J Am Soc Nephrol 11: 1439–1448, 2000 Lithium Nephrotoxicity: A Progressive Combined Glomerular and Tubulointerstitial Nephropathy GLEN S. MARKOWITZ,* JAI RADHAKRISHNAN,† NEERAJA KAMBHAM,* ANTHONY M. VALERI,† WILLIAM H. HINES,‡ and VIVETTE D. D’AGATI* Departments of *Pathology and †Medicine, Columbia Presbyterian Medical Center, New York, New York; and ‡Department of Medicine, Stamford Hospital, Stamford, Connecticut. Abstract. This study examines the clinical features, pathologic surprisingly high prevalence of focal segmental glomeruloscle- findings, and outcome of 24 patients with biopsy-proven lith- rosis (50%) and global glomerulosclerosis (100%), sometimes ium toxicity. The patient population was 50% male, 87.5% of equivalent severity to the chronic tubulointerstitial disease. Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). The significant degree of foot process effacement (mean 34%, Mean duration of lithium therapy for bipolar disorder was 13.6 five of 14 cases with Ͼ50%) suggests a potential direct glo- yr (range, 2 to 25). All patients were biopsied for renal insuf- merular toxicity. Focal segmental glomerulosclerosis corre- ficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), lated with proteinuria Ͼ1.0 g/d (P ϭ 0.0014, Fisher exact test). with associated proteinuria Ͼ1.0 g/d in 41.7%. Nephrotic Despite discontinuation of lithium, seven of nine patients with proteinuria (Ͼ3.0 g/d) was present in 25%. Other features initial serum creatinine values Ͼ2.5 mg/dl progressed to end- included nephrogenic diabetes insipidus in 87% and hyperten- stage renal disease (ESRD). Only three patients, all with initial sion in 33.3%. Renal biopsy revealed a chronic tubulointersti- serum creatinine Ͻ2.1 mg/dl, had subsequent improvement in tial nephropathy in 100%, with associated cortical and medul- renal function. By Kaplan–Meier survival analysis, the only lary tubular cysts (62.5%) or dilatation (33.3%). All of the significant predictor of progression to ESRD was serum cre- renal cysts stained for epithelial membrane antigen, while atinine Ͼ2.5 mg/dl at biopsy (P ϭ 0.008). In conclusion, 51.4% stained with lectin Arachis hypogaea, and only 3.8% lithium nephrotoxicity primarily targets distal and collecting stained with Tetragonolobus purpureas, indicating they origi- tubules, with a higher incidence of proteinuria and associated nated from distal and collecting tubules. The degree of tubular glomerular pathology than recognized previously. Renal dys- atrophy and interstitial fibrosis was graded as severe in 58.3%, function is often irreversible despite lithium withdrawal, and moderate in 37.5%, and mild in 4.2% of cases. There was a early detection is essential to prevent progression to ESRD. Lithium is a therapeutic agent currently in widespread use for the water channel aquaporin-2, expressed on the apical plasma treatment of bipolar disorder. Although this agent is highly effec- membrane of principal cells of the collecting duct (2). Acute tive in reducing symptoms of manic depression, a frequent side lithium intoxication due to lithium overdose may be seen in effect is renal toxicity. A major biochemical action of lithium in patients on chronic lithium therapy or in lithium-naı¨ve indi- the kidney is competition with magnesium, thereby inhibiting viduals. Acute effects include a change in mental status, acute magnesium-dependent G proteins that activate vasopressin-sensi- renal failure, and volume depletion. The primary management tive adenylyl cyclase (1). Lithium nephrotoxicity can be divided of acute lithium intoxication is hemodialysis (1). into three main categories: nephrogenic diabetes insipidus, acute The predominant form of chronic renal disease associated with intoxication, and chronic renal disease. lithium therapy is a chronic tubulointerstitial nephropathy (CTIN) Nephrogenic diabetes insipidus (NDI) is the most common that is heralded by the insidious development of renal insuffi- renal side effect of lithium therapy. Patients present with ciency, with little or no proteinuria, often in the setting of chronic polyuria and polydipsia due to a urinary concentrating defect NDI. Biopsy findings in patients with lithium-induced CTIN that can lead to significant volume depletion. Experimental include tubular atrophy and interstitial fibrosis, typically out of studies have shown that the development of NDI involves proportion to the degree of glomerulosclerosis or vascular disease lithium-induced downregulation of the vasopressin-regulated (3–6). The majority of studies have shown infrequent and rela- tively mild renal insufficiency attributable to lithium therapy (7). Only one case of end-stage renal disease (ESRD) secondary to Received November 4, 1999. Accepted December 22, 1999. lithium-associated CTIN has been reported (8). Correspondence to Dr. Vivette D. D’Agati, Department of Pathology, Colum- Much less has been written about the potential glomerular bia Presbyterian Medical Center, 630 West 168th Street, VC14-224, New toxicity of lithium. There are many documented cases of min- York, NY 10032. Phone: 212-305-7460; Fax: 212-342-5380; E-mail: [email protected] imal change disease occurring in association with lithium ther- 1046-6673/1108-1439 apy (9,10). Some cases have resolved following lithium with- Journal of the American Society of Nephrology drawal and recurred after its reintroduction, providing strong Copyright © 2000 by the American Society of Nephrology evidence of an etiologic relationship (9,10). Only three cases of 1440 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 1439–1448, 2000 focal segmental glomerulosclerosis (FSGS) in patients receiv- been treated with lithium in standard doses for a mean of 13.6 ing lithium carbonate have been described (11). yr (range, 2 to 25 yr). All patients presented with renal insufficiency (Table 3). Materials and Methods The mean initial serum creatinine was 2.8 mg/dl with a range of 1.3 to 8.0 mg/dl. The patient who presented with a serum All renal biopsies processed from 1986 to 1999 in the Renal Pathology creatinine of 8.0 mg/dl required emergent hemodialysis and Laboratory at Columbia Presbyterian Medical Center were reviewed for a history of lithium therapy. Twenty-four biopsies from patients treated remained dialysis-dependent. Only two patients were known to with lithium were identified from among 6514 native kidney biopsies have previous episodes of acute lithium intoxication (patients 7 (0.37%). All cases were processed for light microscopy, immunofluores- and 18). Proteinuria was a common presenting feature: 10 cence, and electron microscopy according to standard techniques. The patients (41.7%) had a 24-h protein measurement of Ͼ1.0 g/d, tissue available for electron microscopy included glomeruli in 15 cases and six patients (25%) had nephrotic-range proteinuria. Three and tubules in 24 cases. Each case was reviewed independently by two of these six patients (patients 1, 2, and 19) met two of the three renal pathologists. Tubular atrophy and interstitial fibrosis were graded additional criteria for the diagnosis of nephrotic syndrome on a scale of mild, moderate, and severe, corresponding to involvement (hypoalbuminemia, hypercholesterolemia, and peripheral ede- Ͼ of 0 to 25, 26 to 50, and 50% of the cortex sampled, respectively. ma). Hematuria and leukocyturia were present in two and three Tubular cysts were defined as tubules with a diameter of at least five patients, respectively. Interestingly, ultrastructural analysis re- times that of normal tubules. Tubular profiles with a diameter 2 to 4 times vealed underlying thin basement membrane disease in one of that of normal tubules were considered to have tubular dilatation, likely representing incipient cysts. The percentages of globally and segmentally the three patients with hematuria (patient 10). Clinical evi- sclerotic glomeruli were recorded. dence of NDI was present in 87% of patients. Patient charts were reviewed retrospectively for presenting symp- All 24 renal biopsy samples were believed to be adequate for toms, laboratory data at presentation, and follow-up (up to 11 yr). diagnosis, with a mean glomerular count of 29.3 (range, 4 to Nephrotic-range proteinuria was defined as a 24-h urine collection of Ͼ100; median 20). The predominant pathologic finding ob- Ͼ3.0 g/d. Hypoalbuminemia was defined as serum albumin Ͻ3.3 served in all 24 of the biopsy samples was CTIN, characterized g/dl, and hypercholesterolemia was defined as serum cholesterol by tubular atrophy and interstitial fibrosis, out of proportion to Ͼ200 mg/dl. Nephrogenic diabetes insipidus was diagnosed based on the extent of glomerular or vascular disease (Table 4, Figure 1, clinical criteria of polyuria, polydipsia, and consistently low urine- A and B). Tubular atrophy and interstitial fibrosis were graded Ͻ specific gravities ( 1.010). as mild in one patient, moderate in nine patients, and severe in Renal cysts remained in the tissue block from eight of the biopsy 14 patients. In all patients, the degree of tubular atrophy and samples. To determine the nephron segments forming cysts, these cases were stained with lectins Tetragonolobus purpureas (TP) for interstitial fibrosis was either equal to (21.7%) or greater than proximal tubules, and Arachis hypogaea (AH) for collecting tubules, (78.3%) the degree of arteriosclerosis. Tubulointerstitial dis- and with antibody to epithelial membrane antigen (EMA) for distal ease tended to be patchy, with geographic zonation, particu- and collecting