Introduction

People who inject drugs (PWID) may be at risk of serious cardiovascular and kidney diseases, including AA amyloidosis, related to chronic inflammatory conditions and poor overall health. Certain drug injecting practices (e.g. subcutaneous injecting, reuse of injecting equipment) are associated with chronic or recurrent abscesses and other skin and soft tissue infections (SSTIs)1. Currently, there are few studies looking at early risk markers of cardiovascular disease and chronic kidney disease among PWID, though there is some evidence to suggest that PWID are at increased risk of developing end-stage renal disease2,3,4,5. Other injecting practices believed to precipitate inflammation relate to the over-use of acidifiers used to dissolve brown heroin which is the predominant type of heroin available in Europe6. It is well established that chronic inflammation is associated with both cardiovascular disease and chronic kidney disease7,8.

Albuminuria is one of the two biochemical markers used to identify the presence of both cardiovascular disease and chronic kidney disease9. The presence of albuminuria is a key risk marker for predicting progression to end-stage renal disease, and for identifying other serious sequelae including AA amyloidosis9. A person with elevated albuminuria but with normal estimated glomerular filtration rate (eGFR) has the same cardiovascular risk as a person with an low eGFR (<60) without albuminuria9,10. Albuminuria has been associated with additional microvascular pathologies (e.g. involving the skin, brain, lungs) which suggests that albuminuria may also be a marker of systemic microvascular disorder11. Albuminuria is associated with cardiovascular risk factors including; overweight/obesity, diabetes, high blood pressure, and tobacco smoking10.

Population-level estimates reveal a high prevalence of albuminuria in the UK. A 2004 study among those aged 40–79 years in Norfolk, UK estimated the prevalence of microalbuminuria as 11.2% (13.9% in women, 8.1% in men) and macroalbuminuria as 0.7% (0.7% in women, 0.8% in men)12. The 2009 and 2010 Health Surveys for England estimated that 8% of adults surveyed had abnormal levels of albumin in their urine (7.9% microalbuminuria, 0.5% macroalbuminuria)10.

This paper aims to describe the prevalence of albuminuria among PWID, and to inform the clinical use and interpretation of albuminuria testing amongst this population.

Methods

We undertook a cross-sectional survey, as part of the UK National Institute for Health Research-funded Care & Prevent study, aimed at assessing the evidence for AA amyloidosis amongst PWID13. We developed a computer-assisted questionnaire to identify patterns of drug use and potential risk factors for SSTIs and AA amyloidosis. The questionnaire was conducted with current or past PWID aged 18 years and over who were recruited in London at eight drug treatment services and a mobile health service working with homeless people (UCLH Find & Treat Service). Participants completed the questionnaire followed by a urine screen for albuminuria. Participants were asked questions relating to: demographics, injecting history, injection practices, HIV and hepatitis C virus (HCV) status, SSTI history, and other conditions associated with albuminuria. Potential confounders were age, sex, and tobacco smoking.

Urine was initially tested using laboratory urinalysis and/or point of care (POC) testing using CLINITEX Microalbumin Reagent Strip (Siemens Healthcare GmbH), however, the POC testing yielded a high number of false positives (See Text Box 1) and was abandoned in favour of laboratory urinalysis. Albumin levels between 2.8 and 29.9 mg/mmol were considered abnormal (i.e. microalbuminuria), and ≥30 mg/mmol were deemed highly abnormal (i.e. macroalbuminuria). Participants with macroalbuminuria were referred to the University College London (UCL) National Amyloidosis Centre at Royal Free Hospital in North London for diagnostic assessment for AA amyloidosis.

Survey data were collected in Open Data Kit (https://opendatakit.org/) and transferred into Stata 15 (StataCorp: College Station, TX) for analysis.

All participants were provided with study information sheets and gave written consent prior to answering the questionnaire and providing a sample for urinalysis. Participants were reimbursed for their time with a £10 gift voucher. All methods were carried out in accordance with the relevant guidelines and regulations. This study has been reported against the STROBE reporting checklist for observational studies14.

Patient and public involvement

The survey was developed in collaboration with the Lambeth and Camden Drug User Forums. Members of the National Amyloidosis Centre Patient Network helped develop the participant information sheets. Groundswell, a local homelessness charity15, provided input to the study as well as peer support16,17 (See GRIPP2 Reporting Checklist Appendix 1).

Sample size

We aimed to collect urine samples from 400 participants based on feasibility (rates of service attendance) and an estimated 5% prevalence of proteinuria (95% CI, 3–7%).

Quantitative variables

The main outcomes of interest were any albuminuria; microalbuminuria (a biomarker for other health outcomes, such as cardiovascular disease) and macroalbuminuria (a biomarker for AA-amyloidosis). Exposures were chosen a priori as plausible factors in the causal chain and were based on the literature, our clinical experience, and our prior research involving PWID. Exposures include: injecting practices, location of injection sites, number of injection sites used, SSTI history, severity of past or current SSTI, housing status, overuse of acidifier (for dissolving drugs prior to injection), and self-reported lifetime diagnoses of health conditions (e.g. necrotising fasciitis, COPD, sepsis, endocarditis). Smoking status was added to the survey following commencement of data collection owing to the unexpectedly high prevalence of microalbuminuria, and is thus only available for 75% of the total sample, and 95% of the subsample of participants for whom we have laboratory results.

Statistical analysis

Associations between potential risk factors and albuminuria were tested using crude logistic regressions. Bivariate associations found to have a significance of ≤0.1 were introduced into the multivariate logistic model to examine independent associations with albuminuria. We used a 95% confidence interval for the calculation of population point estimates of albuminuria. We further estimated a ratio of the prevalence of albuminuria in our PWID sample to the prevalence in the general population using data from the Health Survey for England 2016, which included urinalysis. We fit a poisson regression model on the combined data with albuminuria as the dependent variable and drug injection as the independent variable, adjusting for age group and sex. We then additionally adjusted for smoking status (current, former, or non-smoker).

Ethics Approval

The study was approved by the NHS Health Research Authority (218143), the NHS Research Ethics Committee (17/LO/0872), and the London School of Hygiene & Tropical Medicine Observational Research Ethics Committee (12021–1). Participants gave informed consent to participate in the study.

Results

Of the 455 participants who completed the survey, 442 consented to urinalysis. Three-hundred and sixteen laboratory urinalyses were returned. The 139 samples not included in the analysis were either tested using the POC CLINITEX Microalbumin Reagent Strips only (e.g. for services with no laboratory pathway) or they were rejected by the laboratory (e.g. the sample container was damaged). We compared the personal characteristics of those from whom we obtained a sample to those from whom we did not using the Mann–Whitney U test (for age) and Pearson χ-squared and found no significant difference between the two groups (See Appendix 2).

Descriptive data

The majority of the 316 participants were white (73%) and male (75%), both their mean and median age was 46 years old (IQR 39–52). The average age at first injection drug use was 24 years (See Table 1). Of the 316 participants, 169 (54%) reported a diagnosis of HCV, 77 (24%) deep vein thrombosis (DVT), 45 (14%) chronic obstructive pulmonary disease (COPD), 27 (9%) kidney disease, and seven (2%) necrotising fasciitis. Seventeen (5%) participants reported receiving an HIV diagnosis (See Table 2).

Table 1 Participant Characteristics.
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Table 2 Participant Lifetime Morbidities.
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The majority of participants reported having a history of street homelessness (n = 242, 77%), with 57% (n = 180) currently living in unstable accommodation. The majority reported a typical injecting practice which included injecting one or more times per day (n = 227, 72%), and/or injection into the femoral vein (lifetime: n = 136, 43%, past 12 months: n = 62, 32%) (See Table 3). One-hundred and thirteen (39%) reported over-use of acidifier (defined as more than half a sachet of citric acid or vitamin C6) when preparing a £10 bag of heroin. Three hundred participants provided data on smoking status; 272 (91%) reported current or past smoking.

Table 3 Injection Practices.
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Outcome data

Of the 316 urinalysis results, sixty-one (19.3% [95% CI 15.3–24.0]) were positive for albuminuria with ≥2.8 mg/mmol albumin/creatinine ratio. Of these, 52 (16% [95% CI 12.8–21.0]) were classified as having microalbuminuria, and nine (3% [95% CI 1.5–5.4]) had macroalbuminuria. Men and women differed slightly but not significantly: 21.2% (95% CI 16.4–26.9) of men and 15% (95% CI 8.6–24.8) of women were found to have albuminuria. The prevalence of albuminuria generally increased with age: 13.6% (95% CI 6.1–27.7) in participants aged ≤35, and 21.4% (95% CI 16.1–27.9) in those aged ≥45, however this was not significant (p > 0.05). The nine participants with macroalbuminuria were referred to the UCL National Amyloidosis Centre and were offered Groundswell peer support (four declined to attend, three attended, and two died before their appointment).

Main results

In a series of crude analyses the following associations were found with albuminuria (See Table 4 for associations): acidifier overuse (OR 1.77, p = 0.061), COPD (OR 2.15, p = 0.033), HCV (OR 1.86, p = 0.037), DVT (OR 1.69, p = 0.090), HIV (OR 3.18, p = 0.025), and injecting in three body sites (OR 2.49 p = 0.079). There was no significant association between SSTIs (OR 0.87, p = 0.643) or groin injecting (OR 1.36, p = 0.282).

Table 4 Associations Between Albuminuria and Risk Factors.
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Based on these associations we performed logistic regression using listwise deletion of observations with missing smoking status and adjusted for a priori confounders (i.e. age, gender, and current smoking). We found higher odds of having albuminuria amongst those who: reported using more than half a sachet of acidifier per £10 of heroin (aOR 1.71 [95% CI 0.90–3.25]); had been previously diagnosed with COPD (aOR 1.85 [95% CI 0.84–4.06]), HCV (aOR 1.72 [95% CI 0.93–3.20]), HIV (aOR 3.16 [95% CI 1.06–9.41]), and injecting in three body sites (aOR 2.08 [95% CI 0.71–6.06]).

Further adjustment for other covariates suggested that the risk factor with the largest association with albuminuria was HIV (aOR 4.11 [95% CI 1.37–12.38]) followed by over-use of acidifier in injection preparation (aOR 2.10 [95% CI 1.04–4.22]).

In order to determine the age-adjusted prevalence ratio we compared our sample to the Health Survey for England data for 2016. Accounting for smoking status and stratified by age, we excluded the youngest (<25) and oldest (65+) age groups as they included small numbers of observations. The adjusted prevalence ratio suggests that albuminuria is twice as prevalent (1.97 [95% CI 1.49–2.60]) in our population compared to the general population in England.

Discussion

Statement of principal findings

This study sought to determine the prevalence of albuminuria amongst PWID in London. Previous studies have estimated that albuminuria in the general adult population in the UK is less than 10%12,18,19. Our findings suggest prevalence amongst PWID is twice that at 19% (15.3–24.0%). However, the age distribution in our sample differs markedly from that of the general adult population18. Adjusting for current smoking the prevalence ratio decreased to 1.65 (95% CI 1.17–2.31), suggesting that about one-third of the increased prevalence relates to smoking. Within our sample of PWID, overuse of acidifier and HIV were important predictors of albuminuria.

HIV is known to be associated with proteinuric renal lesions20. Additionally, we hypothesise that persistent overuse of acidifier in injection solution is precipitating venous sclerosis (owing to endothelial stress), thus complicating venous access and resulting in multiple venous injection attempts (and possible accidental subcutaneous injecting) and/or transition to intentional subcutaneous injecting21. Subcutaneous injecting introduces substances and/or bacteria directly into tissues which, in turn, causes persistent localised inflammation1. Alternatively, we cannot rule out the possibility that over-use of acidifier is directly causing local or systemic inflammation6. Chronic inflammation is strongly associated with cardiovascular and renal disease of which albuminuria is a biomarker9.

These data suggest that PWID are a high-risk group to develop cardiovascular and renal complications. A recent study of mortality among people who use heroin in South London found 2.8 times the risk of cardiovascular mortality compared to the general population22. If the associations (as observed in the general UK population) between albuminuria and future risk of cardiovascular disease are also true for PWID, one would expect the stroke risk in this population to be increased by 90% relative to a person with no albuminuria23, whilst the absolute risk of cardiovascular mortality increases by about 30% for a doubling of albuminuria24.

Strengths and weaknesses of the study

Initially, urine sample testing was carried out using a POC testing machine; however, false positives were identified following confirmatory laboratory testing We believe this to be a result of high levels of dehydration amongst PWID. Our prevalence estimate may have been improved by testing twice (as per NICE guidelines); however, this would have been difficult given our study population9. The Health Survey for England albuminuria data were collected based on the same protocol used for the present study (i.e. a single sample) therefore increasing its comparability with our study population18.

The absence of a significant association between SSTIs and albuminuria was surprising as we anticipated SSTIs would be a key factor in activating the inflammatory cascade. It is possible that our participants underreported past SSTIs or that our sample was underpowered to draw out this association. Our study may also have been underpowered to detect other meaningful predictor variables. Fnally, we cannot rule out the possibility that HIV and excessive use of acidifier may be contributing to a systemic microvascular disorder.

Unanswered questions and future research

Future studies should investigate long-term outcomes of PWID realted to cardiovascular and renal risk, though we appreciate the challenges of following up a difficult to capture population. Future trials should investigate whether cardiovascular and renal disease may be delayed by blood pressure lowering therapy or a poly-pill (i.e. a pill containing a combination of several medications) in those with albuminuria. In addition, studies could explore the reversibility of albuminuria through risk reduction and/or entry into substance use treatment (e.g. opioid agonist therapy). We encourage evaluations of the efficacy and cost-effectiveness of albuminuria screening amongst PWID.

Conclusion

Albuminuria is twice as prevalent among PWID compared to the general population and may identify those with high cardiovascular and renal risk. Clinicians, such as general practitioners, should be aware of the risk and consider albuminuria testing of PWID. Finally, dehydration may be common amongst PWID and may affect the diagnostic accuracy of POC testing for albuminuria. We encourage careful interpretation of albuminuria tests among this population.