Hereditary interstitial kidney disease: known genes and ... · sclerosis of glomeruli and tubular...

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For citation purposes: Srivastava S, Sayer JA. Hereditary interstitial kidney disease: known genes and opportunities for diagnosis. OA Nephrology 2013 Apr 01;1(1):5.

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Hereditary interstitial kidney disease:known genes and opportunities for diagnosis

S Srivastava, JA Sayer*

AbstractIntroductionInherited forms of tubulointerstitial kidney disease with an autosomal dominant pattern cause slowly pro-gressive renal failure, often leading to end-stage renal disease. The di-agnosis may be missed as there are limited renal and extrarenal pheno-types. Typically, the urine is inactive, with normal or small kidneys on re-nal ultrasounds and sometimes small cortical or corticomedullary cyst formation. Extrarenal phenotypes may include childhood anaemia and gout, out of keeping with the degree of renal failure. In order to make a di-agnosis, a detailed family history anda high index of suspicion is essential. Genetic screening for mutations in MUC1, UMOD and REN will allow a precise diagnosis to be made, allow-ing screening of at-risk cases and aid transplantation decisions. This revie-w discusses known genes and oppo-rtunities for diagnosis in hereditary kidney disease.ConclusionWe discuss the phenotypes common to all forms of autosomal dominant hereditary interstitial kidney disease and outline the key features that may help to refine a precise clinical and molecular diagnosis.

IntroductionHereditary interstitial kidney diseas-es may be classified into autosomal dominant and autosomal reces-sive disorders. Autosomal recessive

diseases include nephronophthisis, which typically leads to end-stage renal disease in the first three dec-ades of life1. Nephronophthisis is a ciliopathy and may be associated with a range of extrarenal manifes-tations, in keeping with the fact that the underlying gene defects are all in genes encoding primary ciliary proteins2. Autosomal dominant in-terstitial kidney diseases have been classified into various types depend-ing on their linkage to disease loci. These include medullary cystic kid-ney disease type 1 (MCKD1)3, med-ullary cystic kidney disease type 2 (MCKD2; also known now as uro-modulin-associated kidney disease, UAKD)4 and REN-related kidney dis-ease5. We review the clinical features and the underlying molecular genet-ics of each of these dominant causes of interstitial kidney disease.

Discussion

age of end-stage renal disease (ESRD) is 50 years of age6,7. Gout may occur, but it is not a particularly prominent phenotype. Urine is usually bland; if proteinuria is present it is typically in the subnephrotic range. Renal ul-trasound may identify renal cysts, but these are not essential for diag-nosis. Renal biopsy findings reveal a focal global sclerosis of glomeruli and tubular atrophy with interstitial fibrosis6.

The most important investigation is a detailed family history, in order to establish whether an autosomal dominant pattern of renal disease is present. MCKD1 patients histori-cally were those that demonstrated linkage to a disease locus on chro-mosome 1q213,7–9. This gene locus of ~2Mb, containing numerous genes, has taken over 10 years to solve.

However, after this long and ex-haustive search of the locus, a gene that was missed by massively paral-lel sequencing approaches has now been identified. In a landmark study, Kirby et al. detail how, in six families, using cloning, resequencing and de novo assembly, they found mutations (single cytosine insertions) in one al-lele of the large variable-number tan-dem repeat (VNTR) sequence in the MUC1 gene10.

The clinical presentation in these families was very similar, with urinalysis revealing minimal pro-teinuria only; renal biopsies where available showed tubulointerstitial fibrosis and cortical (rather than medullary) renal cysts were found only occasionally. Renal ultrasound scanning also revealed small echo-genic kidneys. The age of renal fail-ure in these families ranged from 25 to 79 years10.

* Corresponding author Email: [email protected]

Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, United Kingdom

The authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies.MCKD1The clinical phenotype of patients with MCKD1 includes slowly pro-gressive renal failure in an autosomal dominant pattern. The age of onset of chronic kidney disease varies be-tween families and within families, and the rate of progression is not precisely known; but the typical

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REN-related kidney diseasePatients with REN-related kidney disease typically present between 20 and 30 years of age with gout and chronic kidney disease. The urine is typically bland with an absence of proteinuria and ESRD occurs usually after 40 years of age26,27.

The key distinguishing features are secondary to the renin–angiotensin pathway distur-bance including hypoproliferative anaemia secondary to low erythro-poietin levels that may occur as early as 12 months of age. The mechanism of anaemia is thought to be secondary to reduced levels of angiotensin, which resolves during adolescence, but it may recur with the onset of chronic kidney disease. The anaemia is responsive to erythropoietin and is similar to those of patients receiving angio-tensin-converting enzyme (ACE) inhibitors28.

Mutations in UMOD also account for a phenotype known as familial juvenile hyperuricaemic nephropa-thy (FJHN). This phenotype was first described in 1960 in a family with early-onset gout, hyperuricaemia and renal disease22. UMOD mutations may also cause features of glomeru-locystic kidney disease, with marked dilatation of Bowman’s space23. To-gether, MCKD2 and FJHN are referred to as UAKD24.

The hyperuricaemia associated with UMOD mutations is a result of a reduced fractional excretion of uric acid and predisposes to early gout. The exact mechanisms, given the molecular defect is limited to the TAL of the loop of Henle, are not well understood. There may also be a mild urinary concentrating defect15. There are no specific treat-ments for UAKD, although raised serum urate can be treated with allopurinol4. Febuxostat is an alternative uric acid–lowering agent if allopurinol is not tolerated. The question remains whether lowering serum uric acid would impact upon the progression of chronic kidney disease. No randomized trials addressing this question have been published.

protein in the loop of Henle, distal convoluted tubule and the collecting ducts10. Developmental studies have shown that MUC1 is expressed in the human kidney during nephrogenesis including in the cap mesenchymal cells undergoing mesenchymal to epithelia transition, the ureteric bud tips and the collecting tubules as well as in the renal vesicles, comma bod-ies and S-shaped bodies. There was no glomerular expression of MUC113. These data implicate MUC1 as a key player in human renal development.

Kirby et al., in addition to the six index families, performed a geno-typing screen of 21 additional un-solved families. Thirteen of these had a MUC1 mutation, suggesting that MUC1 mutation screening will be a fruitful way of solving such families10. Widespread use of such genotyping for the first time will al-low a precise diagnosis to be made in families linked to chromosome 1q21, screening of other family members and also allow the diagnosis of spo-radic cases. The ability to identify a disease-causing mutation also al-lows diagnostic workup for living-related transplantation to be more precise.

Whilst testing is not yet available in routine genetic testing labor-atories, we anticipate that dedicated renal genetics research laboratories will offer genetic testing for MUC1 once a streamlined approach for analysis has been devised.

MCKD2The clinical presentation of MCKD2

The MUC1 gene encodes the pro-tein mucin-1, which is a widely ex-pressed protein, localized on the surface of epithelial cells. The pro-tein contains a heavily glycosylated extracellular domain containing the VNTR11 and a self-cleavage module to allow the release of the extracellular domain12. The insertion mutation is predicted to cause a frameshift mu-tation, which disrupts the cleavage module and causes retention of the

is not hugely different to that of MCKD1, with insidious loss of renal function over time and a bland urine. A key feature, however, is the inci-dence of gout that occurs in around half of cases and may commence early, during the second decade of life4. ESRD occurs typically between the fourth and sixth decades of life, somewhat earlier than MCKD1, but again intra- and interfamilial vari-ability is seen. Occasionally, it may be present in children less than 10 years of age14. Renal ultrasound may reveal small kidneys and occasional medul-lary cysts15. Histologically, there is a diffuse tubulointerstitial fibrosis and tubular atrophy15, and uric acid crys-tals are not seen16.

Mutations in the gene UMOD, which encodes the urinary protein uromodulin (formerly known as Tamm–Horsfall protein), underlie MCKD2. Interestingly, uromodulin, like mucin-1, is also a mucopro-tein17, although its expression pat-tern seems to be restricted to the thick ascending limbs (TALs) of the loop of Henle18. Like mucin-1, uro-modulin is a glycosylated protein that is expressed on the apical sur-face of epithelial cells and is released into the urine following proteolytic cleavage19. The biological function of uromodulin has recently been re-viewed20. Intriguingly, like many of the nephrocystin proteins, uromod-ulin may play a role in the primary cilium where it has been shown to colocalize with nephrocystin-121.

Mutational analysis of the UMOD gene is widely available and is a straightforward gene to screen with 11 coding exons. The majority of mutations occur in exons 4 and 5, al-though mutations in other exons are reported25.



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Recognition and molecular testing To help identify and screen patients with hereditary interstitial kidney diseases, we suggest a simple algo-rithm (Figure 1). We suggest that in patients with features suggestive of autosomal dominant interstitial kid-ney disease, a molecular genetic ap-proach should be taken to identify the known genetic causes of his con-dition.

ConclusionA clinical diagnosis of autosomal dominant hereditary interstitial kid-ney disease should be sought in cases of familial renal failure. There may be extrarenal features such as early gout or anaemia. Mutation screening for MUC1, UMOD and REN can now be undertaken to allow a precise molec-ular diagnosis to be made. Only then can families with these disorders be given appropriate management targeted to the underlying genetic defect, and counselling and screen-ing of at-risk members can proceed. It remains to be seen whether there will be families that remain unsolved despite screening the known genetic causes. If so, this will open the door

Homozygous and compound het-erozygous mutations were described in REN before the milder dominant forms of REN-related disease were identified. Patients with renal tubular dysgenesis with a severe phenotype of in utero death or perinatal death secondary to anuria and pulmonary hypoplasia were found to have bial-lelic mutations in REN31. This phe-notype is similar to the defects seen with the use of ACE inhibitor or angi-otensin II receptor antagonists dur-ing pregnancy32,33.

although the presence of diabet-es is variable. The pattern of inh-eritance is autosomal dominant and the presence of cystic kidneys, gout and a bland urine in such a patient could mimic MCKD2. Indeed, the cystic change can be so dramatic that mutations in HNF1b may also mimic autosomal dominant poly-cystic kidney disease (ADPKD)37.

We are also beginning to under-stand more about the phenotypic variability of ADPKD, where hypo-morphic mutations can give very mild cystic change38, which again given its dominant pattern of inher-itance could mimic MCKD. A high in-dex of suspicion is required, and it is important for the physician to ques-tion any diagnostic label that may have been applied erroneously to a family with inherited kidney disease.

In a screen of 39 families with hyperuricaemia and CKD (in whom mutations in UMOD and TCF2/HN-F1b had been excluded), just one family with a novel REN mutation (c.28T > C; p.W10R) was identified. This study confirms the rarity of REN mutations, even in this cohort29. It is also noteworthy that all the reported mutations to date have been found in exon 1.

centres. It is at present a rare cause of hereditary interstitial kidney disease, although its true in-cidence is not known.Cases of biallelic mutations Given the only very recent discovery of MUC1 mutations10, no examples of homozygous or compound het-erozygous mutations have yet been reported. For UMOD, there is a single report detailing three patients from a consanguineous Spanish family with a homozygous mutation and many other family members heterozygously affected. Here, the disease pheno-type, as expected, was more severe in homozygously affected family members, with an early onset of hyperuri-caemia (8–14 years of age) and a more rapid progression to ESRD (22 years of age in one case)30. Interestingly, all three homozygously affected patients had renal cysts in comparison with none of the patients with a heterozy-gous UMOD mutation30.

Secondary to low renin levels, the blood pressure may be low and there may be hyperkalaemia. A model, where renin deficiency leads to relative aldosterone deficiency, which results in a fluid-depleted state, leading to increased proximal reabsorption of uric acid and hyper-uricaemia, has been proposed26. Consistent with this, in cases studied, the fractional excretion of uric acid was low26. Only a handful of families with REN mutations have been reported. Zivna et al. reported two families with early-onset anaemia, hyperu-ricaemia and progressive renal failure26. Two novel mutations resulting from a deletion (p.L-eu16del) or an amino acid exchange (p.Leu16Arg) were identified in the signal seque-nce of REN. Both mutations lead to either a reduction or complete absence of prorenin and renin biosynthesis and se-cretion26. A third mutation was identified (p.Cys20Arg) in another family with an autos-omal dominant pattern of ana-emia, polyuria, hyperuricaemia and chronic kidney disease. Functional analysis of the mu-tation demonstrated accumulat-ion of non-glycosylated prepro-renin in the cytoplasm, lead-ing to ultrastructural damage of the kidney27.

The REN gene is a small gene (with 10 coding exons), and genetic testing, although not widely available, can be performed by interested academic medical

Differential diagnosis of autosomal dominant hereditary interstitial kidney diseaseIt is worth remembering that muta-tions in TCF2 encoding the transcrip-tion factor homeobox transcription factor hepatocyte nuclear factor 1 beta (HNF1b) can have a diverse range of phenotypes including cystic kidney disease, hyperuricaemia and gout34–36. This disorder is also known as renal cysts and diabetes (RCAD),

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Figure 1: Diagnostic work pattern for the evaluation of patients with autosomal dominant hereditary interstitial kidney disease. ADPKD, autosomal dominant polycystic kidney disease; ESRD, end-stage renal disease; FE urate, fractional excretion of urate; RCAD, renal cysts and diabetes syndrome; USS, ultrasound scan.

for further gene discovery research in these families.

Abbreviations listACE, angiotensin-converting enzyme; ADPKD, autosomal dominant polycys-tic kidney disease; ESRD, end-stage renal disease; FJHN, familial juvenile hyperuricaemic nephropathy; HNF, hepatocyte nuclear factor; MCKD, medullary cystic kidney disease; RCAD, renal cysts and diabetes; TAL, thick ascending limb; UAKD, uromod-ulin-associated kidney disease; VNTR, variable-number tandem repeat

AcknowledgementsSS and JAS acknowledge grate-fully the funding from the Northern Counties Kidney Research Fund and Kidney Research UK. SS is a Kidney Research UK Clinical Research Train-ing Fellow.



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