Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

Renal endothelin receptor type B upregulation in rats with low or high renin hypertension.

OBJECTIVES: To evaluate the role of endothelin-1 (ET-1) in hypertension, we investigated density and distribution of ETA and ETB receptors in hearts and kidneys of deoxycorticosterone acetate (DOCA)-salt and 1 kidney -- 1 clip (1K1C) hypertensive rats. METHODS: Five groups of uninephrectomized Wistar rats were put on a low salt diet. Three groups of rats drank tap water and two groups received saline. One group of each regimen received DOCA subcutaneously and two corresponding groups without DOCA served as controls. The fifth group of rats had the renal artery clipped to induce 1K1C hypertension. At 6 weeks, mean arterial pressure (MAP) was recorded and membrane binding assays using 125I-ET-1 were carried out. RESULTS: MAP was increased from control 122 +/- 3 to 155 +/- 6 and 218 +/- 11 mmHg in DOCA-salt and 1K1C rats, respectively, and cardiac weight index was increased. ETA receptors were predominantly expressed in the heart, whereas ETB receptors were predominant in the kidney. In the kidneys, the density of the ETB receptor subtype was upregulated in DOCA-salt and 1K1C rats from 160 +/- 8 to 217 +/- 12 and 190 +/- 2 fmol/mg (P < 0.05), respectively, and ETA tended to be downregulated (P = 0.057). Plasma renin activity was decreased in DOCA-salt rats from 17 +/- 3 to 0.17 +/- 0.01 ng/ml per h and increased in 1K1C rats on low salt diet to 30 +/- 5 ng/ml per h. CONCLUSIONS: Since ETB is the predominant endothelin receptor in the kidneys, upregulation of the ETB receptor mediating vasodilation and downregulation of the ETA receptor mediating vasoconstriction would be compatible with a mainly renal counter-regulatory effect of endothelin-1 to hypertension. Both low and high renin models of hypertension may be affected.

Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is an important cause of renal artery stenosis, particularly in young females. Polymorphisms of the renin-angiotensin (RA) system have been implicated in the pathogenesis of hypertension and atherosclerotic vascular disease, and may play a role in the development of FMD. Examination of polymorphisms by PCR for angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT(1)R) A1166C and angiotensinogen (AGT) M235T and T174M was undertaken in 43 patients with typical multifocal renal arterial FMD (MF-FMD) and in 89 controls. The age of NIF-FMD patients at the time of diagnosis of hypertension did not differ (38.6 + 11.1 years vs 35.5 +/- 10.3 years, P = 0.12) from controls and the proportion (95% vs 86%, P = 0.14) of females was similar. Allele frequencies did not differ significantly between groups, except that MF-FMD patients had a significantly higher frequency of the ACE I allele than control subjects (0.62 vs 0.47, P = 0.026). Since the ACE I allele is associated with lower circulating ACE levels and possibly lower tissue levels of angiotensin II (Ang II), and since Ang II modulates vascular smooth muscle cell growth and synthetic activity, the I allele might predispose to defective remodelling of the arterial media, and thus to the development of MF-FMD. This contrasts with atherosclerotic renal artery stenosis, coronary stent restenosis and carotid intimal thickening, which are diseases affecting the arterial intima, and which are associated with increased frequency of the D allele.

Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.

Renal sodium handling in acute and chronic salt loading/depletion protocols: the confounding influence of acute water loading.

OBJECTIVES: Renal tubular sodium handling was measured in healthy subjects submitted to acute and chronic salt-repletion/salt-depletion protocols. The goal was to compare the changes in proximal and distal sodium handling induced by the two procedures using the lithium clearance technique. METHODS: In nine subjects, acute salt loading was obtained with a 2 h infusion of isotonic saline, and salt depletion was induced with a low-salt diet and furosemide. In the chronic protocol, 15 subjects randomly received a low-, a regular- and a high-sodium diet for 1 week. In both protocols, renal and systemic haemodynamics and urinary electrolyte excretion were measured after an acute water load. In the chronic study, sodium handling was also determined, based on 12 h day- and night-time urine collections. RESULTS: The acute and chronic protocols induced comparable changes in sodium excretion, renal haemodynamics and hormonal responses. Yet, the relative contribution of the proximal and distal nephrons to sodium excretion in response to salt loading and depletion differed in the two protocols. Acutely, subjects appeared to regulate sodium balance mainly by the distal nephron, with little contribution of the proximal tubule. In contrast, in the chronic protocol, changes in sodium reabsorption could be measured both in the proximal and distal nephrons. Acute water loading was an important confounding factor which increased sodium excretion by reducing proximal sodium reabsorption. This interference of water was particularly marked in salt-depleted subjects. CONCLUSION: Acute and chronic salt loading/salt depletion protocols investigate different renal mechanisms of control of sodium balance. The endogenous lithium clearance technique is a reliable method to assess proximal sodium reabsorption in humans. However, to investigate sodium handling in diseases such as hypertension, lithium should be measured preferably on 24 h or overnight urine collections to avoid the confounding influence of water.

Free-breathing renal MR angiography with steady-state free-precession (SSFP) and slab-selective spin inversion: initial results.

BACKGROUND: The aim of our study was the investigation of a novel navigator-gated three-dimensional (3D) steady-state free-precession (SSFP) sequence for free-breathing renal magnetic resonance angiography (MRA) without contrast medium, and to examine the advantage of an additional inversion prepulse for improved contrast. METHODS: Eight healthy volunteers (mean age 29 years) and eight patients (mean age 53 years) were investigated on a 1.5 Tesla MR system (ACS-NT, Philips, Best, The Netherlands). Renal MRA was performed using three navigator-gated free-breathing cardiac-triggered 3D SSFP sequences [repetition time (TR) = 4.4 ms, echo time (TE) = 2.2 ms, flip angle 85 degrees, spatial resolution 1.25 x 1.25 x 4.0 mm(3), scanning time approximately 1 minute 30 seconds]. The same sequence was performed without magnetization preparation, with a non-slab selective and a slab-selective inversion prepulse. Signal-to-noise ratio (SNR), contrast-to-noise (CNR) vessel length, and subjective image quality were compared. RESULTS: Three-dimensional SSFP imaging combined with a slab-selective inversion prepulse enabled selective and high contrast visualization of the renal arteries, including the more distal branches. Standard SSFP imaging without magnetization preparation demonstrated overlay by veins and renal parenchyma. A non-slab-selective prepulse abolished vessel visualization. CNR in SSFP with slab-selective inversion was 43.6 versus 10.6 (SSFP without magnetization preparation) and 0.4 (SSFP with non-slab-selective inversion), P < 0.008. CONCLUSION: Navigator-gated free-breathing cardiac-triggered 3D SSFP imaging combined with a slab-selective inversion prepulse is a novel, fast renal MRA technique without the need for contrast media.

Kidney-Induced Hypertension Depends on Superoxide Signaling in the Rostral Ventrolateral Medulla

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Renal artery clipping attenuates the progression of adriamycin nephropathy

This study was designed to analyze the impact of diminished renal perfusion pressure due to renal clipping on the rat model of adriamycin nephropathy. Male Wistar rats, divided into four groups (n = 9 per group) were injected with saline as control (C), adriamycin 3 ml/kg (Ad), saline with the left renal artery clipped (Rv), and adriamycin plus clip (AdRv). After 24 weeks mean arterial pressure (MAP), inulin, and p-aminohippurate (PAH) clearances were performed to evaluate renal function. Morphologic analysis included histologic criteria of percentage of glomerulosclerosis and tubulointerstitial lesion index (TILI). The MAP (mm Hg) was similar between Rv (143 +/- 13) and AdRv (154 +/- 20), but higher (P < .05) than C (120 +/- 8) and Ad (124 +/- 11). Inulin clearance (mL/min/100 g) in Ad (0.2 +/- 0.05) was smaller than in C (0.53 +/- 0.17) and Rv (0.4 +/- 0.01) (P < .05), and was at an intermediate level in AdRv (0.33 +/- 0.2). The level of PAH (mL/min/100 g) was normal at 1.76 in C, and diminished more in Ad (0.58) than in Rv (1.06) and AdRv (1.18) (P < .05). Both Ad and the AdRv nonclipped kidneys had the highest degree of glomerulosclerosis (33% and 25%) and TILI (7% and 8%), respectively, compared with C and Rv (both 0%), whereas the clipped kidneys displayed intermediate degrees (9% and 5%) (P < .05 v nonclipped). The data suggest that diminished perfusion pressure of the clipped kidney, by decreasing the intraglomerular pressure, protects the glomerulus from damage and attenuates the evolution of adriamycin nephropathy. Am J Hypertens 1998;11:1124-1128 (C) 1998 American Journal of Hypertension, Ltd.

Juxtaglomerular cell tumor as a rare cause of hypertension in adults

The juxtaglomerular cell tumor is a cause of secondary hypertension in adults. A 35-year-old female patient suffering from hypertension and low serum potassium had a 3 × 3 cm solid mass at the lower pole of left kidney diagnosed by abdominal sonography. Partial nephrectomy was performed and the postoperatory was uneventful. Normalization of blood pressure was observed within the first month.

Evaluation of albuminuria and its relationship with blood pressure in dogs with chronic kidney disease

Background Microalbuminuria and hypertension have long been associated with a guarded prognosis in human patients with a variety of diseases. In veterinary medicine, tests for microalbuminuria have been used for detecting early kidney damage, but there is little information regarding its association with high blood pressure in dogs with chronic kidney disease (CKD). Objective The objective of this study was to evaluate albuminuria and its association with arterial hypertension in dogs with CKD. Methods Urinary albumin:creatinine (UAC) ratio, urinary protein:creatinine (UPC) ratio, and systolic blood pressure were determined in 39 clinically healthy dogs and 40 dogs with CKD. Results UAC in dogs with CKD (range, 0.002-7.99; median, 0.38) was statistically different from that of control dogs (range, 0.0005-0.01; median, 0.002). Microalbuminuria (UAC 0.03-0.3) and macroalbuminuria (UAC > 0.3) were detected in 32.5% and 50% of dogs with CKD, respectively. Sixty percent (24/40) of dogs with CKD had systolic pressure >= 180 mmHg; in these dogs, UAC ratio (range, 0.006-7.99; median, 1.72) was significantly higher than in dogs with CKD and systolic pressure < 180 mmHg (range, 0.002-4.83; median, 0.10). Of hypertensive dogs with CKD, those with UPC > 1.0 usually had macroalbuminuria, those with UPC 0.5-1.0 usually had microalbuminuria, and those with UPC < 0.5 usually lacked albuminuria. Conclusions UAC ratio was higher in hypertensive than in normotensive dogs with CKD. Tests designed to detect microalbuminuria may be useful for hypertensive dogs with CKD and a UPC < 1.0 to detect the onset and magnitude of albuminuria. Once macroalbuminuria is overt, the UPC ratio itself can be used for the same purpose.

Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice.

Dyslipidemia is a known risk factor for cardiovascular diseases and may associate with renal injury. Using mouse models with various degrees of hypercholesterolemia and hypertryliceridemia, we investigated the effects of lipids on the renin-angiotensin system (RAS). ApoE-/- mice were fed either a high fat diet (HF-ApoE-/-; mice developed hypertriglyceridemia and severe hypercholesterolemia) or regular chow (R-ApoE(-/-); mice developed less severe hypercholesterolemia only). Renal histopathology in the HF-ApoE-/- revealed massive lipid accumulation especially at the glomerular vascular pole. In these mice plasma renin concentration was significantly reduced (489+/-111 ng/(ml h) versus 1023+/-90 ng/(ml h) in R-ApoE-/- mice) and blood pressure was consequently significantly lower than in R-ApoE-/- (104+/-2 mmHg versus 115+/-2 mmHg, respectively). A model of renin-dependent renovascular hypertension (two-kidney, one clip) was generated and HF-ApoE-/- mice proved unable to increase renin secretion, and blood pressure, in response to diminished renal perfusion as compared to regular chow fed mice (665+/-90 ng/(ml h) versus 2393+/-372 ng/(ml h), respectively and 106+/-3 mmHg versus 140+/-2 mmHg, respectively). Hypertriglyceridemia and severe hypercholesterolemia are associated with renal lipid deposition and impaired renin secretion in ApoE-/- mice exposed to high fat diet. These observations further characterize the phenotype of this widely used mouse model and provide a rationale for the use of these mice to study lipid induced organ damage.

Salt subtraction in patients on maintenance hemodialysis. Efficacy and limitations.

In 6 hypertensive patients with terminal renal failure maintained on hemodialysis, the effects of 'salt subtraction' and of sequential ultrafiltrating were evaluated. Following each of 3 weekly hemodialysis sessions, salt subtraction was carried out by ultrafiltrating 1 liter and simultaneously infusing an equal volume of 5% dextrose. This resulted in a net sodium loss without hypovolemia. After a 2-week period of this procedure, the blood pressure prior to dialysis was lower (156/76 +/- 12/5 mm Hg) than after a comparable number of sequential ultrafiltration sessions (181/88 +/- 10/6 mm Hg; mean +/- SEM). This difference was not statistically significant. At the same time, body weight was comparable at 64.4 +/- 3 and 64.7 +/- 4 kg, respectively. Neither plasma renin activity nor plasma catecholamines responded with a clear increase to either procedure. The limited effect on blood pressure and the renin system of a marked sodium removal during salt subtraction suggests that sodium must still be present in excess in these patients. The procedure of salt subtraction appears safe and subjectively well tolerated, but it can probably not be used as the sole means of decreasing total body sodium without associating dietary measures to reduce sodium intake.

Treating high blood pressure: is reaching the target more important than the means? No, the means are important.

All major antihypertensive drug classes i.e. diuretics, beta-blockers, calcium antagonists and blockers of the renin-angiotensin system have been shown to effectively lower blood pressure and hence to reduce cardiovascular outcomes in hypertensive patients. These drugs decrease cardiovascular complications in hypertension essentially because they reduce systemic blood pressure. Nevertheless, there is growing evidence that the extent of the benefits differed between drug classes suggesting that the various classes of antihypertensive agents are not equivalent in their ability to protect against target organ damages and cardiovascular and renal endpoints. More recently, evidence has also accumulated to demonstrate that even combination therapies are not equally effective in reducing the occurrence of cardiovascular complications in hypertension. These recent observations suggest that the means to lower blood pressure are as important as the achieved target blood pressure in the management of hypertensive patients.

Cellular localization, expression and regulation of neuropeptide Y in kidneys of hypertensive rats.

Neuropeptide Y (NPY) is a key modulator of the autonomic nervous system playing pivotal roles in cardiovascular and neuronal functions. In this study, we assessed the cellular localization and gene expression of NPY in rat kidneys. We also examined the relationship between NPY gene expression and renin in two rat models of hypertension (two-kidney, one-clip renal hypertension (2K1C), and deoxycorticosterone-salt-induced hypertension (DOCA-salt)) characterized by a similar blood pressure elevation. In situ hybridization and immunohistochemistry, using anti-NPY or anti-C-flanking peptide of NPY (CPON) antibodies, showed that NPY transcript and protein were colocalized in the tubules of rat kidneys. During experimental hypertension, NPY mRNA was decreased in both kidneys of the 2K1C animals, but not in the kidney of DOCA-salt rats. In 2K1C rats, renal NPY content was also decreased. The difference in NPY gene expression between 2K1C rats (a high renin model of hypertension) and DOCA-salt rats (a low renin model of hypertension) suggests that circulating angiotensin II plays a role in local renal NPY gene expression and that the elevated blood pressure per se is not the primary factor responsible for the control of NPY gene expression in the kidney.