Chronic kidney disease leads to hypoxia inducible factor-1alpha to hypoxia inducible factor-2alpha switch in the gastrocnemius muscle.

Hipoxia inducible factor-1 and HIF-2 are responsible for the adaptation of cell metabolism to hypoxia. Previously, a more severe capillary rarefaction was found in locomotor than in postural muscles of uremic animals. The aim of this study was to analyze the expression patterns of HIF and prolyl hydroxylases (PHDs) in functionally different skeletal muscles in uremic rats, an experimental model of chronic kidney disease (CKD). Rats were randomized to sham operation - CON, uninephrectomy - CKD1/2 or subtotal nephrectomy - CKD5/6. After 4 weeks, expression of HIF-1α and -2α and PHD proteins was measured using WB in locomotor, gastrocnemius muscle (MG) and postural, longissimus thoracis muscle (ML). Serum concentrations of creatinine (Cr), hemoglobin (Hb), haptoglobin (Hp), MCP-1, AGEs, homocysteine (Hcy) were measured. HIF-1α increased in MG and ML for CKD1/2 versus CON. HIF-1α decreased in MG and increased in ML for CKD5/6 versus CON and CKD1/2. HIF-2α increased in MG for CKD5/6 and CKD1/2 versus CON. HIF-2α was not detected in ML in any group. PHD1 was not detected in MG in any group. PHD1 in ML was not detected in CON, but increased in CKD5/6 and CKD1/2. PHD2 decreased in MG but increased in ML for CKD5/6 versus CKD1/2 and CON. PHD3 did not differ between groups in MG, but in ML decreased in CKD5/6 versus CON and CKD1/2. There were significant differences for CKD5/6 and CKD1/2 versus CON in: Cr (1.2 ± 0.2; 0.7 ± 0.1 versus 0.8 ± 0.3 mg/dl), Hb (11.4 ± 3.1; 13.7 ± 0.7 versus 14.1 ± 1 g/dl), Hp (1.6 ± 0.6; 1.6 ± 0.6 versus 0.7 ± 0.4 mg/ml), AGEs (5.1 ± 0.6; 4.3 ± 1.2 versus 4.6 ± 0.9 AU), Hcy (7.2 ± 1.2; 5.1 ± 0.5 versus 4.9 ± 0.5 µM), MCP-1 (609 ± 255; 489 ± 265 versus 292 ± 113 pg/ml), respectively. CKD had a different effect on protein expression patterns of HIF-1α, -2α and PHDs depending on muscle type. A HIF-1α to HIF-2α switch in glycolytic MG in CKD5/6 might be a protective mechanism against tissue hypoxia and oxidative stress.

Morphometric analysis of muscle fibre types in rat locomotor and postural skeletal muscles in different stages of chronic kidney disease.

Muscle weakness and progressive loss of skeletal muscle mass are serious complications of chronic kidney disease (CKD). The pathogenesis of this condition is still poorly understood. The study investigated fibre type distribution and diameter in functionally different skeletal muscles: locomotor, gastrocnemius muscle (MG) and postural, longissimus thoracis muscle (ML) together with an evaluation of metabolic disturbances and nutritional parameters of rats with different stages of CKD. Wistar rats were randomized to a sham operation - CON, uninephrectomy - CKD1/2 or subtotal nephrectomy - CKD5/6. After 4 weeks, serum concentration haemoglobin (Hb), haptoglobin (Hp), MCP-1, advanced glycation end products (AGEs), and homocysteine (Hcy) were measured. Muscle specimens were stained for myofibrillary ATPase and NADH-diaphoreses activity according to Ziegan's method. There was a significant increase in the percentage of IID/X with a concomitant decrease of IIB fibres in ML in CKD1/2 vs. CON and CKD5/6. IIB fibre diameters in ML were smaller (53.4±7.3 vs. 58.1±8.1 and 59.8±11.2; p=0.08) for CKD5/6 vs. CKD1/2 and CON, respectively. There were significant differences for CKD5/6 and CKD1/2 vs. CON in: Hb (11.4±3.1; 13.7±0.7 and 14.1±1 g/dl), Hp (1.6±0.6; 1.6±0.6 and 0.7±0.4 mg/ml), AGEs (5.1±0.6; 4.3±1.2 and 4.6±0.9 AU), Hcy (7.2±1.2; 5.1±0.5 and 4.9±0.5 M), MCP-1 (609±255; 489±265 and 292±113 pg/ml), respectively. We concluded that early stages of CKD could induce the process of compensatory fast to slow fibre transformation, while in more advanced CKD this process may be blocked and atrophy of fast-twitch fibres may occur, predominantly in non-locomotor muscles. These disturbances can be secondary to CKD-related metabolic burden and inflammation.

Long graft cold ischemia time is associated with increased arterial stiffness in renal transplant recipients.

BACKGROUND: Increased pulse wave velocity (PWV), an indicator of arterial stiffness, is associated with greater cardiovascular risk among renal transplant recipients. PWV depends on recipient-related factors and, as shown in recent studies, also on donor age. There is a lack of information whether graft-related factors influence arterial function in recipients. Graft cold ischemia time (CIT) significantly influences renal transplant outcomes. It was shown in an experimental model of aortic grafting that increased CIT promoted arteriosclerosis. The aim of the present study was to evaluate the relationship between renal graft CIT and PWV. METHODS: Carotid-femoral PWV were measured in 103 cadaveric kidney recipients of mean age 45 +/- 12 years. We analyzed clinical data of recipient and donor ages, genders, body mass index, blood pressure, CIT, delayed graft function, and type of immunosuppressive therapy to compare patients with CIT < 24 (n = 24) versus CIT > or = 24 hours (n = 79). RESULTS: PWV was lower among patients with shorter CIT (8.3 +/- 1.6 vs 9.2 +/- 2.0 respectively; P < .05). No significant differences were observed between the groups regarding donor and recipient ages, blood pressure, glomerular filtration rate, or immunosuppressive and cardiovascular therapy. A significant positive correlation was noted between PWV and CIT (r = .23; P = .019). Multiple regression analysis demonstrated that recipient age, therapy with cyclosporine, fasting glucose, systolic blood pressure, and CIT were independently associated with PWV. CONCLUSIONS: Long CIT was associated with increased arterial stiffness. Further studies are necessary to understand the cause effect relationship of this finding.

Parathormon, calcium, phosphorus, and left ventricular structure and function in normotensive hemodialysis patients.

Clinical and experimental data suggest that Parathormon (PTH), calcium, and phosphorus participate in left ventricular hypertrophy (LVH) and affect myocardial contractility in end-stage renal disease. Cellular calcium overload and interstitial fibrosis induced by PTH may lead to impairment of left ventricular diastolic function. Hyperphosphatemia is an independent risk of cardiovascular mortality in dialysis patients. The aim of the study was to estimate the influence of PTH and calcium-phosphorus metabolism on left ventricular structure and function in hemodialysis patients, without hypertension and antihypertensive drug therapy (SBP = 126.2 +/- 11.1 DBP = 75.8 +/- 6.5 mmHg). Echocardiographic findings in a group of 22 normotensive HD patients had been compared to 43 hypertensive HD patients. Relationships between PTH, calcium-phosphorus metabolism and echocardiography in normotensive group were then evaluated. Left ventricular mass index (LVMI) was lower in normotensive patients: 128.3 +/- 46.2 versus 165.8 +/- 46.7 (p < 0.01). The prevalence of LVH was 55% in normotensive HD patients compared to 86% in hypertensive group (p < 0.01). In normotensive group we found correlation between PTH and LVMI (r = 0.44; p < 0.05). There were also significant relationships between calcium and posterior wall thickness (r = -0.44; p < 0.05), phosphorus and LVMI (r = 0.47; p < 0.05). A significant correlation was observed between both phosphorus, calcium x phosphorus product and E/A ratio: r = -0.47 and r = -0.43, respectively (p < 0.05 both). Disturbances of calcium-phosphorus metabolism and secondary hyperparathyroidism contributes to left ventricular hypertrophy, and impaired left ventricular diastolic function in normotensive hemodialysis patients.

[Does any relationship exist between metabolic disturbances and some markers of renal damage in patients with untreated essential hypertension?]. / Czy istnieja zaleznosci pomiedzy niektórymi zaburzeniami metabolicznymi a wybranymi wskaznikami uszkodzenia nerek u chorych z nieleczonym pierwotnym nadcisnieniem tetniczym?

The essential arterial hypertension is the second (after diabetes mellitus) cause of chronic renal failure which means a great social and economic burden to the society. It is well known that hypertension is a metabolic syndrome resulting in tissue injury. We tried to investigate the possible influence of some metabolic disturbances on renal function in nontreated essential hypertension. We have compared 25 patients with nontreated essential hypertension (11 women, 14 men) with 14 healthy volunteers (7 women, 7 men) matched for age. The patients' group was characterized by significantly higher urine excretion of NAG (N-acetyl-beta-D-glucosaminidase) (2.75 +/- 1.69 vs 1.82 +/- 1.46 p < 0.05) and a tendency to significantly higher urine fractional sodium excretion without significant difference in albumin excretion. These findings suggest that the tubular damage is present. We noticed the negative linear correlation between mean arterial pressure and (MAP) and NAG urine excretion in the group of hypertensive patients which may reflect the renal ischemia in tubulo-interstitial pathology. Our data suggests that in nontreated arterial hypertension the renal blood flow disturbances are the important cause of the deterioration of tubular function (which are earlier to glomerular damage).