December 2022 – Renal

Genetic mutation.

This is a case of karyomegalic interstitial nephritis (KIN), also known as karyomegalic nephropathy or systemic karyomegaly, which is a rare chronic tubulointerstitial nephritis most frequently caused by a genetic mutation in the FAN1 gene. In this case, whole exome sequencing later revealed a pathogenic homozygous frameshift mutation in FAN1 resulting in premature FAN1 protein truncation. Along with the morphologic and clinical findings, this further supports a diagnosis of autosomal recessive KIN.

The kidney biopsy contains tubules with pleomorphic, bizarre, and enlarged nuclei. Multinucleation and irregular nuclear membrane contours are frequently seen. Though rare macronucleoli are seen, nucleoli are generally inconspicuous to small. The tubular nuclei are approximately 2-5x larger than usual. Viral cytopathic effect is not appreciated. Overall, there is moderate tubular atrophy and interstitial fibrosis with associated mononuclear inflammation. Immunofluorescent microscopy studies are essentially negative. Electron microscopy reiterates the nuclear irregularities and enlargement in the tubules and the absence of viral cytopathic effect. These findings are most consistent with karyomegalic interstitial nephritis (KIN).

Karyomegalic interstitial nephritis (KIN) is rare, with approximately 50 cases reported in the literature. The known cases have generally presented in young adults (median: 33 years) and mostly in individuals of European and Maori descent. Presentation is variable: early-onset end-stage kidney disease is often seen, and cases may also exhibit elevated serum markers of hepatocyte damage, mild anemia, and recurrent upper respiratory infections. Most cases have been linked to autosomal recessive mutations in FAN1, which encodes Fanconi anemia-associated nuclease-1, a protein that repairs DNA interstrand crosslink damage and controls DNA ploidy in renal tubular cells. This protein is most highly expressed in kidney, liver, and neuronal tissue. Nuclear changes can be seen in these other tissues, but the kidney is most likely to be affected pathologically by fibrosis and inflammation. Often, along with the characteristic karyomegaly, kidney biopsies will show chronic inflammatory changes — interstitial fibrosis, tubular atrophy, and mononuclear inflammation, as in this case. Ki67 expression is typically reduced, and mitotic figures are usually absent. Of note, karyomegalic cells can shed in urine and can mimic viral cytopathic effect or even carcinoma in urine cytology specimens.

Patients often slowly but inevitably progress to renal failure, likely due to inadequate DNA repair after injury. Though kidney malignancies with FAN1 mutations have not been reported, FAN1 mutations have been implicated as risk factors in colorectal and pancreatic cancers. There is no effective treatment available for KIN. At least one reported case has shown recurrence of KIN in an allograft kidney transplant, though the donor kidney was the patient’s sibling, raising the possibility of quiescent KIN present in the donor. 

Though KIN is sometimes associated with chemotherapeutic agents (particularly ifosfamide) and mycotoxins (particularly ochratoxin), there is no known association with magnesium sulfate use. This patient has no history of radiation therapy; further, radiation therapy effect tends to be more restricted in distribution. Viral cytopathic effect from adenovirus, polyomaviruses, and CMV can be somewhat similar in appearance, but electron microscopy and immunohistochemistry can help with the diagnosis in difficult cases. Viral infections also tend to have more tubulitis and can have plasma cells if longstanding. There is no known association between autoimmune disease and KIN. 

References

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