Association of chronic inflammation and accelerated atherosclerosis among an indigenous black population with chronic kidney disease.

INTRODUCTION: Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients. MATERIALS AND METHODS: Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms. RESULTS: Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles. CONCLUSION: The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.

APOL1 Genetic Variants Are Associated with Serum-Oxidized Low-Density Lipoprotein Levels and Subclinical Atherosclerosis in South African CKD Patients.

INTRODUCTION: Apolipoprotein L1 (APOL1) plays an important role in cholesterol metabolism and attenuation of low-density lipoprotein (LDL) oxidation. While protecting against Trypanosoma brucei rhodesiense infection, APOL1 risk alleles confer greater risk for CKD and cardiovascular disease among patients of African descent. OBJECTIVES: We investigated whether APOL1 risk variants are associated with atherosclerosis and oxidized LDL (OxLDL) levels among black South African CKD patients. METHODS: A cross-sectional study of 120 adult CKD patients and 40 controls was undertaken. DNA samples of participants were genotyped for APOL1 G1 and G2 variants. High-sensitivity C-reactive protein, serum lipids, and OxLDL levels were measured, and carotid doppler ultrasonography was performed on all participants. RESULTS: APOL1 alleles rs73885319, rs60910145, and rs71785313 had minor allele frequencies of 9.2, 8.8, and 17.5%, respectively, in the patients, and 8.8, 8.8, and 13.8%, respectively, in the controls. Of the 9 patients with 2 APOL1 risk alleles, 77.8% were compound G1/G2 heterozygotes and 22.2% were G2 homozygotes. Carriers of at least 1 APOL1 risk allele had a 3-fold increased risk of subclinical atherosclerosis (odds ratio 3.19; 95% confidence interval: 1.64-6.19; p = 0.01) compared to individuals with no risk alleles. Patients with 1 or 2 APOL1 risk alleles showed a significant increase in OxLDL levels when compared with those without the APOL1 risk allele. CONCLUSION: These findings suggest an increased risk for atherosclerosis in carriers of a single APOL1 risk variant, and the presence of APOL1 risk variants was associated with increased serum OxLDL levels in black South African CKD patients.

Interleukin-6 gene polymorhisms and interleukin-6 levels are associated with atherosclerosis in CKD patients.

Inflammation is a major risk factor for atherosclerosis. Genetic polymorphisms in the inflammatory cytokine genes have been associated with atherosclerosis. Because levels of inflammatory cytokines are markedly elevated in patients with chronic kidney disease (CKD), we hypothesized that genotypic variations in the interleukin-6 (IL-6) gene are a cause of systemic inflammatory states and atherosclerosis in South African CKD patients. 120 CKD patients and 40 healthy controls were included. Serum IL-6 and high-sensitivity C-reactive protein (hs-CRP) levels were measured. Functional polymorphisms in the IL-6 genes were genotyped using polymerase chain reaction-sequence specific primer (PCR-SSP) methods. Carotid intima-media thickness (CIMT) and the presence of plaque were assessed by B-mode ultrasonography. Serum IL-6 and hs-CRP levels were increased in patients with CKD compared with healthy controls (p < 0.001). In CKD patients, serum IL-6 above the median value was associated with carotid plaque (OR: 2.11; 95% CI: 1.74 - 2.57, p = 0.004), with excess risk confined to the group with high IL-6 levels. Significant associations were found between the IL-6 gene and atherosclerosis in the CKD group (for G/G genotype: OR = 1.21, 95% CI = 1.05 - 1.39, p = 0.012; for GG+GC vs. CC: OR = 1.14, 95% CI = 1.02 - 1.28, p = 0.035). Patients with GG+GC genotype of the IL-6 gene polymorphism had higher levels of IL-6 than those with CC genotype (p = 0.029). In South African CKD patients, the IL-6 gene promoter polymorphism is associated with high serum IL-6 levels and atherosclerosis. The relationship between atherosclerosis and -174G/C polymorphism in the IL-6 gene suggests that IL-6 may be a potential pro-inflammatory mediator of atherosclerosis in CKD patients.

Transforming Growth Factor-ß Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

BACKGROUND: Transforming growth factor-ß (TGF-ß) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-ß isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the TGF-ß1 gene and atherosclerosis in South African CKD patients. METHODS: We studied 120 CKD patients and 40 healthy controls. Serum TGF-ß1, TGF-ß2, TGF-ß3, endotoxin, and inflammatory markers were measured. Functional polymorphisms in the TGF-ß1 genes were genotyped using a polymerase chain reaction-sequence specific primer method and carotid intima media thickness (CIMT) was assessed by B-mode ultrasonography. RESULTS: TGF-ß isoforms levels were significantly lower in the patients with atherosclerosis compared to patients without atherosclerosis (p<0.001). Overall, TGF-ß isoforms had inverse relationships with CIMT. TGF-ß1 and TGF-ß2 levels were significantly lower in patients with carotid plaque compared to those without carotid plaque [TGF-ß1: 31.9 (17.2 - 42.2) versus 45.9 (35.4 - 58.1) ng/ml, p=0.016; and TGF-ß2: 1.46 (1.30 - 1.57) versus 1.70 (1.50 - 1.87) ng/ml, p=0.013]. In multiple logistic regression, age, TGF-ß2, and TGF-ß3 were the only independent predictors of subclinical atherosclerosis in CKD patients [age: odds ratio (OR), 1.054; 95% confidence interval (CI): 1.003 - 1.109, p=0.039; TGF-ß2: OR, 0.996; 95% CI: 0.994-0.999, p=0.018; TGF-ß3: OR, 0.992; 95% CI: 0.985-0.999, p=0.029). TGF-ß1 genotypes did not influence serum levels of TGF-ß1 and no association was found between the TGF-ß1 gene polymorphisms and atherosclerosis risk. CONCLUSION: TGF-ß isoforms seem to offer protection against the development of atherosclerosis among South African CKD patients.

Proteinuria, graft outcomes, and cardiovascular risk among kidney transplant recipients in a South African Public Hospital.

Proteinuria is a marker of poor long-term graft survival and an independent risk factor for total and cardiovascular mortality in the transplant population. We investigated the prevalence of proteinuria and its relationship with graft function and cardiovascular risk factors in kidney transplant recipients (KTRs). Adult KTRs at the Charlotte Maxeke Johannesburg Academic Hospital were recruited. Patients' records were reviewed for information on their posttransplant follow-up. Echocardiography and carotid Doppler were performed for the assessment of cardiac status and carotid intima-media thickness (CIMT), respectively. Proteinuria was analyzed both as a categorical and continuous variable. Graft dysfunction was defined as estimated glomerular filtration rate of <60 mL/min/1.73 m 2 based on the modification of diet in renal disease formula. Framingham's risk score was used to categorize patients' cardiovascular risk. Inferential and modeling statistics were applied as appropriate using Statistical Package for Social Sciences, and P ≤0.05 was considered statistically significant. One hundred KTRs including 63% males were recruited. Proteinuria was present in 51%, the mean ± standard deviation 24 h urinary protein excretion per day was 1.67 ± 2.0 g/day with a range of 0.4-9.4 g/day. Graft dysfunction was found in 52% of patients and 36% had high cardiovascular disease (CVD) risk. Proteinuric KTRs had high CVD risk, P = 0.002. Proteinuria was associated with graft dysfunction, increased left ventricular mass index, increased CIMT, and anemia. Proteinuria is prevalent; it is a marker of graft dysfunction and is associated with markers of atherosclerosis.

Correlation between volume overload, chronic inflammation, and left ventricular dysfunction in chronic kidney disease patients.

BACKGROUND: Fluid overload is common in chronic kidney disease (CKD) patients, potentially driving chronic inflammation and left ventricular dysfunction. We investigated the association between volume overload, chronic inflammation, and left ventricular dysfunction across subgroups of CKD patients. METHODS: The study included 160 participants, comprising peritoneal dialysis (PD), hemodialysis (HD), stage-3 CKD patients, and age- and sex-matched controls (40 in each group). Fluid status was assessed using a body composition monitor (BCM); serum endotoxin, lipopolysaccharide binding protein (LBP), C-reactive protein (CRP). and interleukin-6 (IL-6) levels were measured as markers of inflammation. Echocardiography was done to assess left ventricular dimension and function. RESULTS: Endotoxemia and volume overload were common across the spectrum of CKD patients and were aggravated by worsening kidney function. Among HD cohorts, postdialysis endotoxemia was increased among patients with dialysis-induced hemodynamic instability and was also closely related to ultrafiltration volume. Endotoxin, IL-6, CRP, and LBP levels were elevated in patients with volume overload compared to euvolemic patients (p < 0.05). Patients with elevated circulating endotoxemia had higher left ventricular mass index (LVMI) compared to patients with lower endotoxin levels. Fluid overload correlated with endotoxin levels, IL-6, and LVMI; while LVMI correlated weakly with LBP and CRP. CONCLUSION: CKD patients typically presented with significant endotoxemia and overt volume overload, which may contribute significantly to chronic low-grade inflammation and left ventricular dysfunction. An additive contribution from hemodialysis treatment may strongly enhance the severity of endotoxemia in HD patients.

Volume overload and its risk factors in South African chronic kidney disease patients: an appraisal of bioimpedance spectroscopy and inferior vena cava measurements.

BACKGROUND: Fluid retention occurs early in chronic kidney disease (CKD) resulting in increased cardiovascular morbidity and mortality. This study aimed to assess volume and nutritional status among South African CKD participants and determine the relationship between malnutrition, inflammation, atherosclerosis, and volume overload using a body composition monitor (BCM). We also evaluated the usefulness of BCM measurement in assessing volume overload. METHODS: 160 participants comprising hemodialysis, peritoneal dialysis, stage 3 CKD patients, and healthy controls (40 in each group) were studied. A BCM was used to assess fluid and nutritional status. Cardiac dimension measurements, and inferior vena cava diameter (IVCD) and carotid intima media thickness were assessed by echocardiography and ultrasonography, respectively. Serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were measured as markers of inflammation. RESULTS: Fluid overload and malnutrition were present in 68% and 63% of studied patients, respectively. Using physical examination findings as the reference measurements for volume overload, the area under the concentration curves for BCM and IVCD measurements were 0.866 (sensitivity 82%, specificity 74%, p < 0.001) and 0.727 (sensitivity 57%, specificity 70%, p < 0.001), respectively. Lean tissue index, inflammation, and atherosclerosis were associated with volume overload. CONCLUSIONS: Volume overload and malnutrition were common across the spectrum of South African CKD cohorts; volume overload was associated with malnutrition, inflammation, and atherosclerosis. Bioimpedance spectroscopy (BIS) is a useful and sensitive tool for the assessment of fluid status in clinically euvolumic nondialytic CKD patients.

Solute clearance measurement in the assessment of dialysis adequacy among African continuous ambulatory peritoneal dialysis patients.

Solute clearance measurement is an objective means of quantifying the dose of peritoneal dialysis (PD). Despite continued debate on the interpretation and precise prognostic value of small solute clearance in PD patients, guidelines based on solute clearance values are common in clinical practice. There is limited information on the solute clearance indices and PD adequacy parameters among this predominantly low socioeconomic status PD population. We investigated the solute clearance among continuous ambulatory peritoneal dialysis (CAPD) patients at the Charlotte Maxeke Johannesburg Academic Hospital and its relationship with other parameters of PD adequacy. Seventy patients on CAPD were studied in this cross-sectional study. Solute clearance was assessed using urea clearance (Kt/V). Linear regression analysis was used to determine factors associated with solute clearance, while analysis of variance was used to test the influence of weekly Kt/V on blood pressure (BP), hemoglobin (Hb) and other biochemical parameters. The mean age of the study population was 37.9 ± 12.4 years, 43% were females and 86% were black Africans. The mean duration on CAPD was 19.7 ± 20.8 months. Mean systolic and diastolic BP were 144 ± 28 and 92 ± 17 mm Hg, respectively. The mean Hb was 11.1 ± 2.2 g/dL and the mean weekly Kt/V was 1.7 ± 0.3. Factors like systolic BP, Hb level, serum levels of cholesterol, calcium, phosphate, parathyroid hormone and albumin were not significantly associated with the weekly Kt/V. We conclude that the dose of PD received by the majority of our patients in terms of the weekly Kt/V is within the recommended values and that this finding is significant considering the low socioeconomic background of our patients. There is no significant association between Kt/V and other indices of dialysis adequacy.

Quality of life in patients on continuous ambulatory peritoneal dialysis in an African setting.

To determine the quality of life (QOL) of patients on continuous ambulatory peritoneal dialysis (CAPD), we studied all the CAPD patients attending their monthly follow-up care clinics at three tertiary hospitals in Johannesburg by administering the World Health Organization QOL-Bref questionnaire. The patients were grouped according to age, duration of peritoneal dialysis and gender. Data were analyzed to determine the significant differences in the QOL scores among the subgroups. There were 114 patients [64 males (56.1%), with a mean age of 42.4 ± 11.3 years) and 38 healthy control subjects (22 males (57.9%), with a mean age of 42.1 ± 12.4 years]. Twenty-one patients (18.4%) had hemoglobin <10 g/dL, while 16 patients (14%) had serum albumin <3 g/dL. The mean QOL scores in the physical, psychological, social relationships and environment domains of the CAPD patients were 55.7 ± 15.0, 56.6 ± 16.4, 55.3 ± 24.7 and 56.3 ± 16.6, respectively. The CAPD patients had significantly lower QOL scores compared with controls, and those aged <30 years had better scores in the physical and psychological domains, gender and hemoglobin concentration. Serum albumin levels did not have a significant impact on the QOL of the CAPD patients.

Urinary screening abnormalities in antiretroviral-naive HIV-infected outpatients and implications for management--a single-center study in South Africa.

Few urinary screening studies have been performed to determine the incidence of urinary abnormalities in antiretroviral therapy-naive, HIV-infected outpatients. From published data, the incidence appears to be high, particularly when compared with populations outside sub-Saharan Africa. In South Africa, urinary screening in antiretroviral therapy clinics is not routinely practiced. The aim of this descriptive study was to screen antiretroviral therapy-naive, HIV-infected outpatients attending the HIV clinic for urinary abnormalities, namely leukocyturia, microscopic hematuria, and microalbuminuria/proteinuria. This study showed that 84% of the screened population had AIDS (CD4 count < 200 cells/ mm3), and the incidence of abnormalities on urinary dipstick testing was high: 30% had leukocyturia, 33% had microscopic hematuria, and 44% had microalbuminuria/proteinuria. In patients with leukocyturia, an infective organism was cultured in only 29.1% of cases, predominantly Escherichia coli (70%) with sterile leukocyturia comprising the remainder. There may be an association with tuberculosis (TB) or sexually transmitted infections (STI) in the sterile leucocyturia group, but this remains to be confirmed. In those with a culture positive result the most common organism was E. coli (70%), which exhibited 90% resistance to cotrimoxazole, demonstrating that cotrimoxazole prophylaxis is not effective to prevent urinary tract infection in this group. On the basis of these findings, it has been proposed that urinary screening be considered standard of care in HIV clinics in South Africa. An algorithm has been proposed for use in antiretroviral therapy clinics in South Africa to guide clinicians regarding the cost-effective management of urinary dipstick abnormalities.

Infection and glomerulonephritis.

Glomerular injury, occurring either as primary glomerular disease or as part of a systemic disease process, is usually a result of immune-mediated mechanisms. The morphologic reaction pattern has a diverse spectrum of appearance, ranging from normal by light microscopy in minimal change disease to crescentic forms of glomerulonephritis, with conspicuous disruption of the normal glomerular morphology. The mechanisms of glomerular immune deposit formation include trapping of circulating antigen-antibody complexes and the in situ formation of immune complexes within the glomerulus. While the majority of postinfectious immune-complex-mediated glomerulonephritides are believed to result from the deposition of circulating antigen-antibody complexes, preformed outside of the kidney and secondarily deposited in the kidney, the notion of forming in situ antigen-antibody complexes to either planted antigens or to integral structural components of the glomerulus, through "cross-reacting" autoimmune reactions, is gaining popularity in a variety of forms of glomerulonephritides. Patients with HIV infection may develop a spectrum of renal pathology, the glomerular manifestations of which include both antigen-antibody complex and nonimmune-complex-mediated pathogenetic mechanisms. Similarly, patients with Streptococcal infections, Hepatitis B virus, or Hepatitis C virus infection may develop a spectrum of glomerulonephritides, which are predominantly immune-complex-mediated. Therapy for glomerular diseases due to HIV, hepatitis B, or C virus infections remains a challenge.