Lithium Nephrotoxicity

Lithium is a therapeutic agent currently in widespread use for the treatment of bipolar disorder. Although this agent is highly effective in reducing symptoms of manic depression, a frequent side effect is renal toxicity. A major biochemical action of lithium in the kidney is competition with magnesium, thereby inhibiting magnesium-dependent G proteins that activate vasopressin-sensitive adenylyl cyclase (1). Lithium nephrotoxicity can be divided into three main categories: nephrogenic diabetes insipidus, acute intoxication, and chronic renal disease.

Nephrogenic diabetes insipidus (NDI) is the most common renal side effect of lithium therapy. Patients present with polyuria and polydipsia due to a urinary concentrating defect that can lead to significant volume depletion. Experimental studies have shown that the development of NDI involves lithium-induced downregulation of the vasopressin-regulated water channel aquaporin-2, expressed on the apical plasma membrane of principal cells of the collecting duct (2). Acute lithium intoxication due to lithium overdose may be seen in patients on chronic lithium therapy or in lithium-naïve individuals. Acute effects include a change in mental status, acute renal failure, and volume depletion. The primary management of acute lithium intoxication is hemodialysis (1).

The predominant form of chronic renal disease associated with lithium therapy is a chronic tubulointerstitial nephropathy (CTIN) that is heralded by the insidious development of renal insufficiency, with little or no proteinuria, often in the setting of chronic NDI. Biopsy findings in patients with lithium-induced CTIN include tubular atrophy and interstitial fibrosis, typically out of proportion to the degree of glomerulosclerosis or vascular disease (3,4,5,6). The majority of studies have shown infrequent and relatively mild renal insufficiency attributable to lithium therapy (7). Only one case of end-stage renal disease (ESRD) secondary to lithium-associated CTIN has been reported (8).

Much less has been written about the potential glomerular toxicity of lithium. There are many documented cases of minimal change disease occurring in association with lithium therapy (9, 10). Some cases have resolved following lithium withdrawal and recurred after its reintroduction, providing strong evidence of an etiologic relationship (9, 10). Only three cases of focal segmental glomerulosclerosis (FSGS) in patients receiving lithium carbonate have been described (11).

Materials and Methods

All renal biopsies processed from 1986 to 1999 in the Renal Pathology Laboratory at Columbia Presbyterian Medical Center were reviewed for a history of lithium therapy. Twenty-four biopsies from patients treated with lithium were identified from among 6514 native kidney biopsies (0.37%). All cases were processed for light microscopy, immunofluorescence, and electron microscopy according to standard techniques. The tissue available for electron microscopy included glomeruli in 15 cases and tubules in 24 cases. Each case was reviewed independently by two renal pathologists. Tubular atrophy and interstitial fibrosis were graded on a scale of mild, moderate, and severe, corresponding to involvement of 0 to 25, 26 to 50, and >50% of the cortex sampled, respectively. Tubular cysts were defined as tubules with a diameter of at least five times that of normal tubules. Tubular profiles with a diameter 2 to 4 times that of normal tubules were considered to have tubular dilatation, likely representing incipient cysts. The percentages of globally and segmentally sclerotic glomeruli were recorded.

Patient charts were reviewed retrospectively for presenting symptoms, laboratory data at presentation, and follow-up (up to 11 yr). Nephrotic-range proteinuria was defined as a 24-h urine collection of >3.0 g/d. Hypoalbuminemia was defined as serum albumin <3.3 g/dl, and hypercholesterolemia was defined as serum cholesterol >200 mg/dl. Nephrogenic diabetes insipidus was diagnosed based on clinical criteria of polyuria, polydipsia, and consistently low urine-specific gravities (<1.010).

Renal cysts remained in the tissue block from eight of the biopsy samples. To determine the nephron segments forming cysts, these cases were stained with lectins Tetragonolobus purpureas (TP) for proximal tubules, and Arachis hypogaea (AH) for collecting tubules, and with antibody to epithelial membrane antigen (EMA) for distal and collecting tubules, according to standard techniques (12). Briefly, deparaffinized tissue sections were microwave-digested in ethylenediaminetetra-acetic acid (pH 7.4), quenched in 1% H₂O₂ in ethanol, and then overlaid with peroxidase-conjugated lectins TP and AH (Sigma Chemical Co., St. Louis, MO) at 1:6 and 1:100 dilutions for 60 min at room temperature, respectively. Color reactions were developed with diaminobenzidine (DAB). Immunohistochemical staining for EMA (Dako, Carpinteria, CA) was performed at a dilution of 1:50 with microwave digestion, ABC technique, and DAB color reagent.

Results

The clinical presentations, biopsy findings, and outcomes of each patient are listed in Table 1 and summarized in Tables 2,3,4,5. The patient population included 24 patients, with a male-to-female ratio of 1.0 (Table 2). The majority of the patients were Caucasian (87.5%), and all patients had been diagnosed with bipolar disorder. At the time of biopsy, one patient was diabetic and eight were hypertensive. Patients had been treated with lithium in standard doses for a mean of 13.6 yr (range, 2 to 25 yr).

All patients presented with renal insufficiency (Table 3). 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 creatinine of 8.0 mg/dl required emergent hemodialysis and remained dialysis-dependent. Only two patients were known to have previous episodes of acute lithium intoxication (patients 7 and 18). Proteinuria was a common presenting feature: 10 patients (41.7%) had a 24-h protein measurement of >1.0 g/d, and six patients (25%) had nephrotic-range proteinuria. Three of these six patients (patients 1, 2, and 19) met two of the three additional criteria for the diagnosis of nephrotic syndrome (hypoalbuminemia, hypercholesterolemia, and peripheral edema). Hematuria and leukocyturia were present in two and three patients, respectively. Interestingly, ultrastructural analysis revealed underlyign thin basement membrane disease in one of the three patients with hematuria (patient 10). Clinical evidence of NDI was present in 87% of patients.

All 24 renal biopsy samples were believed to be adequate for diagnosis, with a mean glomerular count of 29.3 (range, 4 to >100; median 20). The predominant pathologic finding observed in all 24 of the biopsy samples was CTIN, characterized by tubular atrophy and interstitial fibrosis, out of proportion to the extent of glomerular or vascular disease (Table 4, Figure 1, A and B). Tubular atrophy and interstitial fibrosis were graded as mild in one patient, moderate in nine patients, and severe in 14 patients. In all patients, the degree of tubular atrophy and interstitial fibrosis was either equal to (21.7%) or greater than (78.3%) the degree of arteriosclerosis. Tubulointerstitial disease tended to be patchy, with geographic zonation, particularly in the less advanced cases. Although a sparse predominantly lymphocytic interstitial infiltrate was often confined to areas of interstitial fibrosis, there was no associated tubulitis.

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Figure 1.

(A) Severe lithium-associated chronic tubulointerstitial nephropathy (CTIN) with diffuse interstitial fibrosis and tubular atrophy and relative sparing of glomeruli (patient 5). Trichrome stain, ×40. (B) Another example of severe lithium-associated CTIN with the additional finding of focal tubular cysts arising in a background of severe interstitial fibrosis and tubular atrophy (patient 24). Periodic acid-Schiff (PAS) stain, ×40. (C) High-power view of tubular cysts lined by simple cuboidal epithelium (labeled C). Adjacent tubules show tubular dilatation (labeled d) (patient 24). PAS stain, ×100.

Tubular cysts, a common finding in patients receiving lithium (13), were observed in 62.5% of the renal biopsies (Figure 1C). Cysts were most frequently identified in the zones of tubular atrophy and interstitial fibrosis, both in the cortex and the medulla. They tended to be sparse and did not exceed 1 to 2 mm in diameter. A pericystic cuff of fibrosis was sometimes present, with associated thickening of the cystic tubular basement membrane. The cystic epithelial cells displayed cytologic features of distal or collecting tubular epithelium, consisting of cuboidal cells with relatively clear cytoplasm and no identifiable brush border. The cytoplasmic ballooning and periodic acid-Schiff-positive granules described by Burrows et al. (14) were rarely observed. Mild epithelial hyperplasia of the cyst lining cells was identified rarely. Dilated tubules displayed similar cytologic features but usually lacked the pericystic fibrous cuff (Figure 1C).

Immunohistochemical staining for segment-specific markers including EMA and lectin staining for TP and AH were performed on the eight biopsies in which cystic tissue remained in the paraffin block (Table 5, Figure 2). Two cases were open renal biopsies with abundant cystic tissue (patients 14 and 24), while the other six cases displayed up to three tubular cysts. A total of 105 cysts was identified and all stained positively with EMA. In contrast, 51.4% stained with AH and 3.8% stained with TP. In some cysts, the lectin markers gave discontinuous staining, with skip areas (Figure 2D). Thus, approximately half of the tubular cysts stained positively for EMA and negatively for AH, and the other half stained positively for both EMA and AH. These staining patterns correspond to distal tubule and collecting duct origin, respectively. In contrast, tubular atrophy affected all three nephron segments.

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Figure 2.

Panel of lectin and immunohistochemical staining of tubular cysts. Two cysts from patient 21 (A, hematoxylin and eosin) stained negatively for Tetragonolobus purpureas (TP) (B), positively in one of two cysts with Arachis hypogaea (AH) (C), and positively in both cysts for epithelial membrane antigen (EMA) (D). Staining for EMA is discontinuous with segmental skip areas along the cyst circumference (D). A representative field from patient 24 contains multiple cysts that stain negatively for TP (E), focally positive for AH (arrow in F), and diffusely positive for EMA (G). Magnification: ×100 in A through D; ×40 in E through G.

Ultrastructural evaluation of cystic and noncystic distal tubular epithelia revealed widespread alterations in tubular epithelial fine structure, predominantly affecting distal and collecting tubules. Major alterations included loss or simplification of apical microvilli, apical blebbing, dilation of the endoplasmic reticulum producing numerous electron lucent vacuoles, increased number of phagolysosomes, decreased organellar content, and a paucity of cytoplasmic organelles in the perinuclear region, producing perinuclear clearing (Figure 3, A and B). Mitochondria often appeared swollen with rare proximal tubular giant mitochondria. Nuclei were typically displaced apically. There was disorganization of the basolateral infoldings of plasma membrane, at times extending up to the apical tight junctions. The basal width of epithelial cells was often irregular, with focal undermining of epithelial attachments to the tubular basement membrane by cytoplasmic extensions from neighboring cells (Figure 3C). There was focal apoptosis of individual cyst lining cells (Figure 3D). Multilayering of tubular epithelia was observed rarely. The tubular basement membrane displayed foci of irregular lamellation with hyaline insudation and focal detachment of tubular epithelial cells with neomembrane formation (Figure 3C).

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Figure 3.

(A) A cystic tubule shows complete loss of apical brush border, focal dilatation of endoplasmic reticulum, and reduced number of organelles, especially in the perinuclear region. (B) High-power view of a collecting tubular epithelial cell shows apical displacement of the nucleus with complete loss of apical differentiation and prominent perinuclear clearing. (C) A distal nephron segment displays diffuse dilatation of endoplasmic reticulum and overlapping cellular interdigitations along the basal and apical aspects. The tubular basement membrane is irregularly lamellated. (D) A distal nephron segment with a single cell demonstrating nuclear condensation and probable early apoptosis (arrow). The adjacent cells have prominent apical nuclei and complete loss of surface differentiation. Magnification: ×2500 in A and D; ×8000 in B; and ×3000 in C.

Each biopsy was carefully examined for the presence of glomerular disease. Global glomerulosclerosis was observed in all biopsies and was common in zones of chronic tubulointerstitial damage. The mean percentage of glomeruli that were globally sclerotic was 57.5% (range, 20 to 90%; median 63.9%). In 12 of the 24 biopsies (50%), lesions of FSGS were identified (Table 4, Figure 4, A and B). Within these 12 biopsies, lesions of FSGS were seen on average in 11.5% of glomeruli (range, 5.6 to 20%; median 10.1%). These lesions were typically characterized by loss of patency of the glomerular capillary lumen, increased matrix material, hyaline insudation, occasional endocapillary foam cells, adhesions to Bowman's capsule, and, in some cases, mild hypertrophy and hyperplasia of overlying visceral epithelial cells. Glomerulomegaly was identified in the majority of cases (77.3%). No biopsy displayed evidence of proliferative glomerulonephritis. Immunofluorescence was negative except for focal nonspecific glomerular and vascular positivity for IgM and C3 in areas of glomerulosclerosis and arteriosclerosis. In the 15 cases in which glomerular tissue was available for ultrastructural analysis, no electron-dense deposits were seen. The degree of foot process fusion ranged from 0 to 90% (mean 34%), with >50% effacement in five of 14 cases (35.7%) (Figure 4C). Podocyte microvillous transformation was commonly seen in cases with >50% foot process effacement.

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Figure 4.

(A) A typical example of focal segmental glomerulosclerosis (FSGS) shows a discrete lesion of sclerosis with focal hyalinosis and adhesion to Bowman's capsule (patient 21). PAS stain, ×250. (B) A glomerulus from the native kidney biopsy of patient 14, who developed recurrent FSGS in the allograft, contains a typical lesion of segmental sclerosis with mild podocyte hypertrophy. PAS stain, ×250. (C) Ultrastructural evaluation of a nonsclerotic glomerulus from patient 12 reveals extensive foot process fusion and focal microvillous transformation of the podocytes. Magnification: ×2500.

Three biopsies were accorded a second diagnosis in addition to lithium-associated CTIN. Patient 10 had a history of microhematuria and had diffuse thinning of the glomerular basement membrane (mean 175 nm), consistent with thin basement membrane disease. Patient 3 had clinical evidence of pyelonephritis, and a renal biopsy displayed an acute polymorphonuclear and granulomatous interstitial nephritis superimposed on a chronic tubulointerstitial nephropathy. An intriguing case was patient 14, who presented with subnephrotic proteinuria and a serum creatinine of 3.8 mg/dl. An open renal biopsy displayed severe tubular atrophy and interstitial fibrosis, many tubular cysts, and multiple glomeruli with lesions of FSGS. The findings were believed to be typical of lithium-associated CTIN. The patient had a past history of attempted suicide when lithium was temporarily withdrawn and, as a result, discontinuation of lithium was not possible. Two months after the biopsy, the patient became fully nephrotic and 5 mo later he progressed to ESRD and was placed on hemodialysis. The patient subsequently received a renal transplant, and his posttransplant course was complicated by the development of severe nephrotic syndrome at 2 mo posttransplant due to biopsy-documented recurrence of FSGS. Throughout this time, the patient continued to receive lithium, suggesting the possibility of recurrent lithium-induced FSGS, although primary FSGS could not be excluded.

Clinical follow-up was available in 19 of the 24 cases (Table 6, Figure 5). The mean follow-up time was 30.6 mo, with a maximum of 11 yr. In all but one patient, lithium was discontinued either before or immediately after the renal biopsy. One patient committed suicide after discontinuation of lithium. Despite lithium withdrawal, eight of the 19 patients progressed to ESRD (42.1%). By Cox regression analysis, the only significant predictor of progression to ESRD was initial serum creatinine at the time of biopsy (P = 0.060). Among the 10 patients with an initial serum creatinine <2.5 mg/dl, only one progressed to ESRD and that occurred 11 yr later. Furthermore, three of the 10 patients experienced a decline in their serum creatinine of ≥0.5 mg/dl. In contrast, seven of the nine patients with an initial serum creatinine of >2.5 mg/dl went on to require hemodialysis, and an additional patient had a rise in serum creatinine from 3.1 to 4.8 mg/dl over a 22-mo period of follow-up (Figure 5). By Kaplan-Meier survival estimates, a serum creatinine of >2.5 mg/dl at the time of biopsy was a significant predictor of progression to ESRD (P = 0.008) (Figure 6), while the presence of FSGS on renal biopsy was not predictive of progression (P = 0.14) (data not shown).

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Figure 5.

Course of renal disease in patients with lithium nephrotoxicity. Changes in serum creatinine from the time of biopsy are displayed. Solid lines indicate patients with evidence of FSGS, and dashed lines represent patients without FSGS.

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Figure 6.

Kaplan-Meier survival curve in patients dichotomized for initial serum creatinine more than or less than 2.5 mg/dl. Serum creatinine >2.5 mg/dl at the time of biopsy is a significant predictor of progression to end-stage renal disease (P = 0.008).

Discussion

Many clinical and pathologic studies have examined the scope of lithium-associated CTIN. The first major analysis that included pathologic correlation was published in 1977 and described 14 patients who presented with either acute intoxication or NDI (3). Although the indication for biopsy was not chronic renal insufficiency, the main pathologic findings were tubular atrophy and interstitial fibrosis (3). Subsequently, 69 patients receiving lithium therapy for >2 yr were examined; 18 patients (26.1%) developed a renal concentrating defect and eight patients (11.6%)—all of whom were treated with lithium for at least 4.5 yr (mean 9.3 yr)—developed an increase in serum creatinine of >0.3 mg/dl during the course of treatment (13). Another study followed 57 patients receiving lithium and found that five individuals (8.8%), all of whom had been treated for >8 yr, went on to develop a “moderately decreased” GFR during the course of therapy (4). This study provides limited data on the 24 subjects who underwent renal biopsy, but the major findings were focal interstitial fibrosis and global glomerulosclerosis (4). A retrospective study of 142 patients receiving lithium for >15 yr found a reduction of the GFR in 21% of patients (15). A separate study examined 46 renal biopsies performed on patients receiving lithium for a mean of 8 yr and found significantly greater tubular atrophy, interstitial fibrosis, and glomerulosclerosis than in biopsies from age-matched control subjects not treated with lithium (primarily patients with proteinuria and “normal” renal biopsies) (5). A prospective study of 65 patients receiving lithium showed a significant decline in creatinine clearance as early as 1 yr after initiation of therapy in the 26 male subjects only (16). A review of lithium nephrotoxicity included data from 14 separate studies and found that 85% of lithium-treated patients have a normal GFR and that the remaining 15% have only mild reductions in renal function (7).

A major point of contention has been whether lithium therapy can lead to marked reductions in renal function or ESRD. Aurell et al. examined renal biopsies in six patients with established renal insufficiency who had been treated with lithium for 4 to 13 yr and found tubular atrophy, interstitial fibrosis, sclerotic glomeruli, and tubular microcysts (6). Unlike many of the previous reports, some of the patients in this study had marked degrees of renal insufficiency. Of note, one patient presented with a GFR of 13 cc/min, which improved to 25 cc/min 3 yr after discontinuation of therapy (6). A single case of lithium-associated CTIN leading to ESRD has been reported in the literature (8).

Our retrospective, biopsy-based study is not a cross-sectional analysis and therefore cannot address the prevalence of lithium nephrotoxicity among lithium-treated patients. The biopsy prevalence of lithium nephrotoxicity is low, representing 0.37% of all native renal biopsy diagnoses in the 14-yr period of 1986-1999. All 24 patients presented with renal insufficiency and many also had significant proteinuria. Indications for renal biopsy were not standardized. In general, referring nephrologists stated that they follow multiple patients on lithium and biopsy those individuals manifesting an “atypical course” or “significant” degrees of renal insufficiency or proteinuria. Two open biopsies (patients 14 and 24) were obtained at the time of nephrectomy for oncocytoma and papillary renal cell carcinoma, respectively.

Lithium-associated CTIN is characterized by tubular atrophy and interstitial fibrosis, typically out of proportion to the extent of glomerular or vascular disease. In our 24 cases, a detailed clinical history, light microscopy, immunofluorescence, and electron microscopy were available for review. In each case, the possibility of a separate etiology for the renal abnormalities, such as glomerulonephritis or hypertensive arterionephrosclerosis, was excluded. Three patients received a second diagnosis, including thin basement membrane disease, interstitial nephritis, and possible primary focal segmental glomerulosclerosis (recurrent in transplant). The association of renal neoplasms in two of the cases, both in the setting of chronic lithium nephrotoxicity with multifocal cysts, raises the question of a possible increased risk of renal neoplasia in this population, as may occur in other cystic diseases. However, an increased risk of renal neoplasms has not been reported in larger cross-sectional studies.

Although CTIN represents a somewhat nonspecific pattern of disease, the presence of tubular cysts is highly characteristic of lithium toxicity, having been reported in up to 40% of cases (13). New Zealand white rabbits treated with lithium develop a pattern of CTIN with tubular cysts that is virtually identical to the human disease, with progressive renal insufficiency (17). Male Wistar rats treated with lithium develop nephrogenic diabetes insipidus and a distal tubulopathy marked by tubular dilatation (18). We were able to find tubular cysts in 62.5% of biopsies and lesser degrees of tubular dilatation in an additional 33.3% of biopsies. Previous studies have not always documented this important and relatively specific finding (4). Of note, some studies have attempted to deny the existence of lithium-associated CTIN by describing similar pathologic findings in patients with affective disorders who have not received lithium (19, 20). Yet the one pathologic finding that was seen only in the lithium-treated group is tubular cysts (20), underscoring the specificity of this morphologic finding.

The potential glomerular toxicity of lithium therapy has been underappreciated. Although lesions of FSGS have been described in only three patients on lithium therapy (11), we identified lesions of FSGS in 50% of the 24 biopsies on lithium therapy. There was a strong correlation between the finding of FSGS and the presence of proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). A potential explanation is that the patients with higher initial serum creatinine levels had lost a significant proportion of their renal parenchyma, causing hyperfiltration in remnant nephrons and development of secondary FSGS. The high prevalence of glomerulomegaly (77.3%), a relatively constant feature of the secondary FSGS mediated by structural-functional adaptations to loss of functioning nephrons, favors this possibility (21). Nonetheless, a few lines of evidence argue against this hypothesis. First, there was no correlation between the degree of renal insufficiency and either the 24-h urine protein or the presence of FSGS. Second, the presence of FSGS did not correlate with the severity of tubular atrophy and interstitial fibrosis. Finally, there was a high incidence (35.7%) of >50% foot process effacement, an uncommon finding in secondary FSGS mediated by hyperfiltration injury (22). Therefore, an alternative hypothesis must be considered. Although some cases of FSGS in the setting of lithium-associated CTIN may occur secondary to the tubulointerstitial changes, others may reflect a direct glomerular (i.e., podocyte) toxicity. This would not be altogether surprising in light of the well-established occurrence of lithium-associated minimal change disease (9,10). Although the high degree of proteinuria in our study reflects in part the indications for biopsy, this potential manifestation of lithium nephrotoxicity has not been recognized previously. A report of 44 biopsies in patients with lithium-associated renal disease in which the mean proteinuria was 250 mg/d described no case of proteinuria exceeding 1000 mg/d (20). The presence of significant foot process fusion in some cases and the recurrence of FSGS in the single transplant patient in whom lithium was not withdrawn lend further support to the hypothesis of potential direct glomerular toxicity.

An important new finding in our cohort of patients is that lithium-associated CTIN can lead to profound renal insufficiency and even ESRD despite discontinuation of therapy. Seven of the 18 patients in whom follow-up was available went on to develop ESRD, and one patient presented with ESRD and a serum creatinine of 8.0 mg/dl. The only reliable predictor of progression to ESRD was the serum creatinine at the time of biopsy (P = 0.060, Cox regression analysis). Eight of nine patients with an initial serum creatinine of >2.5 mg/dl had progression of disease as opposed to one of 10 patients with a serum creatinine <2.5 mg/dl (P = 0.008, Kaplan-Meier survival estimates). One should not infer from these data that a serum creatinine <2.5 mg/dl is necessarily safe because some of the patients had discontinued lithium at some time before biopsy, when they had even lower serum creatinine levels. The development of ESRD in patient 12 who received lithium for only 2 yr and discontinued lithium 10 yr before biopsy exemplifies this point.

Immunohistochemical and lectin staining revealed tubular cysts of predominantly distal tubular (EMA +/AH -) and collecting duct (EMA +/AH +) origin. Although these findings had been predicted based on the predominantly distal nephron toxicity of lithium, ours is the first documentation of the anatomic sites of cystogenesis. The rare cysts expressing lectin TP, in addition to EMA and AH, may represent proximal propagation of cysts from more distal portions of the nephron.

In conclusion, our biopsy-based study in a selected population of lithium-treated patients is not inconsistent with the consensus opinion that only a minority of patients receiving lithium will develop mild renal insufficiency due to lithium-associated CTIN. Furthermore, the importance of lithium for patients with affective disorders is underscored by the fact that one patient (patient 2) who discontinued lithium subsequently committed suicide. However, our data indicate for the first time that a minority of patients receiving lithium will develop significant renal insufficiency with characteristic renal biopsy findings of CTIN and distal/collecting tubular cysts, and that these patients are at risk for progression to ESRD despite prompt withdrawal of lithium. The only predictor of progression to ESRD is the initial serum creatinine. These findings emphasize the need for physician vigilance and regular periodic measurements of renal function for early detection of lithium-induced CTIN. Serum creatinine levels in the range of 2.0 mg/dl, generally considered to represent only “mild” degrees of renal insufficiency among non-nephrologists, may represent a level of inexorably progressive renal injury. Finally, our new finding of a high prevalence of FSGS and nephrotic proteinuria in this biopsy population, independent of the level of renal insufficiency, suggests a potential direct glomerular toxicity.