Journal Information
Vol. 44. Issue. 1.January - February 2024
Pages 1-118
Vol. 44. Issue. 1.January - February 2024
Pages 1-118
Letter to the Editor
Full text access
Eliminating the concept of unknown chronic kidney disease: 2 cases of autosomal dominant tubulointerstitial nephropathy with pathogenic variant MUC-1
Eliminando el concepto de enfermedad renal crónica no filiada: a propósito de 2 casos de nefropatía túbulo-intersticial autosómica dominante con variante patogénica MUC-1
Verónica Andreina Barcia Odor
Corresponding author

Corresponding author.
, Elena Monfá, Benjamin de León, Catherine Martinez-Rosero, Silvia Sanchez-Montero, Carmen Barnes, Cristina Lucas, Arancha Sastre, Jorge Estifan, Mario Prieto
Servicio de Nefrología, Complejo Asistencial Universitario de León, León, Spain
This item has received
Article information
Full Text
Download PDF
Figures (1)
Tables (1)
Table 1. Characteristics of the different NTIADs.
Full Text
Dear Editor,

Confirming a diagnosis for certain renal diseases is only possible with a genetic study. This is the case for autosomal dominant tubulointerstitial kidney disease (ADTKD), as defined by the KDIGO guidelines in 2015.1

ADTKDs manifest as progressive loss of renal function, with negative or anodyne proteinuria and usually with normal urinary sediment. On ultrasound, the kidneys are normal or small size, with inconsistent presence of corticomedullary cysts. Renal biopsy is nonspecific, showing only evidence of interstitial fibrosis and tubular atrophy. The five most frequent known causative genes are: UMOD, MUC-1, REN, HNF1B and SEC61A1, with differential clinical characteristics among them (Table 1).2–5 Penetrance is close to 100% and there may be intra- and interfamilial variability. They constitute the third most common group of monogenic renal disease, after autosomal dominant polycystic kidney disease and type IV collagen disease.4

Table 1.

Characteristics of the different NTIADs.

Causal gene  Features 
RENEarly onset anemia, disproportionate to the degree of renal failure 
Hyperkalemia and hyperuricemia 
Normal or low blood pressure 
HNF1BHypomagnesemia, hyperuricemia, alteration of liver function tests 
Presence of cortical and bilateral renal cysts, renal hypoplasia, glomerulocystic disease, renal agenesis, renal hyperechogenicity in fetal and neonatal period 
MODY5 diabetes, genital malformations and pancreatic atrophy 
MUC-1No characteristic features other than tubulointerstitial fibrosis 
Cortico-medullary cysts may be present 
UMODInappropriate decrease in the fractional excretion of uric acid 
Early hyperuricemia (before the onset of renal insufficiency) 
Defect in the urinary concentration capacity 
Decreased urinary excretion of uromodulin 
Cortico-medullary cysts may be present 
SEC61A1Congenital anemia, leukopenia, and neutropenia 
Delayed growth 
Uvula bifida, abscess formation, cleft lip 

We present 2 cases diagnosed in our center.

The first case is a 23-year-old female patient, with no relevant medical history, who was consulted for renal function deterioration with creatinine of 1.4 mg/dl, CKDEPI 53 ml/min/1.73 m2, urine albumin/creatinine ratio of 7.4 mg/g and no alterations in urinary sediment. On ultrasound, the kidneys were of normal size and morphology, although slightly hyperechogenic, with no evidence of renal cysts. There was nothing remarkable in the anamnesis: she had no history of urinary tract infections or nephritic colic, no nephrotoxic intake and no cardiovascular risk factors (she had blood pressure of 120/70 mmHg). Regarding family history (Fig. 1): her maternal great-grandmother died at 35 years of age of “nephropathy,” her maternal grandmother started dialysis at 45 years of age, her maternal aunt started dialysis at 55 years of age and her mother started dialysis at 48 years of age. In all 3 cases, chronic kidney disease (CKD) was not affiliated and had been related to vascular profile because she had arterial hypertension at 35–40 years of age. We performed more studies (ANA, anti-DNA, ANCA, ENA, C3/C4, IgA/M/G, proteinogram, HIV/HBV/HCV): all were negative or normal. The patient presented progressive deterioration of renal function with no other potential causes. She refused renal biopsy. Given the familial autosomal dominant profile, clinicians requested a genetic study, which detected a pathogenic variant in the MUC-1 gene, causing NTIAD. The patient is now 28 years old, with advanced chronic kidney disease (creatinine 5.2 mg/dl CKDEPI 10 ml/min/1.73 m2), so the progression has been faster than in her other relatives.

Fig. 1.

Family tree.


The second case is a 29-year-old male, with medical history of arterial hypertension of one year with good control with low-dose antihypertensive drugs; he also had meningitis (2015) and previous appendectomy. He was referred to us because of renal function deterioration (creatinine 2 mg/dl, CKDEPI 38 ml/min/1.73 m2), with an urine albumin/creatinine ratio of 290 mg/g, with no alterations in urinary sediment. We had no previous lab analyses or reports (he used to live in another city). Ultrasound revealed the kidneys measured 10 cm and presented poor corticomedullary differentiation and small bilateral cortical cysts. As for family history: his paternal grandfather started dialysis at age 73 (no reports were available, he resided in another city and he was deceased), parents had no history of renal disease and no other known nephrological history in his family. There was no deafness in the family. We performed an extensive study (ANA, anti-DNA, ANCA, ENA, C3/C4, cryoglobulins, IgA/M/G/IgG4, proteinogram, HIV/HBV/HCV): everything was negative or normal. A Fabry screening study (α-galactosidase levels) was also negative. We did not consider performing a renal biopsy due to the important chronicity data in the ultrasound. In view of the non-filial CKD, the patient’s age and the family history, we decided to request a genetic study, which detected a pathogenic variant in the MUC-1 gene, that was the cause of autosomal dominant interstitial nephropathy.

In conclusion, NTIAD should be suspected in young patients with non-infiltrative CKD without glomerulonephritis data and with a family history of nephropathy, whose reliable diagnosis is only possible with a genetic study.6,7 Thanks to technological advances in genetic studies in recent years, there are now affordable and efficient tests for well-selected patients.8,9

K.U. Eckardt, S.L. Alper, C. Antignac, A.J. Bleyer, D. Chauveau, K. Dahan, et al.
Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—a KDIGO consensus report.
Kidney Int, 88 (2015), pp. 676-683
N. Ayaresh, R. Miquel, A. Matamala, E. Ars Criach, R. Torra Balcells.
Revisión de la nefropatía tubulointersticial autosómica dominante.
Nefrologia, 37 (2017), pp. 235-243
N. Ayasreh, G. Bullich, R. Miquel, R. Furlano, P. Ruiz, L. Lorente, et al.
Autosomal dominant tubulointerstitial kidney disease: clinical presentation of patients with ADTKD-UMOD and ADTKD-MUC1.
Am J Kidney Dis, 72 (2018), pp. 411-418
O. Devuyst, E. Olinger, S. Weber, K. Eckardt, S. Kmoch, L. Rampoldi, et al.
Autosomal dominant tubulointerstitial kidney disease.
Nat Rev Dis Primers, 5 (2019), pp. 60
E. Olinger, P. Hofmann, K. Kidd, I. Dafour, H. Belge, C. Schaeffer, et al.
Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.
Kidney Int, 98 (2020), pp. 717-731
D. Connaughton, C. Kennedy, S. Shril, N. Mann, S. Murray, P. Williams, et al.
Monogenic causes of chronic kidney disease in adults.
Kidney Int, 95 (2019), pp. 914-928
M. Quaglia, C. Musetti, G.M. Ghiggeri, G. Battista, F. Settanni, R. Luciano, et al.
Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy.
Clin Transplant, 28 (2014), pp. 995-1003
G. Bullich, A. Domingo-Gallego, I. Vargas, P. Ruiz, L. Lorente-Grandoso, M. Furlano, et al.
A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases.
Kidney Int, 94 (2018), pp. 363-371
J. Oh, J. Shin, K. Lee, C. Lee, Y. Ko, J. Lee.
Clinical application of a phenotype-based NGS panel for differential diagnosis of inherited kidney disease and beyond.
Clin Genet, 99 (2021), pp. 236-249
Nefrología (English Edition)
Article options
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?