The most common kidney side effects of lithium therapy

Lithium is a highly effective therapeutic agent used in psychiatric treatment, mostly for bipolar disorder, but with a frequent side effect: renal toxicity.

Lithium nephrotoxicity can be divided into three main categories: nephrogenic diabetes insipidus, acute intoxication and chronic renal disease.

Chronic lithium nephropathy

Chronic tubulo-interstitial nephropathy is the main form of chronic renal disease associated with lithium therapy. It is characterized by tubular atrophy and interstitial fibrosis, out of proportion to the extent of glomerular or vascular disease, with the particularity of micro cysts formation.

Cysts are described in the literature to be sparse, not to exceed 1 to 2 mm in diameter, located mostly in the zones of tubular atrophy and interstitial fibrosis, both in the cortex and the medulla. Although tubular atrophy affects all three nephron segments, cysts are formed only in the distal tubule and collecting duct.

The psychopathological mechanism of this disease is not well established. It is thought that the toxicity is caused by lithium accumulation in the collecting tubular cells after entering through sodium channels located in the transluminal membrane.

The progression of chronic lithium-induced nephropathy is slow and can lead to renal insufficiency and even end-stage renal disease. Interruption of lithium administration does not assure a recovery of the renal function, but on the contrary, the nephropathy can steel evolve.

Nephrogenic diabetes insipidus:

-  is the most common renal side effect

-  normal or elevated concentration of the antidiuretic hormone

- caused by a downregulation-lithium induced of the vasopressin-regulated water channel aquaporin-2 expressed on the apical plasma membrane of principal cells of the collecting duct

Acute lithium intoxication

- due to lithium overdose

- may be seen both in patients with chronic or acute lithium therapy

- patients may present with acute renal failure, a change in mental status, gastro-intestinal symptoms and volume depletion

- because it has a narrow therapeutic index, a large proportion of patients may experience at least one episode of toxicity during chronic treatment.

MRI protocol and appearance in chronic lithium-induced nephropathy

MRI protocol

In a context of long-term lithium usage, we look for small (1–2 mm) round cystic lesions that affect both the renal cortex and the medulla.

Thus, the most appropriate MRI protocol in evaluating this pathology is highly T2 weighted sequences that were proved to be very useful in depicting structures containing static fluids.

These sequences were first used to perform cholangiography and have found their utility in highlighting the cystic lesions as hyper intense round areas:

• T2 SSFSE= T2 weighted sequence single-shot fast spin-echo and
• SS FSE TE long= Single-shot fast spin echo with long echo time

This ultrafast MRI technique has a different name depending on the MRI vendor:

• GE: SS-FSE (Single-Shot Fast Spin-Echo
• Siemens: HASTE (Half-Fourier Acquisition Single-Shot Turbo Spin Echo imaging)
•  Philips: SSH-TSE (Single-Shot Turbo Spin Echo) and UFSE (Ultra-Fast Spin Echo)
•  Hitachi: Single-shot fast SE
• Canon: FASE ( Fast Advanced Spin Echo) and SuperFASE.

Because of its short acquisition time, T2 SSFSE sequence is less susceptible to motion respiratory artifact that corrupts fast spin echo T2-weighted techniques and has been routinely used in abdominal imaging.

In order to obtain T2 weighted sequences, a long echo time (TE equal or greater than 70 milliseconds) and a long repetition time (TR equal or greater than 2000 milliseconds) is needed. In our hospital, we use a T2 SSFSE with an echo time of 113 milliseconds and a repetition time between 1800 milliseconds and 2000 milliseconds.

SS FSE TE long is a sequence with an even longer echo time and repetition time, thus even more T2 weighted, highly useful in depicting micro cysts. In our hospital, we use a SSFSE TE long with an echo time of 600 milliseconds and a repetition time of 6000 milliseconds.

The disadvantage of increasing the echo time is that we obtain a lower signal-to-noise ratio, leading to a decrease in the anatomical imaging contrast.

MRI appearance of chronic lithium-induced nephropathy

An MRI imaging pattern of abundant micro cysts, distributed uniformly and symmetrically in the cortex and the medulla of normal-sized kidneys, in a patient with a history of long-term lithium therapy, is very characteristic of lithium nephropathy and may avoid the need for renal biopsy (Fig. 1, Fig.2 and Fig. 3).

A normal MRI does not exclude the diagnostic and in such cases the need of a biopsy to confirm the diagnostic is mandatory.

Fig. 1: Frontal SSFSE TE long sequence (TR=6000ms/ TE=600 ms) of a 50 years women treated with lithium for 15 years shows multiple small (1-2 mm) hyper intense round lesions located in the cortex and medulla of the two kidneys.

Fig. 2: Frontal T2 SSFSE (TR=1800-2000 milliseconds/ TE=113milliseconds) of a 64 year old women treated for 48 years with lithium, demonstrates a symmetric distribution of multiple small, hyper intense, round lesions throw out the renal parenchyma.

Fig. 3: Frontal T2 SSFSE (TR=1800-2000 milliseconds/ TE=113milliseconds) and Frontal SSFSE TE long (TR=6000 milliseconds/ TE=600 milliseconds) sequences of a 49 years women in lithium treatment for 44 years, demonstrate a characteristic MRI appearance of lithium nephropathy.

In cases where the micro cysts are less abundant (Fig. 4) or are predominantly located in the cortex (Fig. 5), MRI imaging is less specific. But, in a context of long-standing lithium therapy and moderate renal insufficiency, the diagnosis of lithium nephropathy can still be strongly supported only by MR imaging.

Fig. 4: Frontal SSFSE TE long (TR=6000 milliseconds/ TE=600 milliseconds)sequence of a 69 years man in chronic lithium treatment for 26 years,demonstrates a few small, hyper intense, round lesions located in the two kidneys. In the context of a long-standing lithium therapy, this appearance is highly suggestive for lithium-induced nephropathy.

Fig. 5: Frontal SSFSE TE long (TR=6000 milliseconds/ TE=600 milliseconds)sequence of a 54 years woman in treatment with lithium for 32 years demonstrates multiple small, hyper intense, round lesions, located in the two kidneys, with a distribution predominantly in the cortex. Considering the chronic lithium therapy, this appearance is highly suggestive for lithium-induced nephropathy.

A classification of chronic lithium nephropathy based on the MRI appearance has not yet been established. The number of micro cysts is variable between patients and we can find a different kidney attend regardless of the duration of treatment (Fig. 6). 

Fig. 6: Frontal SSFSE TE long (TR=6000 milliseconds/ TE=600 milliseconds)sequences of three different patients with different attend of the disease: A: a 69 years man who has been taking lithium for 26 years, B: a 59 years old women in chronic lithium treatment for 15 years and C: a 64 years who has been taking lithium for 48 years.

The importance of T2 weighted sequences

In order to make the diagnosis on a kindey MRI, we have to be able to see the presence of the micro cysts even in the less typical cases when we deal with only a few cysts. T2 weighted sequences are the most appropriate to make the micro cysts stand out from the renal parenchyma as hyper intense, round lesions (Fig. 7 and Fig. 8).

Fig. 7: Axial SSFSE TE long (TR=6000 milliseconds/ TE=600 milliseconds) and Axial T1 FS sequence of a 64 years old women in chronic treatment for 48 years with lithium. COR SSFSE TE long sequence demonstrates the presence of multiple small, hyper intense, round lesions, located in the two kidneys that are not seen on an Axial T1 FS sequence.

Fig. 8: Frontal SSFSE TE long (TR=6000 milliseconds/ TE=600 milliseconds) and Frontal T1 FAT SAT sequences of a 51 years woman undergoing a chronic treatment with lithium for 15 years for a psychiatric condition. COR SSFSE TE long shows multiple small, hyper-intense, round lesions, located in the two kidneys that can be clearly missed on the COR T1 FAT SAT sequence.

The difference between SSFSE TE long and T2 SSFSE

 Even though the images obtained by using T2 SSFSE  sequences are highly T2 weighted, thus capable of making visible the micro cysts, it can under appreciate or even miss the diagnosis. By using SSFSE TE long, a sequence with an even longer TE then the TE used in T2 SSFSE sequence, so even more T2 weighted, we are able to see the true extend of the disease (Fig. 9). The SSFSE TE long sequence is particularly useful in the early stages of the disease, helping to make the diagnosis, thus avoiding the need for kidney biopsy (Fig. 10).

Fig. 9: Frontal T2 SSFSE (TR=1800-2000 milliseconds/ TE= 113milliseconds) and Frontal SSFSE TE long (TR=6000 milliseconds/ TE= 600 milliseconds) sequences of a 49 years women in treatment with lithium for 44 years demonstrate a characteristic MRI aspect of lithium nephropathy. Frontal T2 SSFSE (TR=1800-2000 milliseconds/ TE=113 milliseconds) sequence shows a typical renal aspect of chronic lithium nephropathy but only after adding the SSFSE TE long (TR=6000 milliseconds/ TE= 600 milliseconds) sequence we can truly appreciate the extend of the kidney damage.

Fig. 10: Frontal T2 SSFSE (TR= 1800-2000 milliseconds/ TE= 113 milliseconds) and Frontal SSFSE TE long (TR= 6000 milliseconds/ TE= 600 milliseconds) sequences of a 54 years women in treatment with lithium for 32 years. Frontal T2 SSFSE sequence shows a nearly normal aspect of the kidneys with only a few micro cysts seen in the cortex. Only by using the SSFSE TE long sequence we can clearly see the micro cysts and make the imaging diagnosis of chronic lithium nephropathy.