title: Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy.
abstract: This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P = 0. 008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized previously. Renal dysfunction is often irreversible despite lithium withdrawal, and early detection is essential to prevent progression to ESRD.
authors.affiliation: Department of Pathology, Columbia Presbyterian Medical Center, New York, New York.
authors.forename: Glen S
authors.initials: GS
authors.lastname: Markowitz
authors.affiliation: Department of Medicine, Columbia Presbyterian Medical Center, New York, New York.
authors.forename: Jai
authors.initials: J
authors.lastname: Radhakrishnan
authors.affiliation: Department of Pathology, Columbia Presbyterian Medical Center, New York, New York.
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.affiliation: Department of Medicine, Columbia Presbyterian Medical Center, New York, New York.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Valeri
authors.affiliation: Department of Medicine, Stamford Hospital, Stamford, Connecticut.
authors.forename: William H
authors.initials: WH
authors.lastname: Hines
authors.affiliation: Department of Pathology, Columbia Presbyterian Medical Center, New York, New York.
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D007676:Kidney Failure, Chronic / Q000139:chemically induced; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000187:drug effects; D007686:Kidney Tubules, Distal / Q000187:drug effects; D008094:Lithium / Q000506:poisoning*; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000209:etiology; D016019:Survival Analysis
chemical_list: D008094:Lithium