Karyomegalic nephropathy: an uncommon cause of progressive renal failure

Bhandari, Sunil; Kalowski, Steven; Collett, Paul; Cooke, Bridget E.; Kerr, Peter G.; Newland, R. C.; Dowling, John P.; Horvath, John S.

doi:10.1093/ndt/17.11.1914

Cited by 39 publications

(45 citation statements)

References 9 publications

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“…The authors presented three cases that were treated with ifosfamide, but without cisplatin. In this rare form of interstitial nephritis, systemic karyomegaly can affect other organs [13] and renal failure may be progressive [13,14]. Although at present there is no specific treatment to prevent progression of renal impairment, the present patient responded well to the small amount of oral corticosteroid therapy with the favorable clinical outcome.…”

Section: Discussionmentioning

confidence: 61%

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

et al. 2014

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Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarreappearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomegalic interstitial nephritis may be the result of long-term nephrotoxicity of ifosfamide. Since concurrent treatment with cisplatin is one of the risk factors for ifosfamide nephrotoxicity, there is a possibility that cisplatin may have a synergetic effect with ifosfamide for producing karyomegalic interstitial nephritis.

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Section: Discussionmentioning

confidence: 61%

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

et al. 2014

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“…However, it is possible that different DNA lesions may play a role in KIN pathogenesis. Generally, cases of KIN described in the literature exclude exposure to environmental genotoxins such as ochratoxin A, heavy metals, or herbal medicines (Mihatsch et al 1979;Bhandari et al 2002;Uz et al 2011;Radha et al 2014), leaving endogenously derived toxins as more likely candidates. Given the recent data implicating acetaldehyde and formaldehyde in the pathogenesis of FA (Langevin et al 2011;Garaycoechea et al 2012;Hira et al 2013;Pontel et al 2015), the contribution of aldehydes to the pathogenesis of KIN needs to be examined.…”

Section: Fan1 and Organ Dysfunctionmentioning

confidence: 99%

“…The clinical phenotypes of these two diseases are distinct. FA patients display congenital abnormalities, bone marrow failure, and predisposition to cancers (Fanconi 1967;Butturini et al 1994;Alter 2003), whereas KIN patients develop early-onset end-stage kidney disease (Mihatsch et al 1979;Spoendlin et al 1995;Zhou et al 2012) and may also exhibit elevated serum markers of hepatocyte damage, mild anemia, and recurrent upper respiratory infections (Bhandari et al 2002;Palmer et al 2007;Uz et al 2011). Histologically, the kidneys, livers, and brains of KIN patients contain enlarged, polyploid (karyomegalic) nuclei (Spoendlin et al 1995;Zhou et al 2012), which have not been described in FA patients.…”

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confidence: 99%

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

et al. 2016

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Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitinbinding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5 ′ -3 ′ exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit + cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.

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“…It was first identified in 1974 and subsequently elaborated in 1979 in 3 patients with similar clinical and pathological findings [2]. It is recognised that systemic karyomegaly can also affect other organs and that the renal failure may be progressive [3].…”

Section: Introductionmentioning

confidence: 99%

Karyomegalic-like nephropathy, Ewing’s sarcoma and ifosfamide therapy

et al. 2011

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Karyomegalic interstitial nephropathy has been reported as a rare interstitial nephritis in adult patients. Histology shows atypical epithelial cells and large abnormal hyperchromatic nuclei with irregular outlines. We report 3 adolescent patients who all recovered from their initial treatment for Ewing's sarcoma but developed a tubulopathy attributed to ifosfamide therapy. Renal impairment resulted in biopsy, which showed features of karyomegalic nephropathy in all 3. One patient has progressed to haemodialysis. Recognition of the pathology may be important in similar patients. It is surmised that the unusual histological findings in these patients stem from a common pathogenesis which may be related to chemotherapeutic agent related nuclear damage. At present there is no specific treatment to prevent progressive renal impairment.

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Karyomegalic nephropathy: an uncommon cause of progressive renal failure

Abstract: The presence of significant renal impairment, positive urine sediment, abnormal liver enzymes, and early age of onset should alert one to the presence of karyomegalic nephropathy. It represents an underdiagnosed disorder with a high degree of ploidy indicative of karyotypic abnormality.

Cited by 39 publications

References 9 publications

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

Karyomegalic-like nephropathy, Ewing’s sarcoma and ifosfamide therapy

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