HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Farres, M. T. Articles by Le Blanche, A. F. Search for Related Content PubMed PubMed Citation Articles by Farres, M. T. Articles by Le Blanche, A. F.

Chronic Lithium Nephropathy: MR Imaging for Diagnosis¹

¹ From the Departments of Radiology (M.T.F., A.K., A.F.L.B.) and Nephrology (D.S., F.V.), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 4 rue de la Chine, 75020 Paris, France; Department of Nephrology, Université Pierre et Marie Curie, Paris, France (P. Ronco); and Department of Nephrology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, France (P. Remy). Received June 21, 2002; revision requested August 21; final revision received June 4, 2003; accepted June 9. Address correspondence to M.T.F. (e-mail: bedouet.p@wanadoo.fr).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the appearance of lithium nephropathy at magnetic resonance (MR) imaging.

MATERIALS AND METHODS: Sixteen patients with renal insufficiency and clinical and laboratory evidence of nephropathy secondary to therapy with lithium salts were examined with a 1.5-T MR imaging unit with T1-weighted, T2-weighted fast imaging with steady-state precession (true FISP), rapid acquisition with relaxation enhancement, half-Fourier turbo spin-echo, and gadolinium-enhanced (FISP three-dimensional MR angiographic) sequences. Renal size and the presence, number, location and size of parenchymal cysts were analyzed. The cysts in each kidney were defined as rare (fewer than 10 cysts), sparse (between 10 and 30 cysts), abundant (30–60 cysts), or very abundant (more than 60 cysts).

RESULTS: The mean length of both kidneys was 104 mm ± 9 in seven cases, and one or both kidneys were less than 90 mm in length in nine cases. Renal microcysts measuring from 1 to 2 mm were detected in all patients. They were either very abundant (n = 12), abundant (n = 2), or sparse (n = 2). The cysts were located with equal abundance in both the cortex and the medulla in 11 cases and were predominantly located in the renal cortex in five cases. No renal artery stenosis was present.

CONCLUSION: Microcysts secondary to long-term lithium therapy can be detected with MR imaging.

© RSNA, 2003

Index terms: Diabetes insipidus, 81.699 • Kidney, cysts, 81.3119 • Kidney, effects of drugs on, 81.64 • Kidney, MR, 81.12141, 81.12142

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Lithium salts are a well-established treatment for affective disorders. In patients undergoing long-term treatment with lithium salts, the development of nephrotoxicity in the form of nephrogenic diabetes insipidus is not unusual, and, in some cases, chronic renal insufficiency may also occur. Nephrotoxicity is caused by lithium salt–induced damage directly to renal tubuli. Results of a renal biopsy sample will confirm the diagnosis by revealing chronic interstitial nephritis with associated tubular atrophy, cortical and medullary fibrosis, sclerotic glomeruli and tubular dilatation, and cyst formation (1,2). Until now, imaging features have not been described for the diagnosis of these disorders. The purpose of our study was to evaluate the appearance of lithium nephropathy at magnetic resonance (MR) imaging.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Sixteen consecutive patients with affective disorders who were undergoing lithium therapy and who had moderate to severe chronic renal insufficiency were evaluated. There were eight men and eight women who ranged in age from 49 to 79 years (mean, 63.8 years) and who were examined according to the protocol of Hôpital Tenon. Images and medical charts were retrospectively reviewed. The institutional review board did not require its approval or patient informed consent. No patient had a family history of cystic kidney disease. Nephrogenic diabetes insipidus was diagnosed on the basis of clinical criteria—namely, polyuria, polydipsia, and consistently low urine-specific gravities. Serum creatinine level, creatinine clearance, presence of proteinuria or hypertension, and demographic data were recorded by one of four authors (D.S., F.V., P. Ronco, P. Remy). A renal biopsy was considered necessary in only one of the 16 patients.

MR Imaging and Image Evaluation
All patients underwent MR imaging. MR imaging was performed with a 1.5-T MR imaging unit (Vision; Siemens Medical Systems, Erlangen, Germany) with 25 mT/m maximum gradient strength and a 600-µsec rise time by using a surface body coil. Patients’ arms were positioned over their heads. A 22-gauge intravenous catheter was positioned in an antecubital vein and connected to a power injector (MR Spectris; Medrad, Philadelphia, Pa). We performed transverse and coronal breath-hold T1-weighted gradient-echo sequences (fl2D; repetition time msec/echo time msec, 174/4; flip angle, 80°; matrix, 129 x 256; effective section thickness, 6 mm; acquisition time, 22 seconds), transverse and coronal T2-weighted gradient-echo sequences (TrueFISP [fast imaging with steady-state precession] by Siemens Medical Systems; 6.3/3.0; flip angle, 70°; matrix, 256 x 256; effective section thickness, 6 mm; acquisition time, 17 seconds), transverse and coronal rapid half-Fourier single-shot turbo spin-echo sequences (10/87; flip angle, 180°; matrix, 240 x 256; section thickness, 5 mm; field of view, depending on body habitus; acquisition time, 23 seconds), and coronal rapid acquisition with relaxation enhancement (RARE) sequences (2,800/1,100; flip angle, 150°; matrix, 240 x 256; section thickness, 20 mm; field of view, 250 x 250; acquisition time, 7 seconds).

For MR angiography of the renal arteries and to evaluate parenchymal enhancement in the coronal plane, three-dimensional (3D) T1-weighted fat-saturated FISP sequences (5/2; flip angle, 40°; effective section thickness, 2.2–2.6 mm; field of view, 30–32 x 32–35 cm; matrix, 112 x 256; acquisition time, between 22 and 26 seconds) were performed after injection of 15 mL of gadoterate meglumine (Dotarem; Laboratoire Guerbet, Aulnay-sous-Bois, France) at a rate of 2 mL/sec with the power injector and followed by a 25-mL saline flush.

The images were evaluated in consensus by one radiologist (M.T.F) and one nephrologist (P. Ronco). The size of the kidney (craniocaudal maximal diameter), the parenchymal thickness, and the presence and size of parenchymal cysts were noted. Renal size was considered normal when the kidney length was 104 mm ± 9. Parenchymal thickness was considered normal if it was greater than 10 mm. We recorded cysts measuring from 1 to 2 mm in diameter, and their location in the renal parenchyma was defined as follows: medullary, cortical, in both locations at a similar frequency, more abundant in the medulla than in the cortex, or more abundant in the cortex than in the medulla.

The cysts in each kidney were counted and categorized as rare (fewer than 10 cysts), sparse (between 10 and 30 cysts), abundant (30–60 cysts), or very abundant (more than 60 cysts). The number of cysts measuring 3 mm or greater was specified for each kidney. The size of these larger cysts was measured by using the measurement software of the MR imaging unit.

The renal arteries were evaluated and projected in a 3D reconstruction in maximum intensity projection and were classified as normal or stenotic. Conventional angiography reports were used to classify arteries with a reduction in diameter of 50% or greater as stenosed.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The demographic data and laboratory parameters are summarized in the Table.

Microcysts measuring between 1 and 2 mm in diameter were detected in all patients on MR images acquired with the half-Fourier sequences. On T1-weighted MR images, the microcysts were hypointense and could not be differentiated from the remaining parenchyma (Fig 1a). On T2-weighted MR images, the cysts typically appeared as hyperintense regions (Fig 1b). Small cysts could be better identified on images obtained with the half-Fourier single-shot turbo spin-echo and RARE sequences (Figs 1c, 2, 3). After intravenous administration of the contrast agent, very small microcysts could be only partially seen, with the more voluminous cysts appearing as nonenhanced areas while the rest of the parenchyma showed normal enhancement (Fig 1d).

View larger version (116K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. MR images in a 57-year-old man. (a) Coronal T1-weighted gradient-echo MR image (174.9/4.1; flip angle, 80°) shows normal-sized kidneys with several hypointense round structures (arrows) in the lower poles. The rest of the renal parenchyma is homogeneous. (b) Coronal T2-weighted breath-hold TrueFISP MR image (6.3/3.0; flip angle, 70°) shows very abundant, round, hyperintense renal microcysts of just a few millimeters in size in the cortex and medulla. (c) Coronal RARE MR image (2,800/1,100; flip angle, 150°) obtained in a single shot of 20 mm shows a multitude of microcysts measuring from 1 to 2 mm distributed in all areas of the renal parenchyma. (d) Coronal 3D FISP MR image (5.0/2.0; flip angle, 40°). After enhancement of the renal parenchyma with contrast material, the renal microcysts appear as nonenhanced hypointense areas.

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. MR images in a 57-year-old man. (a) Coronal T1-weighted gradient-echo MR image (174.9/4.1; flip angle, 80°) shows normal-sized kidneys with several hypointense round structures (arrows) in the lower poles. The rest of the renal parenchyma is homogeneous. (b) Coronal T2-weighted breath-hold TrueFISP MR image (6.3/3.0; flip angle, 70°) shows very abundant, round, hyperintense renal microcysts of just a few millimeters in size in the cortex and medulla. (c) Coronal RARE MR image (2,800/1,100; flip angle, 150°) obtained in a single shot of 20 mm shows a multitude of microcysts measuring from 1 to 2 mm distributed in all areas of the renal parenchyma. (d) Coronal 3D FISP MR image (5.0/2.0; flip angle, 40°). After enhancement of the renal parenchyma with contrast material, the renal microcysts appear as nonenhanced hypointense areas.

View larger version (101K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. MR images in a 57-year-old man. (a) Coronal T1-weighted gradient-echo MR image (174.9/4.1; flip angle, 80°) shows normal-sized kidneys with several hypointense round structures (arrows) in the lower poles. The rest of the renal parenchyma is homogeneous. (b) Coronal T2-weighted breath-hold TrueFISP MR image (6.3/3.0; flip angle, 70°) shows very abundant, round, hyperintense renal microcysts of just a few millimeters in size in the cortex and medulla. (c) Coronal RARE MR image (2,800/1,100; flip angle, 150°) obtained in a single shot of 20 mm shows a multitude of microcysts measuring from 1 to 2 mm distributed in all areas of the renal parenchyma. (d) Coronal 3D FISP MR image (5.0/2.0; flip angle, 40°). After enhancement of the renal parenchyma with contrast material, the renal microcysts appear as nonenhanced hypointense areas.

View larger version (100K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. MR images in a 57-year-old man. (a) Coronal T1-weighted gradient-echo MR image (174.9/4.1; flip angle, 80°) shows normal-sized kidneys with several hypointense round structures (arrows) in the lower poles. The rest of the renal parenchyma is homogeneous. (b) Coronal T2-weighted breath-hold TrueFISP MR image (6.3/3.0; flip angle, 70°) shows very abundant, round, hyperintense renal microcysts of just a few millimeters in size in the cortex and medulla. (c) Coronal RARE MR image (2,800/1,100; flip angle, 150°) obtained in a single shot of 20 mm shows a multitude of microcysts measuring from 1 to 2 mm distributed in all areas of the renal parenchyma. (d) Coronal 3D FISP MR image (5.0/2.0; flip angle, 40°). After enhancement of the renal parenchyma with contrast material, the renal microcysts appear as nonenhanced hypointense areas.

View larger version (106K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Coronal half-Fourier single-shot turbo spin-echo MR image (10.9/87; flip angle, 180°) in a 73-year-old woman shows the predominance of the high-signal-intensity microcysts in the cortical regions.

View larger version (112K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Coronal half-Fourier single-shot turbo spin-echo MR image (10.9/87; flip angle, 180°) in a 68-year-old man shows very abundant microcysts in the cortical and medullary regions.

In all 14 patients in whom MR angiography could be performed, all renal arteries were of normal diameter.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Lithium nephrotoxicity can be divided into three main categories: acute intoxication, nephrogenic diabetes insipidus, and chronic renal disease. Polyuria-polydipsia syndrome (nephrogenic diabetes insipidus) occurs in about 40% of patients and is usually harmless and reversible (1–3). Patients undergoing long-term maintenance therapy may develop chronic focal interstitial nephritis. In these cases, a progressive nonreversible defect in urinary concentrating ability arises, and chronic renal insufficiency may appear (1,3). Clinical and laboratory findings are often sufficient for the diagnosis of nephropathy secondary to lithium therapy.

However, in situations where it is not obvious that lithium therapy is responsible, if the clinical course is atypical, or when a substantial degree of renal insufficiency or proteinuria is present, a renal biopsy may be required to confirm the diagnosis (2). Renal biopsy findings show chronic interstitial nephritis and may unveil abnormalities such as tubular atrophy, cortical and medullary fibrosis, sclerotic glomeruli, tubular dilatation, and cyst formation (1). Chronic focal tubulointerstitial changes are not specific.

The findings that distinguish patients treated with lithium from those with other disorders are distal tubular dilatation and microcysts (2,3,4). These cysts are present in 33%–62% of patients undergoing lithium therapy (2). They originate from distal and collecting tubules and probably stem from the proliferation of distal tubular cells. They are localized in both the cortex and the medulla. In general, they do not exceed 1–2 mm in diameter. However, the number of renal microcysts present in lithium nephropathy has yet to be clearly defined. In the literature concerning renal biopsies, the cysts are reported to be sparse. Markowitz et al (2) found one to three cysts in six percutaneous biopsy specimens. Notwithstanding, a large number of cysts (10 and 80 cysts) have been described in two cases investigated with open biopsy (2).

MR imaging is highly capable of helping define renal morphologic features (5) and has been demonstrated to be superior to ultrasonography and computed tomography for the visualization of small renal cysts (6). T2-weighted MR imaging sequences are the most appropriate for detecting the presence of fluid-filled cavities. Short-breath-hold strongly T2-weighted sequences such as half-Fourier single-shot turbo spin-echo and RARE have been proved to be very useful because they depict structures containing static fluids, thus making it possible to perform cholangiography and urography (7,8). The half-Fourier single-shot turbo spin-echo sequence depicts fluids as hyperintense (white) regions against a hypointense (dark) background. This specificity makes this sequence very sensitive for detecting small (1–2-mm) renal cysts. MR imaging has an additional advantage over renal biopsy in that MR imaging enables the evaluation of the entire renal parenchyma and thus yields global information on the number and distribution of cysts in the cortex and in the medulla.

Our study results have shown that most of our patients, who had been undergoing long-term lithium therapy and had developed nephrogenic diabetes insipidus, had normal-sized kidneys with very abundant, uniformly and symmetrically distributed renal microcysts; this MR imaging pattern is very characteristic of lithium nephropathy and may aid in diagnosis. When the microcysts are sparse, or if they are abundant or sparse but are predominantly located in the cortex, MR imaging is less specific, but in a context of long-standing lithium therapy and moderate renal insufficiency, diagnosis of lithium nephropathy can be strongly supported by MR imaging findings. In our opinion, the MR imaging pattern is sufficient to confirm the clinical diagnosis and eliminate the need for biopsy. Simple renal cysts are present in the healthy population, being more frequent in men than in women and increasing in number and diameter with age. However, for the age group of 45–59 years in the healthy population, the average number of simple cysts detected at MR imaging is only 1.9 (2.5 for men and 1.2 for women) (6).

Adult cystic kidney diseases encompass a wide spectrum of congenital or acquired abnormalities. They can be differentiated according to the patient’s age at presentation, the location of the cysts, the appearance of the cysts, and the degree of renal functional impairment.

The differential diagnosis for renal cysts that are thought to be secondary to lithium nephrotoxicity should include other cystic diseases. Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder. The criterion for the diagnosis of ADPKD in patients older than 60 years is the presence of more than four cysts in both kidneys (9). At MR imaging, the presence of six or more cysts in women and nine or more cysts in men can be considered as diagnostic of ADPKD (6). In ADPKD, but not in lithium nephrotoxicity, the kidneys are usually enlarged and the renal cysts are variable in size and signal intensity, and, in 70%–75% of patients, the renal cysts are associated with liver cysts (9). In all our patients, the kidneys were normal or slightly diminished in size and the majority of the renal cysts were homogeneous in size (1–2 mm) and signal intensity.

Glomerulocystic kidney disease is a rare condition with sporadic or familial occurrence that is characterized by the presence of small parenchymal cysts and is sometimes associated with renal insufficiency. Patients are usually children or young adults. The cysts are due to cystic dilatation of the Bowman space and initial convoluted tubule and are therefore exclusively located in the renal cortex (10). MR imaging depicts high signal intensity in the renal cortex on T2-weighted images and a normal medulla (11).

Medullary cystic kidney disease is a hereditary disease characterized by chronic renal failure, the presence of cysts in the medulla and corticomedullary junction, and a thinned cortex (12). The location of the cysts is the main feature allowing this entity to be distinguished from lithium nephrotoxicity because in the latter, cystic lesions are mainly located in the cortex or in the cortex and the medulla.

Acquired cystic kidney disease results from the development of renal cysts in patients who have advanced chronic renal failure or who are undergoing dialysis. The kidneys are small, and the cysts range in size from microscopic to several centimeters in diameter and affect both the renal cortex and the medulla (13). Although the patients in our study had moderately elevated serum creatinine levels, none experienced end-stage renal failure and none were undergoing dialysis. The differentiation of lithium nephrotoxicity from acquired cystic kidney disease is based on the uniformity in size and the distribution of cysts in the former.

In summary, we described the typical renal morphologic features at MR imaging in patients with lithium nephropathy. This study was limited by the fact that not all patients underwent renal biopsy. Nevertheless, in patients with chronic renal insufficiency and a history of long-term lithium therapy, MR imaging is a noninvasive, accurate diagnostic modality that is able to reveal the presence of characteristic parenchymal microcysts and allow confirmation of the clinical diagnosis of chronic lithium nephropathy.

	ACKNOWLEDGMENTS

 
We thank Christine Vial, BS, and Lorna St. Ange, MA, for help editing the manuscript.

	FOOTNOTES

 
Abbreviations: ADPKD = autosomal dominant polycystic kidney disease, FISP = fast imaging with steady-state precession, RARE = rapid acquisition with relaxation enhancement, 3D = three-dimensional

Author contributions: Guarantors of integrity of entire study, M.T.F., P. Ronco; study concepts, M.T.F.; study design, M.T.F., P. Ronco; literature research, M.T.F.; clinical studies, D.S., F.V., P. Ronco, P. Remy; data acquisition, A.K., D.S., F.V., M.T.F., P. Ronco, P. Remy; data analysis/interpretation, M.T.F., P. Ronco; manuscript preparation, definition of intellectual content, and editing, M.T.F., P. Ronco; manuscript revision/review, A.F.L.B., P. Ronco; manuscript final version approval, M.T.F.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987; 5:329-345.
2. Markovitz GS, Radhakrishnan J, Kammbham N, Valeri AM, Hines WH, D’Agati VD. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000; 11:1439-1448.[Abstract/Free Full Text]
3. Walker RG. Lithium nephrotoxicity. Kidney Int Suppl 1993; 42:S93-S98.[Medline]
4. Aurell M, Svalander C, Wallin L, Alling C. Renal function and biopsy findings in patients on long-term lithium treatment. Kidney Int 1981; 20:663-670.[Medline]
5. Krestin GP. Genitourinary MR: kidneys and adrenal glands. Eur Radiol 1999; 9:1705-1714.[CrossRef][Medline]
6. Nascimento AB, Mitchell DG, Zhang X, Kamishima T, Parker L, Holland GA. Rapid MR imaging detection of renal cysts: age-based standards. Radiology 2001; 221:628-632.[Abstract/Free Full Text]
7. Balci NC, Mueller-Lisse UG, Holzknecht N, Gauger J, Waidelich R, Reiser M. Breathhold MR urography: comparison between HASTE and RARE in healthy volunteers. Eur Radiol 1998; 8:925-932.[CrossRef][Medline]
8. Regan F, Cavaluzzi J, Nguyen B. Fast MR abdominal imaging using the HASTE sequence. AJR Am J Roentgenol 1998; 170:1471-1476.[Free Full Text]
9. Choyke PL. Inherited cystic diseases of the kidney. Radiol Clin North Am 1996; 34:925-946.[Medline]
10. Bernstein J. Glomerulocystic kidney disease: nosological considerations. Pediatr Nephrol 1993; 4:464-470.
11. Egashira K, Nakata H, Hashimoto O, Kaizu K. MR imaging of adult glomerulocystic kidney disease. Acta Radiol 1991; 32:251-253.[Medline]
12. Levine E, Hartman DS, Meilstrup JW, Van Slyke MA, Edgar KA, Barth JC. Current concepts and controversies in imaging of renal cystic diseases. Urol Clin North Am 1997; 24:523-543.[CrossRef][Medline]
13. Levine E. Acquired cystic kidney disease. Radiol Clin North Am 1996; 34:947-964.[Medline]

This article has been cited by other articles:

				A. Vanacker, J. Van Dorpe, and B. Maes Cystic kidney disease in a patient with long-term lithium therapy NDT Plus, April 1, 2009; 2(2): 179 - 180. [Full Text] [PDF]

				M. Meier, A. Beigel, L. Schiffer, J. Lotz, M. Hiss, M. Mengel, H. Haller, and A. Schwarz Magnetic resonance imaging in a patient with chronic lithium nephropathy Nephrol. Dial. Transplant., January 1, 2007; 22(1): 278 - 279. [Full Text] [PDF]

This Article Abstract Figures Only Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Farres, M. T. Articles by Le Blanche, A. F. Search for Related Content PubMed PubMed Citation Articles by Farres, M. T. Articles by Le Blanche, A. F.