Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy.
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.
Markowitz
Glen S
GS
Department of Pathology, Columbia Presbyterian Medical Center, New York, New York.
Radhakrishnan
Jai
J
Department of Medicine, Columbia Presbyterian Medical Center, New York, New York.
Kambham
Neeraja
N
Department of Pathology, Columbia Presbyterian Medical Center, New York, New York.
Valeri
Anthony M
AM
Department of Medicine, Columbia Presbyterian Medical Center, New York, New York.
Hines
William H
WH
Department of Medicine, Stamford Hospital, Stamford, Connecticut.
D'Agati
Vivette D
VD
Department of Pathology, Columbia Presbyterian Medical Center, New York, New York.
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
D008094:Lithium