Chronic kidney disease (CKD) represents a significant public health issue with the potential to progress to kidney failure. Early stages are often asymptomatic, with the most common causes being diabetes mellitus, hypertension, and inflammatory kidney diseases.^[1,2]CKD is defined as persistent kidney damage lasting ≥3 months, with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² and/or the presence of albuminuria (>30 mg/day).^[3,4] According to international guidelines, CKD is classified into five stages based on eGFR values. Stage 1 indicates an eGFR ≥90 mL/min/1.73 m² with kidney damage present, while Stage 2 implies mild reduction in kidney function with eGFR between 60 and 89. Stage 3 indicates moderate reduction in function, subdivided into 3A with eGFR from 45 to 59 and 3B with eGFR from 30 to 44 mL/min/1.73 m². Stage 4 represents severe kidney damage with eGFR between 15 and 29, and Stage 5 denotes end-stage renal disease with eGFR less than 15 mL/min/1.73 m².^[3] Laboratory diagnostics are essential for early detection, monitoring, and prognosis of CKD. The best indicator of overall kidney function is considered to be eGFR.^[3] Although serum creatinine is most commonly measured, it is subject to variation based on age, sex, muscle mass, and other factors, necessitating the use of validated equations for eGFR calculation. The most commonly used formulas are the Modification of Diet in Renal Disease (MDRD, 1999), Study Formula and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI, 2009), with CKD-EPI showing greater accuracy, especially at higher eGFR values.^[3,5-7]

Systematic reviews and meta-analyses conducted up to 2016 indicated that the global prevalence of CKD among people living with HIV (PLWH) ranged from 5% to 7%, depending on the disease definition and the method used for eGFR estimation. A comprehensive meta-analysis of 61 studies across 60 countries reported a CKD prevalence of 6.4% when utilizing the MDRD equation.^[8] In contrast to some larger European countries, Croatia lacks national epidemiological data that clearly define the prevalence of CKD among PLWH over the past decade. Nevertheless, general population data provide an important context for interpretation. The large epidemiological EH-UH 2 study demonstrated an overall CKD prevalence of approximately 17% in the Croatian adult population, with nearly 10% of individuals classified as stage G3 or higher.^[9] In the absence of national data, it is reasonable to assume that the burden of CKD among PLWH in Croatia aligns with the ranges reported in comparable European healthcare systems, where prevalence is generally estimated between 5% and 10%.

Human immunodeficiency virus (HIV) causes a chronic infection that gradually impairs the immune system and can lead to acquired immunodeficiency syndrome (AIDS). Untreated infection results in a decline of CD4+ T lymphocytes and increases the risk of opportunistic infections and malignancies. Antiretroviral therapy (ART) slows disease progression, improves immune status, and reduces complications.^[10-12] The disease progresses through acute, asymptomatic, and final stages, assessed by CD4+ T-cell counts and HIV RNA levels. Clinical classification is based on CDC guidelines and the European Centre for Disease Prevention and Control.^[13]ART is the cornerstone of HIV treatment, acting by inhibiting various stages of the viral replication cycle, although it does not achieve complete viral eradication. A major breakthrough occurred in 1996 with the introduction of highly active antiretroviral therapy (HAART), which through drug combinations enabled effective viral suppression, reduced morbidity and mortality, and prolonged the life expectancy of infected individuals.^[14] Over time, the term HAART has gradually been replaced by ART, which now denotes standard combination therapy. A typical regimen includes two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) and a third drug from the groups of non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), or integrase inhibitors (INIs).^[15,16] Entry inhibitors, including fusion inhibitors and CCR5 co-receptor antagonists, are also available and used in specific clinical situations. Each drug class targets a distinct stage of the viral life cycle, preventing replication and disease progression to AIDS.^[15,16]CKD is increasingly common among PLWH and often remains unrecognized until advanced stages, when treatment options are limited to dialysis or kidney transplantation.^[17]HIV can directly damage kidneys through HIV-associated nephropathy, immune-mediated glomerulopathies, and toxic effects of ART.^[17] Among the drugs, tenofovir disoproxil fumarate (TDF), indinavir (IDV), and atazanavir (ATV) are associated with higher risk of kidney damage, especially when combined with protease inhibitors.^[18] Conversely, the newer tenofovir alafenamide (TAF) shows lower nephrotoxicity and is increasingly used as a replacement.^[19]

TDF has long been associated with nephrotoxicity, including a decline in eGFR, particularly in PLWH with additional risk factors for CKD. In contrast, TAF demonstrates a more favorable renal safety profile while maintaining antiretroviral efficacy. Switching from TDF to TAF is generally associated with stabilization or improvement of renal function, making TAF the preferred option for PLWH with pre-existing CKD risk factors.^[20,21]

The aim of this study was to present the prevalence of CKD among PLWH who are receiving antiretroviral therapy, and to describe the trends of individual CKD stages in HIV-infected individuals under care at the University Hospital for Infectious Diseases in Zagreb, Croatia.

This retrospective cohort study included 1,143 HIV-positive persons (aged ≥18 years) of both sexes, who were under care at the University Hospital for Infectious Diseases (UHID) in Zagreb, Croatia (the HIV/AIDS Outpatient Clinic and the Reference Centre for Diagnosis and Treatment of HIV/AIDS of the Republic of Croatia), during the five-year follow-up period, from January 2012 to December 2016. HIV-positive individuals under the age of 18 and pregnant women were excluded from the study. Data were collected from medical records, ensuring full anonymity. CKD was defined utilizing the MDRD equation, in accordance with the European AIDS Clinical Society (EACS) guidelines. During the study period, the MDRD formula was widely utilized in HIV cohorts due to its reliable performance in patients with low to moderate eGFR values and its compatibility with established clinical protocols in Croatia. In cases of multiple eGFR measurements within a single calendar year, the value closest to the end of the year was included in the analysis. The following patient characteristics were recorded: age, sex, CD4+ T-cell count, HIV viremia, hepatitis B (HBV) and hepatitis C (HCV) co-infection, presence of AIDS-defining illnesses, mode of HIV transmission, duration of infection, and use of ART at the time of creatinine assessment. Assessment of kidney function in the cohort was part of the standard clinical protocol at the UHID in Zagreb, and the study data were derived from routine measurements of serum creatinine and eGFR. No experimental diagnostic or therapeutic procedures were applied, and the study protocol was approved by the Ethics Committee of the Hospital.

After collection, the data were organized into a matrix suitable for statistical analysis. Categorical variables were presented as frequencies and percentages. The χ² test or Fisher’s exact test (in cases of small sample sizes) was used to compare independent samples. Trends across different CKD categories over the years were analyzed using the Cochran-Armitage trend test. All p-values were two-sided, with a p-value <0.05 considered statistically significant. Statistical analyses were performed using the SAS program package, version 4.9 (SAS Institute Inc., Cary, NC, USA).

During the five-year follow-up period, a total of 1,143 adult PLWH were under the clinical care at the UHID in Zagreb. A total of 4,166 eGFR measurements were performed (3,691 in male and 475 in female patients), allowing for a detailed assessment of renal function over the observed period. The study population was predominantly male. More than one-third of the participants resided in Zagreb, the capital and largest city of Croatia. The vast majority of patients were receiving ART, while fewer than one-third had a history of AIDS-defining illnesses (Table 1).

According to age, the patients were classified into the following groups: 18-29 years, 30-39 years, 40-49 years, and >50 years. The most represented age groups were 30-39 years (32.89%) and 40-49 years (30.17%), followed by the group >50 years (27.0%). The fewest participants were in the age group 18-29 years (9.94%). Analysis of HIV transmission routes showed that the largest proportion (67.86%) was among men who have sex with men (MSM), followed by heterosexual contact (24.94%), injection drug use (3.22%), hemophilia (0.48%), vertical transmission (mother-to-child) (0.26%), and transfusion-related transmission (0.24%). The mode of transmission remained unknown in 3.00% of cases. Initial diagnoses were classified according to the CDC HIV/AIDS classification system, which categorizes patients based on clinical and immunological criteria. The largest group of participants was classified as A2 (symptomatic HIV infection with CD4+ lymphocyte count between 500–999/μL, 27.56%), followed by C3 (AIDS-defining conditions with CD4+ <200/μL, 21.27%), A1 (asymptomatic with CD4+ ≥500/μL, 18.17%), and B3 (symptomatic with CD4+ <200/μL, 13.96%). The smallest group was C1 (AIDS-defining conditions with CD4+ ≥500/μL, 0.31%). Viremia measurements were conducted for most participants, revealing a high proportion with undetectable HIV RNA levels in plasma (83.20% with <50 copies/mL). Trend analysis using the Cochran-Armitage test showed a statistically significant decrease in viremia over the five-year period (p<0.05), confirming the effectiveness of ART.

In this study, HIV-positive individuals were analyzed as a single cohort, without separate stratification based on clinical stage or a history of AIDS diagnosis. Overall, 27.36% of participants had developed AIDS during their lifetime, while 72.64% had not experienced any opportunistic infections by the end of the follow-up period. The Cochran-Armitage test showed a significant downward trend in AIDS incidence over time (p<0.05). During the five-year period, 8.23% of participants were not receiving ART, while 91.77% were on therapy. A statistically significant increase in the proportion of individuals on ART was confirmed (p<0.05). The most commonly prescribed ART regimen was a combination of 2 NRTIs and 1 NNRTI (53.12%), followed by regimens including 2 NRTIs and 1 PI (22.92%). Throughout the study period, a total of 53 different antiretroviral drug combinations were used, tailored to the individual clinical needs of the study population. The most frequently prescribed combination was abacavir/lamivudine/efavirenz (ABC/3TC/EFV), prescribed to 29.12% of participants, followed by abacavir/lamivudine/lopinavir (ABC/3TC/LOP) in 11.35%, and emtricitabine/tenofovir disoproxil fumarate/efavirenz (FTC/TDF/EFV) in 8.69%. Furthermore, a detailed analysis of the ART regimens utilized during the study period revealed that 15 out of 53 different drug combinations contained TDF; overall, 24.18% of participants were receiving a TDF-containing regimen.

Trend analysis of CKD stages over the five-year period showed statistically significant changes (p<0.05). The largest proportion of participants was classified as CKD Stage 2 (61.38%), while advanced stages (Stages 3, 4 and 5) were recorded in 4.99% of all cases (Table 2).

CKD represents a significant public health issue worldwide, with the potential to progress to kidney failure.^[1,2] Early recognition of CKD, especially in the early stages, enables prevention of CKD progression. Programs for the early recognition of CKD are increasingly in the interest of wider medical science, especially regarding the possibility of reducing complications and unnecessary additional economic costs associated with the final stages of CKD.^[3]CKD is increasingly common among PLWH and often remains unrecognized until advanced stages.^[17] During the five-year follow-up of HIV-positive individuals in Croatia, a stable epidemiological trend was observed alongside high availability of ART, which resulted in a reduction of opportunistic infections and improved overall survival. Given that a large proportion of HIV-positive people in Croatia were included in this study, the data obtained can be considered relevant for our HIV population. The sample was sex-imbalanced, with men comprising 88.60% of participants, the most represented age groups were between 30 and 49 years, and the most common route of transmission was male-to-male sexual contact, reflecting the national distribution.^[22] According to the most recent European data from 2024, a higher proportion of men continues to be observed among new HIV diagnoses in the EU/EEA, with MSM remaining the most common mode of transmission (48.3% of all diagnoses with a known transmission route). Additionally, although heterosexual transmission accounts for a significant proportion of cases in some parts of the region, the dominance of MSM as a key risk group remains pronounced.^[23] Antiretroviral therapy has significantly reduced mortality associated with AIDS and opportunistic infections, resulting in prolonged survival of HIV-infected individuals. The majority of our participants (91.77%) were on ART, with 83.20% achieving viral suppression below 50 copies of HIV RNA/mL, indicating good adherence and treatment efficacy. In some individuals (6.53%), viremia was not continuously monitored due to consistently suppressed levels. These results reflect European trends during 2012–2016, according to data from the EuroSIDA study. In Europe, ART coverage increased to approximately 78.2% in 2014–2015. At the same time, the proportion of individuals on ART achieving viral suppression increased to 87.7%, with significant regional differences observed across Europe.^[24] In the contemporary European context (2022–2024), the WHO European Region estimates that 87% of people diagnosed with HIV are receiving ART, and 90% of those on ART achieve viral suppression, demonstrating further progress in reaching treatment targets within the region.^[25] These data indicate a continuing trend of increasing ART coverage and viral suppression in Europe over the past decade, reflecting improved access to therapy, its effectiveness, and the strengthening of care systems for PLWH, including the interpretation of our finding of a high suppression rate in the Croatian cohort.

Renal function, assessed using the MDRD equation for estimating eGFR, showed that most of our patients were in CKD Stage 2 (61.38%). Mild renal impairment was more frequently observed in individuals receiving ART compared to non-ART patients. Higher CKD stages (3A, 3B, 4, and 5) were recorded in 5.26% of patients receiving ART, while such advanced abnormalities were rare (2.03%) among those not on therapy. This may suggest a possible association between certain antiretroviral drugs and renal impairment, particularly TDF. Despite occasional mild reductions in eGFR, advanced CKD remains rare in individuals who regularly receive ART and under good clinical supervision. Therefore, regular monitoring of kidney function and timely adjustment of therapy in at-risk patients is essential.

A study of Spanish HIV-positive patients analyzed the prevalence of CKD (eGFR ≤60) using the MDRD formula. The prevalence of CKD was approximately 4–5%, mostly in Stage 3 CKD, with older age and TDF treatment identified as risk factors.^[26] The most recent meta-analysis by Yazie et al.^[18] includes data from 69 studies, encompassing over 88,000 PLWH receiving TDF-based regimens. The pooled prevalence of CKD was estimated at approximately 7% (95% CI: 6–8%), with lower CD4 counts and female sex identified as significant predictors of CKD. Studies using the MDRD equation to calculate eGFR reported a slightly lower prevalence (~4%), further emphasizing the importance of the method used to assess renal function when interpreting results. These findings support the observation that, although mild reductions in eGFR occasionally occur in patients on ART, more severe renal abnormalities remain relatively rare, especially among well-controlled PLWH under regular clinical monitoring.^[18]

In this retrospective study, potential changes in ART following the detection of renal impairment were not systematically monitored. However, according to current clinical guidelines and standard practice, modifications to ART regimens are generally considered when significant kidney damage is detected to prevent further deterioration of renal function. This underscores the importance of regular monitoring of kidney function and timely clinical intervention. These findings highlight the importance of early diagnosis, individualized treatment approaches, and the prevention of renal complications in PLWH.

One of the limitations of this study is that classical risk factors for CKD, such as diabetes mellitus and arterial hypertension, were not the focus of this retrospective analysis, as they are not directly related to ART. Therefore, the results primarily reflect the prevalence and trends of CKD in the context of HIV infection and ART use. Co-infections with hepatitis B and C were analyzed in our cohort; their prevalence was relatively low (HBV 4.49%; HCV 6.34%), with no increasing trends observed, but they nevertheless remain important factors that require ongoing monitoring.

Five-year monitoring shows that a mild form of CKD (Stage 2) is common among HIV-positive individuals on ART, while more severe stages are rare but still present. The results confirm the importance of regular kidney function monitoring for early detection and slowing disease progression.