Annotated Abstracts of Journal Articles
2014, 2nd Quarter


Annotations by Paula Zimbrean, MD, FAPM
June 2014

  1. Renal replacement therapy associated with lithium nephrotoxicity in Australia
  2. Altered brain functional connectivity in hemodialysis patients with end-stage renal disease: a resting-state functionalMR imaging study
  3. Vitamin D status in chronic dialysis patients with depression: a prospective study

Also of interest:

PUBLICATION #1 — Psychonephrology
Renal replacement therapy associated with lithium nephrotoxicity in Australia
Roxanas M, Grace BS, George CR
Med J Aust 2014 Mar 3; 200(4):226-8

ANNOTATION (Paula Zimbrean)

The Findings: The study reports the incidence of patients receiving renal replacement therapy (RRT) for lithium-induced nephropathy (LiN) as resulted from the analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). There were 0.14 cases per million population per year (95% CI, 0.06–0.22) in 1992–1996 and 0.78 (0.67–0.90) in 2007–2011. As a proportion of all incident RRT patients, LiN increased from 0.19% in 1992–1996 to 0.70% in 2007–2011. LiN patients were more likely than other patients to be women, to be white, to smoke and to have a higher body mass index, but were of similar age and less likely to have undergone renal biopsy.

Strengths and Weaknesses: This is an epidemiological study assessing a relatively rare but important disorder for psychiatrists, LiN. Diagnostic bias is possible with any registry data. There are several possible confounding variables: the nephrologist awareness of irreversible LiN may have increased over time, patients with bipolar disorder might have been referred more often for RRT after developing LiN, patients with bipolar disorder may be receiving better medical care, and the patterns of prescribing lithium might have changed over time. Existing data did not allow for determining the number of patients with ESRD associated with LiN who are not recorded in ANZDATA, because they do not receive RRT.

Relevance: Lithium is a unique psychiatric medication whose use has been limited by its side effects, among which LiN is one of the most severe. Information about incidence of this complication allows better appreciation of the risk/benefit ratio when considering prescribing Li.


Objective: To analyze the annual incidence of end-stage renal disease (ESRD) associated with lithium-induced nephropathy (LiN) in Australia.

Design, Setting and Participants: Retrospective cohort study of patients commencing renal replacement therapy (RRT) in Australia. We compared patients with LiN with all other RRT patients between 1 January 1991 and 31 December 2011, using Australia and New Zealand Dialysis and Transplant Registry data.

Main Outcome Measures: Numbers and characteristics of incident RRT patients, primary kidney disease (LiN or other, based on clinical diagnosis).

Results: LiN contributed to 187 people in Australia commencing RRT between 1 January 1991 and 31 December 2011. The incidence rate increased from 0.14 cases/million population/year (95% CI, 0.06-0.22) in 1992-1996 to 0.78 (95% CI, 0.67-0.90) in 2007-2011. This increase is unlikely to be attributed solely to demographic changes in Australia. LiN patients were more likely than non-LiN patients to be women, to be white, to smoke, and to have a higher body mass index, but were less likely to have undergone renal biopsy.

Conclusions: Rates of ESRD attributed to LiN are increasing rapidly. Currently accepted lithium dosages and duration of treatment might induce ESRD in a large cohort of patients. We encourage clinicians to exercise discretion when prescribing lithium, check renal function regularly, stop lithium if there is a deterioration in two consecutive readings, and consider substitution with other drugs.

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PUBLICATION #2 — Psychonephrology
Altered brain functional connectivity in hemodialysis patients with end-stage renal disease: a resting-state functionalMR imaging study
Zheng G, Wen J, Zhang L, et al
Metab Brain Dis 2014 May 21 [Epub ahead of print]

ANNOTATION (Paula Zimbrean)

The Finding: The study investigated the brain functional connectivity in patients with end stage renal disease ESRD) on hemodialysis (HD). Forty-two connections between every two regions of interests (ROIs) were significantly different (all P<0.05, Bonferroni corrected) in ESRD patients compared with controls and were defined as connectivity of interests (COIs) for further analysis. Among these COIs, 39 (92.9%) connections, either negative or positive, were weaker in ESRD patients than in the controls and only 3 positive ones were stronger in patients. Among the 39 connections weaker in ESRD patients, 24 COIs (61.5 %, 24/39) including 13 positive and 11 negative connections, were related to the frontal lobe regions. Fifteen weaker COIs of ESRD patients were not related to frontal lobe regions, which were mainly between the insula, partial lobes, temporal lobes and basal ganglia. The Z-scores of 29 COIs were associated with alterations in DST scores; 19 COIs related with frontal lobes were correlated with SAS scores; 8 COIs were correlated with SDT scores; 4 COIs related with LTT scores; one connection was correlated with NCT-A. No correlations were found between COIs and SDS scores.

Strengths and Weaknesses: The strengths of the study consist in having a control group, a comprehensive neuropsychiatric battery of tests, and extensive fMRI imaging.
The description of the study in the article is somewhat vague, as the authors call it a retrospective study. However, this appears to be a cross-sectional study with the study group consisting of 71 HD patients currently inpatient, and a control group of 43 age- and gender-matched healthy subjects recruited from the community. A battery of neuropsychiatric tests was administered: number connection test type A (NCT-A), digit symbol test (DST), line-tracing test (LTT), the serial-dotting test (SDT), the self-rating anxiety scale (SAS), and self-rating depression scale (SDS). All subjects underwent fMRI evaluation of the brain including 3D T1 weighted anatomical images for spatial normalization and Axial T2-FLAIR.
Limitations: The high number of COIs found impacts the statistical power to find significant correlations between COIs and specific clinical presentations. The inpatient status of the study group may introduce a potential bias of patients having severe ESRD or other medical comorbidities which may impact the brain connectivity.

Relevance: This study suggests that cognitive and mood disturbances present in ESRD may be related to specific brain connectivity patterns for patients with ESRD. This supports the view that psychiatric problems in ESRD have a biological basis that can be explored, and are not merely an expression of adaptation to medical illness.


The changes of whole brain functional connectivity in hemodialysis (HD) patients with end-stage renal disease (ESRD) are still unclear, which may be associated with multiple factors, such as elevated neurotoxins, anemia, and side effects of hemodialysis. Resting-state functional magnetic resonance imaging (rs-fMRI) data of 71 patients (43 males, 28 females; mean age, 33.4±9.4 years) and 43 age- and gender-matched healthy volunteers (29 males, 14 females; mean age, 30.6±8.8 years) were acquired. Neuropsychological tests including number connection test type A (NCT-A), digit symbol test (DST), line-tracing test (LTT), serial-dotting test (SDT), self-rating depression scale (SDS) and self-rating anxiety scale (SAS) were used to evaluate cognitive and psychiatric conditions in all subjects. Blood biochemistry tests including serum creatinine levels, blood urea, hematocrit, and Ca2+ level were taken in HD patients. Forty-two connections significantly different between HD patients with ESRD and controls were found (all P<0.05, Bonferroni corrected) and identified as connectivities of interests (COIs), among which 39 connections (92.9 %) were markedly decreased in patients. Of the 39 weaker connections, 24 were related to the frontal lobe regions. Widespread weakening of cortical and subcortical network connectivity in ESRD patients was more directly related with neuropsychological impairments and anemia rather than serum creatinine level, blood urea and dialysis duration. In particular, impairments in the medial prefrontal lobe could play an important role in mediating psychological dysfunctions.

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PUBLICATION #3 — Psychonephrology
Vitamin D status in chronic dialysis patients with depression: a prospective study
Zhang J, Zhang P, Ni X, et al
BMC Psychiatry 2014 Apr 28; 14(1):125

ANNOTATION (Paula Zimbrean)

The Finding: The overall incidence of depression was 44% (95% CI: −0.137-0.027). The patients with higher serum VD levels at baseline tended to have fewer depressive symptoms. Administration of vitamin D improved serum vitamin D levels, but did not impact the depressive symptoms.

Strengths and Limitations: The main strength of this study consists in the prospective character, high number of subjects: 484 dialysis patients (382 hemodialysis [HD] cases and 102 peritoneal dialysis [PD] cases), aged 18–60 years), and significant time for follow up (one year). The limitations of the paper consist in lack of control group, relatively low dose of vitamin D used (0.5 μg/day 1,25-Dihydroxyvitamin D orally), and questionable cut-off value for Beck Depression Inventory at 16.

Relevance: This study adds to the existing literature related to the significance of vitamin D serum levels in depression. The results suggest that repletion of vitamin D alone does not impact depression in this population.


Background: Depression is the most widely acknowledged psychological problem among end-stage renal disease (ESRD) patients. Depression may be associated with VD deficiency. The aims of this study are to (a) elucidate the prospective association between HsCRP, VD contents and depressive symptoms in the dialyzed population, and (b) find the effect of calcitriol supplementation on depression in dialyzed patients.

Methods: In this prospective study, 484 dialysis patients (382 hemodialysis [HD] cases and 102 peritoneal dialysis [PD] cases; aged 18-60 years) from two hospitals in southeast China were included. The depression in these patients was evaluated using the Chinese version of Beck’s Depression Inventory (BDI). All subjects answered the BDI-I questionnaire for assessment of depression levels in summer. A cut-off value of 16 was set to include dialysis patients with depression. All patients were divided into two groups depending on the absence (Group1) or presence (Group 2) of depression. The two groups took 0.5 μg/day 1,25-Dihydroxyvitamin D orally for one year. BDI Scores were recalculated for all patients. Sociodemographic, clinical data, and serum VD contents were also collected.

Results: A total of 484 participants (247 men [51.0%] and 237 women [49.0%]) were surveyed. Depressive symptoms were found in 213 (44.0%) patients. The baseline serum VD level (VD2+VD3) was 17.6±7.7 nmol/L. Patients with depressive symptoms have significantly higher serum HsCRP level and significantly lower serum VD level compared with the control group. After one-year follow-up, the supplementation of 0.5 μg/day calcitriol slightly improved the microinflammatory state such as lowering mean serum HsCRP level and improving serum VD level, but not in significantly enhancing the depressive symptoms.

Conclusions: Calcitriol supplementation did not significantly enhance the depressive symptoms in our dialyzed population although patients with low levels of serum VD were more depressed. Therefore, more prospective randomized controlled trials are necessary to reveal the exact cause-and-effect relationship between VD status and depressive symptoms or VD status related to some specific subtypes in dialyzed patients.

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