Nephroangiosclerosis – Wikipedia

The nephroangiosclerosis is a disease characterized by renal damage secondary to high blood pressure.

At the beginning of XX ^{It is} century, the pathologist Karl Theodor Fahr and the Volhard doctor called “nephrosclerosis” ( Nephrosklerose ) Primitive sclerosis of the renal vessels secondarily complicated of high blood pressure (HTA). Subsequently, the conception of nephosclerosis secondary to HTA has gradually spread, reinforced by the highlighting of the role of HTA in the degradation of renal function, these same renal vascular lesions that can however exist in the absence of HTA. From this apparent contradiction was born a etiopathogenic and semantic debate which gave rise to several neighboring definitions for a nosological framework which remains to be specified. One of the definitions was developed by Gabriel Richet.

American literature has generally retained the term “hypertensive nephrosclerosis” ( hypertensive nephrosclerosis ) to characterize the renal damage secondary to chronic systemic hypertension of grade 1 or 2. The synonyms of the most frequently used hypertensive nephrosclerosis are “benign hypertensive nephrosclerosis” ( benign hypertensive nephrosclerosis ) or “benign nephrosclerosis”. The term “arterionephrosclerosis” ( arterionephrosclerosis ) is more general and takes into account the absence of proof of the exclusive accountability of HTA in the renal lesions noted. It thus designates the vascular and parenchymal lesions associated with HTA, which can in particular be secondary to hypertensive nephrosclerosis or to renal involved in age. “Arteriolonephrosclerosis” ( arteriolonephrosclerosis ) implies that renal parenchymal lesions are exclusively due to an arteriolar pathology, which is rarely the case in practice.

European literature has preferentially retained the term ” nephroangiosclerosis »( nephroangiosclerosis ), synonym of ” Benigne nephroangiosclerosis »Or« Common nephroangiosclerosis ». This last appellation excludes the Benin qualifier, used to distinguish this pathology from the acute renal damage secondary to a malignant HTA ( malignant hypertensive nephropathy ). It is indeed manifest that the chronic pathological process discussed here is in no way “benign” in view of the renal, cardiac and neurological damage which can accompany it.

The diagnosis of nephroangiosclerosis (NAS) is suspected before an evocative clinical picture, after exclusion from the other causes of primitive and secondary nephropathies. Renal insufficiency is of variable severity at the time of the discovery of the disease, but the rule is that the NAS leads to a slow and progressive alteration of glomerular filtration. In this context, the diagnosis is conventionally mentioned in a hypertensive patient known without any other nephrological history, when the proteinuria of low speed in the absence of an associated anomaly of the urinary sediment.

Proteinuria [ modifier | Modifier and code ]

Proteinuria detectable by usual methods exists in 4 to 16% of patients considered to have high blood pressure. Proteinuria, if present, is usually low flow, less than 1g/24 hours.

In a retrospective study analyzing 60 patients who had a classified nas, Dasgutta et al biopsy found an average biopsy proteinuria at 2.3 ± 2.4 g/24h. Innes et al had also shown that 40% of their patients recruited on identical criteria had proteinuria greater than 1.4 g/24 hours and 22% of nephrotic proteinuria, greater than 3G/24h. Similarly, by retrospectively, 237 renal biopsies carried out due to nephrotic syndrome, Obialo et al retained the diagnosis of isolated NAS in 5.5% of the cases studied.

These data highlight the great variability of proteinuria among patients with nephroangiosclerosis, a strong proteinuria flow thus translating a glomerular impact of vascular disease. This glomerular involvement can be of ischemic mechanism or on the contrary secondary to a significant rise in glomerular capillary pressure by compensatory hyperfiltration and loss of pre glomerular physiological self -regulation. In both cases, it corresponds to the evolved stage of the NAS.

Urinary sediment [ modifier | Modifier and code ]

The urinary sediment is usually normal but it sometimes has a few hyalins or finely grainy cylinders. Conventionally, there is no microscopic hematuria. This negative element makes it possible in particular to minimize the risk of ignoring a proliferative glomerular nephropathy, in particular linked to mesangial deposits of immunoglobulin A.

However, this assertion should be qualified in light of the results of retrospective studies of patients with NAS. With the reserves imposed by the biases inherent in the indications of the renal histological examination in this context, Innes et al have thus shown that among 185 subjects with isolated NAS, proven histologically, 25% presented a hematuria when taking care initial.

Diagnostic criteria [ modifier | Modifier and code ]

Current clinical practice thus leads to a significant overestimation of the diagnosis of NAS. This excessive interpretation is partly linked to the discretion and the lack of specificity of the initial presentation of the disease, which rarely justifies the use of renal biopsy puncture. Histological analysis, however, remains the only examination of diagnostic certainty.

A recent study has shown that the estimate of the prevalence of the NAS in a population of chronic renal insufficient patients was clearly reduced when strict clinical diagnostic criteria were applied. In the absence of renal biopsy, the prevalence of the diagnosis of NAS, established on uncontrolled clinical criteria, was evaluated at 37% in an epidemiological register of hemodialyseed patients in the United States. By applying to this population the diagnostic criteria of NAS defined by the AASK study, the prevalence was thus reduced to 13.5%. According to Schlessinger’s criteria, this prevalence was even reduced to 1.5%. Thus, certain diagnoses are unknown by the usual clinical practice and falsely classified among the NAS. Among these, we find in particular renovascular ischemic nephropathy, chronic glomerular nephropathies and cholesterol embols. The severity and therapeutic implications of certain differential diagnoses of NAS emphasize the importance of knowing how to question an initial diagnostic presumption whose specificity is uncertain.

Although the imprecision of the diagnosis of NAS encourages a restriction of diagnostic criteria, harmonization of these criteria seems difficult to applicable. By imposing the concept of preexisting HTA, the use of criteria such as those used for the AASK study or by Schlessinger very likely improves the specificity of the diagnosis of chronic vascular nephropathy secondary to HTA ( hypertensive nephrosclerosis ). The high proportion of patients excluded between the classic evaluation of the diagnosis of NAS and the evaluation carried out according to these strict criteria asking important questions for the practice, in particular concerning the choice of methods of estimating the history of HTA (Presence of antihypertensive treatment, simple measurement for the armband or automated ambulatory measurement of blood pressure over 24 hours).

However, the node of the problem is most likely linked to our lack of understanding of the pathophysiology of NAS. We could hypothesize that the diagnostic difficulties of the NAS reside less in the lack of specificity of the clinical translation of its vascular attacks than in the diversity of pathological processes that this generic term includes. The non -exclusive HTA role in the genesis of nas lesions is, as such, an important obstacle. Thus, the probably heterogeneous nature of the conditions leading or predisposing to the lesions of NAS makes it difficult to establish common diagnostic criteria. A better understanding of the NAS pathophysiological mechanisms could probably allow a redefinition of this nosological framework and usefully guide the establishment of targeted diagnostic criteria.

Macroscopie [ modifier | Modifier and code ]

At an advanced stadium, the NAS is responsible for renal atrophy secondary to chronic ischemia. The kidneys, usually symmetrically affected, then have a firm consistency. The capsular surface appears pale, irregular and finely grainy. This aspect is linked to the juxtaposition of atrophic zones from 5 to 10mm in diameter, alternating with preserved regions which are sometimes the seat of a compensatory parenchymal hypertrophy. More rarely, large hypertrophic glomerules are visible on the surface in the form of small reddish domes. More extensive cortical ischemia can also be responsible for significant focal depression of the kidney surface.

Optical microscopy [ modifier | Modifier and code ]

All the constitutive structures of the renal parenchyma are altered during the evolution of the NAS. If the most characteristic lesions are at the level of the arteries, arterioles and glomerules, a non -specific tubular and interstitial impact is also present at an advanced stage of pathology. Sclerosis and arteriolar hyalinosis as well as arterial fibrous endarteritis are observed in other organs during hypertensive disease, but are usually more pronounced at the renal level.

Arteriolar pathology [ modifier | Modifier and code ]

The most frequent and probably the earliest nas lesions are in the related arterioles. By analyzing the morphological aspect of the juxtaglomerular arterioles of 2000 hypertensive patients, Sommers et al demonstrated a correlation between the elevation of the average diastolic blood pressure and the parietal thickening, as well as the reduction of the vascular caliber of the related arterioles. The most usual arterolar lesion, common to NAS and age -related arteal -related, is hyalinosis. This name reflects the homogeneous and glassy character of deposits, recalling the appearance of glass (Gr. Hualos). Its aspect is distinguished from that, more structured, from the collagen matrix constituting fibrosis areas. The hyalins appear eosinophilic, bright red on the Masson trichrome, very positive for coloring by the periodic acid Schiff (Not) and negative during a treatment with the argentation of Jones.

The distribution of hyalin equipment is dictated by the presence of the internal elastic limiting (LEI). Hyalinosis is thus predominantly located in small vessels, especially arterioles, whose wall contains little or no elastin. GLUSTURAL JUXTA arterioles normally have one or two layers of smooth muscle cells and an incomplete or even absent lei, located immediately under endothelial cells. Early accumulation of hyalin material occurs between endothelial cells and CMLs, from one or the other side of the Lei, or encompassing the latter. On a transverse cut of the vessel, hyalinosis generally has a focal layout at an early stage of the disease, then confusing in large deposits sometimes circumferential. Longitudinal cuts make it possible to highlight the segmental nature of the lesions, becoming more continuous near the glomerule. There is frequently an atrophy of the CML layer opposite the hyalins deposits. Severe hyalinosis can be responsible for a complete loss of the arteriolar muscularist.

To the hyalinosis lesions can be added or replace arteriolar sclerosis, resulting from the accumulation of a collagen matrix. These lesions have classically a more structured, less acidophilic appearance, colored green by Masson’s green trichrome and less not positive than hyalinosis.

CML hyperplasia can also meet in the NAS, resulting in an elongation, thickening and tortuous appearance of arterioles. However, these lesions are less frequent than hyalinosis and vascular sclerosis.

Arterial pathology [ modifier | Modifier and code ]

The most frequently encountered arterial changes during the NAS predominate at the level of the arched and interlobar arteries, although the interlobular arteries can be reached. These lesions are common to age -related arteriosclerosis and are essentially characterized by an intimal thickening and the replication of the LEI. Intima thus becomes the seat of fibrous endarteritis, combining mesenchymal cell proliferation (myofibroblasts and fibroblasts) and a progressive accumulation of extracellular matrix. The production of fibrillar collagen that accompanies this process is classically organized in concentric deposits in the arterial wall. A transversal arterial cut can thus show multiple superimposed dense collagen blades, located between the LEI and the endothelial layer and responsible for a progressive reduction in vascular light. Complete occlusion is rare apart from secondary thrombosis, an exceptional phenomenon in the uncomplicated common NAS.

During the evolution of the NAS, these lesions can settle in the absence of alteration of the media. The reciprocal is only rarely true, media lesions are almost always accompanied by intimal fibrosis. Masson Trichrome is a useful coloring for media analysis. The most frequently observed involvement, predominant opposite the fibrosis areas, is a focal atrophy of the smooth muscle layer, sometimes replaced by a collagen matrix. Media hyperplasia is rarer.

Glomerular pathology [ modifier | Modifier and code ]

In a patient with NAS at the stage of moderate renal insufficiency, there are three types of viable glomerules schematically: morphologically normal glomerules, ischemic glomerules and hypertrophic glomerules.

The earliest glomerular lesions generally produce an aspect of ischemic glomerle. This is characterized by a more or less important retraction of the flocculus on its establishment, with the consequence of an apparent enlargement of the urinary room. As the process worsens, the glomerular basal membranes become undulating, pleated and sometimes split. These lesions respect a more readily global than segmental distribution. They can be accompanied by a reduction in the number of identifiable hair curls, a podocyte rarefaction, an accentuation of the mesangial matrix and, ultimately, an accumulation of collagen in the urinary room.

Glomerular hypertrophy appears later. It would be secondary to the nephronic loss induced by the ischemia of the adjacent glomerles, which it would tend to compensate. It manifests itself morphologically by an enlargement of the flocculus, which has dilated hair curls. Favored by a loss of physiological self -regulation of kidney microcirculation, the classic evolution of these glomerules is towards the installation of segmental scar lesions, leading to an aspect of segmental and focal hyalinosis (HSF) which contrasts with more sclerosis global ischemic glomerules.

The terminal evolution of ischemic glomerules would preferably be towards sclerosis characterized by a retraction of the flocculus, surrounded by collagen equipment which occupies the urinary room of Bowman ( obsolescent glomerulosclerosis ). Conversely, the hypertrophic glomerles would evolve towards a more homogeneous glomerulosclerosis, which also concerns the flocculus ( solidified glomerulosclerosis ). The biopsy of a patient with advanced NAS can thus contain both “scar” sclerical glomerules of these two types and viable glomerules presenting on the one hand of more or less advanced ischemic lesions and on the other hand lesions of glomerulosclerosis of segmental provision. The juxtaposition of these aspects sometimes makes it difficult or even impossible to distinguish with a complicated HSF of secondary NAS.

Tubulointerstitial pathology [ modifier | Modifier and code ]

Tubulo-interstitial lesions encountered in the NAS do not have a specific character. Their arrangement is focal length, translating predominant ischemia at the level of certain nephrons. They come in the form of irregular territories of interstitial fibrosis, in which are observed severe glomerular lesions and phenomena of tubular atrophy. The presence of an interstitial infiltrate lymphoplasmocytic of moderate intensity is usual within the fibrosis areas.

More than half of patients with chronic renal failure have high blood pressure. Also, even though only a reduced percentage of hypertensive subjects contracts a chronic kidney disease, HTA is considered to be one of the first two causes of chronic terminal renal failure.

Several retrospective studies have shown that vascular sclerosis lesions characteristic of the NAS were correlated either to the degree of HTA, or to the intensity of the global glomerulosclerosis. The latter is however considered to be the consequence of chronic glomerular ischemia, generally secondary to a reduction in caliber of the upstream arterial network. These data call into question the supposed linear relationship between HTA, vascular sclerosis and glomerulosclerosis, implied in the classic Nephrosclerosis hypertensive appellation. Thus, despite the existence of manifest epidemiological and pathophysiological links between HTA and renal failure, our understanding of chronic renal pathology linked to HTA remains particularly debated.

A simple pathophysiological vision would lead to thinking that the direct consequences of HTA on a given vascular bed are proportional to the degree of exposure of the vessels to the elevation of hydrostatic pressure. The determinants of renal vascular involvement during HTA could thus be schematically subdivided into three categories:

• The hydrostatic pressure resulting from systemic arterial hypertension,
• The degree of transmission of this pressure to arteries, arterioles and renal capillaries
• The proper susceptibility of venal vessels and parenchyma to respond to chronic barotrauma and its indirect consequences.

Role of pressure and endothelial dysfunction [ modifier | Modifier and code ]

The pulsatile character of blood pressure and blood flow are at the origin of hemodynamic stimuli which exerts a permanent mechanical influence on the vessel. Schematicly, it is considered that the vascular smooth muscle cells are mainly subject to parietal tension forces while the endothelial coating is more directly influenced by shear constraints linked to the flow, or Shear Stress. If these physiological stimuli are necessary for survival as well as determining the arterial or venous character of a vessel, their alteration, in particular during HTA, can be responsible for significant modifications of cells and the extracellular matrix vascular.

Vascular CMLs have a complex cytoskeleton and many receivers to integrate these stimuli and translate them into intracellular signals. This mechanicuction leads to a close regulation of genomic expression and the function of the cell (proliferation, apoptosis, migration, remodeling). Certain genes whose expression is increased in the event of an increase in mechanical stimulus play an important role in the pathophysiology of renal inflammation and fibrosis. Among these we find in particular growth factors ( Fibroblast Growth Factor , Platelet Derived Growth Factor , Vascular Endothelial Growth Factor ) as well as constituents of the extracellular matrix (fibronectin, constitutive chains of type I collagen molecules).

In contrast to the CML, entangled in the matrix of the vascular wall, endothelial cells are arranged in a single -tank and are directly exposed to the shear forces created by the flow. The endothelium incorporates both mechanical stimuli such as Sher stress and hormonal stimuli, especially vasoactive peptides. In response it adjusts the production of mediators regulating vasomotor tone, inflammation and homeostasis. Among the vasodilator substances produced by endothelium are nitrogen monoxide (NO), prostacycline, natriuretic peptide of type C and various hyperpolarizing factors derived from endothelium. Endothelin-1 (ET-1), angiotensin II (Ang II), thromboxane A2 and reactive oxygen derivatives are the main mediators of dependent endothelium vasoconstriction. By its close contact with the main cellular and peptide actors of inflammation, the endothelium also plays a strategic role in the regulation of an inflammatory, local or systemic process.

During the evolution of the NAS, the accumulation of hyalin material and constituents of the extracellular matrix at the level of the intima is considered by certain authors as the morphological expression of a functional alteration of the endothelial barrier. In this conception, the endothelial lesion is supposed to be the first step leading to the narrowing of the vascular caliber. The NO pharmacological inhibition animal model by L-Name reproduces a systemic endothelial dysfunction (of). The rats thus processed contracts vascular lesions severe close to those of human NAS, suggesting that can be a major player in the genesis of the morphological anomalies observed. In humans, several studies have shown the existence of one of hypertensive patients. This of was independent of the level of blood pressure, weight, smoking and the presence of dyslipidemia, frequently associated factors in hypertensive patients and which can, in themselves, responsible for one of.

There is currently no experimental model faithfully reproducing the pathological process of the NAS. In addition, the studies of regulations linked to mechanicuction at the level of vascular CMLs are difficult to achieve and interpretation, particularly because of the complex physiological interactions that CML maintain with their in vivo cell and matrix environment. Furthermore, the appearance kinetics and the progressive vascular consequences of the DE should be analyzed at the local level, in order to be able to test the hypothesis of their role in the appearance of nas lesions and their possible causal link with the ‘HTA during the disease. However, the study of it at the level of renal microvascularization cannot be carried out precisely by current techniques.

The most precise data we have in 2008 come essentially from in vitro or ex vivo models and deserve to be interpreted with caution. However, all of these elements suggest that the hemodynamic modifications induced by HTA at the level of the arteries responsible for self -regulating renal blood flow can be, in part, actors in the initiation and worsening of structural modifications observed in the NAS.

Role of self -regulation of renal blood flow [ modifier | Modifier and code ]

Most vascular beds of the body have the ability to stabilize their blood flow when systemic blood pressure (PA) varies within physiological limits. This process is called self -regulation because all the stages involved (detection, signal transduction, effective mechanisms) takes place in the organ concerned. The mechanical effect of elevation of hydrostatic pressure on microcirculation and parenchyma is thus, under usual, controlled conditions.

The kidney has a very large self -regulation capacity, so that the renal blood flow (FSR) remains independent of the systemic PA for a large scale of variation of the latter. This self -regulation takes place in the pre glomerular microcirculation and brings into play two main mechanisms, a myogenic response dependent pressure and a slower reaction of blood flow of blood flow as a function of the composition of the distal tubular fluid (Tubulo Glomerlar Feedback, TGF). In the absence of self -regulation, low infusion pressure would cause downstream ischemia. Conversely, high infusion pressure would lead to the development of segmental glomerulosclerosis lesions by direct transmission of systemic blood pressure.

There are many experimental studies on the alteration of self -regulation of the FSR, most of the time conducted on animal models which reproduce a systemic HTA. Several species of rodents have a spontaneous alteration of renal self-regulation, in particular the rats “Fawn-Hooded”, “Brown Norway” and “Dahl”. In all these species, under the effect of adapted stimuli, the predominant appearance of glomerular lesions of HSF post hyperfiltration is unusually seen, then secondarily of a global alteration of the renal parenchyma. The partial pharmacological inhibition of the renal self -regulation capacity by Nifédipine, experienced in a nephronic reduction model, leads to an analogous way to an acceleration of HSF type lesions.

In humans, an alteration of FSR self-regulation has also been demonstrated in patients with diabetic and non-diabetic nephropathy and in hypertensive subjects of African-American origin. Morphologically, this loss of the FSR self -regulation capacity is accompanied by a dilation of the related arterioles. By analyzing the renal histology of 22 hypertensive patients and control patients, Hill et al showed that there were, predominantly in hypertensive patients, an excellent correlation between the increase in diameter of the related arteriole and the presence Hypertrophy lesions or secondary HSF on the Glumérule d’Aval.

The following question is that of the accountability of the loss of self -regulation of the FSR in the progression of the renal insufficiency linked to the NAS. In two distinct studies, Hill et al and Marcantoni et al analyzed the morphological aspect of the glomerles of hypertensive patients 56.69. In the study by Hill et al, three -quarters of the viable glomerules were of the HSF type, while only 11.2% had an ischemic aspect, suggesting that loss of self -regulation and hyperfiltration play an important role in pathology renal of these patients. An analysis The glomerulosclerosis lesions was also practiced, to distinguish glomerules that have become sclerical by a supposed ischemic mechanism (sclerical glomerles with a retraction of the flocculus, surrounded by not positive collagen material occupying the urinary chamber, 42.2%) of Lesions probably secondary to hyperfiltration (global glomerulosclerosis homogeneous with associated solidification of Flocculus, 58.8%). For the authors, the comparison of the proportion of viable ischemic glomerules (11.2%) with the percentage of post ischemic sclerical glomerules (42.2%) suggests that ischemic glomerles have a short lifespan, relative to hypertrophic glomerules 56 . It could also be discussed that ischemic glomerular lesions appear earlier in the history of pathology and thus lead to a earlier loss of the glomerules concerned. At the same time, Marcantoni and Al found a similar percentage of sclerular glomerules post hypertrophic in the analysis of an American black population, while in their study the post ischemic sclerles were predominant in white subjects.

The data from these observations lead to thinking that the loss of self-regulation of the FSR actually contributes to the progression of the renal lesions of the NAS, but that this contribution is only partial and depends in particular on the underlying genetic heritage.

Role of prothrombotic mechanisms [ modifier | Modifier and code ]

By analyzing a cohort of 41 patients with histological lesions of NAS, Meyrier and Al have shown that vascular sclerosis was not correlated with the degree of blood pressure or the seniority of HTA. Likewise, there was no correlation between the NAS lesions and the left ventricular mass or the appearance of the arteries at the bottom, which are the classic translations of an old HTA on two target organs. This work confirms that NAS lesions are present in non -hypertensive patients. He suggests that the NAS can be a primitive pathology preceding the appearance of HTA and that there are environmental and/or genetic factors contributing to the genesis of these vascular lesions.

In a recent study, Goformth et al tested the pathogenic role of hereditary thrombophilia in the genesis of vascular sclerosis. They studied the renal biopsies of subjects with NAS, after having excluded patients who had glomerulonephritis with immune deposits. Biopsies have been classified into five groups: diabetes, HTA, diabetes and HTA, smoking and vascular sclerosis of indefinite etiology. A DNA sample was analyzed from the frozen biopsy fragment in search of mutations in the genes coding factor V (Factor V Leiden Mutation) or prothrombin (G20210A mutation) and homozygoties in the Methylene Tetrahylene gene reductase reductase , polymorphism responsible for hyperhomocysteinemia (MTHFR C677T). In total, 10 anomalies were highlighted among the 17 patients in the group “Vascular sclerosis of indefinite etiology” (2 mutations factor V Leiden, 3 G20210A mutations, 5 homozygoties MTHFR C677T; p <0.0005 compared to other groups ).

The conclusions of this observation are reinforced by the results of a study carried out by Koupepidou et al in 30 patients with a clinical NAS diagnosis. These authors report an increased prevalence of MTHFR C677T and MTHFR C677T/A1298C polymorphisms in NAS patients compared to a group of control patients. Although the diagnosis of NAS has been asserted histologically only in 6 patients and the independence of results vis-à-vis blood pressure is not specified, these data also suggest that genetic factors regulating the prothrombotic state state can contribute to the development of NAS lesions.

Role of hyperuricemia and metabolic syndrome [ modifier | Modifier and code ]

It is established that HTA is more frequent in obese subjects, with metabolic syndrome and/or hyperuricemia 92. The pathophysiological role of these metabolic factors in the genesis of HTA and NAS lesions is currently the object of growing clinical interest. After discovering the role of uric acid in microcrystalline droppings at the beginning of XIX ^{It is} A century, it was proposed that hyperuricemia participates in the pathogenesis of many cardiovascular diseases including HTA and arteriolosclerosis. Indeed, the natural history of patients with gout showed while 25 to 50% of them were hypertensive and 75% obese, while 90% developed heart disease and 25% a kidney disease.

In recent years, several teams have observed that rodents subjected experimentally to hyperuricemia contracts HTA and lesions of pre glomerular arterioles which are accompanied by a reduction in renal blood flow. In a work of Sanchez-Lozada et al in the Rat “Sprague-Dawley”, morphological and hemodynamic modifications of renal microcirculation secondary to hyperuricemia were prevented by allopurinol 94. The authors propose that the vascular disease caused by the ‘hyperuricemia takes place in two phases. In the first phase, the role of a reduction in NO and activation of the Aldosterone Rénine System (SRAA) would be predominant. Secondly, uric acid would be the main actor in the sustainability of arteriolar involvement, by stimulation of the proliferation of CML. The set of induced vascular morphological alterations appear independently of the level of blood pressure, stressing the possible initiative role of uric acid in the physiopathology of these lesions, close to those observed in humans during the NAS.

The interactions between uric acid and the parameters of the metabolic syndrome are complex. Thus, a pharmacological decrease in uricemia leads to a reduction in hyperinsulinism, hypertriglyceridemia and the weight gain of rats with an experimental metabolic syndrome 93. Kincaid-Smith et al recently observed that a segmental glomerulosclerosis was Present in obese patients, regardless of blood pressure and vascular lesions. They conclude their work by issuing the hypothesis that obesity and insulin resistance play an important role in the pathophysiology of chronic renal insufficiency relating to HTA 95. Larger clinical studies will likely allow us to better understand the contribution of Metabolic syndrome and hyperuricemia in the genesis of the vascular and glomerular lesions of the NAS.

Role of a hereditary predisposition the NAS [ modifier | Modifier and code ]

It would be simplistic and probably false to separate the factors previously mentioned from the list of hereditary determinants of the NAS. Many other tracks concerning genes potentially involved in the genesis of the NAS are explored and deserves to be mentioned, but exceed the framework of this work.

The observation of nas of severity and variable morphological characteristics between two American populations of different ethnic origin underlines the importance of genetic heritage in the expression of this disease. There are thus important differences between the Caucasian NAS and that of the black American subject, more frequent and in which the pathogenic role of blood pressure is better established. This distinction is most likely multifactorial. The literature shows many candidates genes, whose implications in vascular physiology, the genesis of HTA, renal inflammation or the production of extracellular matrix encourage them to think that they can be the object of polymorphisms conferring a predisposition to the development of NAS lesions.

Thus, correlations between specific polymorphisms of angioconvertase, angiotensinogenic and type 1 receptor of angiotensin II have been established with several cardiovascular pathologies, including HTA. The mutations of the gene coding angiotensinogen are more frequent in the US hypertensive population of African origin, compared to Caucasian subjects. The presence of the allele D of the angioconvertase gene, associated with an increased activity of the SRAA, is also correlated with the histological diagnosis of NAS in a study carried out in Caucasian subjects. In hypertensive patients with a clinical diagnosis of NAS with chronic renal failure, there is also a higher prevalence of the DD genotype compared to genotype II, compared to control subjects whose NAS was not accompanied by kidney failure.

The SRAA, by its major implications in the pathophysiology of systemic HTA and the local regulation of renal vasomotor tone, inflammation and production of profibrotating cytokines, constitutes a target of choice for the realization of these cohort studies . There are many other genes for which we can hypothesize a role in the predisposition hereditary to the NAS. Among these, we find in particular regulators of the function of smooth endothelial and muscle cells ( endothelial NO synthase eNOS , asymmetric dimethylarginine ADMA , Et-1 ), mediators of oxidizing stress and the response to hypoxia ( NADPH oxydase , hypoxia inducible factor HIF-1a ), key genes of the tissue inflammatory response ( monocyte chemoattractant protein MCP-1 , interleukin il-6 , tumor necrosis factor TNF-a ) or the genesis of vascular and renal parenchymal fibrosis ( transforming growth factor TGF-b , platelet derived growth factor PDGF-B , plasminogen activator inhibitor PAI-1 ). The next few years will probably clarify some of these tracks and open new research paths to specify our still parcel understanding of the mechanisms leading to the lesions of the NAS.

• Guerrot D. et al. Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit? , American journal of kidney diseases : the official journal of the National Kidney Foundation. 2008; 52:340-5.