Etiology and pathogenesis
The etiology and pathogenesis of diabetic nephropathy are unclear. At present, it is believed that multiple factors are involved, and the disease is caused by the combined effect of certain genetic background and some risk factors.
1.Genetic factors
The proportion of men with diabetic nephropathy is higher than that of women; studies from the United States have found that in the same living environment, African and Mexican people are more prone to diabetic nephropathy than white people; in the same race, certain families are prone to diabetic nephropathy, all of which suggest the existence of genetic factors. 40% to 50% of type 1 diabetes mellitus occurs with microalbuminuria, and only 20% to 30% of type 2 diabetes mellitus occurs during the observation period. The occurrence of diabetic nephropathy suggests that genetic factors may play an important role.
2. Abnormal renal hemodynamics
Renal hemodynamic abnormalities can be observed in the early stage of diabetic nephropathy, manifested as glomerular hyperperfusion and hyperfiltration, elevated renal blood flow and glomerular filtration rate (GFR), and the degree of elevation is more significant after increasing protein intake.
3.Metabolic abnormalities caused by hyperglycemia
Hyperglycemia mainly causes renal damage through renal hemodynamic changes and metabolic abnormalities, among which the mechanisms of renal damage caused by metabolic abnormalities mainly include.
(1) Local disorders of glucose metabolism in renal tissues, which can form glycosylation end metabolites (AGES) through non-enzymatic glycosylation;
(2) Activation of polyol pathway;
(3) Activation of the diacylglycerol-protein kinase c pathway;
(4) abnormal metabolism of the glucosamine pathway. In addition to early hyperfiltration, the above metabolic abnormalities promote glomerular basement membrane (GBM) thickening and extracellular matrix accumulation; increase glomerular hair
4, hypertension
Almost any diabetic nephropathy is accompanied by hypertension, in type 1 diabetic nephropathy hypertension occurs in parallel with microalbuminuria, while in type 2 is often present before the onset of diabetic nephropathy. Blood pressure control is closely related to the development of diabetic nephropathy.
5.Abnormal metabolism of vasoactive substances
The development of diabetic nephropathy can be characterized by abnormalities in the metabolism of various vasoactive substances. These include abnormalities in the metabolism of RAS, endothelin, prostaglandin family and growth factors.
Clinical manifestations and disease staging
Diabetic nephropathy is one of the systemic microangiopathic comorbidities of diabetes mellitus, so it often occurs in combination with microangiopathy of other organs or systems, such as diabetic retinopathy and peripheral neuropathy. It is associated with older age and the combination of more other underlying diseases.
According to the course of diabetic nephropathy and pathophysiological evolution, diabetic nephropathy is divided into five stages as follows.
(1) Glomerular hyperfiltration and renal hypertrophy stage
This initial change is consistent with high blood glucose levels and can be partially relieved with glycemic control. There is no pathological histological damage in this phase.
(2) Normal albuminuria phase
GFR is higher than normal. Renal pathology shows GBM thickening, increased matrix in the thylakoid region, and elevated urinary albumin excretion rate (UAE) after exercise (>20 μg/min), which returns to normal after rest. If the blood sugar can be well controlled in this stage, the patient can be stable in this stage for a long time.
(3) Early diabetic nephropathy stage, also called “persistent microalbuminuria stage”
GFR starts to drop to normal. The kidney pathology appears glomerulonodular lesions and small arterial vitreous lesions, and the UAE continues to rise to 20-200μg/min, resulting in microalbuminuria. The patient’s blood pressure was elevated during this period. Treatment with ACEI or ARB drugs can reduce urinary albumin excretion and slow down the progression of renal disease.
(4) Clinical diabetic nephropathy stage
Typical K-W nodules appear on the pathology. Persistent massive albuminuria (UAE>200μg/min) or proteinuria >500mg/d, about 30% of patients may develop nephrotic syndrome and GFR continues to decrease. This stage is characterized by urinary protein that does not decrease with the decline in GFR. Once the patient enters stage IV, the disease tends to progress progressively, and if not actively controlled, GFR will drop by an average of 1 ml/min per month.
(5) End-stage renal failure
GFR<10ml/min. urine protein amount is reduced by glomerulosclerosis. Uremic symptoms are obvious and need dialysis treatment. The above staging is 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 indicates not only glomerular filtration barrier impairment, but also systemic vascular endothelial dysfunction and is found to be closely associated with cardiovascular complications.
The nephrotic syndrome of diabetic nephropathy is often more markedly edematous than the usual primary glomerular disease and is often associated with severe hypertension. Some patients with end-stage renal failure also have large amounts of proteinuria due to the high capillary transmembrane pressure in the glomeruli and the severely impaired protein barrier function of the glomerular filtration membrane.
Diagnosis and differential diagnosis
Diabetic nephropathy should be considered in diabetic patients with clinical renal impairment. Those with renal disease in the family, significant hypertension, insulin resistance, and significantly high GFR or severe hypertension are at high risk for developing diabetic nephropathy. Microalbuminuria is a marker for the diagnosis of diabetic nephropathy. Microalbuminuria refers to a sustained elevation of UAE of 20-200 μg/min, or urinary albumin of 30-300 mg/24h or urinary albumin: urinary creatinine of 30-300 μg/mg.
Since microalbuminuria is the main clue for clinical diagnosis of early diabetic nephropathy, the American Diabetes Association currently recommends that for patients with type 1 diabetes, screening for urinary microalbumin should be performed 5 years after the onset of the disease; and for type 2 diabetes it should be examined at the same time when diabetes is confirmed. However, a positive test is not sufficient to confirm the diagnosis of persistent microalbuminuria, which needs to be repeated within 3 to 6 months, and if two of the three tests are positive, the diagnosis is confirmed; if negative, the test should be performed once a year.
Microalbuminuria is also associated with a variety of other complications of diabetes, including hypertension, hyperlipidemia, atherosclerosis, and cardiovascular disease. Therefore, the presence of microalbuminuria does not necessarily indicate the development of diabetic nephropathy, and it is controversial whether its presence necessarily progresses to significant proteinuria and then chronic renal decline.
In several large series of long-term observations, it was found that only 30%-45% of diabetic patients with microalbuminuria turned into clinically significant proteinuria in 10 years, and another 30% of microalbuminuria disappeared, which is more obvious in type 2 diabetes. This is more pronounced in type 2 diabetes. Therefore, multiple examinations and continuous follow-up should be performed to determine this.
Significant proteinuria (>500mg/d) or nephrotic syndrome are indicative of significant nephropathy. In type 1 diabetes, any combination of proteinuria with diabetic retinopathy, especially in post-adolescent patients, is almost certainly diabetic nephropathy.
In diabetic patients with type 2 diabetes with proteinuria, other possible causes of proteinuria must be carefully excluded before diagnosing diabetic nephropathy, especially in type 2 diabetic patients in whom the time of onset is not clear. Diabetes mellitus combined with other renal diseases should be considered in the following clinical situations: (1) significant proteinuria without significant diabetic retinopathy; (2) acute kidney injury; (3) nephritic hematuria with urine sediment dominated by abnormal red blood cells or with red blood cell tubular pattern; (4) nephrotic syndrome without hypertension; (5) significant increase in proteinuria in a short period of time. Kidney biopsy should be considered in the above cases to exclude other causes of glomerulopathy.
Treatment
Treatment of diabetic nephropathy varies according to the stage of the disease. Clinically, it is mainly aimed at the following aspects.
1.Control of blood glucose
Glycosylated hemoglobin (HbA1c) should be controlled below 7.0% as much as possible. Strict glycemic control can partially improve the abnormal renal hemodynamics; delay the appearance of microalbuminuria, at least in type 1 diabetes; and reduce the transformation of existing microalbuminuria into obvious clinical proteinuria.
2.Control blood pressure
Hypertension is not only common in diabetic nephropathy, but is also an important factor in the development and progression of diabetic nephropathy. The first choice of antihypertensive drugs is angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB). These drugs have pharmacological effects such as improving intrarenal hemodynamics, reducing urinary protein excretion, inhibiting the activity of thylakoid cells, fibroblasts and macrophages, and improving the permeability of the filtration membrane. They can produce renal protection even in the presence of normal systemic blood pressure and are not dependent on hemodynamic improvement after blood pressure lowering.
The main side effects of ACEI are hyperkalemia, hyperalgesia and dry cough. The target target for blood pressure lowering is 130/80 mmHg in those with proteinuria. β-blockers and diuretics are not advocated for inclusion in first-line use because of their potential glucolipid metabolism disrupting effects, unless combined with tachycardia or significant edema. The renoprotective function of calcium channel blockers (CCBs) in patients with diabetic nephropathy is unclear, but diltiazem appears to be superior to dihydropyridines, which are not recommended for use alone in patients with diabetic nephropathy.
3.Diet therapy
High-protein diet aggravates glomerular hyperperfusion and hyperfiltration, so the principle of high-quality protein is advocated. Protein intake should be mainly animal protein with high bioefficiency, and protein intake should be limited to 0.8g/(kg・d) in the early stage, and can be reduced to 0.6g/(kg・d) in patients with massive proteinuria and renal failure. For patients with intermediate to advanced renal impairment, supplementation with alpha-keto acid is recommended. In addition, it is recommended to replace red meat (e.g. beef, lamb, pork) with fish, chicken, etc., and to add polyunsaturated fatty acids. In addition there is no need to excessively restrict the intake of vegetable proteins such as soy protein.
4.Replacement therapy for end-stage renal disease
Those who enter end-stage renal failure can be treated with renal replacement therapy, but their prognosis is worse than that of non-diabetic patients. Patients with diabetic nephropathy themselves have more frequent diabetic complications, and the symptoms of uremia appear earlier, so the indications for renal replacement therapy should be relaxed appropriately. Generally, those with endogenous creatinine clearance down to 10-15 ml/min or with obvious gastrointestinal symptoms, hypertension and heart failure not easily controlled can enter maintenance dialysis.
The long-term survival rates of hemodialysis and peritoneal dialysis are similar. The former facilitates glycemic control and has better dialysis adequacy, but it is difficult to establish arteriovenous fistulas and cardiovascular accidents are likely to occur during dialysis; the latter is often used for continuous ambulatory peritoneal dialysis (CAPD), which has the advantage of protecting residual renal function in the short term and can be performed in patients with cardiovascular accidents because anticoagulants are not necessary. However, the use of glucose as an osmotic solute makes it difficult to control the patient’s blood glucose level.
5.Organ transplantation
For patients with end-stage diabetic nephropathy, kidney transplantation is currently the most effective treatment, accounting for about 20% of kidney transplant patients in the United States. In recent years, the 5-year survival rate of cadaveric kidney transplantation is 79% and 91% for living kidney transplantation, while the 5-year survival rate for those receiving dialysis is only 43%. The survival rate of living kidneys, especially those from relatives, is significantly higher than that of cadaveric kidney transplants. However, the survival rate of transplanted kidneys in patients with diabetic nephropathy is still 10% lower than that of non-diabetic patients. Kidney transplantation alone does not prevent the reoccurrence of diabetic nephropathy or improve other diabetic comorbidities.
Combined pancreas-kidney transplantation has the potential to normalize glycosylated hemoglobin and creatinine levels and improve other diabetic comorbidities, so patients have a better quality of life than those with kidney transplantation alone.