Improved immunologic response to COVID-19 vaccine with prolonged dosing interval in haemodialysis patients.

Vaccination against 2019 coronavirus disease (COVID-19) can reduce disease incidence and severity. Dialysis patients demonstrate a delayed immunologic response to vaccines. We determined factors affecting the immunologic response to COVID-19 vaccines in haemodialysis patients. All patients within a Swedish haemodialysis network, vaccinated with two doses of COVID-19 vaccine 2-8 weeks before inclusion, were eligible for this cross-sectional study. Severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antibody levels were determined by EliA SARS-CoV-2-Sp1 IgG test (Thermo Fisher Scientific, Phadia AB) and related to clinical and demographic parameters. Eighty-nine patients were included. Patients were vaccinated with two doses of Comirnaty (BNT162b2, 73%) or Spikevax (mRNA-1273, 23,6%). Three patients received combinations of different vaccines. Response rate (antibody titres >7 U/mL) was 89.9%, while 39.3% developed high antibody titres (>204 U/mL), 47 (43-50) days after the second dose. A previous COVID-19 infection associated with higher antibody titres (median (25th-75th percentile) 1558.5 (814.5-3,763.8) U/mL vs 87 (26-268) U/mL, P = .002), while time between vaccine doses did not differ between groups (P = .7). Increasing SARS-CoV-2 antibody titres were independently associated with increasing time between vaccine doses (B 0.241, P = .02), decreasing serum calcium levels (B -0.233, P = .007) and previous COVID-19 (B 1.078, P < .001). In conclusion, a longer interval between COVID-19 mRNA vaccine doses, lower calcium and a previous COVID-19 infection were independently associated with a stronger immunologic vaccination response in haemodialysis patients. While the response rate was good, only a minority developed high antibody titres, 47 (43-50) days after the second vaccine dose.

Skin Autofluorescence, a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products, Decreases During the Summer in Dialysis Patients.

Tissue advanced glycation end products (AGEs) are a measure of cumulative metabolic and oxidative stress and cytokine-driven inflammatory reactions. AGEs are thought to contribute to the cardiovascular complications of hemodialysis (HD) patients. Skin autofluorescence (SAF) is related to the tissue accumulation of AGEs and rises with age. SAF is one of the strongest prognostic markers of mortality in these patients. The content of AGEs is high in barbecue food. Due to the location in northern Sweden, there is a short intense barbecue season between June and August. The aim of this study was to investigate if seasonal variations in SAF exist in HD patients, especially during the barbecue season. SAF was measured noninvasively with an AGE Reader in 34 HD-patients (15 of those with diabetes mellitus, DM). Each time the median of three measures were used. Skin-AF was measured before and after each one HD at the end of February and May in 31 patients (22 men/9 women); the end of May and August in 28 (20 m/8 w); the end of August and March in 25 (19 m/6 w). Paired statistical analyses were performed during all four periods (n = 23, 17 m/6 w); as was HbA1c of those with DM. There was at a median 5.6% increase in skin-AF during the winter period (February-May, P = 0.004) and a 10.6% decrease in the skin-AF during the summer (May-August, P < 0.001). HbA1c in the DM rose during the summer (P = 0.013). In conclusion, skin-AF decreased significantly during the summer. Future studies should look for favorable factors that prevent skin-AF and subsequently cardiovascular diseases.

Skin- and Plasmaautofluorescence in hemodialysis with glucose-free or glucose-containing dialysate.

BACKGROUND: Haemodialysis (HD) patients suffer from an increased risk of cardiovascular disease (CVD). Skin autofluorescence (SAF) is a strong marker for CVD. SAF indirectly measures tissue advanced glycation end products (AGE) being cumulative metabolites of oxidative stress and cytokine-driven inflammatory reactions. The dialysates often contain glucose. METHODS: Autofluorescence of skin and plasma (PAF) were measured in patients on HD during standard treatment (ST) with a glucose-containing dialysate (n = 24). After that the patients were switched to a glucose-free dialysate (GFD) for a 2-week period. New measurements were performed on PAF and SAF after 1 week (M1) and 2 weeks (M2) using GFD. Nonparametric paired statistical analyses were performed between each two periods. RESULTS: SAF after HD increased non-significantly by 1.2% while when a GFD was used during HD at M1, a decrease of SAF by 5.2% (p = 0.002) was found. One week later (M2) the reduction of 1.6% after the HD was not significant (p = 0.33). PAF was significantly reduced during all HD sessions. Free and protein-bound PAF decreased similarly whether glucose containing or GFD was used. The HD resulted in a reduction of the total PAF of approximately 15%, the free compound of 20% and the protein bound of 10%. The protein bound part of PAF corresponded to approximately 56% of the total reduction. The protein bound concentrations after each HD showed the lowest value after 2 weeks using glucose-free dialysate (p < 0.05). The change in SAF could not be related to a change in PAF. CONCLUSIONS: When changing to a GFD, SAF was reduced by HD indicating that such measure may hamper the accumulation and progression of deposits of AGEs to protein in tissue, and thereby also the development of CVD. Glucose-free dialysate needs further attention. Protein binding seems firm but not irreversible. TRIAL REGISTRATION: ISRCTN registry: ISRCTN13837553 . Registered 16/11/2016 (retrospectively registered).

Skin and plasma autofluorescence during hemodialysis: a pilot study.

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P < 0.001). Plasma AF was reduced by 14% (P < 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.

Lifetime risk of severe kidney disease in lithium-treated patients: a retrospective study.

BACKGROUND: Lithium is an essential psychopharmaceutical, yet side effects and concerns about severe renal function impairment limit its usage. AIMS: Our objectives were to quantify the occurrence of chronic kidney disease stage 4 or higher (CKD4 +) within a lithium-treated population, using age- and time-specific cumulative incidence and age-specific lifetime risk as measures of disease occurrence. Additionally, we aimed to investigate the association between the duration of lithium treatment and the risk of CKD4 + . METHODS: We identified patients from the Sahlgrenska University Hospital's laboratory database. We conducted a retrospective cohort study employing cumulative incidence functions that account for competing deaths to estimate cumulative and lifetime risk of CKD4 + . A subdistribution hazards model was employed to explore baseline covariates. For measuring the association between the duration of lithium treatment and CKD4 + occurrence, we used a matched 1:4 case-control study design and logistic regression. RESULTS: Considering a 90-year lifetime horizon, the lifetime risk of CKD4 + for patients initiating lithium treatment between ages 55 and 74 ranged from 13.9% to 18.6%. In contrast, the oldest patient group, those starting lithium at 75 years or older, had a lower lifetime risk of 5.4%. The 10-year cumulative risk for patients starting lithium between ages 18 and 54 was minimal, ranging from 0% to 0.7%. Pre-treatment creatinine level was a predictive factor, with a hazard ratio of 4.6 (95% CI 2.75-7.68) for values within the upper third of the reference range compared to the lower third. Moreover, twenty or more years of lithium exposure showed a strong association with an increased risk of CKD4 + compared to 1-5 years of lithium use, with an odds ratio of 6.14 (95% CI 2.65-14.26). CONCLUSIONS: The risk of CKD4 + among lithium-treated patients exhibited significant age-related differences. Patients under 55 years old had negligible 10-year risk, while the lifetime risk for those aged 75 and older was limited. Duration of lithium treatment, especially exceeding 20 years, emerged as a significant risk factor. For individual risk assessment and prediction, consideration of age, pre-treatment creatinine levels, and the chosen time horizon for prediction is essential.

The low risk for early renal damage during lithium treatment has not changed over time.

BACKGROUND: Modern lithium management guidelines were introduced to improve the renal prognosis of lithium patients. AIMS: To examine whether prospects for severe renal impairment (defined as chronic kidney disease at least stage 4 (CKD4)), in long-term lithium patients, have changed over time after the introduction of lithium monitoring guidelines. METHODS: The time to and hazard for CKD4 were compared between three patient cohorts who started long-term lithium in three consecutive decades: 1980s, 1990s and 2000s. The follow-up time was 10 years after completion of 1-year treatment. The data were collected from Sahlgrenska University Hospital's laboratory database. RESULTS: In all, 2169 patients were included: 623 in Cohort 1 (started lithium during 1980s), 874 in Cohort 2 (1990s) and 672 in Cohort 3 (2000s). Compliance with lithium monitoring guidelines improved, and mean serum lithium decreased, through the cohorts. In all, 22 patients developed CKD4 during follow-up. The time to CKD4 was the same in all three cohorts (overall: 10.96 years, 95% confidence interval: 10.94-11 years). Age and serum creatinine concentration at start were significant risk factors, while sex had no prognostic value. After adjusting for the significant covariates, there was no statistically significant difference in the hazard for CKD4 between the three cohorts. CONCLUSION: The risk for severe renal damage during the first decade of long-term lithium is low, but has not changed over time. Our data suggest that improved compliance with lithium guidelines is not reflected in less risk for severe renal damage.

Starting lithium in patients with compromised renal function - is it wise?

BACKGROUND: Little is known of the risks involved for patients who, at the start of lithium treatment, already have compromised renal function. AIMS: To assess the risk of developing severe renal impairment (chronic kidney disease (CKD) 4-5) among those patients and to explore predictors for the progression. METHODS: A retrospective longitudinal cohort study using data from Sahlgrenska University Hospital's laboratory database 1981-2017. We compared the risk of developing CKD 4-5 in two patient cohorts: an exposed cohort of 83 patients who had high serum creatinine prior to start of lithium and a reference cohort of 83 patients with normal serum creatinine, matched by gender, duration of lithium treatment and age at the start of lithium treatment. The patients' medical charts were reviewed and the Swedish Renal Registry was used to identify patients with renal replacement therapy. RESULTS: There were no significant differences between the exposed and reference cohorts with respect to our matching criteria. Almost half the patients in the exposed cohort versus only 10% of the reference patients progressed to CKD 4-5 (HR 6.7, 95%CI 3.1-14.3, p < 0.001) during a mean observation time of more than 10 years. The progressors were older at the start of lithium treatment and were characterised by a higher burden of comorbid somatic diseases, in particular cardiovascular diseases. CONCLUSIONS: Compromised renal function prior to initiating lithium treatment increases the risk of developing severe renal impairment. Monitoring of renal function should include somatic comorbidity among older patients.

Cardiovascular comorbidity increases the risk for renal failure during prophylactic lithium treatment.

BACKGROUND: The development of lithium-associated kidney damage is still a matter of controversy. We have addressed this question by investigating the role of somatic comorbidity for developing kidney failure in lithium treated patients. METHODS: The study group comprised of 1741 adult patients with normal creatinine levels at the start of lithium treatment. Patients who developed severe renal failure (CKD stages 4-5, n = 109), were matched by sex, time on lithium and age at start of lithium, with 109 controls (CKD stages 1-2) that did not develop severe renal failure. RESULTS: Patients in CKD 4-5 did not differ significantly from controls (CKD 1-2) in sex (females/males were 76/33 in both groups), time on lithium (mean 9.8 years, SD 6.4; vs. 9.6, SD 6.2) or age at start of lithium (mean 61.6 years, SD 13.4; vs. 60.5 years, SD 12.3), respectively. However, comparisons between groups showed a significantly higher prevalence of somatic comorbidity (p < 0.001), especially cardiovascular diseases (p < 0.003), among patients in CKD 4-5. LIMITATIONS: Patients in our study group were relatively old and the findings are therefore not generalizable to patients starting lithium at an early age. The retrospective design, relying on available charts, did not allow to grade severity of comorbid conditions other than need for hospitalisation or chronic drug treatment. CONCLUSIONS: Our findings emphasize the role of somatic comorbidity for renal damage in lithium treated patients and especially the role of cardiovascular comorbidity. Monitoring of somatic comorbidity should be taken into account in treatment recommendations and safety routines in long-term prophylactic lithium treatment.

Compliance with the safety guidelines for long-term lithium treatment in Sweden.

BACKGROUND: Lithium has been used for more than 50 years and guidelines for treatment monitoring have been documented in Sweden since the beginning of the 1980s. AIMS: The aim of this study was to describe compliance over time with the Swedish guidelines for long-term lithium treatment. METHODS: The study material was obtained from Sahlgrenska University Hospital's laboratory database. We analysed data (serum lithium and serum creatinine) of adult patients treated with lithium between 1981 and 2010, and determined compliance with guidelines and serum lithium levels over time. RESULTS: Our study material included 2841 patients and 25,300 treatment-years. The compliance with guidelines' recommendations regarding lithium and creatinine monitoring increased from 36% in 1981 to 68% in 2010. Women were on average 2% more compliant than men ( p < 0.01). Most lithium samples (87-94%) were within recommended intervals throughout the study period. The average lithium level decreased from 0.70 mmol/L in 1981 to 0.58 mmol/L in 2001, and remained stable thereafter. CONCLUSIONS: Compliance with lithium monitoring guidelines improved slowly but steadily over time. It took three decades to reach a compliance rate of just below 70%. Gender differences were small, but with a significantly better compliance rate for women. Serum lithium was kept within the recommended target interval to a large extent, throughout the study period.

Comparing changes in plasma and skin autofluorescence in low-flux versus high-flux hemodialysis.

BACKGROUND: Tissue advanced glycation end products (AGE) are increased in hemodialysis (HD) patients, especially those with cardiovascular complications. Skin autofluorescence (skin-AF) can noninvasively estimate the accumulation of AGE in tissue. The aim was to clarify whether HD using a high-flux (HF) dialyzer favors plasma-or skin-AF removal compared to low-flux (LF) dialysis. MATERIAL AND METHODS: 28 patients were treated with either an HF-HD or LF-HD but otherwise unchanged conditions in a cross-over design. A glucose containing dialysate was used. Skin-AF was measured noninvasively with an AGE reader before and after HD. Fluorescence (370 nm/465 nm) of plasma (p-AF) was determined as total and nonprotein-bound fractions. Correction for hemoconcentrations were made using the change in serum albumin.Paired and nonpaired statistical analyses were used. RESULTS: Skin-AF was unchanged after LF- and HF-dialysis. Total, free, and protein- bound p-AF was reduced after a single LF-HD by 21%, 28%, and 17%, respectively (P<.001). After HF HD total and free p-AF was reduced by 5% and 15%, respectively (P<.001), while protein bound values were unchanged. The LF-HD resulted in a more pronounced reduction of p-AF than did HF HD (P<.001). Serum albumin correlated inversely with p-AF in HF-HD. CONCLUSIONS: In the dialysis settings used there was no significant change in skin AF after dialysis, with LF or with HF dialysis. Although only limited reduction in plasma fluorescence was observed, this was more pronounced when performing LF dialysis. These data are not in overwhelming support of the use of HF dialysis in the setting used in this study.

Effects of 10 to 30 years of lithium treatment on kidney function.

Long-term lithium treatment is associated with end-stage renal disease, but there is little evidence of a clinically significant reduction in renal function in most patients. We previously found that 1.5% of people who took lithium from the 1960s and 1970s developed end-stage renal disease; however, none of the patients who started after 1980 had end-stage renal disease. Here we aimed to study the prevalence and extent of kidney damage during the course of long-term lithium treatment since 1980. We retrieved serum lithium and creatinine levels from 4879 patients examined between 1 January 1981 and 31 December 2010. Only patients who started their lithium treatment during the study period and had at least 10 years of cumulative treatment were included. The study group comprised 630 adult patients (402 women and 228 men) with normal creatinine levels at the start of lithium treatment. There was a yearly increase in median serum creatinine levels already from the first year of treatment. About one-third of the patients who had taken lithium for 10-29 years had evidence of chronic renal failure but only 5% were in the severe or very severe category. The results indicate that a substantial proportion of adult patients who are treated with lithium for more than a decade develop signs of renal functional impairment, also when treated according to modern therapeutic principles. Our results emphasise that lithium treatment requires continuous monitoring of kidney function.