end-stage renal disease in blacks with lupus nephritis. Am J Kidney Dis 1997;29(5):729–32. 74. Richman IB, Taylor KE, Chung SA, Trupin L, Petri M, Yelin E, et  al. European genetic ancestry is associated with a decreased risk of lupus nephritis. Arthritis Rheum 2012;64(10):3374–82. 75. Freedman BI, Edberg JC, Comeau ME, Murea M, Bowden DW, Divers J, et  al. The Non-Muscle Myosin Heavy Chain 9 Gene (MYH9) is not associated with lupus nephritis in African Americans. Am J Nephrol 2010;32(1):66–72. 76. Lin CP, Adrianto I, Lessard CJ, Kelly JA, Kaufman KM, Guthridge JM, et  al. Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis. Genes Immun 2012;13(3):232–8. 77. Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF, et  al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996;97(5):1348–54. 78. Sanchez E, Nadig A, Richardson BC, Freedman BI, Kaufman KM, Kelly JA, et  al. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Ann Rheum Dis 2011;70(10):1752–7. 79. Kawasaki A, Furukawa H, Kondo Y, Ito S, Hayashi T, Kusaoi M, et  al. TLR7 single-nucleotide polymorphisms in the 3ʹ untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study. Arthritis Res Ther 2011;13(2):R41. 80. Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, et  al. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 2008;4(5):e1000084. 81. Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, et al. Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol 2003;170(9):4818–25. 82. Lee YH, Ji JD, Song GG. Fcgamma receptor IIB and IIIB polymorphisms and susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Lupus 2009;18(8):727–34. 83. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et  al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008;40(2):204–10.

IV. PATHOPHYSIOLOGY

REFERENCES

84. Benoit G, Machuca E, Antignac C. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol 2010;25(9):1621–32. 85. Santin S, Bullich G, Tazon-Vega B, Garcia-Maset R, Gimenez I, Silva I, et  al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2011;6(5):1139–48. 86. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, et  al. Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol Cell 1998;1(4):575–82. 87. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, et  al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000;24(4):349–54. 88. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, et  al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 2006;38(12):1397–405. 89. Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa SF, Liu J, et  al. Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant 2008;23(4):1291–7. 90. Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, et al. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 2003;300(5623):1298–300. 91. Gigante M, Pontrelli P, Montemurno E, Roca L, Aucella F, Penza R, et  al. CD2AP mutations are associated with sporadic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS). Nephrol Dial Transplant 2009;24(6):1858–64. 92. Mele C, Iatropoulos P, Donadelli R, Calabria A, Maranta R, Cassis P, et  al. MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N Engl J Med 2011;365(4):295–306. 93. Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 1997;17(4):467–70. 94. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, et  al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005;308(5729):1801–4. 95. Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, et  al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005;37(7):739–44. 96. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000;24(3):251–6. 97. Brown EJ, Schlondorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, et  al. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 2010;42(1):72–6. 98. Poulat F, Morin D, Konig A, Brun P, Giltay J, Sultan C, et  al. Distinct molecular origins for Denys-Drash and Frasier syndromes. Hum Genet 1993;91(3):285–6. 99. Han KH, Lee H, Kang HG, Moon KC, Lee JH, Park YS, et  al. Renal manifestations of patients with MYH9-related disorders. Pediatr Nephrol 2011;26(4):549–55. 100. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009;41(6):712–7. 101. Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, et al. New loci associated with kidney function and chronic kidney disease. Nat Genet 2010;42(5):376–84. 102. Chambers JC, Zhang W, Lord GM, van der HP, Lawlor DA, Sehmi JS, et  al. Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 2010;42(5):373–5.

225

103. Pattaro C, Kottgen A, Teumer A, Garnaas M, Boger CA, Fuchsberger C, et  al. Genome-wide association and functional follow-up reveals new loci for kidney function. PLoS Genet 2012;8(3):e1002584. 104. Okada Y, Sim X, Go MJ, Wu JY, Gu D, Takeuchi F, et  al. Metaanalysis identifies multiple loci associated with kidney function-related traits in east Asian populations. Nat Genet 2012;44(8):904–9. 105. Chasman DI, Fuchsberger C, Pattaro C, Teumer A, Boger CA, Endlich K, et al. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. Hum Mol Genet 2012;21(24):5329–43. 106. Liu CT, Garnaas MK, Tin A, Kottgen A, Franceschini N, Peralta CA, et al. Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. PLoS Genet 2011;7(9):e1002264. 107. Boger CA, Gorski M, Li M, Hoffmann MM, Huang C, Yang Q, et al. Association of eGFR-related loci identified by GWAS with incident CKD and ESRD. PLoS Genet 2011;7(9):e1002292. 108. Ellis JW, Chen MH, Foster MC, Liu CT, Larson MG, de Boer I, et al. Validated SNPs for eGFR and their associations with albuminuria. Hum Mol Genet 2012;21(14):3293–8. 109. Boger CA, Chen MH, Tin A, Olden M, Kottgen A, de Boer I, et  al. CUBN is a gene locus for albuminuria. J Am Soc Nephrol 2011;22(3):555–70. 110. Scolari F, Caridi G, Rampoldi L, Tardanico R, Izzi C, Pirulli D, et al. Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis 2004;44(6):987–99. 111. Moskowitz JL, Piret SE, Lhotta K, Kitzler TM, Tashman AP, Velez E, et al. Association between genotype and phenotype in uromodulin-associated kidney disease. Clin J Am Soc Nephrol 2013;8(8):1349–57. 112. Bleyer AJ, Hart TC. Medullar cycstic disease. In: Lifton RP, Giebisch G, Somlo S, Seldin DW, editors. Genetic diseases of the kidneys. London: Academic Press; 2009. p. 447–62. 113. Christodoulou K, Tsingis M, Stavrou C, Eleftheriou A, Papapavlou P, Patsalis PC, et  al. Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet 1998;7(5):905–11. 114. Scolari F, Puzzer D, Amoroso A, Caridi G, Ghiggeri GM, Maiorca R, et  al. Identification of a new locus for medullary cystic disease, on chromosome 16p12. Am J Hum Genet 1999;64(6):1655–60. 115. Lens XM, Banet JF, Outeda P, Barrio-Lucia V. A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease. Am J Kidney Dis 2005;46(1):52–7. 116. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, et  al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002;39(12):882–92. 117. Choi SW, Ryu OH, Choi SJ, Song IS, Bleyer AJ, Hart TC. Mutant Tamm-Horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate. J Am Soc Nephrol 2005;16(10):3006–14. 118. Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, et  al. A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol 2003;14(11):2883–93. 119. Bleyer AJ, Hart TC, Shihabi Z, Robins V, Hoyer JR. Mutations in the uromodulin gene decrease urinary excretion of TammHorsfall protein. Kidney Int 2004;66(3):974–7. 120. Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, et  al. Allelism of MCKD, FJHN and GCKD caused

IV. PATHOPHYSIOLOGY

226

121.

122.

123.

124.

125.

126.

127.

128.

129.

18.  Genetics and Chronic Kidney Disease

by impairment of uromodulin export dynamics. Hum Mol Genet 2003;12(24):3369–84. Mo L, Zhu XH, Huang HY, Shapiro E, Hasty DL, Wu XR. Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli. Am J Physiol Renal Physiol 2004;286(4):F795–802. Raffi H, Bates JM, Laszik Z, Kumar S. Tamm-Horsfall protein knockout mice do not develop medullary cystic kidney disease. Kidney Int 2006;69(10):1914–5. Gudbjartsson DF, Holm H, Indridason OS, Thorleifsson G, Edvardsson V, Sulem P, et al. Association of variants at UMOD with chronic kidney disease and kidney stones – role of age and comorbid diseases. PLoS Genet 2010;6(7):e1001039. Kirby A, Gnirke A, Jaffe DB, Baresova V, Pochet N, Blumenstiel B, et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 2013;45(3):299–303. Pemberton LF, Rughetti A, Taylor-Papadimitriou J, Gendler SJ. The epithelial mucin MUC1 contains at least two discrete signals specifying membrane localization in cells. J Biol Chem 1996;271(4):2332–40. Spicer AP, Rowse GJ, Lidner TK, Gendler SJ. Delayed mammary tumor progression in Muc-1 null mice. J Biol Chem 1995;270(50):30093–101. Bollee G, Dahan K, Flamant M, Moriniere V, Pawtowski A, Heidet L, et  al. Phenotype and outcome in hereditary tubulo­ interstitial nephritis secondary to UMOD mutations. Clin J Am Soc Nephrol 2011;6(10):2429–38. Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet’al P, Kalbacova M, et  al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet 2009;85(2):204–13. Bingham C, Ellard S, van’t Hoff WG, Simmonds HA, Marinaki AM, Badman MK, et al. Atypical familial juvenile hyperuricemic

130. 131.

132. 133.

134. 135.

136.

137.

138.

139.

nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation. Kidney Int 2003;63(5):1645–51. Hildebrandt F, Attanasio M, Otto E. Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 2009;20(1):23–35. Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, et al. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 2012;150(3):533–48. Schurman SJ, Scheinman SJ. Inherited cerebrorenal syndromes. Nat Rev Nephrol 2009;5(9):529–38. Scheinman SJ. Dent’s disease. In: Lifton RP, Giebisch G, Somlo S, Seldin DW, editors. Genetic diseases of the kidney. London: Academic Press; 2009. p. 213–26. Lowe M. Structure and function of the Lowe syndrome protein OCRL1. Traffic 2005;6(9):711–9. Hoopes Jr. RR, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, et  al. Dent disease with mutations in OCRL1. Am J Hum Genet 2005;76(2):260–7. Shrimpton AE, Hoopes Jr. RR, Knohl SJ, Hueber P, Reed AA, Christie PT, et  al. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol 2009;112(2):27–36. Bokenkamp A, Bockenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, et  al. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 2009;155(1):94–9. Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999;285(5424):103–6. Konrad M, Schaller A, Seelow D, Pandey AV, Waldegger S, Lesslauer A, et  al. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 2006;79(5):949–57.

IV. PATHOPHYSIOLOGY