Journal Article Annotations
2025, 2nd Quarter

Psychonephrology

Annotations by Shivali Patel, MD and Rebekah Nash, MD, PhD
July, 2025

Early stage chronic kidney disease as a risk factor for suicide: a nationwide observational cohort study.
Predicting 10-year risk of chronic kidney disease in lithium-treated patients with bipolar disorder: A risk model development and internal cross-validation study.

Of interest:

Depression in chronic kidney disease: Particularities, specific mechanisms and therapeutic considerations, a narrative review.

PUBLICATION #1 — Psychonephrology

Early stage chronic kidney disease as a risk factor for suicide: a nationwide observational cohort study.

Hyuk Huh, Kyungdo Han, Minsang Kim, Young Sun Shin, Yeo Jin Yu, Sehyun Jung, Jeong Min Cho, Seong Geun Kim, Semin Cho, Soojin Lee, Eunjeong Kang, Yaerim Kim, Dong Ki Kim, Sehoon Park

Abstract: J Nephrol s40620-025-02219-3. Epub 2025 Apr 9.

Background:
Chronic kidney disease (CKD) is associated with poor psychological well-being. Whether early-stage CKD is a risk factor for suicide warrants further research.

Methods:
This nationwide, retrospective, cohort study aimed to evaluate the risk of suicide in patients with early-stage CKD and identify the associated risk factors. A total of 3.945,198 individuals aged ≥ 19 years who underwent the 2009 national health screening in South Korea were studied. Among them, 202,291 patients had early-stage CKD (estimated glomerular filtration rate (eGFR) ≥ 30 and < 60 mL/min per 1.73 m² and/or dipstick albuminuria ≥ 1 +). The study outcome was suicide as confirmed by the nationwide death register based on death certificates.

Results:
The study population had a mean age of 59 ± 15 years, and 47% were male. We identified 930 suicides (incidence rate, 0.45 per 1000 person-years) in the CKD group and 11,332 suicides (incidence rate, 0.27 per 1000 person-years) in the non-CKD group. Early-stage CKD was significantly associated with an increased risk of suicide in multivariable analysis adjusted for demographic characteristics; lifestyle habits; comorbidities, including diabetes and hypertension; economic status; and depression, bipolar disorder, schizophrenia (hazard ratio, 1.18; 95% confidence interval 1.10‒1.26). Suicide incidence was higher in individuals with proteinuria but preserved kidney function (eGFR > 60 mL/min per 1.73 m² and dipstick albuminuria > 1 +) than in those without CKD.

Conclusion:
Healthcare providers may need to examine the mental health of patients with early-stage CKD to prevent suicide.

Annotation

The finding:
This was a retrospective cohort study which evaluated the association between early-stage CKD (chronic kidney disease) (eGFR >30 and <60 mL/min per 1.73 m² and/or dipstick albuminuria >1) and suicide risk. Individuals with advanced CKD or previously diagnosed end-stage renal disease were excluded, and data from 3,945,198 individuals aged >19 years who underwent the 2009 South Korea national health screening were analyzed. Within this population, 202,291 individuals were diagnosed with early-stage CKD. Individuals with early-stage CKD had a significantly increased risk of suicide, even after multivariable analyses adjusted for demographic characteristics including lifestyle factors (smoking, heavy drinking), presence of psychiatric disorders (depression, bipolar disorder, or schizophrenia), and economic status (hazard ratio 1.18; 95% confidence interval 1.10-1.26). The risk of suicide was also elevated in those with preserved GFR (eGFR>60 mL/min per 1.73 m²) and albuminuria only. A subgroup analyses revealed that CKD was not associated with increased risk of suicide in individuals with depression, bipolar disorder, or schizophrenia; however, CKD was a significant risk factor for suicide in individuals without these psychiatric disorders. A majority of those who died by suicide were older in age (64.0± 14 years), male (67.4%), and had a higher prevalence of diabetes and hypertension. Other factors associated with increased suicide risk included low-income status, current smoking, diabetes, hypertension, depression, and migraines. Elevated body mass index and regular exercise were associated with lower suicide risk.

Strength and weaknesses:
Strengths of this study included a large study population which excluded individuals with known ESRD or advanced CKD and the use of multivariate models to adjust for factors which independently may increase suicide risk. In terms of weaknesses, this was a retrospective and observational study; hence it is unclear if confounding variables such as genetic loading, social isolation, acute stressors, sleep impairment, and substance use (apart from tobacco and alcohol), may have also influenced the results. Additionally, the study population included individuals who completed the national health screen and likely selected for relatively healthier volunteers. Finally, the study examined individuals in South Korea, which has one of the highest suicide rates among the Organization for Economic Cooperation and Development countries; thus, the results may not be generalizable to those in other nations.

Relevance:
There may be an increased risk of suicide throughout all stages of kidney disease, including early-stage CKD even in the case of preserved GFR and albuminuria only. Hence, it is important for C-L psychiatrists to be proactive in monitoring suicidal ideation, risk factors, and comorbidities in all individuals with reduced GFR and/or proteinuria.

PUBLICATION #2 — Psychonephrology

Predicting 10-year risk of chronic kidney disease in lithium-treated patients with bipolar disorder: A risk model development and internal cross-validation study.

Joe Kwun Nam Chan, Marco Solmi, Christoph U Correll, Corine Sau Man Wong, Heidi Ka Ying Lo, Francisco Tsz Tsun Lai, Wing Chung Chang

Abstract: Eur Neuropsychopharmacol. 2025 Jun:95:24-30. doi: 10.1016/j.euroneuro.2025.03.008. Epub 2025 Apr 11.

Lithium is a first-line maintenance treatment for bipolar-disorder (BD) but has increased risk for chronic-kidney-disease (CKD). There is a paucity of research on risk-model development predicting CKD during/following lithium treatment, and none was conducted in Asian regions. This study aimed to derive and validate 10-year risk prediction model for CKD-stage 3 in first-diagnosed BD patients receiving ≥ 1 prescription of lithium during 2002-2018 in Hong-Kong, using electronic-medical-record database of public-healthcare services. Literature-informed predictor selection included demographics, physical comorbidities, mean lithium serum-levels and non-lithium psychotropic use. The risk-equation was developed using Least-Absolute-Shrinkage-and-Selection-Operator (LASSO) Cox-proportional hazards regression model with 4-fold internal cross-validation over 1,000 iterations. We identified 2,258 lithium-treated BD patients, with CKD incidence of 12.6 per 1000 person-years (95 %CI=11.1-14.4) over a median follow-up of 7.7 years (interquartile range=3.7-12.3). Our results showed that older age at BD-diagnosis, male sex, physical comorbidities, higher mean lithium serum-level, fewer antipsychotic and mood-stabilizing anticonvulsant use, and greater antidepressant exposure were independent risk factors predicting CKD, with an event-per-variable ratio of 25.2. The 10-year risk prediction model had satisfactory area-under-the-curve (AUC) (0.74 [95 %CI=0.66-0.83]), with good calibration (calibration slope=0.88 [95 %CI=0.61-1.15]; observed/expected risk ratio=1.14 [95 %CI=0.86-1.42]), and discrimination performances (Harrell’s C-index=0.75 [95 %CI=0.68-0.82]; Royston and Sauerbrei’s D statistic=1.45 [95 %CI=0.99-1.92]). In conclusion, this CKD risk-model for lithium-treated BD patients demonstrated satisfactory prediction performance in a predominantly-Chinese population. Further research including external validation is needed to verify model performance to facilitate implementation of this CKD risk prediction tool for individualized clinical decision-making and outcomes in real-world practice.

Annotation (unstructured)

Annotation

The finding:
Using a territory-wide health database (all Hong Kong residents receiving public healthcare; coverage starting in 1995), the authors created a predictive model of CKD (chronic kidney disease) in patients diagnosed with bipolar disorder and prescribed lithium. In particular, the study cohort (n = 2258) included all individuals in the database ≥ 15 years old receiving an initial (first ever) bipolar disorder diagnosis between 01-01-2002 and 12-31-2018 and > 1 lithium prescriptions who were then followed from time of lithium prescription until diagnosis of CKD 3 (or higher), departure from the healthcare database, death, or the end of the study (12-31-2018). The median follow-up time (interquartile range, IQR) was 7.7 (3.7 – 12.3) years, over which 227 CKD cases were identified. Potential predictors of CKD were collected, including demographics, Charlson Comorbidity Index, mean lithium serum levels, other psychiatric medication use, and a model was created (using 4-fold cross validation and Least Absolute Shrinkage and Selection Operator (LASSO) for a Cox proportional hazards regression model applied to select predictors to estimate regression coefficients) and tested. The model demonstrated reasonable overall fit (AUC =0.74), discrimination (75% chance of correctly distinguishing between outcomes), and good calibration indices (calibration slope = 0.88 [95% CI=0.61-1.15]; the ideal slope = 1). The model identified older age, male sex, physical comorbidity (higher CCI score, diabetes, hypertension), higher mean lithium serum concentration, and antidepressant use as risk factors of CKD, while use of antipsychotics or mood-stabilizers reduced risk of CKD. Only 10% of cohort developed CKD over the duration of the study.

Strength and weaknesses:
The study had three primary limitations. First, considering it can take 10-20 years to develop CKD after starting lithium, the relatively short follow up time (median 7.7 years) put the study at risk for missing subsequent CKD events. Second, the study utilized mean serum lithium concentrations, thus missing any acutely elevated serum lithium concentrations reflecting lithium toxicity. Third, the model was only internally validated; it would benefit from external validation in a separate population. However, the study did have several strengths including the use of routinely available data points in the model, which can enhance this study group’s (or another group’s) ability to validate the model in another population; the authors also took steps to limit over-fitting of the model. Additionally, the authors leveraged a large, fairly comprehensive health database, creating a robust dataset. While the authors were unable to capture certain variables such as life-style factors (e.g., smoking), or certain lab values (no baseline GFR or data regarding proteinuria or albuminuria for those in the cohort), the authors did exclude individuals with pre-existing kidney disease from the cohort, and while the authors were unable to confirm adherence to the prescribed lithium, they were able to collect lithium levels, reducing the impact of this limitation.

Relevance:
When considering the risks and benefits of lithium versus other mood stabilizers for patients with numerous medical comorbidities and potentially elevated risk of CKD, studies such as this one can help inform our understanding of relative risk to each patient and how to frame risk-benefit discussions with patients. This study added to the growing body of evidence supporting a more nuanced approach to risk of CKD and dialysis dependent kidney failure for individuals prescribed lithium, acknowledging the multitude of factors associated with risk of kidney disease, beyond just lithium use. However, this study, along with several other recent studies, is limited by the relatively short follow up period, making a true determination of long-term risk much more difficult. Additionally, as highlighted by the authors, the particulars of the model created by this study require replication and validation in additional populations before establishing clinical utility.

PUBLICATION #3 — Psychonephrology

Depression in chronic kidney disease: Particularities, specific mechanisms and therapeutic considerations, a narrative review.

Antoine Lefrère, Stéphane Burtey, Stanislas Bobot, Raoul Belzeaux, Mickaël Bobot.

Abstract: Behav Brain Res. 2025 Apr 12:483:115467. doi: 10.1016/j.bbr.2025.115467. Epub 2025 Feb 7.

Introduction:
Depression is highly prevalent during chronic kidney disease (CKD) with studies suggesting prevalence rates ranging from approximately one-quarter to half of CKD patients. CKD and depression have a bidirectional relationship, each disorder aggravating the other, leading to more complex and challenging patient management. Depression during CKD is multifactorial and is associated with increased risk of adverse events and hospitalization.

Methods:
We conducted a narrative review of experimental and observational studies in animals and humans, as well as meta-analyses, to explore specific mechanisms of depression in CKD and its treatment.

Results:
In depression the gut-brain axis is central. CKD leads to an accumulation of gut-derived uremic toxins. One key factor is the accumulation of tryptophan-derived uremic toxins like kynurenines or indoxyl sulfate, whose serum concentration increases progressively with the stage of CKD (up to 100-fold in stage 5), and which plays an important role in depression mechanisms, by activating aryl hydrocarbon receptor, decreasing brain concentrations of serotonin by approximately 40 %, increasing brain inflammation, via activation of microglia and astrocytes and release of TNFα, IL-6 and NO. Randomized controlled studies found limited or no benefits of antidepressants for depressive symptoms in CKD and hemodialysis patients.

Conclusion:
Chronic inflammation, in relation to uremic toxin accumulation during CKD, seems to be a complex but important mechanism for treatment resistance in depression. Future research should consider inhibitors of uremic toxins inhibitors and anti-inflammatory molecules as potential therapeutic agents, to improve the prognosis of depression in CKD patients.

Annotation (unstructured)

This narrative review details the significant bidirectional relationship between depression and CKD, whereby CKD is a risk factor for depression and depression is a risk factor for CKD and may negatively impact CKD outcomes. The review also highlights important factors which should be considered when treating patients who have both conditions. Specifically, chronic inflammation, accumulation of tryptophan-derived uremic toxins, pharmacokinetic changes, and increased blood-brain barrier permeability in CKD may contribute to treatment resistance in depression. Hence, it is vital to routinely screen for depression in patients with CKD and emphasize interventions beyond psychotropic medications in these patients, such as psychotherapy and lifestyle modifications.