According to the MDRD study, the turning point of GFR decline in K/DOQI staging (30 ml/min, 60 ml/min) was closely related to the occurrence of CKD complications, and the occurrence of complications such as hypertension, anemia, decreased serum ferritin, elevated iPTH, renal bone disease, and low calcium and high phosphorus increased significantly when GFR dropped to 60 ml/min, and when GFR further decreases to 30 ml/min, the incidence of the above complications increases linearly.
I. Pathological features and formation mechanism of chronic kidney disease progression
(A) Glomerulosclerosis
It has become a consensus that the progression of CKD is associated with the occurrence of glomerulosclerosis. It is generally believed that glomerulosclerosis occurs in stages, with initial glomerular endothelial cell damage and inflammatory response, followed by activation of thylakoid cell proliferation and accumulation of extracellular matrix, and finally leading to glomerular fibrosis. Endothelial cell injury induced by immune and non-immune factors (hemodynamic or hypermetabolic) initiates the first phase of glomerulosclerosis.
For example, increased systemic blood pressure is transmitted to the remnant glomeruli, leading to increased intracapillary pressure and endothelial cell damage. The damaged endothelium has a prohypercoagulant, inflammatory, and proliferative tendency mediated by, for example, procoagulants, inflammatory factors, cytokines, growth factors, and chemokines. This allows the entry of platelets and inflammatory cells (leukocytes and monocytes) into the glomerular capillaries. Infiltrating monocytes allow proliferation of thylakoid cells through direct cell-cell contact on the one hand, and through the release of mitogenic factors (e.g. PDGF) on the other.
The transcription factor NF-κB plays an important role in regulating the proliferative response of thylakoid cells. Proliferation-activated thylakoid cells exhibit a mesenchymal cell phenotype, express α-SMA, and have increased synthesis of extracellular matrix components (ECM). Recent studies have revealed that glomerular epithelial cells may also be involved in the pathological changes of glomerulosclerosis. Glomerular epithelial cells have no ability to divide, and under the action of injury factors, they stretch along the GBM, leaving part of the GBM exposed and further interacting with the mural epithelial cells to form adhesions, and the epithelial cells continuously extend in the exposed areas of the GBM, aggravating proteinuria.
It has also been hypothesized that damage to the epithelium leads to adhesion of the glomerular capillary plexus to the capsule wall, and as plasma components continue to filter through, deposits of amorphous material appear around the glomerulus, which may sometimes extend all the way to the neck of the tubule, leading to impaired tubular junctions, resulting in tubular atrophy and interstitial fibrosis. Pro-fibrotic factors, such as transforming growth factor T G F – β, stimulate excessive production of E C M by glomerular lamina propria cells while inhibiting ECM degradation, which in turn leads to glomerulosclerosis.
Capillary plexus and glomerular capsule adhesions can also infiltrate glomeruli with periglomerular fibroblasts, which in turn leads to glomerulosclerosis.
(B) Tubulointerstitial fibrosis
The pathological significance of tubulointerstitial fibrosis in the progression of chronic kidney disease has received much attention in recent years. It has also become a more important indicator to evaluate the degree of renal impairment and prognosis. The inflammatory response, proliferation of interstitial fibroblasts and excessive deposition of interstitial ECM all lead to the formation of fibrosis. Renal tubular epithelial cells play an important role in the pathological changes of TIF. Damaged tubular epithelial cells show antigen-presenting cell activity, express cell adhesion molecules, release inflammatory mediators, endocrine hormones, chemokines, cytokines and growth factors, and synthesize more ECM under certain stimuli.
Recent evidence suggests that tubular epithelial cells can secrete these mediators in response to proteinuria stimulation, and that further tubular epithelial cell transdifferentiation to myofibroblasts (EMT) can occur to promote ECM synthesis. When proximal tubular epithelial cells were cultured with cultures containing high concentrations of albumin, NF-κB was activated, and the latter is an important transcription factor that upregulates the transcription of many chemokines and growth factors.
Various hormones such as angiotensin II, growth factors and cytokines spilled from the damaged glomeruli may also stimulate tubular cells to release various chemokines to induce inflammatory cells including monocytes into the renal tubules and interstitium. These cells release large amounts of growth factors which in turn activate interstitial fibroblasts. Activated renal interstitial fibroblasts acquire the characteristics of myofibroblasts, express α-SMA, and proliferate to invade the glomerular and peritubular spaces. These cells synthesize increased ECM, including interstitial collagen I and III, allowing excessive accumulation of ECM in the renal interstitium and formation of fibrosis.
(C), vascular sclerosis
The process of renal sclerosis progression as a whole also includes the process of vascular sclerosis. Hyaline degeneration of small renal arteries may be present in early CKD even in the absence of severe hypertension, and these vascular changes are often independent of severe systemic hypertension. In chronic glomerulonephritis vascular sclerosis is associated with the progression of renal disease, and in diabetic glomerulosclerosis hyaline degeneration of the small arteries entering the glomerulus is seen. Lesions of the post-globular arteries can exacerbate interstitial ischemia and fibrosis.
In the fibrotic kidney the number of peritubular capillaries is reduced and function is impaired. A large body of laboratory evidence suggests that ischemia and thus hypoxia is an important influencing factor in fibrosis formation, which stimulates tubular epithelial cells and renal interstitial fibroblasts to synthesize large amounts of ECM components and reduces their degradation. In experimental models of renal fibrosis, loss of peritubular capillaries is associated with a decrease in renal expression of pro-angiogenic factors such as vascular endothelial cell growth factor.
In addition overexpression of thromboxane and anti-angiogenic factors can lead to persistent microvascular ischemia and further reduction in numbers. Intervention with VEGF reduces microvascular loss and protects peritubular capillaries, thereby improving renal function and delaying the onset of renal fibrosis. In addition, extravascular membrane cells are an important source of renal interstitial myofibroblasts, which can promote the progression of interstitial fibrosis.
II. Clinical prevention and treatment countermeasures of chronic kidney disease
The overall goal of CKD prevention and treatment is to slow down the progression of renal damage, prevent the occurrence of cardiovascular complications, prevent other complications such as renal bone disease and anemia, and ultimately improve the survival rate and quality of life of patients.
(I) Early detection and diagnosis.
CKD often lacks clinical manifestations in the early stage, so early screening has become the focus of research in various countries, usually urine examination is the most commonly applied method, as for the determination of the screening population there are two types: one for the general population and the other for the high-risk population. Early detection of glomerulonephritis and early treatment can greatly improve the prognosis.
This type of study, which is conducted indiscriminately in the general population, is able to understand the prevalence and incidence of CKD, but its cost2benefit is relatively low. In contrast, screening in high-risk populations can identify more asymptomatic patients, and its cost-effectiveness is significantly higher than that of the general population-based studies described above.
In pediatrics and adolescence, the following conditions should be added as risk factors for CKD:
(1) Family history of polycystic kidney or other hereditary kidney disease;
(2) Low birth weight infants;
(3) history of perinatal hypoxia, renal artery or vein embolism, or other acute kidney injury;
(4) High-risk patients with dysplasia, hypoplasia, urological disease (especially obstructive urological disease), obesity, etc. In addition, ultrasound examination of pregnant women reveals fetal urological malformations.
(II) Prevention and treatment
How to prevent CKD patients at an early stage and slow down the progress of chronic renal failure is the main problem faced by clinical workers. The so-called early prevention.
Primary Prevention refers to the timely and effective treatment of existing kidney diseases or diseases that may cause kidney damage to prevent the occurrence of CKD.
Secondary Prevention refers to the treatment of patients with mild to moderate impairment of kidney function to slow down the progress of the disease and prevent the occurrence of ESRD.
1. Treatment of primary disease.
There are various primary diseases that cause renal lesions. Patients with CKD who are first diagnosed must actively look for the primary disease, and some of the primary diseases, such as allergic purpura, systemic lupus erythematosus, polyarteritis nodosa and Wegener’s granulomatosis, may be reduced or even cured after active treatment of renal damage.
2.Control of deteriorating factors
Many factors may aggravate the condition of CKD, and these predisposing factors must be dispelled.
(1) Dehydration and hypotension lead to insufficient blood flow and decreased renal perfusion, resulting in renal ischemia and hypoxia;
(2) Use of nephrotoxic drugs, such as nephrotoxic antibiotics, contrast agents, and prostaglandin synthesis inhibitors;
(3) Obstruction inside and outside the kidney, such as intrarenal urate crystals, urinary stones, edema caused by severe nephrotic syndrome compressing the renal tubules;
(4) Infection, bacterial infection toxins can directly damage the renal tubules, infection-induced water-electrolyte disorders or circulatory failure can aggravate the damage to the kidney;
(5) Severe hypertension causes spasm of the small renal arteries, especially the small arteries into the bulb, and decreases renal blood flow, or hypertension causes heart failure and decreases renal blood flow, or the treatment of hypertension causes ischemia in the kidney due to a rapid drop in blood pressure;
(6) Water-electrolyte disturbance;
(7) Large amount of proteinuria, high protein diet;
(8 ) High catabolic state in the body;
(8) Heart failure, etc.
The above factors, if detected and controlled in time, can often reverse renal function, and should be taken seriously clinically.
3, inhibit the formation of fibrosis to slow down the progression of chronic kidney disease
(1), control blood pressure
The MDRD study suggests that the blood pressure of patients with severe proteinuria should be controlled at a lower level than that of patients with mild to moderate proteinuria. Analysis of the study showed that lowering M A P slows the decline in G F R. For patients whose G F R declines by 2 to 3 ml/min per year, blood pressure needs to be controlled below 130/85 mmHg.
The A C E I intervention study (R E I N study) and the A R B intervention study (RENAAL study) showed that controlling blood pressure at 125/75 mmHg, the decline in GFR may be close to normal, about 2 ml min-1 y-1. The NKF proposes that the target for blood pressure control should be based on C K D staging. stage CKD1 to 4, patients with proteinuria < 1 g/24 h control blood pressure below 135/85 mmHg, and proteinuria if > 1 g/24 h, then control blood pressure below 125/75 mmHg.
So how to choose antihypertensive drugs? Angiotensin II (Ang II) has been shown to be nephrotoxic, and RAS blockers (ACEI and ARB) have unique advantages over other antihypertensive drugs. The unique advantage of ACEI over other antihypertensive agents is related to its anti-proteinuric effect in addition to antihypertensive effect.
The REIN study suggests that early and long-term treatment with ACEI can stabilize G F R and thus prevent progression to E S R D . Moreover, ACEI is beneficial in patients with mild, moderate and severe renal insufficiency. Meta-analysis of 11 studies showed that ACEI reduced the relative risk of ESRD by 31%. The early protein-lowering effect of antihypertensive therapy also predicts some benefit in long-term renal function.
Experiments suggest that ARB and ACEI have similar effects in reducing proteinuria and delaying the progression of renal disease, but there are also differences. ACEI does not completely block the conversion of Ang I to Ang II because of the presence of other protein hydrolases, such as Chymases, which activate Ang II production from the bypass pathway. However, ACEI inhibits the degradation of bradykinin in vivo, which has a vasodilating effect on lowering blood pressure, which enhances the antihypertensive and urinary protein-lowering effects of ACEI. On the other hand, ARB may induce AngII binding to its other receptor, AT2, thereby activating the vasodilatory, antiproliferative signaling pathway.
The combined use of A C E I and ARB has a synergistic effect on antihypertensive and urinary protein lowering when neither is used at maximum dose. Therefore, NKF recommends A C E I, ARB, salt intake restriction, and diuretics as first-line agents for patients with CKD1-4 stage. Patients with renal insufficiency should be especially careful with ACEIs because these drugs reduce the hyperfiltration state of the residual glomerulus, which may lead to further deterioration of renal function and a mild to moderate (10% to 30%) increase in blood creatinine, but it is not necessary to discontinue them.
It is also because ACEI can reduce the glomerular filtration fraction that it can protect the residual renal function. However, if there is a further increase in creatinine or even hyperkalemia, ACEI must be discontinued and replaced by other antihypertensive drugs. Recently, Hou et al. suggested through long-term follow-up that even proteinuric patients with blood creatinine levels above 3 mg/dL may benefit from the use of ACEI and did not significantly increase the side effects in patients.
(2) Reducing proteinuria
Any patient with CKD should be treated with proteinuria even if the amount of urine protein is small. The degree of proteinuria is related to the rate of GFR decrease. However, proteinuria will gradually worsen with the prolongation of the disease and GFR will further decrease. When proteinuria reaches 500 mg/d, protein-lowering therapy should be performed because protein is reabsorbed and degraded by tubular cells after filtration, and then a large amount of protein undetectable by existing clinical tests is released into the urine, so existing tests always underestimate the protein load of renal tubular epithelial cells (about 2 g/d).
Therefore, the benefit we receive from interventions for microalbuminuria is much higher than the apparent amount of reduction in microalbuminuria. However, some renal diseases have a low risk of developing ESRD, such as hormone-sensitive MCD and congenital nephritis, and do not require overemphasis on renal protection therapy.
(3), Lipid lowering
Hyperlipidemia is a characteristic of CKD patients, and lipid-lowering drugs can reduce lipids, but there is no research data to confirm that lipid reduction is beneficial for improving renal function. simvastatin, an HMG-CoA degrading enzyme inhibitor, was taken continuously for two years in a group of CKD patients, and its effect of delaying the progression of renal disease was not found. In this study, there was no improvement in renal function, although lipids were reduced and proteinuria was reduced. However, Meta-analysis of 12 lipid-lowering intervention studies suggested that lowering blood lipids could delay the progression of CKD.
(4), Anti-platelet and anticoagulation
Antiplatelet therapy was previously thought to slow the progression of membranoproliferative glomerulonephritis (MPGN), but long-term follow-up studies have not found this effect. A recent study suggests that antiplatelet therapy may reduce proteinuria in patients with MPGN. Another study suggests that antiplatelet therapy combined with warfarin anticoagulation is beneficial in chronic glomerulonephritis (CGN), but this has not been confirmed by a large number of clinical trials.
(5), Inhibition of aldosterone
Aldosterone may play an important role in the development of nephropathy. Some studies have found that anserine is effective in preventing the development of experimental hypertensive nephrosclerosis and protecting renal function, while aldosterone significantly inhibits the renal protective effect of ACEI.
Spironolactone has been studied extensively in congestive heart failure, and in the RALES (the Randomized Aldactone Evaluation Study) study, which looked at the efficacy of spironolactone with ACEI, tab diuretics and digoxin as the base treatment, the results showed that the spironolactone group reduced mortality from all causes by 30%. Even with a relatively small dose of spironolactone 25 mg, it showed a protective effect independent of the antihypertensive effect. The safety and efficacy of aldosterone inhibitors in the treatment of proteinuria in kidney disease needs to be further investigated.
(6) Vasopeptidase inhibitors
Vasopeptidase inhibitors are a relatively new class of cardiovascular drugs that block both ACE and the peptide chain endonuclease Endopeptidase (NEP), which degrades atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, Adrenomedullin, Urodilatin, and bradykinin. These peptides are vasodilatory, promote sodium excretion (Natriuresis), and reduce angiotensin and sympathetic nervous system activity.
The combined application of ACEI and NEP inhibitors is highly effective in lowering blood pressure and can be used in the treatment of heart failure, but studies in chronic kidney disease are lacking. Animal studies have found similar renoprotective effects of NEP inhibitors as ACEIs and possibly more potent, but human studies are lacking. Unfortunately, such drugs have a negative effect of life-threatening angioedema, so their safety and future use in the treatment of proteinuria in renal disease remains to be evaluated.
(7), Inhibition of inflammatory response
In the process of progression of chronic kidney disease into ESRD there is the involvement of inflammatory response, and a large number of inflammatory cells infiltrate the kidney tissue after stimulation, and release various inflammatory mediators (IL-1, IL-6, etc.), cytokines, growth factors, chemokines, etc.. Their interactions are complex, and some new interventions have been found in experimental animal models with potential to delay the progression of CKD, but relevant clinical studies are lacking.
For example, anti-fibrotic factors: hepatocyte growth factor, osteogenic protein-1; pro-vascular growth factor: VEGF; anti-fibrotic hormone class: Relaxin; and also: inhibitors of Aminoguanidine/AGEs, heparin analogs/mucopolysaccharides, etc.
(8), regulation of ECM
In patients with CKD, the metabolism of ECM, a component of the extracellular matrix of renal tissue, is disturbed, with increased synthesis and decreased degradation, so excessive accumulation in the renal interstitium promotes the formation of fibrosis. Currently, there are more studies on tissue matrix metalloproteinase-inhibitor-1 and PAI-1, but they are still limited to in vitro cell culture systems or animal experiments, and are still some distance away from clinical application.
(9) Stem cells
Stem cells are progenitor cells with the ability to differentiate into various organ cells throughout the body. In recent years, many scientific researchers have devoted themselves to the study of stem cells in order to apply them to tissue repair, but the reports are mixed and there is no clinical application yet.
4.Dietary treatment
(1) Protein: Animal models of chronic kidney disease have shown that a low-protein diet has a certain renoprotective effect, while in humans it is still debated. Early clinical studies have certain shortcomings, first of all it lacks strict control, using blood creatinine value as an indicator to evaluate CKD, while ignoring the effect of low protein diet on creatinine metabolism and secretion. A number of rigorously designed prospective randomized controlled studies in recent years have come to the opposite, but non-positive, conclusion.
The largest of these studies, the MDRD study, followed 840 patients for 3 years, did not conclude that a low-protein diet significantly delayed the progression of CKD. in patients with a GFR of 13-24 ml min-1-1-1.73 m-2, dietary protein intake was positively correlated with the rate of progression of their renal insufficiency.
The K/DOQI nutritional guidelines state that patients with GFR <25 ml/min need to control protein intake to 0.6 g/kg. However, as a clinician one has to consider the whole issue. A long-term low protein diet increases the incidence of complications and mortality, is it worthwhile to delay renal replacement therapy at this cost?
(2) Phosphorus: Low phosphorus diet can effectively control the occurrence of hyperphosphatemia and renal osteodystrophy in the early stage of CKD, and can reduce the incidence of cardiovascular calcification and mortality, so most scholars advocate low phosphorus diet, but there is still some controversy, and some studies have found that low phosphorus diet is not beneficial to CKD patients.
(3) Lipids: It has been observed that dietary fish oil intake can benefit patients by lowering blood lipids and has anti-inflammatory effects. In a study of a group of patients with IgA nephropathy taking fish oil, with a 50% increase in blood creatinine as the event endpoint, significantly fewer patients in the fish oil group than in the placebo group reached the observed endpoint. The Canadian and Australian nephrology communities advocate the use of fish oil for the treatment of IgA nephropathy.
(4 ) Salt: Although there are no specific studies to evaluate the role of salt intake in CKD, its anti-hypertensive effect can benefit patients with chronic renal insufficiency. Clinical evidence suggests that restricting salt intake can improve the antihypertensive and proteinuric effects of A C E I and A R B. The NKF proposes that salt intake should be restricted in the general population with blood pressure in a critical state (140/90 mmHg) and in patients with CKD1 to 4 stages, and that the latter should be treated in combination with antihypertensive drugs.
5.Chinese medicine treatment
Chinese medicine has accumulated considerable experience in the treatment of kidney disease. Although the exact renoprotective effect of various herbal medicines is still lack of strictly designed clinical experiments, the renoprotective effect of various herbal medicines in China has attracted worldwide attention, and there are more researches such as Cordyceps, Rhubarb, Salvia, etc. Among them, Cordyceps has certain preventive and curative effect on nephritis, renal failure, kidney injury caused by drugs and ischemia, and it shows various mechanisms of action;
It can reduce inflammatory cell infiltration, inhibit immune complex deposition, anti-lipid peroxidation, regulate immunity, promote renal tubular epithelial cell proliferation, inhibit glomerular thylakoid cell proliferation, regulate lipid and glucose metabolism and slow down the process of fibrosis by inhibiting TGF-β. Rhubarb, on the other hand, has laxative effect, antioxidant, inhibits various growth factors and promotes ECM protease activity, thus delaying the progression of kidney disease.
In summary, the main measures to delay the progression of chronic kidney disease according to the evidence-based medicine are summarized as follows.
(1) Blood pressure and proteinuria must be long-term tested and effectively controlled (confirmed by evidence-based medicine).
(2) High protein diet should be avoided in CRF patients, but it should be noted that dietary restriction of protein intake (0.6 g・kg-1・d-1) may lead to the development of malnutrition. Therefore, appropriately advancing dialysis by a few months when the patient’s nutritional status is still good is beneficial to the patient’s prognosis, while waiting until malnutrition occurs increases mortality (Perspective). If the patient is required to have a protein-restricted diet, the patient’s nutritional status should be evaluated regularly and regularly.
(3) Patients with hypertension and proteinuria need to restrict salt intake (sodium 60-80 mmol/d, i.e. NaCl 4-6 g/d). The need for salt restriction is even greater when ACEI and ARB are used in this patient (confirmed by evidence-based medicine).
(4) Reducing saturated fatty acid intake in CRF patients and controlling hypercholesterolemia with Statins can reduce the incidence of coronary heart disease in high-risk groups. (Opinion).
(5) Attention should be paid to the prevention of early complications of CFR, such as anemia, metabolic acidosis, low calcium and high phosphorus and renal osteodystrophy (confirmed by evidence-seeking medicine). The control of hyperphosphatemia should be accompanied by the prevention and control of vascular calcification (including coronary arteries), the incidence of cardiovascular events and mortality.
(6) Avoid the application of nephrotoxic drugs, including non-steroidal anti-inflammatory drugs, antibiotics with nephrotoxicity, intravenous contrast agents, and close testing of renal function when ACEI is applied.