The Case | Unusual cause of chronic renal failure with elevated liver enzymes

Abstract

A 45-year-old male patient was diagnosed with renal failure during workup of newly developed hypertension 2 years ago. At that time, serum creatinine concentration was 1.5mg/dl and there was also evidence of liver disease, with liver enzymes being markedly elevated (ALT 124U/l, AST 55U/l (normal range for both <50U/l), and γ-GT 188U/l (normal range <60 U/l)). However, thorough workup, including liver biopsy, could not reveal any specific cause. Upon progression of renal failure, the patient was referred for further nephrological evaluation. The patient had no complaint, and the physical examination was completely unremarkable. Serum creatinine concentration was 1.8mg/dl (158μmol/l) and estimated glomerular filtration rate was 41ml/min per 1.73m2. Dip-stick proteinuria was negative; however, selective analysis revealed microalbuminuria (39mg/g crea, normal range <20mg/g crea) and a high excretion of α1-microglobulin (71mg/g crea, normal range <13mg/g crea). In the urine sediment, there was no evidence of erythrocyturia or leucocyturia. Sonography revealed atrophied kidneys bilaterally with a size of 8–9cm. To identify the cause of the patient’s renal failure, kidney biopsy was performed (Figure 1). What is the diagnosis? Karyomegalic interstitial nephritis (KIN) is a rare cause of chronic renal failure, and was first described and named in 1979 by Mihatsch.1.Mihatsch M.J. Gudat F. Zollinger H.U. et al.Systemic karyomegaly associated with chronic interstitial nephritis. A new disease entity?.Clin Nephrol. 1979; 12: 54-62PubMed Google Scholar So far, very few cases have been reported in the literature.2.Bhandari S. Kalowski S. Collett P. et al.Karyomegalic nephropathy: an uncommon cause of progressive renal failure.Nephrol Dial Transplant. 2002; 17: 1914-1920Crossref PubMed Scopus (31) Google Scholar Hallmark findings are tubulointerstitial nephritis and karyomegaly of the tubular epithelium1.Mihatsch M.J. Gudat F. Zollinger H.U. et al.Systemic karyomegaly associated with chronic interstitial nephritis. A new disease entity?.Clin Nephrol. 1979; 12: 54-62PubMed Google Scholar that is due to increased ploidy of the cells.2.Bhandari S. Kalowski S. Collett P. et al.Karyomegalic nephropathy: an uncommon cause of progressive renal failure.Nephrol Dial Transplant. 2002; 17: 1914-1920Crossref PubMed Scopus (31) Google Scholar The disease affects other organs as well, such as liver, and leads to end-stage kidney disease (ESRD) in the fourth decade of life. Morphologically, there are similarities to the toxic nephropathy induced by ochratoxin A or ifosfamide, which are known to cause DNA interstrand cross-linking.3.Boorman G.A. McDonald M.R. Imoto S. et al.Renal lesions induced by ochratoxin A exposure in the F344 rat.Toxicol Pathol. 1992; 20: 236-245Crossref PubMed Scopus (106) Google Scholar,4.McCulloch T. Prayle A. Lunn A. et al.Karyomegalic-like nephropathy, Ewing’s sarcoma and ifosfamide therapy.Pediatr Nephrol. 2011; 26: 1163-1166Crossref PubMed Scopus (17) Google Scholar Karyomegaly and polyploidy are most likely secondary to a cell cycle arrest rather than cell fusion or cell proliferation.2.Bhandari S. Kalowski S. Collett P. et al.Karyomegalic nephropathy: an uncommon cause of progressive renal failure.Nephrol Dial Transplant. 2002; 17: 1914-1920Crossref PubMed Scopus (31) Google Scholar Very recently, recessive mutations in the gene FAN1 encoding for the Fanconi anemia–associated nuclease 1 have been found to cause KIN.5.Zhou W. Otto E.A. Cluckey A. et al.FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.Nat Genet. 2012; 44: 910-915Crossref PubMed Scopus (169) Google Scholar FAN1 is an endonuclease involved in the DNA repair of regions with interstrand cross-link damage.6.Yoshikiyo K. Kratz K. Hirota K. et al.KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents.Proc Natl Acad Sci USA. 2010; 107: 21553-21557Crossref PubMed Scopus (67) Google Scholar Cells lacking FAN1 exhibit increased sensitivity to cross-linking agents such as cisplatin or mitomycin C, which cause chromosomal instability in these cells.6.Yoshikiyo K. Kratz K. Hirota K. et al.KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents.Proc Natl Acad Sci USA. 2010; 107: 21553-21557Crossref PubMed Scopus (67) Google Scholar In our patient, point mutations of both alleles of the FAN1 gene (compound heterozygosity) were identified, giving rise to the diagnosed KIN.4.McCulloch T. Prayle A. Lunn A. et al.Karyomegalic-like nephropathy, Ewing’s sarcoma and ifosfamide therapy.Pediatr Nephrol. 2011; 26: 1163-1166Crossref PubMed Scopus (17) Google Scholar Although KIN is a very rare disorder, it is conceivable that some cases of chronic interstitial nephritis might be related to mutations or polymorphisms in the FAN1 gene, leading to reduced rather than abolished nuclease activity, which itself increases the individual susceptibility to interstrand cross-linking agents derived from the environment.5.Zhou W. Otto E.A. Cluckey A. et al.FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.Nat Genet. 2012; 44: 910-915Crossref PubMed Scopus (169) Google Scholar