Journal Article Annotations
2022, 1st Quarter

Psychonephrology

Annotations by Sahil Munjal, MD
January, 2022

Determinants of Kidney Function and Accuracy of Kidney Microcysts Detection in Patients Treated With Lithium Salts for Bipolar Disorder.
Lithium toxicity at therapeutic doses as a fallout of COVID-19 infection: a case series and possible mechanisms.

PUBLICATION #1 — Psychonephrology

Determinants of Kidney Function and Accuracy of Kidney Microcysts Detection in Patients Treated With Lithium Salts for Bipolar Disorder.

Nahid Tabibzadeh, Anne-Laure Faucon, Emmanuelle Vidal-Petiot, Fidéline Serrano, Lisa Males, Pedro Fernandez, Antoine Khalil, François Rouzet, Coralie Tardivon , Nicolas Mazer, Caroline Dubertret, Marine Delavest, Emeline Marlinge, Bruno Etain, Frank Bellivier, François Vrtovsnik, Martin Flamant

Abstract: Front Pharmacol. 2022 Jan 7;12:784298. doi: 10.3389/fphar.2021.784298. eCollection 2021.

Objectives:
Early kidney damage during lithium treatment in bipolar disorder is still hypothetical. We aimed at identifying the determinants of a decreased measured glomerular filtration rate (mGFR) and the accuracy of kidney MRI imaging in its detection.

Methods:
In this cross-sectional cohort study, 217 consecutive lithium-treated patients underwent mGFR and kidney MRI with half-Fourier turbo spin-echo and Single-shot with long echo time se-quences.

Results:
Median age was 51 [27–62] years, and median lithium treatment duration was 5 [2–14] years. 52% of patients had a stage 2 CKD. In multivariable analysis, the determinants of a lower mGFR were a longer lithium treatment duration (β −0.8 [−1; −0.6] ml/min/1.73 m2 GFR decrease for each year of treatment), a higher age (β −0.4 [−0.6; −0.3] ml/min/1.73 m2 for each year of age, p < 0.001), albuminuria (β −3.97 [−6.6; −1.3], p = 0.003), hypertension (β −6.85 [−12.6; −1.1], p = 0.02) and hypothyroidism (β −7.1 [−11.7; −2.5], p = 0.003). Serum lithium concentration was not associated with mGFR. Renal MRI displayed renal microcyst(s) in 51% of patients, detected as early as 1 year after lithium treatment initiation. mGFR and lithium treatment duration were strongly correlated in patients with microcyst(s) (r = −0.64, p < 0.001), but not in patients with no microcysts (r = −0.24, p = 0.09). The presence of microcysts was associated with the detection of an mGFR <45 ml/min/1.73 m2 (AUC 0.893, p < 0.001, sensitivity 80%, specificity 81% for a cut-off val-ue of five microcysts).

Conclusion:
Lithium treatment duration and hypothyroidism strongly impacted mGFR independent-ly of age, especially in patients with microcysts. MRI might help detect early lithium-induced kid-ney damage and inform preventive strategies.

Annotation

The finding:
This cross-sectional study looked at a cohort of lithium-treated patients and found that lithium treatment duration, age, albuminuria, hypertension and hypothyroidism were inversely correlated with renal function (mGFR). Fifty-one percent of patients with renal MRIs had micro-cysts, often uniformly and symmetrically distributed throughout the kidneys. mGFR and lithium treatment duration were correlated in patients with microcysts—but were not correlate in pa-tients without microcysts.

Strength and weaknesses:
This study boasted a larger sample size compared to previous studies of MRI and microcysts. A third of patients were missing lithium levels, and the use of a single plasma lithium measurement is not representative of long-term cumulative exposure to the drug. Also, the lithium level was not measured the same day as the renal evaluation. There was a very low preva-lence of diabetes in the sample size. Given the cross-sectional design, the predictive value of lithi-um treatment duration on mGFR decline could not be analyzed.

Relevance:
The study adds to an already established risk of renal function decline in certain patients with chronic lithium treatment. Here, the strongest determinant of mGFR decline was the lithium treatment duration, then age. The association with hypothyroidism is also an interesting finding which needs replication. There was a strong relationship between the presence of microcysts and mGFR decrease. MRI might be a useful tool to detect microcysts even during early stages of treat-ment; here, some study patients developed microcysts as soon as 1 year after lithium treatment. Study authors point out that the presence of these microcysts may inform strategies to prevent irreversible kidney damage, perhaps by decreasing lithium exposure or other nephrotoxic agents. It is not clear if these changes are reversible, and any potential benefit of treatment discontinuation should be weighed against the risk of destabilization and suicidality.

PUBLICATION #2 — Psychonephrology

Lithium toxicity at therapeutic doses as a fallout of COVID-19 infection: a case series and possible mechanisms.

Naveen Manohar Pai, Vidhyavathi Malyam, Manisha Murugesan, Sundarnag Ganjekar, Sydney Moirangthem, Geetha Desai

Abstract: Int Clin Psychopharmacol. 2022 Jan 1;37(1):25-28. doi: 10.1097/YIC.0000000000000379.

Lithium, a mood stabilizer used in the treatment of bipolar disorder is known for its anti-inflammatory properties with the discussion of its potential use in COVID-19 infection. The SARS-CoV-2 virus causing COVID-19 infection is known to enter the target cells through angiotensin con-verting enzyme-2 receptors present in abundance in the lung and renal tissue. Recent research supports the evidence for direct renal injury by viral proteins. Here we report two patients with bipolar disorder presenting with lithium toxicity in the presence of COVID-19 infection. Two pa-tients with bipolar disorder, maintaining remission on lithium prophylaxis, presented to the psy-chiatric emergency with recent-onset fever and altered sensorium. Both the patient’s investiga-tions revealed lithium toxicity, elevated serum creatinine, urea and inflammatory markers. Hyper-natremia, hyperkalaemia, and hyperchloremia were seen in one patient. Lithium and other psycho-tropic medications were stopped immediately, and COVID-19 treatment was initiated. Patient with clinical signs of lithium toxicity, hypernatremia, hyperkalaemia, and hyperchloremia developed ventricular tachycardia. He survived and regained consciousness after 2 weeks of aggressive con-servative management. However, another patient died of acute respiratory failure on day 3. Possi-ble direct infection of the kidney by SARS-CoV-2 viral proteins can manifest with acute kidney inju-ry and lithium toxicity among patients on long-term lithium therapy. Health professionals treating COVID-19 infection among individuals on lithium therapy should be aware of the possibility of lithi-um toxicity in the background of renal injury.

Annotation

The finding
Two cases are described of patients whose bipolar disorder was in remission on lithium but who then developed nephrotoxicity after COVID-19 infection.

Strength and weaknesses:
Other confounding variables may have indirectly affected renal function and led to lithium toxicity including dehydration, electrolyte and acid-base imbalance, cardiac insufficiency, inflammatory cascade secondary to COVID-19 or other surreptitious medications.

Relevance:
C-L psychiatrists should monitor lithium levels more frequently in patients with COVID-19. It has been proposed that some of lithium’s anti-inflammatory effects might be beneficial in patients with COVID-19 infection. However, the virus may cause renal damage and subsequently lithium toxicity. This case series describes how COVID-19 patients can develop acute renal injury due to direct viral infection of the kidney. SARS-CoV-2 spike protein binds to the angiotensin converting enzyme 2 receptor to enter human renal cells. Larger studies are needed to ascertain the direct effect of the virus on renal function, as damage may also be immune-mediated.