Serum electrolyte abnormalities in black African people living with human immunodeficiency virus (HIV) and diabetes mellitus (PLWH/DM) is unknown.
The aim of this study was to analyse serum electrolytes (sodium, potassium, calcium and phosphate) and factors associated with electrolyte abnormalities in black African PLWH/DM versus HIV-uninfected patients with DM.
We conducted a retrospective case-control study in 96 black African PLWH/DM (cases) and 192 HIV-uninfected patients with DM (controls), who were visiting the Edendale Hospital DM clinic, from 01 January 2016 to 31 December 2016. Pearson’s correlation, multivariate linear and logistic regression analyses were utilised.
Hypocalcaemia was the most frequent electrolyte abnormality in PLWH/DM and HIV-uninfected patients with DM (31.25% vs. 22.91%), followed by hyponatraemia (18.75% vs. 13.54%). Median (IQR) corrected serum calcium levels were significantly lower in PLWH/DM compared with HIV-uninfected patients with DM (2.24 [2.18–2.30] mmol/L vs. 2.29 [2.20–2.36] mmol/L;
Hypocalcaemia and hyponatraemia were the most frequent electrolyte abnormalities and occurred more frequently in PLWH/DM compared with HIV-uninfected patients with DM. People living with HIV and DM have significantly lower corrected serum calcium levels compared with HIV-uninfected patients with DM. Furthermore, hyponatraemia is a marker of impaired glycaemic control.
Low- and middle-income countries account for 80% of the global diabetes mellitus (DM) burden.
Electrolytes play a vital role in maintaining homeostasis and are paramount in mediating enzymatic reactions, cellular function and electrical gradients.
The Atherosclerosis Risk in Communities (ARIC) study concluded that African American patients had an approximately twofold greater incidence of type 2 DM compared with white patients.
Electrolyte abnormalities are associated with increased morbidity and mortality, even if they are chronic or of mild severity and may remain clinically silent until an advanced stage.
The objective of this retrospective case–control study was to determine, compare and identify associated factors regarding serum electrolyte abnormalities (sodium, potassium, calcium and phosphate) in black African PLWH/DM versus black African HIV-uninfected patients with DM who attended the Edendale Hospital DM clinic from 01 January to 31 December 2016.
This quantitative retrospective case–control study was conducted in 96 black African PLWH/DM (cases) and 192 black African HIV-uninfected patients with DM (controls) attending the Edendale Hospital DM clinic, Pietermaritzburg, KwaZulu-Natal, South Africa, over 1 year from 01 January to 31 December 2016. Records of patients attending the DM clinic were analysed retrospectively from datasheets. Electrolytes were measured during routine outpatient visits at the Edendale Hospital DM clinic. Black African PLWH/DM included in the study could have either type 1 or type 2 DM, be on ART or antiretroviral-naïve, have any degree of renal function that was determined by the estimated glomerular filtration rate (eGFR) and be on medication for comorbidities. Patients with incomplete records were excluded from the study. Sample sizes were determined by applying a power analysis in G*Power, which used an alpha of 0.05, a power of 0.80 and a medium effect size of 0.4. The ratio of cases and controls was 1:2, and participants were selected by random sampling, matched by eGFR. Estimated glomerular filtration rate was stratified by the Kidney Disease Outcomes Quality Initiative (KDOQI) classification. Data were anonymised with reference numbers. Variables analysed included the following:
age (years)
sex
HIV status
type of DM
duration of DM (years)
duration of HIV (years)
duration of ART (years)
type of ART
eGFR (mL/min/1.73m2)
levels of serum sodium, potassium, corrected calcium and phosphate (mmol/L)
levels of glycated haemoglobin (HbA1c) (%).
The following serum electrolyte reference ranges, as per the National Health Laboratory Services (NHLS), were utilised:
sodium: 136 mmol/L – 145 mmol/L
potassium: 3.5 mmol/L – 5.1 mmol/L
calcium: 2.20 mmol/L – 2.55 mmol/L
phosphate: 0.78 mmol/L – 1.42 mmol/L
Any electrolyte values below the lower limit of normal were considered hypo-electrolyte abnormalities, whilst those above the upper limit of normal were considered hyper-electrolyte abnormalities. Corrected serum calcium levels were utilised and calculated as follows: measured total calcium (mmol/L) + 0.02 (40 [g/L] – serum albumin [g/L]). The 2017 Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) guidelines advocate for an HbA1c ≤ 7% to prevent micro- and macro-vascular complications. Therefore, in this study, adequate glycaemic control was defined as HbA1c ≤ 7%. Estimated glomerular filtration rate was calculated by using the Modification of Diet in Renal Disease (MDRD) formula. Serum electrolytes, eGFR and HbA1c were measured by using the Siemens Dimension® analyser.
Data were captured by using Microsoft Excel, version 2016 (Microsoft, USA). Statistical analyses were conducted by using Statistical Analysis Software (SAS), version 9.4 (SAS Institute Inc., Cary, NC, USA). Continuous variables were expressed as medians with interquartile ranges (IQRs). Categorical variables were expressed as frequencies and percentages. Continuous variables were compared by using the Wilcoxon rank-sum test as data were asymmetrically distributed. Categorical variables were compared by using either the Chi-square test or Fisher’s exact test if there were less than five observations in any cell. Pearson’s correlation coefficient assessed the correlation between HbA1c and electrolytes. Multinomial logistic regression assessed factors associated with electrolyte abnormalities. Linear regression analyses assessed the effect of measured covariates on electrolytes. Multivariable models were stratified by HIV status and were adjusted for gender, age, use of TDF, type of DM, duration of DM, duration of HIV, HbA1c and eGFR. A two-tailed value of
Ethical approval to conduct the study was obtained from the Biomedical Research and Ethics Committee (BREC) of the University of KwaZulu-Natal (reference number BE576/18). Permission was obtained from Edendale hospital to utilise the DM clinic datasheet for data collection.
Ninety-six black African PLWH/DM (cases) and 192 black African HIV-uninfected patients with DM (controls) were reviewed. People living with HIV and DM were significantly younger than HIV-uninfected patients with DM (median [IQR]: 46.5 [39–53.5] years vs. 56 [47–64] years;
Demographic and clinical characteristics of people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus.
Parameter | PLWH/DM ( |
HIV-uninfected patients with DM ( |
|||||
---|---|---|---|---|---|---|---|
% | IQR | % | IQR | ||||
Age (years), median | 46.5 | - | 39–53.5 | 56 | - | 47–64 | < 0.001 |
1.000 | |||||||
Female | 66 | 68.75 | - | 132 | 68.75 | - | |
Male | 30 | 31.25 | - | 60 | 31.25 | - | |
Duration of DM (years), median | 5 | - | 2–9 | 7 | - | 3–13 | 0.006 |
Duration of HIV (years), median | 7 | - | 3–10 | - | - | - | - |
Duration on ART (years), median | 6 | - | 2–9 | - | - | - | - |
Sodium (mmol/L), median | 140 | - | 136.5–142 | 140 | - | 138–142 | 0.072 |
Potassium (mmol/L), median | 4.35 | - | 3.90–4.70 | 4.3 | - | 3.90–4.70 | 0.903 |
Calcium (mmol/L), median | 2.24 | - | 2.18–2.30 | 2.29 | - | 2.20–2.36 | 0.001 |
Phosphate (mmol/L), median | 1.03 | - | 0.91–1.21 | 1.08 | - | 0.93–1.23 | 0.406 |
HbA1c (%), median | 9.45 | - | 7.1–11.5 | 9.7 | - | 7.35–11.50 | 0.836 |
HbA1c > 7% | 73 | 76.04 | - | 153 | 79.69 | - | 0.543 |
eGFR < 60 mL/min/1.73m2 | 12 | 12.5 | - | 24 | 12.5 | - | 1.000 |
0.691 | |||||||
Type 1 | 12 | 12.5 | - | 20 | 10.41 | - | |
Type 2 | 84 | 87.5 | - | 172 | 89.58 | - | |
0.457 | |||||||
Hyponatraemia | 18 | 18.75 | - | 26 | 13.54 | - | |
Hypernatraemia | 2 | 2.08 | - | 7 | 3.65 | - | |
0.851 | |||||||
Hypokalaemia | 6 | 6.25 | - | 15 | 7.81 | - | |
Hyperkalaemia | 8 | 8.33 | - | 19 | 9.90 | - | |
0.292 | |||||||
Hypocalcaemia | 30 | 31.25 | - | 44 | 22.91 | - | |
Hypercalcaemia | 1 | 1.04 | - | 3 | 1.56 | - | |
0.959 | |||||||
Hypophosphataemia | 5 | 5.21 | - | 12 | 6.25 | - | |
Hyperphosphataemia | 6 | 6.25 | - | 12 | 6.25 | - | |
On ART | 86 | 89.58 | - | - | - | - | - |
On TDF ART | 65 | 67.71 | - | - | - | - | - |
PLWH/DM, people living with human immunodeficiency virus and diabetes mellitus; HIV, human immunodeficiency virus; DM, diabetes mellitus; IQR, interquartile range; HbA1c, glycated haemoglobin; eGFR, estimated glomerular filtration rate; ART, antiretroviral therapy; TDF, tenofovir.
Hyponatraemia was the second most frequent electrolyte abnormality, which occurred in 18 (18.75%) PLWH/DM and 26 (13.54%) HIV-uninfected patients with DM (
Correlation of electrolytes and glycated haemoglobin in people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus.
Electrolyte | PLWH/DM |
HIV-uninfected patients with DM |
||
---|---|---|---|---|
Sodium | −0.340 | 0.001 | −0.28 | < 0.001 |
Potassium | 0.090 | 0.397 | −0.08 | 0.283 |
Calcium | 0.764 | 0.475 | 0.05 | 0.475 |
Phosphate | 0.110 | 0.302 | −0.05 | 0.473 |
PLWH/DM, people living with HIV and diabetes mellitus; HIV, human immunodeficiency virus; DM, diabetes mellitus.
Adjusted and un-adjusted odds ratio estimates for the associations of electrolyte abnormalities with glycated haemoglobin in people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus.
Parameter | PLWH/DM |
HIV-uninfected patients with DM |
||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariate |
Multivariate |
Univariate |
Multivariate |
|||||||||
OR | 95% CI | aOR | 95% CI | OR | 95% CI | aOR | 95% CI | |||||
Hyponatraemia | 1.39 | 1.13–1.71 | 0.007 | 1.55 | 1.19–2.02 | 0.003 | 1.22 | 1.01–1.46 | 0.009 | 1.26 | 1.04–0.54 | 0.009 |
Hypernatraemia | 0.99 | 0.57–1.73 | - | 0.16 | 0.00–10.50 | - | 0.64 | 0.44–0.95 | - | 0.67 | 0.44–1.02 | - |
Hypokalaemia | 1.10 | 0.84–1.45 | 0.565 | 1.20 | 0.72–1.99 | 0.736 | 0.98 | 0.79–1.22 | 0.215 | 0.99 | 0.80–1.23 | 0.089 |
Hyperkalaemia | 1.11 | 0.88–1.42 | - | 1.05 | 0.82–1.35 | - | 0.83 | 0.68–1.02 | - | 0.75 | 0.58–0.97 | - |
Hypocalcaemia | 0.91 | 0.78–1.07 | 0.467 | 0.89 | 0.75–1.06 | 0.426 | 0.89 | 0.77–1.03 | 0.226 | 0.91 | 0.79–1.05 | 0.321 |
Hypercalcaemia | 0.76 | 0.32–1.84 | - | 0.03 | 0.00–1.27884E12 | - | 0.82 | 0.51–1.34 | - | 0.78 | 0.43–1.42 | - |
Hypophosphataemia | 0.80 | 0.54–1.20 | 0.017 | 0.76 | 0.48–1.22 | 0.078 | 1.01 | 0.79–1.29 | 0.199 | 1.01 | 0.79–1.29 | 0.250 |
Hyperphosphataemia | 1.53 | 1.12–2.11 | - | 1.44 | 1.00–2.07 | - | 0.79 | 0.61–1.02 | - | 0.79 | 0.60–1.04 | - |
OR, odds ratio; aOR, adjusted odds ratio; CI, confidence interval; DM, diabetes mellitus; HbA1c, glycated haemoglobin; PLWH/DM, people living with HIV and diabetes mellitus; HIV, human immunodeficiency virus.
Linear regression analysis for the associations of electrolytes with clinical factors in people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus.
Parameter | PLWH/DM |
HIV-uninfected patients with DM |
||||||
---|---|---|---|---|---|---|---|---|
Univariate |
Multivariate |
Univariate |
Multivariate |
|||||
Estimate | Estimate | Estimate | Estimate | |||||
Sodium | 0.05 | 0.346 | 0.09 | 0.145 | −0.03 | 0.111 | −0.02 | 0.336 |
Potassium | −0.01 | 0.905 | 0.01 | 0.999 | 0.04 | 0.281 | −0.04 | 0.360 |
Calcium | −0.01 | 0.526 | −0.01 | 0.663 | −0.01 | 0.018 | −0.01 | 0.031 |
Phosphate | −0.01 | 0.167 | −0.01 | 0.033 | −0.01 | 0.939 | −0.01 | 0.226 |
Sodium | −0.59 | 0.001 | −0.51 | 0.004 | −0.43 | < 0.001 | −0.45 | < 0.001 |
Potassium | 0.02 | 0.397 | 0.02 | 0.512 | −0.02 | 0.283 | −0.02 | 0.290 |
Calcium | 0.01 | 0.764 | 0.01 | 0.681 | 0.02 | 0.475 | 0.01 | 0.637 |
Phosphate | 0.01 | 0.302 | 0.01 | 0.740 | −0.01 | 0.473 | −0.01 | 0.296 |
Sodium | −0.02 | 0.820 | 0.02 | 0.850 | −0.07 | 0.047 | −0.02 | 0.507 |
Potassium | −0.02 | 0.181 | −0.04 | 0.018 | 0.02 | 0.004 | 0.01 | 0.042 |
Calcium | 0.01 | 0.547 | 0.01 | 0.370 | 0.01 | 0.900 | 0.01 | 0.187 |
Phosphate | 0.01 | 0.475 | −0.01 | 0.834 | 0.03 | 0.096 | 0.01 | 0.251 |
Sodium | 0.14 | 0.195 | 0.08 | 0.473 | - | - | - | - |
Potassium | −0.02 | 0.334 | −0.02 | 0.345 | - | - | - | - |
Calcium | 0.01 | 0.653 | 0.01 | 0.268 | - | - | - | - |
Phosphate | 0.01 | 0.710 | 0.01 | 0.255 | - | - | - | - |
Sodium | 2.96 | 0.054 | 2.48 | 0.111 | 1.83 | 0.024 | 1.75 | 0.037 |
Potassium | −0.56 | 0.017 | −0.68 | 0.007 | 0.04 | 0.711 | −0.49 | 0.001 |
Calcium | 0.02 | 0.514 | −0.04 | 0.164 | 0.02 | 0.436 | 0.02 | 0.495 |
Phosphate | −0.21 | 0.003 | −0.25 | 0.001 | −0.07 | 0.139 | −0.08 | 0.077 |
Sodium | 1.57 | 0.155 | 1.69 | 0.116 | −0.73 | 0.208 | −0.58 | 0.318 |
Potassium | 0.19 | 0.252 | 0.26 | 0.123 | −0.54 | 0.000 | 0.07 | 0.504 |
Calcium | −0.03 | 0.219 | 0.02 | 0.546 | −0.02 | 0.231 | −0.03 | 0.231 |
Phosphate | 0.10 | 0.059 | 0.09 | 0.072 | 0.08 | 0.012 | 0.09 | 0.006 |
Sodium | 1.13 | 0.465 | 2.88 | 0.114 | 0.41 | 0.640 | −0.08 | 0.943 |
Potassium | −0.04 | 0.877 | 0.04 | 0.888 | −0.10 | 0.501 | −0.12 | 0.513 |
Calcium | 0.03 | 0.455 | 0.01 | 0.774 | 0.04 | 0.248 | −0.02 | 0.517 |
Phosphate | 0.03 | 0.681 | −0.03 | 0.682 | −0.01 | 0.997 | −0.01 | 0.925 |
Sodium | −0.58 | 0.597 | 0.50 | 0.629 | - | - | - | - |
Potassium | −0.07 | 0.695 | −0.08 | 0.613 | - | - | - | - |
Calcium | −0.04 | 0.095 | −0.05 | 0.078 | - | - | - | - |
Phosphate | −0.05 | 0.337 | −0.07 | 0.169 | - | - | - | - |
DM, diabetes mellitus; HbA1c, glycated haemoglobin; eGFR, estimated glomerular filtration rate; ART, antiretroviral therapy; TDF, tenofovir; PLWH/DM, people living with HIV and diabetes mellitus; HIV, human immunodeficiency virus.
The duration of HIV was not significantly associated with hypokalaemia on adjusted multinomial logistic regression analysis (OR: 0.85; 95% CI: 0.59–1.23;
Serum-corrected calcium was the only electrolyte with median (IQR) levels significantly lower in PLWH/DM compared with HIV-uninfected patients with DM (2.24 [2.18–2.30] mmol/L vs. 2.29 [2.20–2.36] mmol/L;
Adjusted multinomial logistic regression in PLWH/DM and HIV-uninfected patients with DM found no factors significantly associated with hypophosphataemia or hyperphosphataemia. Notably, the use of TDF was not significantly associated with hypophosphataemia in PLWH/DM (OR: 1.69; 95% CI: 0.20–14.12;
Serum sodium abnormalities in DM vary depending on the degree of water and sodium change.
Our study demonstrated that PLWH/DM had a higher frequency of hyponatraemia compared with HIV-uninfected patients with DM (18.75% vs. 13.4%). The increased frequency of hyponatraemia in PLWH/DM could be attributed to the additive effect of HIV on sodium homeostasis. Hyponatraemia is a common electrolyte disorder in PLWH and a possible marker of HIV severity, as patients with hyponatraemia have significantly lower CD4 counts, higher viral loads and an increased prevalence of acquired immunodeficiency syndrome (AIDS).
People living with HIV and DM may be at a higher risk of hyponatraemia because of contributory factors from both HIV and DM. Furthermore, hyponatraemia in the black African population may indicate a greater degree of sodium imbalance compared with other ethnic groups as the black population physiologically have increased sodium retention with lower plasma renin and aldosterone levels.
Hyperkalaemia is common in DM.
Notably, our study determined that for every unit increase in DM duration, the odds of hypokalaemia significantly increased by 97% in PLWH/DM. This could be attributed to patients with comorbid HIV and DM developing a greater degree of insulin resistance, as both conditions progress,
Calcium homeostasis is strongly regulated by parathyroid hormone and vitamin D. Factors contributing to hypocalcaemia in HIV and DM include vitamin D deficiency, hypoparathyroidism and hypomagnesaemia.
The mechanism of vitamin D deficiency in HIV is multifactorial and involves the inhibitory effect of pro-inflammatory cytokines that reduces renal 1-α hydroxylation of vitamin D and the consumption of vitamin D by macrophages and lymphocytes.
Consequently, the presence of comorbid HIV and DM in the black African population potentially increases the risk of vitamin D deficiency and hypocalcaemia, which might negatively impact HIV and DM control. The role of vitamin D in the pathogenesis and control of HIV and DM and the effect of vitamin D supplementation need to be further explored, particularly in the black African population.
The risk of TDF-induced nephrotoxicity with isolated hypophosphataemia, proximal tubular dysfunction or Fanconi syndrome increases in the presence of renal impairment.
This study determined that electrolyte abnormalities in black African PLWH/DM are common, with hypocalcaemia and hyponatraemia being the most frequent electrolyte abnormalities. However, the current SEMDSA guidelines only recommend that serum potassium needs to be measured at diagnosis and monitored annually.
The limitations of this study included CD4 count and viral load not being documented for a majority of patients as management and monitoring of HIV occurs at designated HIV clinics. Therefore, the association between HIV control and electrolyte abnormalities could not be determined. Possible TDF-induced proximal tubular dysfunction and electrolyte loss were not assessed with urine electrolytes as they were not routinely performed in the DM clinic. Patients in this study could have been on medication or could have comorbidities which may affect electrolytes. However, by including these patients the study was more representable and reproducible as the majority of patients suffering from DM were usually part of a metabolic syndrome which requires chronic treatment to improve outcomes. In addition, the use of oral antidiabetic medication or insulin and the respective doses were not included. This could have been used to compare the DM treatment requirements in PLWH/DM and HIV-uninfected patients as both groups had similar HbA1c levels. Lastly, because of the retrospective nature of the study, causality could not be determined. However, this is a newly explored topic, and this study is useful in providing preliminary data for future prospective studies.
Serum electrolyte abnormalities in black African PLWH/DM are common. Hypocalcaemia and hyponatraemia were the most frequent electrolyte abnormalities and occurred more frequently in PLWH/DM compared with HIV-uninfected patients with DM. Serum calcium levels were significantly lower in black African PLWH/DM compared with HIV-uninfected patients with DM. Importantly, hyponatraemia is a potential marker of impaired glycaemic control as elevated HbA1c levels significantly increased the odds of hyponatraemia in both groups; however, the odds were greater in PLWH/DM. Ultimately, black African PLWH/DM are highly vulnerable to electrolyte abnormalities because of multifactorial pathophysiological factors. Further large prospective studies regarding electrolyte abnormalities in black African PLWH/DM will assist in identifying contributory factors and implementing tailored guidelines that could facilitate prevention, earlier detection, closer monitoring and appropriate intervention to reduce associated adverse effects in this high-risk population, particularly in the South African context.
This study contributes towards the Master of Medical Science degree of Dr Preyanka Pillay, which is supervised by Dr Somasundram Pillay.
The authors declare that they have no competing interests.
P.P. contributed to the conception and design of the study as well as the collection, analysis and interpretation of the data. P.P. wrote and edited the manuscript. S.P. contributed to the conception and design of the study and critically reviewed and edited the manuscript. N.M. contributed to the statistical analysis and interpretation of data; she also critically reviewed and edited the manuscript. All authors gave final approval of the version to be published.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data are available upon request from the corresponding author.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.