Journal Information
Vol. 44. Issue. 4.July - August 2024
Pages 459-614
Share
Share
Download PDF
More article options
Vol. 44. Issue. 4.July - August 2024
Pages 459-614
Letter to the Editor
Full text access
Karyomegalic nephropathy- Letter to the Editor
Nefritis kariomegálica – Carta al Editor
Visits
548
Rocio Gimena Muñoza,
Corresponding author
rociogimu3@gmail.com

Corresponding author.
, Jessy Korina Peña Esparragozab, Carolina Castillo Torresc, Fuensanta Moreno Barriod
a Nephrology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
b Nephrology Department, Hospital Universitario La Paz, Madrid, Spain
c Pathology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
d Universidad Alcalá de Henares, Nephrology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
This item has received
Article information
Full Text
Bibliography
Download PDF
Statistics
Figures (2)
Full Text
Dear Editor,

Karyomegalic tubulointerstitial nephritis is a rare disease of uncertain etiology which has been linked to a genetic condition related to FAN1 gene. It is characterized by chronic tubulointerstitial nephritis with karyomegalic tubular epithelial cells (characteristic of the disease) lining the proximal and distal tubules and with enlarged hyperchromatic nuclei. It is a systemic entity that inevitably leads to end-stage renal disease.1 Involvement of other extrarenal organs may be present and is usually mild. It may consist of recurrent upper respiratory tract infections and liver damage, as evidenced by elevated liver enzymes.2 The disease was first described by Burry in 1974,3 and the term karyomegalic nephritis was coined by Mihatsch in 1979.4 The exact pathogenesis of this disorder is unknown; however, it is thought to be associated with mitotic blockage linked to certain genotypes.5

A 51-year-old male patient with no cardiovascular risk factors was admitted to the Nephrology Department of our hospital due to acute renal failure (maximum creatinine 2.49 mg/dl, CKD-EPI 28 ml/min/1.73 m2), fever and elevated liver enzymes. Urinalysis showed microhematuria of 5–10 red blood cells/field, proteinuria 350 mg/24 h and absence of eosinophils. A glomerular immunological study was performed, with normal immunoglobulins, negative antinuclear antibodies, normal complement (C3 and C4), normal electrophoresis in blood and urine. Given the persistent alteration of renal function without a clear cause, we decided to perform a renal biopsy.

The biopsy included renal parenchyma consisting of cortex and medulla, with 32 glomeruli; 16 of them were sclerosed and the remaining showed slight segmental proliferation. The characteristic lesion is observed in the interstitium, at the level of the tubular cells, which show large, hyperchromatic and pleomorphic nuclei (Fig. 1). In the rest of the interstitium, histological lesions of acute tubular damage are observed (Fig. 2), associated with a patchy lymphoplasmacytic inflammatory infiltrate of moderate intensity, foci of fibrosis and tubular atrophy. The immunohistochemistry study was negative for LMP-1 (EBV), CMV, Herpes virus. Ki67 (cell proliferation index) was negative in atypical cells and less than 5% in tubular cells. The direct immunofluorescence study shows no significant deposits with the antisera studied. Electron microscopy showed a glomerulus with no significant lesions. Based on these data, the following diagnoses were made: Histological lesion pattern: (1) Global sclerosis in 50% of the glomeruli, with no defined lesion pattern in the non-sclerosed glomeruli. (2) Acute tubular damage at different stages with marked nuclear atypia in tubular epithelial cells. Note: The negativity of Ki67 in most of the atypical cells rules out the possibility of regenerative changes and suggests investigating the following entities as etiological causes: heavy metal nephrotoxins, infection by viruses other than those for which we testedalready and karyomegalic interstitial nephritis.

Fig. 1.

Tubular cells with large, irregular and hyperchromatic nuclei, associated with acute tubular damage, lymphoplasmacytic inflammatory infiltrate, glomerular sclerosis and arteriosclerosis.

(0.12MB).
Fig. 2.

Tubular cells with large, irregular and hyperchromatic nuclei, associated with acute tubular damage.

(0.11MB).

Given these results, we proceeded to investigate possible infectious causes. Microbiological and serological tests for hepatitis B, hepatitis C, HIV, toxoplasma, syphilis, rickettsia, leishmania, Herpes Simplex, CMV and EBV were all negative. Given that the patient worked in damp environments (in basements), we thought of Ochratoxin A, derived from fungus, but this test was also negative. The patient was then referred to the Clinical Genetics Unit of our hospital to investigate a possible genetic etiology. The unit found a homozygous mutation in the FAN1 gene associated with karyomegalic interstitial nephritis with an autosomal recessive inheritance pattern. The patient is a carrier of the probably pathogenic variant c.1578-1G > T in homozygosis in the FAN1 gene.

This is one of the rare cases of karyomegalic interstitial nephritis confirmed via genetic study published in the literature. The prevalence of this entity is very low (<1/1,000,000) and there are very few cases described. FAN 1 is considered an effector of the Fanconi pathway, a DNA damage response signaling pathway dedicated to repair DNA inter-strand crosslink damage. However, no FAN1 mutations were detected in Fanconi anemia6 because Fanconi anemia involves other nucleases in its pathogenesis.7 These differences in cellular phenotypes lines may explain the lack of apparent phenotypic similarities between FAN1-negative individuals, compared to those who present karyomegalic interstitial nephritis, and Fanconi individuals who have clinical disease.8

We would like to highlight the fact that there is a high percentage of individuals treated with renal replacement therapy, diagnosed with fibrotic nephropathy of unknown cause, in which further studies should be done as well as genetic causes should be considered. Also, to emphasize the importance of renal biopsy as a diagnostic tool, and the importance of giving a name and surname to the renal diseases we treat.

References
[1]
F. Baba, L. Nanovic, J.B. Jaffery, A. Friedl.
Karyomegalic tubulointerstitial nephritis-- a case report.
Pathol Res Pract., 202 (2006), pp. 555-559
[2]
S. Bhandari, S. Kalowski, P. Collett, B.E. Cooke, P. Kerr, R. Newland, et al.
Karyomegalic nephropathy: an uncommon cause of progressive renal failure.
Nephrol Dial Transplant, 17 (2002), pp. 1914-1920
[3]
A.F. Burry.
Extreme dysplasia in renal epithelium of a young woman dying from hepatocarcinoma.
J Pathol, 113 (1974), pp. 147-150
[4]
M.J. Mihatsch, F. Gudat, H.U. Zollinger, C. Heierli, H. Thölen, F.W. Reutter, et al.
Systemic karyomegaly associated with chronic interstitial nephritis. A new disease entity.
Clin Nephrol, 12 (1979), pp. 54-62
[5]
G. Monga, G. Banfi, M. Salvadore, O. Amatruda, C. Bozzola, G. Mazzucco.
Karyomegalic interstitial nephritis: report of 3 new cases and review of the literature.
Clin Nephrol, 65 (2006), pp. 349-355
[6]
P. Knipscheer, M. Räschle, A. Smogorzewska, M. Enoiu, T.V. Ho, O.D. Schärer, et al.
The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.
Science, 326 (2009), pp. 1698-1701
[7]
W. Zhou, E.A. Otto, A. Cluckey, R. Airik, T.W. Hurd, M. Chaki, et al.
FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.
Nat Genet, 44 (2012), pp. 910-915
[8]
M. Godin, A. Francois, F. Le Roy, J.P. Morin, E. Creppy, J. Hemet, et al.
Karyomegalic interstitial nephritis.
Am J Kidney Dis, 27 (1996), pp. 166
Copyright © 2023. Sociedad Española de Nefrología
Idiomas
Nefrología (English Edition)
Article options
Tools
es en

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

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