Ettore Guidi

Hypertension in Man with a Kidney Transplant: Role of Familial versus Other Factors

Genetic factors are clearly involved in the pathogenesis of essential hypertension in man. In at least three rat models of genetic hypertension it is possible to transplant the hypertension with the kidney. To see whether or not the same is true for humans, we carried out a 2-year retrospective study of 50 selected recipients of a cadaver kidney. We correlated the following factors by multivariate statistical analyses: presence or absence of hypertension in the family of donor and recipients; donors and recipients age; mean blood pressure (MBP) and antihypertensive therapy (AHT) score during dialysis; months of dialysis and body surface before transplantation; body weight, plasma creatinine, prednisone dosage and cumulative rejections with MBP and AHT score at various time intervals after transplantation. The results obtained showed that, considering the recipients coming from normotensive families, the AHT score after transplantation was significantly greater (p less than 0.05 1st and p less than 0.01 2nd year) in the patients receiving a kidney removed from donors with hypertensive families than in patients receiving a kidney removed from donors with normotensive families. This difference was not present when the recipients coming from hypertensive parents were considered. AHT score after transplantation is also correlated with AHT score on dialysis (p less than 0.01 1st and 2nd year), body weight (p less than 0.02 1st and p less than 0.01 2nd year), cumulative rejections (p less than 0.025 1st and 2nd year) and inverse MBP after dialysis (p less than 0.025 2nd year).

Effect of familial hypertension on glomerular hemodynamics and tubulo-glomerular feedback after uninephrectomy☆

Familial hypertension, glomerular hemodynamic alterations, and dysregulation of tubulo-glomerular feedback (TGFB) have all been associated with the development of chronic renal failure. In the present study we evaluated renal and glomerular hemodynamics and TGFB responses in healthy kidney donors either with or without familial hypertension, before and after nephrectomy. Para-amino-hippurate plasma clearance (CPAH) and inulin plasma clearance (CInu) were measured in 15 kidney donors before and 1 year after nephrectomy. All subjects were normotensive and were kept in a sodium-replete state. Both clearances were measured after 40 min of constant infusion of PAH and Inu, as well as 20, 30, 50, and 60 min after the intravenous administration of acetazolamide (5 mg/kg). Glomerular hemodynamics were calculated by means of the Gomez formulae. Nephrectomy caused the expected decreases in CPAH and CInu and increase in the filtration fraction (all P < .0001). The decrease in renal resistances of the remaining kidney was greater at the afferent (-24%, P = .0075) than at the efferent arteriolar level (-17%, P < .0001). The TGFB activation was not altered by nephrectomy or by familial hypertension. Effective renal plasma flow (ERPF) decrease after TGFB activation appeared earlier than glomerular filtration rate (GFR) decrease before (P = .01), but not after, nephrectomy (P = .48). The presence of familial hypertension was associated with increased glomerular pressure (P = .0004). This study suggests that uninephrectomy in healthy human subjects causes a greater decrease in afferent arteriolar resistances, but that TGFB responses are not quantitatively altered. Familial hypertension is associated with a tendency toward higher glomerular pressures.

Genetic and experimental hypertension in the animal model-similarities and dissimilarities to the development of human hypertension

In this article, we present the results we have obtained from experimental and genetic models of human essential hypertension, in order to investigate those findings relevant to understanding the time course and the mechanisms underlying the human disease. With experiments on the renal artery constriction in the conscious dog, we have shown that a kidney lesion can produce a form of hypertension not different, in the established phase, from the essential one and that the onset of this form follows a phasic pattern during which the initial stages are crucial for understanding the mechanisms leading to hypertension. We also consider a rat model (MHS) that spontaneously develops a form of hypertension very similar to the human disease. In this model, we have demonstrated by a kidney cross-transplantation experiment and functional studies that the kidney is responsible for the rise in blood pressure and that the organ dysfunction is probably due to a primary abnormality in ion handling of the cell membrane. This cellular alteration, detected both in MHS erythrocytes and in their kidney proximal tubular cells, should be the cause for the higher rate of kidney Na+ reabsorption observed in the MHS. Comparing this animal model with, at least, a subgroup of humans prone to develop hypertension or already hypertensive, it is possible to detect a series of similarities in the kidney function, hormonal pattern, and cellular function of the two species that allows us to argue that the MHS is a suitable model from which to draw conclusions relevant to the pathogenesis of essential hypertension in some humans.

Acute and long-term effects of ACE inhibition on renal haemodynamics in glomerular and interstitial nephropathies

Background Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for the treatment of hypertension in patients with non-diabetic nephropathies. However, not every trial has reported better results with ACE inhibitors (ACE-I) than with other drugs. This study investigates whether the acute and chronic effects of ACE inhibition on renal and glomerular haemodynamics are similar in glomerular and interstitial nephropathies. Methods We studied 20 hypertensive patients, on their usual diet, with mild-to-moderate chronic renal failure secondary to non-diabetic nephropathy. After a three-week wash out period, we determined plasma clearances of para-amino-hippurate and inulin before, and after acute oral administration of either enalapril or ramipril. This same test was carried out after one and two years of treatment with the same drug. Results Acute ACE inhibition causes a decrease of renal perfusion, glomerular filtration and pressure with an increase of afferent resistances. Long-term ACE inhibition is associated only with a decrease in renal perfusion, with a non-significant tendency to higher filtration fraction and lower afferent resistances. All the renal haemodynamic modifications mentioned above are present only in patients with glomerular diseases. Conclusions Renal and glomerular haemodynamic responses are not similar after acute and chronic ACE inhibition. Only patients with glomerular diseases show acute or long-term responses to ACE inhibition.

Genetic hypertension and the kidney

The relationship between the kidney and genetic hypertension has been assessed in light of the changes seen in some kidney and cell functions during the phases preceding and accompanying the development of “genetic” types of hypertension in rats and humans. Comparison of the kidney function of normotensive subjects likely to develop hypertension with that of matched controls resistant to hypertension showed, in the former, a higher glomerular filtration rate (GFR), greater tubular reabsorption, larger 24-h urinary output, larger fraction of cardiac output to the kidney, and lower plasma renin activity. After the transplantation of a kidney from a subject in the hypertension-prone group, recipients had higher blood pressure and required more antihypertensive therapy than recipients of kidneys from the hypertension-resistant group. In humans this finding is not as clear as in rats. During the development of hypertension most of these differences in kidney function in the two groups of subjects tend to disappear. The changes in cell function, measured particularly in rats, were consistent with the organ function changes. Cell volume and sodium content were lower, while the transport rate across the cell membrane was faster in proximal tubular cells of rats with genetic hypertension than in the appropriate controls. This is in keeping with the concept of a primary increase in proximal tubular reabsorption leading, on the one hand, to an increase in GFR and renal blood flow and a decrease in renin and, on the other, to an increase in blood pressure. The same differences in proximal tubular cell function were found in the two groups of rats when their red blood cells (RBC) were compared. Genetic analysis and bone marrow transplantation studies showed that the RBC function of genetically hypertensive rats was primarily determined within their stem cells and was genetically linked to hypertension. In view of these two last findings and the similarities between red blood cells and proximal tubular cells, it is suggested that hypertension in rats may be caused by a genetic modification of the membranes of proximal tubular cells. In humans the same mechanisms might be present, but such a proposal remains highly hypothetical.

Tubulo-Glomerular Feedback Activation in Humans before and after Nephrectomy

Background/Aims: Tubulo-glomerular feedback (TGF) is a key mechanism for controlling glomerular filtration. Nephrectomy for kidney donation provides a good opportunity for studying TGF status before and after a defined loss of renal function. Methods: A total of 22 kidney donors were studied before and one year after nephrectomy. Effective renal plasma flow and glomerular filtration rate were measured by means of para-amino-hippurate and inulin plasma clearances before and after intravenous acetazolamide. Results: TGF activation was not dependent on sex, age or familiality for hypertension either before or after nephrectomy, however, it increased the filtration fraction before, but not after nephrectomy. Nephrectomy did not affect TGF response, but elicited a correlation between TGF response and renal plasma flow, not present in the intact state. Donors with a more activated TGF before nephrectomy had a lower filtration fraction that increased after nephrectomy, while subjects with a less activated TGF before nephrectomy had a higher basal filtration fraction that showed a blunted increase after nephrectomy. Conclusion: TGF is a stable mechanism quantitatively unaltered by nephrectomy, age, sex, menopausal status or family history of hypertension. However, its degree of activation before nephrectomy determines different responses to the loss of a kidney.