Diabetic nephropathy is a progressive decrease in proteinuria and glomerular filtration rate (GFR) due to long-term diabetes.[1]diabetesnephropathyIt is one of the most important complications of diabetic patients.The incidence of kidney disease in China is also on the rise and has become the second cause of end-stage kidney disease, second only to various glomerulinephritis。[2]Because of its complex metabolic disorder, once it develops to end-stage renal disease, it is often more difficult to treat than other kidney diseases. Therefore, timely prevention and treatment is of great significance for delaying diabetic nephropathy.
Foreign name
diabetic nephropathy
Visiting department
Endocrinology Department, Nephrology Department
Multiple population
Diabetics
Common causes
It is related to heredity, metabolic abnormalities caused by hyperglycemia, etc
common symptom
The main clinical manifestations are chronic hyperglycemia and proteinuria
diabetesnephropathyThe etiology and pathogenesis are still incomplete.It is believed that the disease is caused by multiple factors under the joint action of certain genetic background and some risk factors.
1. Risk factors
(1) Genetic susceptibility: genetic factorsIt may be an important determinant of the incidence and severity of diabetic nephropathy.[3]If one of the siblings or parents of a diabetic patient has diabetic nephropathy, the possibility of diabetic nephropathy is significantly increased,This phenomenon has been observed in both type 1 and type 2 diabetic patients[4-5]
(2) Age:The older and longer the duration of type 2 diabetes, the higher the risk of albuminuria[6];For type 1 diabetes, patients diagnosed before the age of 5 years have a very low risk of progression to ESRD;However, for older patients at the time of diagnosis, the relationship between the age of diagnosis and progression to ESRD is still unclear[7]
(3) Blood pressure: Prospective studies have found that patients with higher systemic blood pressure are associated with subsequent diabetic nephropathy.
(4) Glomerular filtration rate: patients with glomerular hyperfiltration seem to have a higher risk of diabetic nephropathy
(5) Blood glucose control: patients with poor blood glucose control (high HbA1c) are more likely to have diabetic nephropathy
（6）Obesity: High BMI is associated with an increased risk of CKD in diabetic patients[8]
2．Pathogenesis[9]
oneAbnormal glucose metabolism
In the state of diabetes, the systemic organs appear glucose metabolism disorder, in which the glucose metabolism of kidney, nerve, eye and other tissues/organs is significantly enhanced, at this time, about 50% of glucose is metabolized in the kidney, which reduces the risk of ketoacidosis and hypertonic coma in the body on the one hand;On the other hand, it also aggravates the sugar load of the kidney.Reasons for increased glucose metabolism in the kidney include:
① The activity of glucose transporter 1 (Glut 1) in renal cells increased, and the number and affinity of insulin receptors in renal tissue cells increased;
② High glucose in cells causes excessive production of various injury mediators, such as IGF-1, and promotes the activity of Glut 1, so that more glucose enters the cells;
③ Hyperglycemia leads to increased production of reactive oxygen species;
④ Activation of polyol pathway, activation of diacylglycerol protein kinase C (PKC) pathway, and change of hexosamine pathway
⑤ Protein nonenzymatic glycosylation (end products of protein glycosylation) increased.
twoRenal hemodynamic changes
High glomerular perfusion, high transmembrane pressure and high filtration play a key role in the development of diabetic nephropathy.The increase of glomerular volume and capillary surface area leads to the increase of glomerular blood flow, capillary pressure and proteinuria.
threeoxidative stress
In the state of diabetes, the autoxidation of glucose leads to overload of mitochondria and excessive production of reactive oxygen species (ROS);On the other hand, the antioxidant capacity of the body decreases, and the amount of NADPH in the cells is insufficient.ROS can induce multiple injury mediators, promote the synthesis and degradation of extracellular matrix in glomerulus, and lead to glomerular fibrosis;ROS can also cause the disappearance of epithelial cell adhesion, destruction of tubular basement membrane and increased infiltration of interstitial cells, leading to tubulointerstitial fibrosis
fourImmunoinflammatory factors
There is a complex interaction network between complement system and pattern recognition receptor in natural immunity, which may play an important role in the pathogenesis of diabetic nephropathy.In addition, monocyte macrophages and mast cells, various transcription factors, chemotactic molecules, adhesion molecules, inflammatory factors and end products of glycosylation metabolism may be involved in the pathogenesis.Macrophages and tumor necrosis factor alpha may become important intervention targets.
fiveGenetic factor
At present, it is believed that diabetic nephropathy is a polygenic disease, and genetic factors play an important role in determining the susceptibility to diabetic nephropathy.
Clinical manifestations and disease stages
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Diabetic nephropathy is one of the complications of diabetic systemic microvascular disease, so diabetic nephropathy is often accompanied by other organ or system microvascular diseases, such as diabetesRetinopathyAnd peripheralneuropathyChange.The onset of diabetic nephropathy in patients with type 1 diabetes is about 10 to 15 years, while that in patients with type 2 diabetes is relatively short, which is related to older age and more other basic diseases.
According to the course and pathophysiological evolution of diabetic nephropathy, Mogensen has proposed to divide diabetic nephropathy into the following five stages:
1. Glomerular hyperfiltration and renal hypertrophy
This initial change is consistent with the hyperglycemia level, which can be partially alleviated after blood glucose control.There was no histopathological injury in this period.
2. Normal albuminuria
GFR is higher than normal.Renal pathology showed that GBM was thickened, matrix in mesangial area increased, urinary albumin excretion rate (UAE) increased after exercise (>20 μ g/min), and returned to normal after rest.If the blood sugar can be well controlled in this phase, the patient can stay in this phase for a long time.
3. Early diabetic nephropathy, also known as "continuous microalbuminuria"
GFR began to decline to normal.Renal pathology showed nodular glomerular lesions and hyaline arterioles.UAE continued to rise to 20-200 μ g/min, resulting in microalbuminuria.The patient's blood pressure is elevated in this period.Treatment with ACEI or ARB drugs can reduce the excretion of urinary albumin and delay the progression of kidney disease.
4. Clinical diabetic nephropathy
Pathologically, typical K-W nodules appear.If continuous massive albuminuria (UAE>200 μ g/min) or albuminuria>500 mg/d, about 30% of patients may have nephrotic syndrome, and GFR continues to decline.The characteristic of this phase is that urinary protein does not decrease with the decrease of GFR.Once the patient enters Phase IV, the disease often progresses. If not actively controlled, GFR will decline by 1ml/min on average every month.
GFR<10ml/min。Urinary protein factorGlomerulosclerosisAnd decrease.uremiaThe symptoms are obvious and dialysis treatment is needed.
The above stages are mainly based on type 1 diabetic nephropathy, while type 2 diabetic nephropathy is not obvious.
Proteinuria is closely related to the progression of diabetic nephropathy.Microalbuminuria not only indicates glomerular filtration barrier barrier dysfunction, but also indicates systemic vascular endothelial dysfunction and is found to be closely related to cardiovascular complications.
Nephrotic syndrome and general primary diabetic nephropathyGlomerulopathyIn contrastedemaThe degree is often more obvious, and often accompanied by severehypertension。Due to the high transmembrane pressure of the capillaries in the glomerulus and the serious damage of the function of the glomerular filtration membrane protein barrier, part of the patients in the final stagerenal failureThe patient may also have a large amount of proteinuria.
inspect
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1. Qualitative determination of urine sugar
It is a simple method for screening diabetes, but false negative or false positive can occur in diabetic nephropathy, so blood glucose measurement is the main basis for diagnosis.
2. Urinary albumin excretion rate (UAE)
20~200 μ g/min is an important index for the diagnosis of early diabetic nephropathy;Diabetic nephropathy is diagnosed when the UAE continues to be more than 200 μ g/min or the urine protein is positive in routine examination (the quantitative urine protein is more than 0.5g/24h).
3. Urine sediment
Generally, urinary tract infection is indicated when the change is unclear and there are many white blood cells;A large number of red blood cells suggest that there may be hematuria caused by other reasons.
4. Urea nitrogen and creatinine
In the late stage of diabetic nephropathy, endogenous creatinine clearance rate decreased and blood urea nitrogen and creatinine increased.
GFR increased;The increase of renal volume measured by B ultrasound is consistent with early diabetic nephropathy.GFR decreased significantly in uremia, but the renal volume often did not decrease significantly.
Diagnosis and differential diagnosis
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Diabetic nephropathy is usually diagnosed according to the increase of UACR or the decrease of eGFR and the exclusion of other CKDs.Diabetic nephropathy should be considered when diabetic patients have kidney damage clinicallyhypertension、insulin resistance High GFR or severe hypertension are high risk factors for diabetic nephropathy.Microalbuminuria is a sign of diabetic nephropathy.The microalbuminuria finger UAE continued to increase by 20-200 μ g/min, or the urine albumin was 30-300 mg/24h, and the urine creatinine was 30-300 μ g/mg.
As microalbuminuria is the main clue for clinical diagnosis of early diabetic nephropathy, the American Diabetes Association suggests that for patients with type 1 diabetes, screening of microalbuminuria should be carried out five years after onset;Type 2 diabetes should be checked at the same time when it is diagnosed.However, if one test is positive, it cannot be diagnosed as continuous microalbuminuria, and it needs to be rechecked within 3-6 months. If two of the three tests are positive, it can be diagnosed;If it is negative, it should be checked once a year.
Microalbuminuria is also associated with many other complications of diabetes, including hypertensionHyperlipidemia、atherosclerosisAnd cardiovascular diseases.Therefore, the presence of microalbuminuria does not necessarily mean the occurrence of diabetic nephropathy. Whether it will inevitably progress to obvious proteinuria and then chronic renal failure after its occurrence remains controversial.In several large series of long-term observations, only 30%~45% of diabetic patients with microalbuminuria turned to clinically dominant albuminuria in 10 years, and 30% of microalbuminuria disappeared, which is more obvious in type 2 diabetes.Therefore, multiple examinations and continuous follow-up should be conducted before judgment.
Obvious proteinuria (>500mg/d) or nephrotic syndrome all indicate obvious renal disease. In type 1 diabetes, if there is proteinuria and diabetesRetinopathyIn particular, patients after puberty can almost be identified as diabetic nephropathy.
Type 2 diabetic patients with proteinuria must carefully exclude other possible causes of proteinuria before diagnosis of diabetic nephropathy, especially for type 2 diabetic patients who cannot determine the onset time.Diabetes combined with other kidney diseases should be considered in the following clinical situations: ① There is obvious proteinuria but no obvious diabetesRetinopathy；②acuteRenal injury；③nephritisnaturehematuria, the urine sediment is mainly deformed red blood cells or has red blood cell tube type; ④Nephrotic syndrome without hypertension; ⑤In the short term, proteinuria increased significantly.Renal biopsy should be considered to exclude glomerulopathy of other causes in the above cases.
treatment
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The treatment of diabetic nephropathy varies according to different disease stages.Clinically, it mainly focuses on the following aspects:
1. Control blood sugar
Glycosylated hemoglobin (HbA1c) should be controlled below 7.0%.Strict control of blood glucose can partially improve abnormal renal hemodynamics;At least in type 1 diabetes can delay the emergence of microalbuminuria;Those who have reduced microalbuminuria will become obvious clinical albuminuria.
2. Control blood pressure
Hypertension is not only common in diabetic nephropathy, but also an important factor leading to the occurrence and development of diabetic nephropathy.Angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB) is the first choice for antihypertensive drugs.These drugs have pharmacological effects such as improving renal hemodynamics, reducing urinary protein excretion, inhibiting the activity of mesangial cells, fibroblasts and macrophages, and improving the permeability of filtration membrane.Even if the blood pressure of the whole body is normal, it can also produce renal protection function, and does not depend on the improvement of hemodynamics after blood pressure reduction.Side effects of ACEI mainly includeHyperkalemia, renal dysfunction and dry cough.The target of blood pressure reduction is 130/80mmHg in patients with proteinuria.Beta blockers and diuretics are not recommended to be included in the first-line medication because of their potential effects on glucose and lipid metabolism disorders, unless tachycardia is combined or obviousedema。The renal protective function of calcium channel blockers (CCB) in patients with diabetic nephropathy is still unclear, but diltiazem seems to be superior to dihydropyridine, which is not recommended for patients with diabetic nephropathy alone.
3. Dietotherapy
High protein diet aggravates glomerular hyperperfusion and hyperfiltration, so it advocates the principle of high-quality protein.Protein intake should be dominated by animal protein with high biological potency. Protein intake should be limited to 0.8g/(kg · d) in the early stagerenal failure% of patients could be reduced to 0.6 g/(kg · d).It is advisable to supplement α - ketoacid for patients with middle and late stage renal function damage.In addition, it is suggested to replace red meat (such as beef, mutton, pork) with fish, chicken, and add polyunsaturated fatty acids.In addition, it is not necessary to excessively limit the intake of vegetable protein, such as soybean protein.
4. Alternative treatment for end-stage renal disease
Enter the end stagerenal failureThose with diabetes mellitus can be treated with renal replacement therapy, but their prognosis is worse than those without diabetes mellitus.
Diabetic complications are common in patients with diabetic nephropathy,uremiaSymptoms appear earlier, the indications of renal replacement therapy should be appropriately relaxed.The clearance rate of general endogenous creatinine drops to 10-15ml/min or is accompanied by obvious gastrointestinal symptoms, hypertension andheart failureThose who are difficult to control can enter maintenance dialysis.The long-term survival rates of hemodialysis and peritoneal dialysis are similar. The former is conducive to blood sugar control and dialysis adequacy is good, but it is difficult to establish arteriovenous fistula, and cardiovascular and cerebrovascular accidents are prone to occur during dialysis;The latter is often used for continuous ambulatory peritoneal dialysis (CAPD), which has the advantage of protecting the residual renal function in the short term. Since anticoagulant is not necessary, it can also be used in patients with cardiovascular and cerebrovascular accidents, but it is difficult to control the blood sugar level of patients with glucose as the osmotic solute.
5. Organ transplantation
For patients with end-stage diabetic nephropathy,renal transplantIt is the most effective treatment, accounting for aboutrenal transplant20% of patients.Corpses in recent yearsrenal transplantThe 5-year survival rate was 79%renal transplant91%, while the 5-year survival rate of dialysis patients was only 43%.The survival rate of living kidneys, especially those from relatives, is significantly higher than that of cadaversrenal transplant。However, the survival rate of kidney transplantation in diabetic nephropathy patients is still 10% lower than that in non diabetic patients.Kidney transplantation alone cannot prevent the recurrence of diabetic nephropathy, nor can it improve other diabetic complications.
Combined pancreas kidney transplantation may restore the glycosylated hemoglobin and creatinine levels of patients to normal, and improve other diabetic complications. Therefore, the quality of life of patients is better than that of simple kidney transplantation.
