Antihypertensive prescribing patterns in non-dialysis dependent chronic kidney disease: Findings from the Salford Kidney Study.

BACKGROUND: Hypertension is commonly observed in patients living with chronic kidney disease (CKD). Finding an optimal treatment regime remains challenging due to the complex bidirectional cause-and-effect relationship between hypertension and CKD. There remains variability in antihypertensive treatment practices. AIM: To analyze data from the Salford Kidney Study database in relation to antihypertensive prescribing patterns amongst CKD patients. METHODS: The Salford Kidney Study is an ongoing prospective study that has been recruiting CKD patients since 2002. All patients are followed up annually, and their medical records including the list of medications are updated until they reach study endpoints [starting on renal replacement therapy or reaching estimated glomerular filtration rate (eGFR) expressed as mL/min/1.73 m2 ≤ 10 mL/min/1.73 m2, or the last follow-up date, or data lock on December 31, 2021, or death]. Data on antihypertensive prescription practices in correspondence to baseline eGFR, urine albumin-creatinine ratio, primary CKD aetiology, and cardiovascular disease were evaluated. Associations between patients who were prescribed three or more antihypertensive agents and their clinical outcomes were studied by Cox regression analysis. Kaplan-Meier analysis demonstrated differences in survival probabilities. RESULTS: Three thousand two hundred and thirty non-dialysis-dependent CKD patients with data collected between October 2002 and December 2019 were included. The median age was 65 years. A greater proportion of patients were taking three or more antihypertensive agents with advancing CKD stages (53% of eGFR ≤ 15 mL/min/1.73 m2 vs 26% of eGFR ≥ 60 mL/min/1.73 m2, P < 0.001). An increased number of patients receiving more classes of antihypertensive agents was observed as the urine albumin-creatinine ratio category increased (category A3: 62% vs category A1: 40%, P < 0.001), with the upward trends particularly noticeable in the number of individuals prescribed renin angiotensin system blockers. The prescription of three or more antihypertensive agents was associated with all-cause mortality, independent of blood pressure control (hazard ratio: 1.15; 95% confidence interval: 1.04-1.27, P = 0.006). Kaplan-Meier analysis illustrated significant differences in survival outcomes between patients with three or more and those with less than three antihypertensive agents prescribed (log-rank, P < 0.001). CONCLUSION: Antihypertensive prescribing patterns in the Salford Kidney Study based on CKD stage were consistent with expectations from the current United Kingdom National Institute of Health and Care Excellence guideline algorithm. Outcomes were poorer in patients with poor blood pressure control despite being on multiple antihypertensive agents. Continued research is required to bridge remaining variations in hypertension treatment practices worldwide.

The association of ECG and echocardiographic abnormalities with sudden cardiac death in a dialysis patient cohort.

BACKGROUND: Cardiovascular mortality is greater in dialysis patients than the general population. More specifically, sudden cardiac death (SCD) accounts for 26% of dialysis patient deaths. However, SCD risk assessment tools used in the general population are not adequate for dialysis patients indicating that the hierarchy of pathopysiological factors appears to be different. The aim of this study was to use simple bedside tests to determine parameters independently predictive of cardiovascular mortality and SCD in dialysis patients. METHOD AND RESULTS: This was a sub-study of the Chronic Renal Insufficient Standards Implementations Study, a longitudinal cohort study of outcomes in CKD. ECG and echocardiographic abnormalities were assessed in a cross-section of prevalent dialysis patients. Patients were followed up until death or transplantation. Forward stepwise Cox regression then determined factors independently associated with all-cause, cardiovascular and SCD mortality. 323 patients were included (age 61.5 ± 14.6 years, 113 deaths, 66 cardiovascular deaths, 18 SCD). A number of factors were independently associated with all-cause mortality. These were age, time on dialysis, smoking, the difference between QRS and T-wave axes, resting heart rate, and pulmonary artery pressure (PAP) >35 mmHg. The only parameters predictive of SCD were elevated PAP (HR = 5.99, p = 0.05) and mitral regurgitation (HR = 6.71, p = 0.01). CONCLUSION: That PAP is associated with SCD in dialysis patients demonstrates that the pathophysiological mechanism is likely to be different in these patients compared to the general population. Because of this, a population specific approach to risk stratification is advisable.

The clinical significance of hyperkalaemia-associated repolarization abnormalities in end-stage renal disease.

BACKGROUND: Hyperkalaemia is a common potentially fatal complication of chronic kidney disease (CKD). It may manifest as electrocardiogram (ECG) changes, the earliest of which is T-wave 'tenting'. However, this occurs in less than half of episodes of hyperkalaemia. The aim of this study was to determine what other clinical features relate to the probability of T-wave tenting; and if there is a longer-term survival difference between patients who develop tenting and those who do not. METHOD: One hundred and forty-five patients with end-stage renal disease who had standard 12-lead ECG and concurrent serum potassium measurement were enrolled. The presence of tenting and the ratio of the amplitude of the tallest precordial T-wave and R-wave were determined (T:R). RESULTS: Tenting was as common in normal range serum potassium as hyperkalaemia (33 versus 31%) and less common than in left ventricular hypertrophy (44%). T:R was less sensitive (24 versus 33%) but more specific (85 versus 67%) than tenting at correctly identifying hyperkalaemia ≥ 6.0 mmol/L. Tenting became less common with increasing age. Dialysis patients were more likely to show increased T:R that pre-dialysis Stage 5 CKD. Elevated T:R was not associated with worse cardiovascular outcome but was associated with increased risk of sudden death over a mean follow-up of 3.8 years (hazard ratio = 8.3, P = 0.021). CONCLUSIONS: The reason for the variability in T-wave changes is not clear. The ratio of precordial T-wave to R-wave amplitude is a more specific measure than tenting but both are poorly sensitive at detecting hyperkalaemia. The greater risk for sudden death may represent a susceptibility to cardiac arrhythmia during repolarization.

Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects.

BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent worldwide. Furthermore, obesity is now a global problem with major health implications. There is a clear association between obesity and the development of CKD but it is not known whether obesity is a risk factor for the progression of pre-existing kidney disease. We examined the relationship between the body mass index (BMI) and the rate of progression of CKD in non-diabetic adults. METHODS: The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a prospective observational study in a predominantly white population in Greater Manchester. From the CRISIS database, we assessed rate of progression of CKD in 499 adults attending the hospital. Baseline measurements including BMI were obtained and estimated glomerular filtration rate (eGFR) was monitored. The rate of deterioration of eGFR was derived over time, defined as ΔeGFR (mL/min/1.73 m2/year) and assessed using univariate analysis of variance. RESULTS: In the groups as a whole, no relationship between BMI and ΔeGFR was shown. Dividing the subjects into obese (BMI≥30) and non-obese (BMI<30) groups and further breakdown into CKD stages 3, 4 and 5, also showed no relationship between BMI and ΔeGFR. Univariate analysis of variance was used. CONCLUSIONS: Neither BMI as a continuous variable nor obesity (BMI≥30) as a categorical variable was associated with an increased rate of progression of existing CKD in this predominantly white population.

How accurately do nephrologists predict the need for dialysis within one year?

BACKGROUND/AIMS: Knowing when patients with chronic kidney disease will need dialysis can improve patient counselling and timing of vascular access. We aimed to assess the accuracy of clinician judgement in predicting the need for dialysis within 12 months. METHODS: We asked the nephrologists in a dedicated pre-dialysis clinic to predict the time until initiation of dialysis for patients. We compared predicted with actual time to dialysis and the accuracy of predictions made by different grades of clinician. Multivariate logistic regression compared clinical parameters that correlated with predicted and actual time to dialysis. RESULTS: One hundred and eighty-four patients were included. The sensitivity of clinician judgement as a predictor of dialysis within 12 months was 95% and the specificity was 62%. Consultants were correct in 71% of cases and trainees in 68% of cases. Estimated glomerular filtration rate (eGFR) was the only independent correlate of predicted time to dialysis [odds ratio (OR) = 1.6 per 1 ml/min/1.73 m(2) reduction, p < 0.001]. eGFR was also associated with actual time to dialysis (OR = 1.6 per 1 ml/min/1.73 m(2), p < 0.001) along with age (OR = 0.94 per year increase, p = 0.005) and itch (OR = 3.7, p = 0.048). CONCLUSION: Clinical judgement is sensitive but not specific in predicting the need for dialysis. Educating the clinicians may improve the specificity of judgement and improve the accuracy of prognostic information given to patients.

Sudden cardiac death in hemodialysis patients: an in-depth review.

Sudden cardiac death (SCD) is the leading cause of death in hemodialysis patients, accounting for death in up to one-quarter of this population. Unlike in the general population, coronary artery disease and heart failure often are not the underlying pathologic processes for SCD; accordingly, current risk stratification tools are inadequate when assessing these patients. Factors assuming greater importance in hemodialysis patients may include left ventricular hypertrophy, electrolyte shift, and vascular calcification. Knowledge regarding SCD in hemodialysis patients is insufficient, in part reflecting the lack of an agreed-on definition of SCD in this population, although epidemiologic studies suggest the most common times for SCD to occur are toward the end of the long 72-hour weekend interval between dialysis sessions and in the 12 hours immediately after hemodialysis. Accordingly, it is hypothesized that the dialysis procedure itself may have important implications for SCD. Supporting this is recognition that hemodialysis is associated with both ventricular arrhythmias and dynamic electrocardiographic changes. Importantly, echocardiography and electrocardiography may show changes that are modifiable by alterations to dialysis prescription. The most effective preventative strategy in the general population, implanted cardioverter-defibrillator devices, are less effective in the presence of chronic kidney disease and have not been studied adequately in dialysis patients. Last, many dialysis patients experience SCD despite not fulfilling current criteria for implantation, making appropriate allocation of defibrillators uncertain.

Structural remodeling of resistance arteries in uremic hypertension.

BACKGROUND: Structural remodeling of the resistance vasculature is present in many forms of human and experimental hypertension. In particular, an increase in the ratio of wall thickness to lumen diameter develops, and might in itself maintain hypertension by increasing vascular resistance. Because uremia is associated with raised peripheral resistance, hypertension, and histologic changes suggestive of vascular remodeling, we sought to formally examine the structural and mechanical (elastic) properties of isolated pressurized resistance arteries in uremic hypertension. METHODS: Cremaster, cerebral and mesenteric arteries from subtotally nephrectomised Wistar-Kyoto rats, normotensive control Wistar-Kyoto rats, and spontaneously hypertensive rats were mounted on a pressure myograph and relaxed in calcium-free buffer. Wall thickness and lumen diameter were measured at increasing lumen pressures from 10 to 200 mm Hg, and from this wall:lumen ratio, wall cross-sectional area, and an index of elasticity were derived. RESULTS: In uremic hypertensive animals increased wall:lumen ratio and decreased lumen diameter was seen in cremaster and mesenteric arteries, although no significant changes were observed in cerebral arteries, compared to normotensive controls. In spontaneously hypertensive animals increased wall thickness and wall:lumen ratio was seen in cerebral and mesenteric arteries, decreased lumen diameter in cremaster and mesenteric arteries, and increased wall cross-sectional area in cerebral arteries, compared to normotensive controls. Elasticity of the arterial wall in uremic and spontaneously hypertensive animals did not differ from normotensive controls. CONCLUSION: Cremaster and mesenteric resistance arteries undergo predominantly eutrophic inward remodeling in uremic hypertension, broadly similar to that seen in spontaneous hypertension.

Calpain is activated in experimental uremia: is calpain a mediator of uremia-induced myocardial injury?

BACKGROUND: The cysteine proteases calpain and caspase-3 are known mediators of cell death. The aim of this study was to assess their contribution to the tissue damage found in experimental uremia. METHODS: Calpain and caspase-3 activities were measured in the hearts of rats that were sham-operated (control), sham-operated and spontaneously hypertensive (SHR), and those rendered uremic by 5/6 nephrectomy (uremic). In an in vitro study, heart myoblasts (Girardi) were incubated with human serum from healthy subjects (control serum conditioned media, CSCM) or uremic patients (uremic serum conditioned media, USCM), in the presence and absence of calpain and caspase-3 inhibitors. After 48 hours the activity of calpain and caspase-3 was measured, and cell injury determined by DNA fragmentation (ELISA) and lactate dehydrogenase (LDH) release. An in situ assay was designed to study how USCM affects calpain activity over time. RESULTS: In the in vivo study, mean calpain activities were almost identical in the control and SHR groups, but calpain and caspase-3 activities were much elevated in the uremic group (P < 0.01 and 0.001 respectively vs. control). The SHR group had significantly higher mean arterial blood pressure (P < 0.001 vs. control, 0.01 vs. uremic). In the in vitro study calpain activity and DNA fragmentation were markedly higher in USCM treated cells compared to CSCM (both P<0.05). Both were reduced in USCM cells containing calpain inhibitors (E64d, calpastatin, or PD 150606). LDH release was raised also in USCM treated cultures (P < 0.05), which only the E64d treatment could significantly reduce (P < 0.02). Caspase-3 activities were similar in USCM and CSCM groups. The in situ assay showed significant increases in calpain activity in USCM treated cells compared to CSCM after just 3.5 hours (P<0.01). CONCLUSIONS: In vivo results suggest that the increases in calpain and caspase-3 activity in uremic rat hearts were primarily due to uremia and not to hypertension. In vitro data demonstrate that uremia-induced cell injury can be attenuated by calpain inhibition. Therefore, it is likely that calpain is a mediator of uremia-induced myocardial injury.

The myogenic response in uremic hypertension.

BACKGROUND: The constriction of resistance arteries in response to an increase in transmural pressure, the myogenic response, is thought to be an important determinant of peripheral vascular resistance and therefore of arterial blood pressure. Since raised peripheral resistance is known to occur in uremic hypertension, abnormal myogenic constriction might be responsible. We sought to assess the myogenic response of resistance arteries from the subtotal nephrectomy rat model of uremic hypertension. METHODS: Uremic Wistar-Kyoto (WKYU) rats, and sham-operated normotensive (WKYC) and spontaneously hypertensive (SHRC) controls were studied in parallel. Skeletal muscle arteries were mounted on a pressure myograph and allowed to develop myogenic constriction. The active internal diameter was measured at increasing lumen pressures from 20 to 200 mm Hg. Vascular smooth muscle then was relaxed in a calcium free solution containing nitroprusside, and the passive internal diameter measured at the same pressure steps. The ratio of active to passive diameter at any given pressure was used to assess the myogenic response. RESULTS: Myogenic constriction was not increased in either WKYU or SHRC compared to WKYC at pressures up to 180 mm Hg. CONCLUSIONS: Increased myogenic tone is not the cause of uremic hypertension.

Altered L-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells.

Results regarding the nitric oxide (NO) system in uraemia are contradictory. L-arginine, the precursor of NO, is also metabolized by arginase to form ornithine and urea. In the present study, endothelial NO production and arginine metabolism in uraemia were assessed. In addition an in vivo model was used to examine excess consumption of NO in uraemia. NO and amino acid measurements were made from basal and stimulated (by bradykinin) uraemic and control endothelial cells. Reverse-transcriptase PCR was used to assess endothelial NO synthase (eNOS) and inducible NOS (iNOS) expression. Finally, aortae of uraemic rats were stained for nitrotyrosine (a marker of peroxynitrite). Basal uraemic cells produced more NO than the control cells. L-arginine levels were greater in uraemic (supernatants/cells), but ornithine levels were higher in control (supernatants/cells). Following stimulation, NO levels in supernatants were similar, but the rise in NO production was greater in control compared with uraemic cells; l-arginine levels still remained higher in uraemic supernatants/cells. Differences in ornithine concentration (supernatants/cells) disappeared following bradykinin stimulation, due to a rise in ornithine levels in the uraemic group. There was no difference in eNOS expression, nor was iNOS detected in either group. Only aortae from uraemic rats showed evidence for nitrotyrosine staining. These studies demonstrated increased basal NO release in uraemic endothelial cells, perhaps by inhibition of arginase and hence diversion of arginine to the NO pathway. The increased NO produced under basal conditions may be inactive due to excessive consumption, resulting in peroxynitrite formation. Interestingly, bradykinin appears to restore arginase activity in uraemia, resulting in normalization of NO production.