Biallelic variants in Fanconi Anemia-associated Nuclease 1 (FAN1) cause karyomegalic tubulointerstitial nephropathy (KIN), a condition poorly characterized in terms of kidney survival, patient survival, and clinical characteristics. Therefore, we undertook a cross-sectional collaborative study to better characterize KIN-FAN1. To gather data, we distributed a REDCap survey on clinical characteristics and genetic variants of KIN-FAN1 to colleagues and case report authors. Based on the survey, we identified 86 families affected (122 individuals) from 22 countries. There were 56 families (83 individuals) with a genetic diagnosis of KIN-FAN1, including 38 distinct FAN1 variants, and 30 families (39 individuals) with KIN with no predisposing risk factors and without molecular FAN1 testing. The median age at presentation was 38.5 years (interquartile range: 29-43), 62% male. Of the cohort, 46% had asymptomatic elevation of liver function tests, 39% had pulmonary complications, and 6% developed cancer. The median age of kidney failure was 45 years (95% confidence interval (CI): 38-56). Of the cohort, 27.1% died at a median age of 55 years (95% CI: 43-75). Pulmonary complications was/were the cause of death in 15.4% of patients on dialysis and 23.1% of kidney transplant recipients. Compared to other variants, patients with the p.W707X-FAN1 variant were at a significantly higher risk of pulmonary complications (adjusted odds ratio: 8.26 (95% CI: 1.7-40.1) and had a significantly shorter lifespan (hazard ratio: 3.24 (95% CI: 1.13-9.28). No genetic covariates were statistically associated with the progression to kidney failure. Patients with KIN-FAN1 develop kidney failure at a median age of 45 years. Survival is compromised with many dying of pulmonary disease.

Karyomegalic interstitial nephritis (KIN) is a rare hereditary form of chronic interstitial nephritis that was first described over 50 years ago. It is characterized by karyomegalic tubular epithelial cells and progressive chronic kidney disease, often leading to end-stage renal disease by the fifth decade of life. Recent studies have identified FAN1 mutations as a key genetic contributor, with additional associations to environmental factors and toxic exposures, such as ochratoxin A, alkylating agents, and heavy metals, which may act as potential triggers of the disease. We present a detailed analysis of KIN cases, highlighting genetic diversity, clinical manifestations, and management challenges, complemented by a comprehensive review of the literature.

Chronic kidney disease of unknown etiology (CKDu) is a form of chronic kidney disease commonly found in certain rural populations globally. This condition is characterized by chronic tubulointerstitial nephropathy, yet it lacks specific signature lesions and is believed to have a multifactorial etiology, often associated with environmental toxins. Karyomegalic Interstitial Nephritis (KIN), although a rare form of chronic interstitial nephropathy leading to end-stage kidney disease, is not classified under CKDu. In this case report, we explore the diagnostic journey of a 40-year-old male farmer from Guatemala. He presented with headache, fever, and facial pain, but laboratory tests revealed significant kidney impairment and liver dysfunction. The pivotal point in his diagnostic workup was a kidney biopsy, which showed severe chronic tubulointerstitial scarring and enlarged, hyperchromatic nuclei in the tubular epithelial cells, confirming KIN. This diagnosis marked a departure from the initial suspicion of Mesoamerican Nephropathy (MEN). This case underscores the critical need for a comprehensive evaluation in atypical presentations of chronic kidney disease, particularly emphasizing the importance of being vigilant for KIN in areas where MEN is commonly diagnosed.

Patients with ifosfamide-induced renal damage present with Fanconi syndrome. Karyomegalic nephropathy/interstitial nephritis (KNIN) is a rare form of chronic tubulo-interstitial nephritis that was initially considered a type of familial nephropathy. However, several reports of drug-induced KNIN, i.e., KNIN-like nephropathy, have been reported in recent years. We present the case of an 18-year-old man who presented with Fanconi syndrome and progressive renal dysfunction after receiving chemotherapy including ifosfamide and cisplatin for right femoral osteosarcoma. Renal biopsy revealed numerous atrophied tubular epithelial cells with large, polymorphic nuclei, and the definitive diagnosis was KNIN. Most patients with KNIN-like nephropathy who receive ifosfamide are concomitantly treated with cisplatin, indicating that ifosfamide and cisplatin might act synergistically to increase the risk for KNIN-like nephropathy. Further investigation in case series is warranted to reveal potential treatment approaches and to evaluate prognosis.

Karyomegalic interstitial nephritis (KIN) is an uncommon autosomal recessive disease, which is characterized by enlarged and hyperchromatic nuclei of the renal tubular epithelial cells. It is associated with mutations in Fanconi anemia-associated nuclease 1 gene, which is responsible for DNA repair, and these pathogenic mutations are responsible for progressive renal failure in young adults. We present a case of a 29-year-old female with end-stage renal disease who had a family history of early-onset renal failure in two of the siblings. Her elder sister with chronic kidney disease stage III was advised to be biopsied to look for any familial causes. Stained sections of renal biopsy revealed normal glomeruli. Tubular epithelial cells showed nuclear changes focally like hyperchromasia, karyomegaly, and anisonucleosis. On direct immunofluorescence, all glomeruli were negative for deposits with all antisera. Based on these findings, a final opinion of KIN was given.