Hypertension in children with chronic kidney disease: pathophysiology and management.

Arterial hypertension is very common in children with all stages of chronic kidney disease (CKD). While fluid overload and activation of the renin-angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension. Moreover, several drugs commonly administered in CKD, such as erythropoietin, glucocorticoids and cyclosporine A, independently raise blood pressure in a dose-dependent fashion. Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes, an active screening approach should be adapted in patients with all stages of CKD. Before one starts antihypertensive treatment, non-pharmacological options should be explored. In hemodialysis patients a low salt diet, low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria, due to their additional anti-proteinuric properties. Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin-angiotensin system blockade. Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target, but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes.

Acute blood pressure effects and chronic hypotensive action of calcimimetics in uremic rats.

A previous study in subtotally nephrectomized (SNX) rats suggested beneficial effects of the calcimimetic R-568 beyond the control of mineral metabolism. This study analyzed potential blood pressure (BP)-lowering effects of R-568. Male Sprague-Dawley rats received two-stage subtotal nephrectomy or sham operation. Telemetry devices were inserted into the abdominal aorta, and BP was measured every 5 min. R-568 (20 mg/kg per d) or solvent was infused for 4 wk followed by once-daily subcutaneous injections for 2 wk. Total body sodium was measured by neutron activation analysis. The uremia-induced increase of mean arterial pressure from baseline to day 42 in SNX solvent rats (103+/-5 to 128+/-14 mmHg, P=0.006) was attenuated by R-568 (104+/-5 to 111+/-8 mmHg; P<0.0001 for difference of slopes). The circadian rhythm was abrogated in SNX rats and not restored by R-568. In sham-operated rats, R-568 had only a minor transient antihypertensive effect. R-568 injection induced a transient rise of mean arterial pressure by 23+/-4 and 26+/-10 mmHg in sham and SNX rats but only by 9+/-3 and 10+/-5 mmHg in solvent-treated rats (P<0.01 versus baseline and solvent versus R-568). Plasma angiotensin-converting enzyme activity and aldosterone levels were similar; food intake and physical activity did not differ throughout the study. In healthy rats, total body sodium was higher after 14 d of R-568 compared with solvent infusion (37.1+/-4 versus 32.5+/-1.4 mmol/kg; P=0.01). The calcimimetic R-568 causes an initial BP increase in sham-operated and uremic rats, which in uremic rats is followed by a marked and sustained antihypertensive effect.

Ultradian but not circadian blood pressure rhythms correlate with renal dysfunction in children with chronic renal failure.

Whereas the diurnal fall of BP (dipping) is an important prognostic marker in patients with chronic renal failure (CRF), the integrity of physiologic ultradian (i.e., shorter than 24 h) cardiovascular rhythms in patients with CRF is unknown. Also, the relationship between conventional dipping analysis and Fourier spectral rhythm analysis has not been examined in renal hypertension. The prevalence and dimensions of the circadian and three ultradian (12, 8, and 6 h) cardiovascular rhythms were studied by ambulatory BP monitoring in 214 children (aged 3 to 18 yr) with CRF (stage 2 to 4 chronic kidney disease) and no antihypertensive treatment compared with 938 healthy control subjects, and the relationship of rhythm characteristics to conventional dipping parameters, renal function, proteinuria, and serum electrolytes was assessed. The CRF cohort exhibited significantly reduced amplitudes of the circadian and all ultradian cardiovascular rhythms studied (all P < 0.01). Moreover, all BP and most heart rate rhythms showed significantly delayed acrophases (time of peak; P < 0.01). Whereas conventional BP dipping parameters (day/night difference, day/night ratio) and the 24-h BP amplitude were independent of renal function, the 8-h BP amplitude was positively correlated with GFR (r = 0.3, P = 0.01) and inversely correlated with the urinary protein/creatinine ratio (r = -0.27, P < 0.05), and the 6-h BP amplitude was inversely correlated with proteinuria (r = -0.3, P < 0.02). Children who displayed 24- or 12-h cardiovascular rhythms had significantly lower serum calcium levels than children without these rhythms. In summary, children with CRF display not only blunted circadian but also blunted ultradian cardiovascular rhythms. Ultradian but not circadian rhythms or conventional dipping parameters are quantitatively associated with renal function and proteinuria.

Normative values for circadian and ultradian cardiovascular rhythms in childhood.

To assess the prevalence and characteristics of physiological circadian (24-hour) and ultradian (12-, 8-, and 6-hour) rhythms of mean arterial blood pressure (BP) and heart rate (HR), we analyzed 24-hour ambulatory BP profiles from 938 healthy school children aged 5 to 18 years. Cosine harmonics were fitted by Fourier analysis, and an amplitude and acrophase (time of peak) were calculated for each rhythm. Ninety percent of children displayed circadian rhythmicity of BP, independent of age, whereas circadian HR rhythmicity decreased with puberty from 96% to 87% (P<0.0001). Puberty had marked effects on the prevalence of ultradian rhythmicity: 12- and 6-hour rhythms increased for BP (27% to 47%, P<0.0001; 18% to 25%, P=0.01) and HR (36% to 47%, 17% to 31%, both P=0.001), whereas 8-hour BP rhythms decreased (34% to 23%, P=0.002). Median amplitudes were 10.1, 5.9, 5.6, and 5.2 mm Hg for the 24-, 12-, 8-, and 6-hour BP rhythms, respectively, and 13.4, 7.7, 6.8, and 6.4 bpm for HR. The acrophase occurred at approximately 14:00 hours, 8:00 hours, 5:30 hours, and 2:00 hours (military time) for the four BP rhythms, and at 13:30 hours, 08:30 hours, 01:50 hours, and 02:00 hours for HR. For the combined curve, the peak-trough difference was 25.9 mm Hg and 35 bpm for BP and HR, respectively, with the peaks occurring at 13:50 hours and 13:10 hours. There was marked association between BP and HR rhythms, both for prevalence (P<0.0001 for coupling of BP and HR rhythms of the same period length) and timing, with a median time lag of BP after HR acrophase of only 21, 16, 13, and 5 minutes for the four rhythms, respectively.

Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure.

Ambulatory blood pressure monitoring (ABPM) provides superior information for diagnosis and treatment of pediatric hypertension, but for reasons of practicality, clinic blood pressure measurements (CBP) are still the primary diagnostic tool. Regular home blood pressure measurements (HBP) may be an alternative to ABPM, but this technique awaits validation in practice. We analyzed the concordance of ABPM, CBP and HBP in 118 pediatric patients (3-19 y) with chronic renal failure. HBP readings (10.5 +/- 5.4 per patient) were averaged for one week around the day of ABPM and CBP. Mean arterial pressure (MAP) measured by HBP (84.0 +/- 10 mm Hg) was significantly lower than both CBP (86.1 +/- 14.1 mm Hg, P< 0.05) and daytime ABPM (90.3 +/- 10.4 mm Hg, P< 0.05). HBP detected hypertensive patients with greater specificity (82 versus 70%), but lower sensitivity (52 versus 70%) than CBP. The fraction of patients rated erroneously hypertensive was 23% with CBP, but only 14% with HBP. The 95% limits of agreement with ABPM were narrower for HBP (-23 to10 mm Hg) than for CBP (-30 to 21 mm Hg). CBP, but not HBP measurements, were less precise in the upper BP range. The accuracy of HBP measurements did not change with use over a six months time period. In conclusion, HBP was superior to CBP in predicting ABPM, but neither CBP nor HBP detected hypertension with enough sensitivity or specificity to replace ABPM. The greater specificity of HBP compared with CBP makes it a more suitable tool for diagnosis, rather than screening, of hypertension in children.