Journal of Nephrology

Shah, Sudhir V.; Feehally, John

doi: 10.1093/joneph/21.1.1pmid: N/A

McFarlane, Philip A.

doi: 10.1093/joneph/21.1.6pmid: N/A

People undergoing dialysis have a substantially shortened survival and a high rate of cardiovascular events. Recent clinical trials have failed to demonstrate a survival benefit of reducing traditional or dialysis-specific cardiovascular risk factors. The reasons for the failure of these clinical trials are unclear. One candidate explanation is that they lacked sufficient statistical power to detect important outcome differences. Several errors in trial design or execution can lead to trials being underpowered. An overestimation of the attributable risk of the condition of interest is a common error. Statistical models that partition attributable risk can be invalid when multiple risk factors are present, as is the case in dialysis patients. Diabetes investigators faced similar challenges in their early clinical trials. However, using only 160 people with diabetes, the Steno-2 Study demonstrated a 50% reduction in cardiovascular risk in people. This impressive result was achieved because patients in the experimental arm of the Steno-2 Study underwent reduction of multiple cardiovascular risk factors simultaneously. A Steno-2 Study approach would be an attractive trial design for dialysis investigators. It could be done with fewer resources than conventional randomized trials, and a positive result would strongly argue against therapeutic complacency in the dialysis unit. However, a variety of limitations to this approach exist. Most significantly, if positive, it would not be possible to determine which individual components of the intervention led to the improved outcomes. Despite the limitations, the Steno-2 design should currently be an attractive option for dialysis investigators.

Wagner, Carsten A.

doi: 10.1093/joneph/21.1.14pmid: N/A

Autosomal recessive and autosomal dominant polycystic kidney disease (ADPKD and ARPKD) are 2 major variants of inherited diseases leading to the cystic degeneration of the kidney and other organs. Primary cilia have moved into the focus of research as it is becoming increasingly clear that dysfunction of this special cell organelle represents the main underlying mechanism of disease. At the same time, we also learn that the primary cilium plays an important role in the regulation of cell proliferation and transport processes along the nephron in the healthy kidney. Three recent publications implicate 2 novel players in ciliogenesis and cyst formation: the von Hippel Lindau tumor suppressor gene (pVHL) and collectrin.

Tentori, Francesca

doi: 10.1093/joneph/21.1.17pmid: N/A

Zoccali, Carmine; Leonardis, Daniela; Enia, Giuseppe; Postorino, Maurizio; Mallamaci, Francesca

doi: 10.1093/joneph/21.1.20pmid: N/A

London, Gérard M.

doi: 10.1093/joneph/21.1.23pmid: N/A

Epidemiological studies have emphasized the relationship between blood pressure (BP) and the incidence of cardiovascular diseases. Severity of hypertension was in the past judged on the basis of diastolic BP. More recent epidemiological studies have directed attention to systolic pressure as a better guide to cardiovascular and allcause mortality. Traditionally, hypertension was appreciated by measures of BP recorded in peripheral arteries, usually brachial artery which was assumed to reflect pressures in all parts of arterial system. All these studies neglected that peripheral systolic BP differs from pressure recorded in the aorta and central arteries. While mean and diastolic pressures are almost constant along the arterial tree, due to the stiffness and geometric heterogeneity of large arteries and the timing and magnitude of wave reflections systolic BP and pulse pressure are amplified from the aorta to peripheral arteries, and brachial systolic BP only indirectly reflects the systolic BP in the aorta and central arteries. Several recent studies have shown that the effects of antihypertensive drugs are not the same in peripheral and central arteries, fact which could account for different effects of various drugs on end-organ damage, such as regression of left ventricular hypertrophy. Moreover, it has been shown that aortic and central artery pressure (or their determinants) are stronger predictors of end-organ damage and cardiovascular outcome than conventionally measured brachial pressure. These studies have focused the attention on the physical properties of large arteries and on the way they influence the level of systolic and pulse pressures along the arterial tree.

Breunig, Frank; Wanner, Christoph

doi: 10.1093/joneph/21.1.32pmid: N/A

Fabry disease is an X-linked lysosomal storage disorder which is caused by a deficiency of the lysosomal enzyme a-galactosidase A. The lack of enzyme causes a progressive intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (GL3). Affected organs are, among others, the vascular endothelium, heart, brain and kidneys, as well as the central and peripheral nervous system. With the approval of enzyme replacement therapy (ERT) in 2001, a specific treatment approach was opened for the first time. Randomized and placebo-controlled trials have shown the safety and efficacy of ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Long-term treatment outcomes in patients with severe organ manifestations, in particular proteinuria and renal function impairment, are still critical and warrant further investigation. Besides ERT being an optimized adjunctive therapy, timely initiation of ERT is important to assure optimal medical care. Subsequent follow-up assessments should be carried out in all patients on a regular basis to evaluate treatment outcomes.

Panichi, Vincenzo; Mantuano, Emanuela; Paoletti, Sabrina; Santi, Samuele; Rizza, Giovanni Manca; Cutrupi, Sebastiano; Pizzini, Patrizia; Spoto, Belinda; Tripepi, Giovanni; Zoccali, Carmine

doi: 10.1093/joneph/21.1.38pmid:

Furuland, Hans; Linde, Torbjörn; Englund, Anders; Wikström, Björn

doi: 10.1093/joneph/21.1.45pmid: N/A

Background: Cardiac autonomic function can be measured by heart rate variability (HRV). Dialysis patients have an abnormally low HRV and are at increased risk for sudden death. A reduction in HRV is associated with anemia. HRV was therefore measured in patients with chronic kidney disease (CKD) after hemoglobin normalization.Methods: Sixteen nondiabetic patients with CKD stage 4 (glomerular filtration rate 23.7 ± 13.9 ml/min) and renal anemia received epoetin aiming at a hemoglobin level of 135- 150 g/L. HRV was measured by 24-hour Holter electrocardiogram at baseline and after hemoglobin normalization and in a reference group consisting of 16 volunteers without impairment of renal function.Results: Hemoglobin level increased from 100.7 ± 12.6 g/L to 142.4 ± 7.2 g/L during the study. At baseline, HRV measured in the time domain as the standard deviation of all normal RR intervals in the entire 24-hour electrocardiogram (SDNN) was 116.3 ± 39.2 ms compared with 147.5 ± 27.2 ms in the reference group (p<0.05). The frequency domain measures low-frequency power and total power were 367.7 ± 350.2 ms2 and 1,368.9 ± 957.4 ms2 compared with 717.3 ± 484.5 ms2 and 2,228.3 ± 1142.4 ms2 (p<0.05) in the reference group. After hemoglobin normalization there was an increase in low-frequency power to 498.3 ± 432.7 ms2 (p<0.05) and in total power to 1,731.0 ± 1,069.4 ms2 (p<0.05) while SDNN remained at 120.9 ± 33.8 ms (p=ns).Conclusions: CKD patients not yet on dialysis had a reduced HRV, indicating impaired autonomic function, compared with a reference group without impaired renal function. Hemoglobin normalization improved but did not fully normalize HRV. The clinical significance of this deserves further investigation.

Takahashi, Sachiko Nonaka; Fujita, Takayuki; Takahashi, Teruyuki; Wada, Yuki; Fuke, Yoshinobu; Satomura, Atsushi; Matsumoto, Koichi

doi: 10.1093/joneph/21.1.53pmid: N/A

The degree of tubulointerstitial fibrosis is a poor prognostic indicator in IgA nephropathy (IgAN). Recently, connective tissue growth factor (CTGF) was observed to be strongly up-regulated in human proliferative and fibrogenic diseases. Renal biopsy specimens were obtained from the 20 patients with IgAN. Based on a previously reported study (MDRD study), all cases were categorized into 2 groups. Group A included patientswith urinary protein (u-protein) <1.0 g/day, and group B, those with u-protein ≥1.0 g/day. Expressions of transforming growth factor ß1 (TGF-ß1) and CTGF mRNAs in tubular epithelial cells (TECs) were examined in all cases using rapid in situ hybridization (rISH). Significantly strong and diffuse expressions of TGF-ß1 and CTGF mRNAs were observed in proximal TECs in group B, while the expressions of these 2 mRNAs were weak in proximal TECs in group A and in glomerular resident cells in both groups. These results closely correlated with the degree of disorder in conventional pathohistological findings and clinical parameters except for u-protein level. The increase of u-protein level is one of the most important factors influencing the expression of TGF-ß1 and CTGF mRNAs in TECs. Therefore, the authors conclude that both u-protein level and expressions of these 2 mRNAs in TECs were significantly correlated with the degree of tubulointerstitial damage in IgAN.