The kidney is both an important organ for blood pressure regulation and one of the main target organs for hypertension damage. The kidneys play an important role in the regulation of blood volume, electrolyte balance and the renin-angiotensin system (RAS). The kidneys are rich in blood vessels and are highly susceptible to damage from hypertension. Normal renal function plays an important role in maintaining stable blood pressure. Once renal function is impaired, hypertension will be aggravated, and hypertension will further aggravate renal damage, thus forming a vicious circle that will eventually lead to renal insufficiency and damage to the heart, brain and other important organs.
Clinically, the change of kidney structure and function caused by hypertension is called hypertensive renal damage, mainly small arterial nephrosclerosis. If hypertension persists for 5-10 years, it can cause renal small artery sclerosis (intimal thickening of the arcuate and interlobular arteries, glassy changes of the small arteries entering the bulb), wall thickening and lumen narrowing, and then secondary ischemic damage to the renal parenchyma, including ischemic glomerular wrinkling and sclerosis, tubular atrophy, interstitial inflammatory cell infiltration and fibrosis, leading to benign small artery nephrosclerosis; while acute hypertension or malignant Malignant small arterial renal sclerosis due to hypertension is relatively rare at present.
In recent years, due to the increasing number of hypertensive patients, the incidence of benign small artery renal sclerosis is also increasing significantly. The disease is more common in Western countries and is the 2nd cause of end-stage renal failure (about 25%), second only to diabetic nephropathy. In China, benign small arterial nephrosclerosis is the 2nd (14.8%) and 3rd (8.9%) cause of end-stage renal failure in peritoneal dialysis and hemodialysis patients, respectively, and is second only to chronic nephritis in peritoneal dialysis and to chronic nephritis and diabetic nephropathy in hemodialysis. However, the harmful effects of hypertension on the kidneys are not fully recognized.
1, the severity of kidney damage caused by hypertension disease
According to the literature, about 18% of patients with hypertension eventually develop renal insufficiency. In patients with hypertension treated with antihypertensive therapy, 4%-16% of patients have abnormal urinary protein excretion. The proportion of patients with hypertension who develop kidney damage varies by region, ethnicity, age, and gender: hypertension causing end-stage renal disease (ESRD) is highest in the United States (28.5%), followed by Europe (13%), and lower in Japan (6%).
The prevalence of hypertension containing ERSD in black Americans is about 6 times higher than that in white Americans with hypertension. ERSD caused by hypertension is predominant in elderly people over 65 years of age, and men are more likely to have kidney damage due to hypertension than women, indicating that environmental factors and genetic background have an important role in renal damage in hypertension. The annual number of patients entering RESD due to hypertension in China has not been reported.
2.Pathological changes of hypertensive kidney damage
The most common renal pathological changes in benign hypertension are dominated by glomerulosclerosis, which is manifested by glassy changes in the small inlet arteries, interlobular arteries and myoendothelial hypertrophy in the arcuate arteries. As the vessel wall thickens and luminal narrowing develops, the glomeruli and tubules show ischemic changes. Glomerular capillary wrinkling, increased thylakoid matrix, and thickened balloon wall eventually lead to atrophy and sclerosis; while the normal renal units compensate for hypertrophy, so the appearance of the kidney is fine granular atrophic kidney.
The typical changes of blood vessels caused by malignant hypertension are fibrinoid necrosis of small arterial walls and heavy intimal hyperplasia in an onion skin-like appearance. Glomerular capillary loops may show stage fibrinoid necrosis and capillary lumen thrombosis.
3, the mechanism of hypertensive renal damage
3.1 Hemodynamics: The incidence of benign small arterial nephrosclerosis is positively correlated with the severity and duration of hypertension. When hypertension occurs, the small arteries of the kidney are in a state of constriction. Renal vascular resistance (RVR) is elevated and renal blood flow (RBF) is decreased. In the early stage, the glomerular filtration rate (GFR) can remain within the normal range because the small outflowing arteries are more significantly constricted than the small incoming arteries. As hypertension continues to progress, the small renal arteries become sclerotic and less compliant, which, together with the thickening of the walls of the small arteries and the narrowing of the lumen, further decreases the RBF and leads to ischemic renal parenchymal damage. The renal tubules are more sensitive to ischemia than the glomeruli, and glomerular hyperperfusion during hypertension maintains normal GFR, making the load on the tubules not reduced and thus more likely to aggravate tubular injury.
The earliest clinical manifestation of hypertensive kidney damage is tubular dysfunction, mainly manifested as tubular concentration dysfunction, increased nocturia, low relative density and low osmotic concentration urine. When ischemic damage occurs in the glomerulus, abnormalities in urine composition are seen, manifesting as mild to moderate proteinuria with less tangible cellular components in the urine.
Since glomerulosclerosis due to hypertension is not observed in some of the glomeruli, it is believed that hypertensive renal damage is not exclusively ischemic, and the presence of intra-glomerular hyperperfusion, hyperpressure and hyperfiltration (the “three highs”) is the main pathogenic mechanism that promotes renal parenchymal damage, especially glomerulosclerosis. Intra-glomerular hypertension and high stress cause functional impairment of vascular endothelial cells, producing active factors such as angiotensin II (Ang II), endothelin-1 (ET-1), thromboxane A2 (TXA2), transforming growth factor β2 (TGF-β2), and platelet-derived growth factor (PDGF), leading to vasoconstriction, stimulating thylakoid cell proliferation and collagen deposition, and promoting extracellular matrix ( ECM) synthesis and secretion are increased. Intraglomerular hypertension can also lead to epithelial cell damage in the glomerular dirty layer, which increases the permeability of the basement membrane and causes proteinuria. These lesions eventually lead to glomerulosclerosis and loss of kidney units. The “triple high” phenomenon in the glomerulus is associated with the following factors.
(1) In primary hypertension, although the small arteries entering the glomerulus are constricted, the strength of the constriction is far from adequate in relation to the increased blood pressure, thus allowing systemic hypertension to pass into the glomerular capillaries.
(2) After the onset of benign small arterial nephrosclerosis, the glomerulus becomes hyperperfused, hyperpressurized and hyperfiltered because some of the renal units are destroyed and the remaining renal units are compensated for the excretion of metabolic waste. Therefore, the kidneys of patients with essential hypertension are characterized by both ischemic hypoperfused renal units and hyperperfused renal units, with the latter predominating.
3.2 Non-hemodynamic.
(1) Gender and race: men are more likely than women to be predisposed to hypertensive small artery lesions. In the United States, primary hypertension with renal impairment is five to six times more common in blacks than in whites. Under the same blood pressure conditions, blacks are more likely to have kidney damage, which may be related to the fact that blacks have more salt-sensitive types.
(2) Lithium-sodium countertransport abnormalities: Patients with essential hypertension have increased lithium-sodium countertransport, resulting in increased GFR and filtration fraction, increased proximal tubular sodium reabsorption, increased plasma renin activity, and increased microproteinuria.
(3) Metabolic abnormalities: including insulin resistance, hyperuricemia, hyperlipidemia, and other factors that promote the development of vascular lesions in hypertensive patients.
(4) Oxidative stress: It has been found that the rate of urinary protein excretion was significantly increased in hypertensive SD rats with chronic perfusion of aldosterone and salt; meanwhile, the expression of renal cortical NADPH oxidase subunits p22phox, Nox-4 and gp91phox mRNA was significantly elevated; and the levels of lipid peroxidation reaction products (TBARS) in renal cortex and urine were significantly increased.
Strikingly, antioxidant treatment decreased blood pressure, normalized renal cortical and urinary TBARS levels, and decreased urinary protein excretion rate in hypertensive SD rats, suggesting that NADPH oxidase-mediated oxidative stress is involved in aldosterone-induced hypertensive renal damage. Oxidative stress was also found to mediate renal damage through activation of mitogen-activated protein kinases (MAPKs) pathway. Oxidative stress also plays a key role in renal damage due to essential hypertension. Local endothelial cell damage and reduced nitric oxide production may be responsible for the increased reactive oxygen species.
3.3 Other factors: Genetic polymorphisms in the angiotensin-converting enzyme gene (ACEI/D) are significantly associated with renal atherosclerosis in essential hypertension. The angiotensin II type 1 receptor (AT1R) genotype has a significant effect on renal function in the hypertensive patient group. the AC genotype or the C allele may worsen renal function. In addition, body mass index and smoking are also influential factors for the development of renal damage in hypertensive patients.
4, the diagnosis of hypertensive kidney damage
4.1 Early diagnostic indicators: In the earlier stages of hypertensive patients with existing renal impairment, the kidneys generally do not have obvious structural and functional changes, and there are almost no or very few clinical symptoms and signs. Urea nitrogen and creatinine cannot reflect the glomerular filtration function in the early stage, and it is difficult to judge the kidney damage earlier with conventional monitoring methods. Since the tubules and glomeruli are damaged to different degrees during the course of primary hypertension, urine microprotein detection can be used as a sensitive indicator for early diagnosis, which can reflect glomerular filtration function, proximal tubular reabsorption and catabolic function at an earlier stage. Urinary microalbumin includes urinary microalbumin, β2-microglobulin (β2-MG), urinary retinol-binding protein (RBP), and N-hexosyl-β-aminoglucosidase (NAG).
The so-called microalbuminuria refers to urinary albumin excretion rate above the currently established normal criteria but not up to the clinical diagnosis of proteinuria, with values of 20-200 μg/ml (30-300 mg/24h). The amount of urinary microalbumin excretion can reflect the degree of glomerular damage. β2-MG is an intrinsic component of all nucleated cells in the body, almost all of which is filtered by the glomerulus and 99% is reabsorbed by the renal tubules, and is a sensitive indicator for determining tubular and interstitial renal damage. RBP is mainly used to transport retinol from the liver to the epithelial cells, and its clinical significance is basically similar to that of β2-MG, but it is more stable than β2-MG. NAG is a lysosome from the proximal tubule, which is relatively stable in the urine and cannot be filtered by the glomerulus.
NAG is currently considered to be the most sensitive indicator of renal tubular damage. The detection of urinary microprotein is a simple and non-invasive test. Regular joint detection of urinary microprotein in hypertensive patients can provide a clinical diagnostic basis for early glomerular and tubular damage, so that comprehensive therapeutic measures can be taken early to prevent renal arteriosclerosis, which is important to stop or delay renal damage in hypertensive patients.
4.2 Clinical diagnostic index: The occurrence of benign renal small arteriosclerosis is positively correlated with the degree and duration of hypertension, generally after the primary hypertension lasts for 5 to 10 years. The first clinical symptom may be increased nocturia, mainly due to the ischemic lesion of renal tubules, and the urinary concentration function begins to decrease, followed by proteinuria, indicating that glomerular lesions have occurred. In clinical diagnosis of hypertensive benign small arterial nephrosclerosis is mainly based on.
(1) A history of definite and persistent hypertension;
(2) The age of onset of hypertension is between 25 and 45 years, but the duration of the disease is often more than 10 years, and the older the age, the higher the incidence;
(3) Other organ damage associated with hypertension, such as left ventricular hypertrophy and fundic vasculopathy;
(4) Clinical manifestations of interstitial renal tubular damage, such as increased nocturia, low urinary osmolality, decreased urinary concentration, some patients may show mild proteinuria and a small amount of red blood cell urine, and a few show elevated serum creatinine;
(5) Renal ultrasound examination of both kidneys shrink in the advanced stage of the disease, and CT examination of the kidney surface is granular and uneven;
(6) Discharge of primary kidney with hypertension in cases;
(7) generally do not do renal biopsy, when the kidney biopsy, can present the pathological changes mainly renal small arteriosclerosis.
5, the prevention and treatment of hypertensive kidney damage
5.1 Prevention of hypertensive kidney damage: the main focus is on the prevention and treatment of hypertensive disease. At present, with the in-depth and extensive research on the pathogenesis of hypertension at home and abroad, it is found that hypertension is a disease with many different pathogenesis, not only with hemodynamic abnormalities, but also with disorders of fat and sugar metabolism and poor remodeling of target organs such as heart, brain and kidney. Therefore, its treatment should improve the above metabolic disorders and prevent and reverse the adverse remodeling of target organs while effectively controlling blood pressure levels, which is the key to reduce the occurrence of cardiovascular complications and morbidity and mortality.
The pathogenesis of hypertension varies from patient to patient and at different stages of the disease course, so anti-hypertensive treatment should be individualized. The ultimate goal of hypertension prevention and treatment should be to control risk factors, protect target organs, and improve patient survival.
5.2 Principles of antihypertensive drug use.
(1) The lowest effective dose of any drug should be used when starting treatment to reduce adverse effects. If individual drug therapy is effective but blood pressure control is not satisfactory, the drug dose should be increased as long as the patient tolerates it well;
(2) Try to apply long-acting agents to achieve all-weather treatment, the advantages of which are good patient compliance, smooth lowering of blood pressure, and better for reducing cardiovascular risk events and protecting target organ damage than short-acting agents;
(3) Reasonable choice of combination drugs to achieve the highest antihypertensive effect with the least adverse reactions, if a drug is poorly effective or intolerant, currently generally prefer to add a small dose of the second non-identical drugs, rather than increasing the dose of the first drug, so that the first and second drugs are in the low dose range, then the efficacy and less adverse reactions.
5.3 Antihypertensive goals: The 7th Report of the US Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension (JNC-VII) and the 2003 World Health Organization and National Hypertension Society (WHO/ISH) guidelines advocate controlling blood pressure below 130/80 mm Hg in patients with chronic kidney disease. 2003 European hypertension guidelines state that when urine protein is >1 g/d blood pressure should be reduced to a lower level and should be <125/75 mmHg.
The results of the American Renal Disease Dietary Modification Trial (MDRD) evidence-based medical trial stated that mean arterial pressure (MAP) should be controlled below 125/75mmHg when urine protein is >1g/d, and below 130/80mmHg when urine protein is <1g/d. However, there are still many studies and clinical trials showing that although the patients' blood pressure is strictly controlled, their renal function still deteriorates gradually. Therefore, it is crucial to select appropriate anti-hypertensive drugs to stop the further development of renal damage in patients with hypertensive nephrosclerosis.
5.4 Drug selection
5.4.1 Angiotensin-converting enzyme inhibitors (ACEI): At present, it is believed that among antihypertensive drugs, ACEI is the most effective drug to protect the kidney and is particularly effective in delaying the progression of renal damage, and should be preferred. This class of drugs can delay the progression of renal damage through both hemodynamic and non-hemodynamic effects. Their renal protective effects include.
(1) Improving renal hemodynamics;
(2) Reducing proteinuria;
(3) Inhibiting ECM deposition and delaying glomerulosclerosis;
(4) Maintaining the function of the kidney in regulating water-sodium balance;
(5) Improve insulin sensitivity;
(6) Improving abnormal lipid metabolism;
(7) restoring the responsiveness of the renal vasculature in patients with unregulated hypertension;
(8) Anti-oxidative stress.
In patients with renal insufficiency, ACEI can be applied to lower blood pressure and protect renal function when Scr<265μmol/L. However, blood potassium and Scr changes must be carefully monitored after drug administration, especially within the first two months of starting the drug. If the increase in Scr does not exceed 30% of the basal value, it is a normal drug reaction and ACEI should not be discontinued; if the increase in Scr exceeds 30% to 50% of the basal value, it is an abnormal drug reaction and ACEI should be discontinued in a timely manner; this abnormal reaction is likely to occur when the effective circulating blood volume is insufficient and the renal artery is narrowed. The use of ACEI decreases Ang II production and dilates the small glomerular arteries, disrupting this metabolic mechanism and causing a significant decrease in GFR and a significant increase in Scr.
This abnormal response of glomerular hemodynamics can generally be recovered after timely discontinuation of ACEI. When Scr is back to its original level and the renal ischemic factors are corrected, ACEI can be used again to control the system hypertension and protect the kidney. However, for experienced nephrologists, ACEI can be used when the Scr level is 354 μmol/L or even 442 μmol/L, but close monitoring of Scr and potassium is required. In addition, during the course of treatment with ACEI all the time, if the Scr rises gradually, even if it is greater than 265 μmol/L, the drug should not be stopped.
This situation indicates that renal function has improved after treatment but eventually progresses to the rising Scr stage. Once the drug is discontinued, the rise in Scr will accelerate. If the patient has progressed to end-stage renal failure into dialysis treatment, ACEI can also be used again to control hypertension.
Two points should be noted when choosing ACEI drugs: (1) Drugs with high penetration to renal tissues, such as benazepril and ramipril, should be used, as they can effectively inhibit the renal local renin-angiotensin system (RAS) to maximize therapeutic benefits. (2) For patients with renal insufficiency, it is advisable to choose drugs with dual renal and extrarenal excretion, such as fosinopril, benazepril and ramipril, because if the drug can only be excreted from the kidney, it is easy to accumulate in the body and increase the adverse effects.
5.4.2 Angiotensin receptor antagonists (ARB): Ang II has at least four receptors (AT1R, AT2R, AT3R, AT4R), of which the pathogenic effects are mainly mediated through AT1R. This class of drugs has similar efficacy to ACEI and has the following advantages.
(1) The effects are not affected by ACE gene polymorphisms;
(2) Inhibition of non-ACE-catalyzed Ang II pathogenic effects;
(3) Promoting the beneficial effect of Ang II binding to AT2R. In addition, the adverse effects of ARB are less severe than those of ACEI.
(1) ARB is mostly excreted in bile and is less likely to accumulate in renal insufficiency;
(2) ARB does not affect kinase, and there are no adverse effects such as cough and angioedema. Of course, ARB does not have all the effects of ACEI: for example, ACEI reduces the degradation of Ang-1~7 and kinase. ang-(1~7) acts on specific Ang-1~7 receptors, which can cause vasodilation, blood pressure decrease and anti-proliferative effect; bradykinin can elevate nitric oxide, prostacyclin, endothelial-derived hyperpolarizing factor and t-PA, which has vasodilation, anti-proliferative and anti-proliferative effects. No such effects were found for ARB.
ARB, like ACEI, can be the drug of choice for the treatment of renal substantive hypertension, including hypertension after the development of benign small arterial nephrosclerosis, and the combination of ACEI and ARB is more effective. Currently, renin blockers have been successfully developed and are in the clinical validation stage, and will likely be used in the clinic soon. It is believed that renin blockers will have a more complete blocking effect on RAS and will bring greater benefits to hypertension treatment. When applying ARB and ACEI, excessive sodium intake will significantly affect the antihypertensive efficacy. Therefore, when taking these two types of drugs must limit salt, and advocate the combination of small dose diuretics, Ccr25>ml/min with thiazide diuretics; Ccr<25ml/min need to use tab diuretics.
5.4.3 Calcium channel blockers (CCB): The efficacy of CCB is very precise, but dihydropyridine CCB dilates the small inlet arteries more than the small outlet arteries. The current view is that when treating renal substantial hypertension with dihydropyridine CCB, including hypertension after the onset of benign small arterial nephrosclerosis, the intra-glomerular hemodynamic changes are beneficial (“three highs” decrease) or detrimental (“three highs” elevated), it depends on whether the systemic hypertension can be reduced to the target value.
Studies have shown that after the systemic hypertension is reduced to the target value, the benefit of reducing hypertension can overcome the disadvantage of expanding the small arteries into the glomerulus, and the “three highs” in the glomerulus can be improved. In addition, dihydropyridine CCBs also have some non-hemodynamic effects. These drugs can reduce renal hypertrophy, reduce the capture of macromolecules by thylakoid tissue, attenuate the mitogenic reaction of growth factors, inhibit free radical formation, promote nitric oxide production, improve mitochondrial calcium load and reduce residual renal unit metabolism, etc. These effects may also play a renal protective role. CCB has the following advantages over ACEI and ARB in the treatment of hypertension: the hypotensive effect is not affected by sodium intake; it can still be used in patients with renal failure; and it does not cause hyperkalemia.
5.4.4 Other antihypertensive drugs: such as diuretics, β-blockers and α-blockers have blood pressure-dependent glomerular hemodynamic protective effects, and indirectly reduce the “three highs” in the glomerulus by lowering systemic hypertension. For this reason, they are mostly used as complementary drugs in antihypertensive therapy.
In addition to active treatment of hypertension, antioxidant therapy and active management of risk factors for hypertensive renal damage, such as insulin resistance, hyperuricemia and hyperlipidemia, are important for the course and prognosis of patients with benign small artery nephrosclerosis. Renal insufficiency due to benign small arterial nephrosclerosis also requires treatment. Before entering end-stage renal failure, it should be treated with non-dialysis conservative therapy; after entering end-stage renal failure, it should be promptly treated with dialysis or renal transplantation.