A number sign (#) is used with this entry because of evidence that autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4) is caused by heterozygous mutation in the renin gene (REN; 179820) on chromosome 1q32.

Autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4) is a progressive renal disorder characterized by early-onset anemia and increased serum uric acid with a bland urinalysis and without proteinuria. Although the anemia tends to improve with age, progressive renal insufficiency results in end-stage kidney disease between 40 and 70 years. Renal ultrasound may show small echogenic kidneys, and biopsy shows tubular atrophy and interstitial fibrosis, sometimes with cysts and secondary glomerulosclerosis (summary by Zivna et al., 2009).

For discussion of the revised nomenclature and genetic heterogeneity of ADTKD, see ADTKD1 (162000).

Stiburkova et al. (2003) described a 4-generation Belgian family (BE1) segregating autosomal dominant hyperuricemic nephropathy. The first symptoms in affected individuals were mild anemia, slowly progressive renal failure, and hyperuricemia from the age of 10 years. The patients had small echogenic kidneys on renal echography. End-stage renal disease developed at 60 years of age in 1 of the male patients and was treated with kidney transplantation.

Hodanova et al. (2005) restudied family BE1, noting that renal cysts were not reported and that gout was not a feature in any of the patients. End-stage renal disease had developed in 3 patients, at ages 50, 66, and 68 years, respectively; 1 patient was successfully treated with kidney transplantation. Analysis of urine biochemical parameters revealed that uromodulin (UMOD; 191845) was reduced or absent in the patients' urine, but no abnormality of electrophoretic mobility of residual UMOD protein was observed. Significant reductions in excretion of urate and calcium were also found in affected individuals compared to unaffected family members. Examination of kidney tissue from 3 affected family members showed that UMOD staining was significantly and uniformly reduced in the epithelium of the loop of Henle, and minimal signs of tubulointerstitial injury were observed.

Zivna et al. (2009) studied the Belgian family BE1, which they designated family A, and 2 other families of European ancestry (B and C) with a very similar clinical presentation. The youngest BE1 family member, evaluated while still asymptomatic at 4 years of age, was found to have low hemoglobin and inulin clearance and elevated serum uric acid levels. Renal ultrasound at age 7 years showed small kidneys with no evidence of cyst formation, and kidney biopsy revealed focal tubular atrophy and dystrophy, focal and segmental glomerular sclerosis, and interstitial fibrosis. In the 3 families, hemoglobin values were consistently low in children with the disease, and the anemia responded well to erythropoietin; affected adults in the fourth and fifth decades of life, however, had normal hemoglobin levels if renal failure was not severe. Hyperuricemia was present in many but not all patients, and the fractional excretion of uric acid was low in all individuals studied. Kidney failure was slowly progressive, with end-stage renal disease developing at ages 50, 66, and 68 years in family A and at ages 43, 50, and 63 years in family B.

The transmission pattern of ADTKD4 in the families studied by Zivna et al. (2009) was consistent with autosomal dominant inheritance.

Stiburkova et al. (2003) performed linkage analysis in 15 families segregating autosomal dominant hyperuricemic nephropathy, including the 4-generation Belgian family BE1; 6 of the families showed linkage to chromosome 16p11 (see 162000), but linkage to that region was excluded in family BE1.

Hodanova et al. (2005) performed 2-point linkage analysis in family BE1 and obtained a lod score of 1.69 at a region containing markers D1S398 and D1S202 on chromosome 1. Fine mapping of the candidate region yielded a maximum multipoint lod score of 3.27; haplotype analysis revealed a single haplotype segregating with disease, and recombination events narrowed the candidate interval to a 37.2-Mb critical region bound by markers D1S3470 and D1S2644, containing about 300 genes. Analysis of 9 candidate genes in the region failed to reveal a deleterious mutation.

After corroborating the results of linkage analysis by Hodanova et al. (2005) in family BE1, Zivna et al. (2009) performed genomewide linkage analysis and identified a single region with a statistically significant lod score of 3.24 on chromosome 1q31-q41. Haplotype analysis defined a 25-Mb candidate region between the SNP_A-1517951 and SNP_A-1509750 markers.

In the proband from a 4-generation Belgian family segregating autosomal dominant hyperuricemic nephropathy, originally reported by Stiburkova et al. (2003) as family BE1, Zivna et al. (2009) analyzed 6 candidate genes in the critical region on chromosome 1q31-q41 and identified a heterozygous 3-bp deletion in the REN gene (179820.0004). The deletion was present in all affected individuals, and was not found in unaffected family members or in 385 unrelated Caucasian controls. The identical mutation was present on a distinct haplotype in another family with hyperuricemic nephropathy (family B). In a third affected family, of Portuguese origin (family C), Zivna et al. (2009) identified a missense mutation in the REN gene (179820.0005) that segregated with disease and was absent in 185 Caucasian controls and 50 Portuguese controls.