The delivery of renal replacement therapy in Scotland--why the geographic variation?

BACKGROUND: The incidence of patients starting renal replacement therapy (RRT) for established renal failure (ERF) in Scotland has fallen from 2005 to 2011 due to a reduction in older patients starting RRT; there are significant differences between NHS Health board areas. AIM: To understand the apparent inequality in provision of RRT between NHS board areas in Scotland. DESIGN: Retrospective population analysis of Scottish renal registry (SRR) data, population statistics and quality outcomes framework summary statistics. RESULTS: The incidence of patients starting RRT for ERF in Scotland fell from 123 per million population (pmp) in 2005 to 96 pmp in 2011. The incidence of ≥75 year olds fell from 406 to 274 pmp. There are significant differences between NHS board areas when standardized for age and social deprivation. There is no relationship between the population prevalence of CKD as reported by QOF and the incidence of RRT for ERF. Those areas with high incidence rates of ≥75 year olds have higher 90-day [Spearman's rank correlation: coefficient = 0.662; P = 0.03] and 1-year [Spearman's rank correlation: coefficient = 0.776; P = 0.003] mortality rates. CONCLUSION: The significant variation in provision of RRT for ERF between Scottish NHS Board areas is not explained by age or social deprivation. There is evidence of change in practice towards RRT for patients aged ≥75 years but variation between NHS Board areas. This disparity must be further investigated to ensure equity of access to RRT for those who will benefit from it, and to non-dialytic care for those who would not.

Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats.

BACKGROUND: Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background. METHODS: Using a single homozygous TGRmRen2-27 male as transgene donor, we produced two F1 populations with (a) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH. RESULTS: Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 +/- 9.5 vs. 91.8 +/- 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH. CONCLUSIONS: Our study demonstrates the application of a transgene as a "major gene" to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.

Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27.

BACKGROUND: Activation of the renin-angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin- -) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. OBJECTIVE: Tissue renin-angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. METHOD: Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 microg/kg per day) from 28 to 120 days of age, untreated rats acting as controls (n = 40). The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treatment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. RESULTS: Sixty-three per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats. The degree of medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. CONCLUSIONS: Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal 'vasculotoxic' agent in malignant hypertension.

Developmental studies demonstrate age-dependent elevation of renin activity in TGR(mRen2)27 rats.

The objective of the present study was to determine the relationship between plasma renin levels, and the development of hypertension and cardiac hypertrophy in TGR (mREN2)27 hypertensive rats. Systolic blood pressure and left ventricular mass index (LVMI) were measured in transgenic heterozygote and normotensive Sprague Dawley control rats at 25, 35, 45, 55, 65, and 75 days of age together with determinations of plasma active renin and prorenin, and renal and adrenal tissue renin, which were assayed at pH 6.5, 7.4, and 8.5. The systolic blood pressure and the LVMI of the transgenic rats were significantly increased compared to control rats by 55 and 65 days of age, respectively. Plasma active renin of the transgenic rats, measured at physiological pH, was significantly higher from 55 days of age, increasing in parallel with blood pressure and remaining significantly higher than controls at all age groups tested. Assays of both plasma and adrenal renin at various pHs showed a profile of angiotensin I generation that matched mouse renin more closely than that of rat renin. The ratio of angiotensin I (Ang I) generation at pH 8.5 and pH 6.5 was 0.5 for normal rat plasma but was between 3 and 5 for mouse plasma. Plasma prorenin and adrenal tissue renin from transgenic rats exhibited a pH profile consistent with the major portion being mouse renin. However, the low level of kidney renin observed in the transgenic rats exhibited a pH ratio (8.5/6.5) identical to that of normal rat renin (0.5), suggesting that residual renin within the kidney was predominantly of rat origin. These data indicate that plasma renin levels closely parallel the development of high blood pressure and LVMI and show that interpretation of the renin status of this strain is critically dependent on the assay conditions used. Under the conditions used in this study it was found that the TGR(mRen2)27 rat is a high mouse plasma renin model of hypertension.

Endothelin in the kidney in malignant phase hypertension.

A role for endothelin in malignant phase hypertension has been suggested on the basis of reported increases of circulating plasma immunoreactive endothelins in animal models. Recently, a hypertensive rat model that exhibits a genetically determined tendency for developing spontaneous onset malignant hypertension has been described. Expression of the three genes endothelin-1, endothelin-2, and endothelin-3 was quantified in the kidney by specific RNase protection assays in rats with established malignant hypertension, in rats with benign hypertension with and without a genetic susceptibility to malignant hypertension, and in normotensive Sprague-Dawley rats. Endothelin-1 mRNA levels were significantly elevated in the group with malignant hypertension compared with the other three groups. For determination of whether endothelin-1-mediated effects were crucial in the transition from benign to malignant phase hypertension, an oral nonspecific combined endothelin-A and endothelin-B receptor antagonist (bosentan) was given to hypertensive rats susceptible to malignant hypertension. No hypotensive effects were observed, and no significant difference in the incidence of malignant hypertension was observed between treated and control groups. In conclusion, although increased endothelin-1 mRNA expression was found in kidney tissue from rats developing malignant hypertension, blockade of endothelin-1-mediated effects did not prevent the transition from benign phase hypertension. Hence, increased renal endothelin-1 expression in this model of malignant hypertension does not appear to have a causative role and may simply reflect cellular damage and ischemia.

A genetic model of malignant phase hypertension in rats.

A genetic model of malignant phase hypertension in rats is described which closely parallels the natural history of untreated human malignant phase hypertension. Although the factors initiating transition from essential hypertension to the accelerated phase in humans remain unknown, we report the characteristics of a genetically determined and reproducible phenotype which was found to result from a cross between hypertensive transgenic Ren-2 rats and normotensive Sprague-Dawley (Edinburgh) rats. Male F1 hybrids developed malignant phase hypertension with a penetrance of 73.5% (95% confidence limits 65.7 to 81.3%) by 100 days of age. Phenotypic features included an accelerated rise in blood pressure, fibrinoid necrosis, activation of the renal renin-angiotensin system and microangiopathic hemolytic anemia. In an analytical cross no significant difference in blood pressure was observed between malignant phase and non-malignant phase animals prior to transition, implying that a factor in addition to hypertension appears necessary for inducing transition to the malignant phase phenotype. Segregation of the malignant phenotype suggested that susceptibility is determined by at most two genetic loci.

Spontaneous development of malignant phase hypertension in transgenic Ren-2 rats.

Spontaneous development of malignant phase hypertension in TGR(mREN2)27 heterozygotes occurs as a consequence of crossing TGR(mREN2)27 homozygotes with Edinburgh Sprague-Dawley rats. Similarities to human malignant phase hypertension are seen with an accelerated rise in blood pressure, fibrinoid necrosis of renal afferent arterioles, renal failure and evidence of renin-angiotensin system activation. It appears that introduction of an additional genetic factor or factors into a monogenic model of hypertension results in malignant phase hypertension.