NephMadness 2015: Genetic Nephrology Region

Conall O'Seaghdha, MB MRCPI; Paul Phelan, MD


March 02, 2015

Editorial Collaboration

Medscape &

In This Article

Conall O'Seaghdha, MB MRCPI, Selection Committee member for the Genetic Nephrology Region

Editor's Note: The following "Scouting Report" will help you complete your bracket in the NephMadness Tournament. Read it carefully to make your selections, and discuss your thoughts in our Comments section. This article first appeared on the AJKD BLOG.

Meet the Competitors: AD Tubulointerstitial Nephritis vs AR Tubulointerstitial Nephritis

This match-up of local rivals should be a humdinger! We have learned a lot more about the line-ups of both teams through recent genetic advances, although autosomal dominant (AD) Tubulointerstitial Nephritis may be the pre-match favorite due to its star performer uromodulin-associated kidney disease (UMOD) Nephropathy. Overall, however, this appears to be an evenly matched contest and a highlight of the NephMadness first round.

AD Tubulointerstitial Nephritis

There have been a variety of names for these conditions, including medullary cystic kidney disease (MCKD), despite medullary cysts being far from universal, and familial juvenile hyperuricemic nephropathy. Modern genetic techniques have helped us hugely in characterizing these disorders and providing a molecular diagnosis in the face of nonspecific clinical data. Therefore, in the current era they are termed autosomal dominant (AD) tubulointerstitial nephritis.

AD tubulointerstitial nephritis comprises a group of familial disorders characterized by:

  • Bland urinary sediment

  • Minimal hematuria

  • Minimal proteinuria

  • Progressive CKD

Histology is:

  • Generally nonspecific

  • Tubulointerstitial pattern of injury

  • Variable amount of tubular atrophy and interstitial fibrosis depending on the point in the natural history of the condition that the biopsy is performed.

UMOD Nephropathy

UMOD codes for uromodulin (also known as Tamm–Horsfall protein), which is expressed exclusively in the thick ascending limb of the loop of Henle and is the most common protein in normal urine.

Missense mutations in UMOD cause tubulointerstitial nephropathy with hyperuricemia, previously named MCKD type 2 or juvenile hyperuricemic nephropathy type 1. Common variants in UMOD have also been demonstrated in large genome-wide association studies (GWAS) to confer independent risk for both hypertension and kidney disease illustrating the shared risk for both phenotypes within this locus (see the GWAS in Nephrology team description for more).

The UMOD story got a lot more interesting when Trudu et al published an intriguing set of experiments establishing a link between uromodulin, hypertension, and kidney disease via activation of the renal sodium co-transporter NKCC2. UMOD risk variants identified in the above-mentioned GWAS are located in the promoter region of the gene, leading to a theory that they altered UMOD expression. This was confirmed using human nephrectomy specimens and a large population cohort with urinary uromodulin levels.

To model the effect in vivo, the authors used a transgenic mouse which over-expressed UMOD leading to salt-sensitive hypertension and interstitial nephritis. Moreover, they demonstrated that phosphorylated NKCC2 levels rose in tandem with UMOD gene dosage. In contrast to wild-type mice, the transgenic UMOD mice had marked improvement in blood pressure with furosemide (an inhibitor of NKCC2). Hypertensive humans with the variant showed a similar response to furosemide. We have known about the existence of uromodulin for some time but we are only beginning to understand it.

MUC1 Nephropathy

This disease, previously referred to as MCKD type 1, is due to a mutation in the variable-number tandem repeat region of the MUC1 (Mucin 1) gene. The locus at chromosome 1q21 was identified by linkage mapping in 1998, but the gene has only recently been discovered due to difficulty with sequencing this highly repetitive region and was previously missed using next-generation sequencing.

Mucin 1 lies on the tubular cell apical surface and has a role in signal transduction pathways. The frameshift mutation results in the formation of a truncated protein which cannot fold properly, promoting aggregation, and subsequent deposition in tubular cells. These mutations could also occur sporadically in which case the lack of a family history would make the diagnosis even more difficult. It is certain that there are individuals and families with MUC1 nephropathy who are labelled as having hypertensive (or other) nephropathy with bland urinalysis and tubulointerstitial fibrosis on biopsy.

Other Mutations

Mutations in the gene coding for renin ( REN ) also cause AD tubulointerstitial kidney disease. Low renin expression has been demonstrated in renal biopsies of affected family members. It is thought that the toxic effects of the mutant protein reduce the viability of renin-expressing cells in and the juxtaglomerular apparatus, leading to nephron dropout and progressive tubulointerstitial injury.

HNF1B encodes a transcription factor, hepatocyte nuclear factor 1β, involved in the early development of the kidney, liver, pancreas, and genital tract. Mutations in HNF1B may be sporadic or dominantly inherited and cause diabetes mellitus, pancreatic atrophy, abnormal liver function, early-onset gout, and mental retardation. Renal involvement may be evident early as cystic dysplastic kidneys, solitary kidney, or later as a tubulointerstitial pattern of injury. The prevalence of spontaneous whole-gene HNF1B deletions may be as high as 50% in affected cases, explaining a lack of family history in many kindred. Some mutations may be incompatible with life and overall, HNF1B mutations appear to be the most frequent monogenic cause of developmental kidney disease. An excellent review of the spectrum of HNF1B nephropathy has recently been published.

With a big-name player like UMOD Nephropathy and rising stars such a MUC1 & HNF1B Nephropathy, AD Interstitial Nephritis may possess the right blend to go deep in this year's tourney.

AR Tubulointerstitial Nephritis

Familial tubulointerstitial nephritis may also be inherited as an autosomal recessive (AR) trait. It is usually termed nephronophthisis, a rare disorder but one of the most common causes of ESRD in pediatric populations. The incidence is estimated at 1-20 cases per 1,000,000 live births.

It presents earlier than AD interstitial nephritis, occurring in the first 3 decades of life. It may also have extra-renal manifestations, the commonest being retinitis pigmentosa. There are many syndromal forms of nephronophthisis/AR tubulointerstitial nephritis with Bardet-Biedl syndrome being perhaps the most well known and others being Jeune syndrome, Joubert syndrome, and Senior-Løken syndrome. Bardet-Biedl syndrome is characterized by retinal degeneration, obesity, learning difficulty, and a variety of other features such as polydactyly, hypogonadism, and hypercholesterolemia which show variable penetrance.

Histologically, nephronophthisis appears similar to AD interstitial nephritis with tubular atrophy, interstitial fibrosis and even corticomedullary cysts present. Genetic testing is the only way to distinguish nephronophthisis from AD interstitial nephritis, apart from mode of inheritance. Similar to AD tubulointerstitial nephritis, there has been much progress recently in the molecular characterization of this phenotype.

The use of positional cloning and next-generation sequencing has facilitated the discovery of many nephronophthisis genes (NPHP). Their protein products, termed nephrocystins, localize to primary cilia placing nephronophthisis in the realm of other renal ciliopathies such as AD & AR polycystic kidney disease. Primary cilia are microtubule-like sensory organelles present on many cell types, including the apical surface of renal tubular cells.

Currently 17 NPHP genes have been discovered, which together explain <50% of total cases (NPHP1 itself causes approximately 30% of cases). NPHP1-9 genes were discovered using a combination of genome-wide linkage and direct sequencing approaches in large pedigrees. More recent discoveries have been aided by next-generation sequencing. However, simultaneous analysis of all known mutations using massively parallel sequencing only led to a molecular diagnosis in 25% of cases, highlighted what remains to be discovered.

Employing a candidate gene approach has proved useful (for NPHP16/ANKS6) by first identifying cilia gene products using proteomics and working back to the genes of interest. With >1000 known cilia proteins, this may enable the identification of many more nephronophthisis genes.

Nephronophthisis may also display polygenic inheritance, where mutations may be found in 2 or more susceptibility genes. Several families have been described that harbor mutations in several NPHP genes, which are known to interact. Furthermore, families with a nephronophthisis phenotype have been described having a single mutation in an isolated NPHP gene, suggesting they may have mutations in other, yet undiscovered NPNP genes as the condition is AR.

These polygenic phenomena may also explain some of the incompletely penetrant extra-renal manifestations in certain individuals and families. For example, modifier effects of co-existing ANH1 and NPHP6 mutations have been suggested to cause extra-renal manifestations in Joubert syndrome due to NPHP1 mutations.

While not as celebrated as its bitter rival, AR Tubulointerstitial Nephritis has made big progress of late thanks to modern genetic advances. It will fancy its chances against its conference rival in this big first round matchup.

Table 1. NPHP Genes So Far Identified

NPHP Gene Name Location Gene Product
NPHP1 NPHP1 2q13 Nephrocystin 1
NPHP2 INVS 9q31.1 Inversin
NPHP3 NPHP3 3q22.1 Nephrocystin 3
NPHP4 NPHP4 1p36.31 Nephrocystin 4
NPHP5 IQCB1 3q13.33 IQ motif-containing protein B1
NPHP6 CEP290 12q21.32 Centrosomal protein of 290 kDa
NPHP7 GLIS2 16p13.3 Zinc finger protein GLIS2
NPHP8 RPGRIP1L 16q12.2 Retinitis pigmentosa GTPase regulator-interacting protein 1-like
NPHP9 NEK8 17q11.2 Serine/threonine-protein kinase Nek9
NPHP10 SDCCAG8 1q43 Serologically defined colon cancer antigen 8
NPHP11 TMEM67 8q22.1 Meckelin
NPHP12 TTC21B 2q24.3 Tetratricopeptide repeat protein 21B
NPHP13 WDR19 4p14 WD repeat-containing protein 19
NPHP14 ZNF423 16q12.1 Zinc finger protein 423
NPHP15 CEP164 11q23.2 Centrosomal protein of 164 kDa
NPHP16 ANKS6 9q22.33 Ankyrin repeat and SAM domain-containing protein 6
NPHP17 IFT172 2p23.3 Intraflagellar transport protein 172


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