Pediatric diabetic nephropathy

　　I. Etiology

　　1. Genetic susceptibility: Recent studies have found that DN has a family aggregation phenomenon. In type 2 diabetes mellitus (2-DM), there are more relevant literature reports. Whether in patients with type 1-DM or type 2-DM, if the proband has concurrent DN, the incidence of DN in his or her siblings after developing DM will significantly increase. Even if the blood glucose control is poor, only 35% of patients with type 1-DM will eventually develop end-stage DN. Even if blood glucose is strictly controlled to approach normal levels (including the DCCT study), it has been proven to significantly improve or prevent DN, but it cannot completely prevent the occurrence and development of DN. Therefore, there are currently clues suggesting that DN has a genetic susceptibility.

　　(1) Susceptibility Patterns: Currently, it is speculated that there are 3 types of susceptibility patterns for diabetic nephropathy (DN):

　　① Major Gene Effects (majorgene effect): Refers to the occurrence of DN due to the interaction of a certain major gene polymorphism (or mutation) with poor glycemic control.

　　② Moderate Gene Effects (moderategene effects): Refers to the occurrence of DN due to the interaction of several gene polymorphisms (or mutations) with poor glycemic control, where these disease alleles act independently and exhibit synergistic effects. As for the overall effect produced by the action of these alleles, it depends on their frequency of occurrence in the population; if their frequency of occurrence is similar in the population, then the effect produced by each is relatively average; if the frequency of occurrence of a certain gene is higher, this allele then produces a major genetic effect, while the other several alleles produce minor genetic effects.

　　③ Polygenic Effects (polygenic effects) or Minor Gene Effects (minorgene effects): Refers to the occurrence of DN due to the interaction of many gene polymorphisms (or mutations) with poor glycemic control, where each allele only plays a minor role in the genetic susceptibility to DN.

　　(2) Susceptibility Genes: Many authors have been searching for susceptibility genes of diabetes nephropathy (DN), and several possible candidate genes have been found, but no consistent conclusions have been drawn. The search for susceptibility genes of DN in type 1 diabetes mellitus (1-DM) research is extensive, and most studies have shown that the frequency of genetic polymorphisms (or mutations) of angiotensin II type-1 receptor (angiotensin II type-1 receptor, AT1R) is significantly higher in DN patients than in patients without concurrent DN. It is believed that it may play a major genetic effect. As for the relationship between the angiotensinogen (AGT) gene and the angiotensin-converting enzyme (ACE) gene polymorphisms (or mutations) and DN, no consistent conclusions have been reached. In terms of studying major genetic effects and minor genetic effects, the transmission disequilibrium test (TDT) is highly specific compared to case-control studies. Some have used the TDT method to study the relationship between AGT and ACE gene polymorphisms (or mutations) and DN, finding that they are related to DN and may play a minor genetic effect. In type 2 diabetes mellitus (2-DM), a large-scale study of a Pima Indian family found that the frequency of AT1R gene polymorphisms (or mutations) is significantly higher in DN patients than in patients without concurrent DN, suggesting that it may play a major genetic effect; however, no consistent results were found in other population studies. In addition, the study of the frequency of gene polymorphisms (or mutations) of AGT, ACE, kinin, and atrial natriuretic peptide aldose reductase, etc., and their relationship with DN has not reached a consistent conclusion. Since many parents of patients with concurrent DN in 2-DM are no longer alive, it is difficult to use TDT for family studies, and it cannot be determined whether these genes are the ones that play a minor genetic effect.

　　2. The occurrence and development of diabetic nephropathy (DN) is not only related to heredity, but high blood glucose also plays a very important role. A large number of studies have shown that strict control of blood glucose can significantly reduce the risk of developing DN. How high blood glucose leads to DN has not been fully elucidated. However, many studies have shown that high blood glucose can activate many local endocrine hormones (or cytokines) in the kidneys. Current research finds that these substances are closely related to the occurrence and development of DN. Of course, the pathogenesis of DN also includes factors such as abnormal hemorheology, dysfunction of erythrocyte oxygen transport, and enhanced sorbitol shunt, etc. However, to varying degrees, these factors are related to local endocrine hormones (or cytokines) in the kidneys.

　　(1) Renin-angiotensin system (RAS): Studies have found that the level of angiotensin II (ATII) in the renal tissue of DM rats is significantly increased, and the expression of AT1R in the renal tissue is also significantly increased. Both clinical and experimental studies have proven that the application of ACE inhibitors can effectively prevent the occurrence and development of DN.

　　(2) Local kidney growth factors: Studies have found that various local kidney growth factors are closely related to the occurrence and development of DN, such as insulin-like growth factor, platelet-derived growth factor, and transforming growth factor-β (transforming growth factor-β, TGF-β). They can stimulate the proliferation of glomerular mesangial cells and increase the deposition of extramesangial matrix. Among them, TGF-β1 has been studied extensively. Some studies have shown that the expression of TGF-β1 in the renal tissue of DM rats is significantly increased, and it is important to note that after the application of ACE inhibitors, it can decrease significantly. Therefore, it is believed that it may play a key role in the pathogenesis of DN.

　　(3) Endothelin (endothelin, ET): ET has a strong vasoconstrictive effect, among which ET1 is the strongest. Currently, it is known that it can stimulate the proliferation of mesangial cells. Experimental studies have found that ET1 and its receptor expression in renal tissue of DM rats are significantly increased, and the use of ET1 receptor antagonists can prevent and treat DN. In addition, in vitro studies have shown that TGF-β1 can increase the expression of ET1 in renal tubular cells.

　　(4) Nitric oxide (nitric oxide, NO): NO has a strong vasodilatory effect and is synthesized from L-arginine as a donor under the action of nitric oxide synthase (NOS). There are two types of NOS: constitutive NOS and inducible NOS (inducible NOS, iNOS). In the early renal tissue of DM rats, iNOS expression and NO content increase, which is believed to be related to the increase in renal blood flow in the early stage of DM rats. In the late renal tissue of DM rats, iNOS expression does not increase significantly, while the expression of constitutive NOS and NO content decreases significantly. Some people believe that L-arginine treatment can prevent the occurrence of DN in DM rats, while the long-term use of NOS inhibitors can accelerate the glomerular lesions in DM rats, suggesting that NO can prevent the occurrence and development of DN. The above studies suggest that NO can protect the late glomerular lesions in DM rats, and many studies have shown that NO in renal tissue can be mutually regulated with ATⅡ and TGF-β1.

　　Second, pathogenesis

　　1. Glomerulosclerosis has two types: nodular sclerosis and diffuse sclerosis. The former is a typical Kimmelstiel-Wilson (K-W) lesion, seen in about half of the patients, and this lesion appears in the peripheral capillary loops of the glomerulus, which is specific for the diagnosis of diabetic nephropathy. The latter is more common but not unique to diabetic nephropathy.

　　2. Vascular damage is manifested as arteriosclerosis, with both glomerular and efferent arterioles showing glassy degeneration, which is different from that seen in patients with non-diabetic hypertension.

　　3. Tubulointerstitial damage includes degenerative changes in tubular epithelial cells, tubular atrophy, interstitial edema, fibrosis, and cell infiltration.

　　What diseases can childhood diabetes nephropathy be complicated with:

　　Diabetes complicated with nephrotic syndrome can lead to hypoproteinemia due to massive proteinuria, causing significant edema. It can also result in hypercholesterolemia, weakened immune resistance, frequent infections, hypertension, renal function decline, and eventually renal insufficiency in the late stage, leading to uremia.

　　1. Main clinical manifestations

　　1. Proteinuria:It is the first clinical manifestation of diabetic nephropathy, initially intermittent, and then becomes persistent. The determination of urinary albumin or microalbumin by radioimmunoassay can diagnose proteinuria earlier, which is beneficial for controlling the condition.

　　2. Edema:Diabetic nephropathy edema is often caused by a large amount of proteinuria, indicating that it has developed to the late stage of diabetic nephropathy. It is often accompanied by a decrease in GFR and other clinical manifestations of renal function decline, suggesting poor prognosis.

　　3. Hypertension:It appears later, and the blood pressure is often elevated when the diabetic nephropathy stage is reached, which may be closely related to the structural and functional changes of the resistant blood vessels in the diabetic kidney. In addition, water and sodium retention is also one of the factors causing hypertension. Hypertension can exacerbate the development of kidney lesions and the deterioration of renal function, therefore, it is crucial to control hypertension.

　　Secondly, it can be generally divided into 5 stages

　　1. Functional change stage:Early kidney hypertrophy and hyperfiltration, high perfusion rate, the focus of this stage is to control blood sugar.

　　2. Structural change stage:At 2 to 5 years of illness, the kidneys begin to undergo structural changes, and proteinuria appears during strenuous exercise.

　　3. Early nephropathy:At 5 to 15 years of the course, 30% to 40% progress to this stage, with increased proteinuria and the beginning of renal function decline.

　　4. Diabetic nephropathy stage:At 10 to 30 years of illness, a large amount of proteinuria appears, accompanied by edema and hypertension, and renal function also deteriorates.

　　5. Uremic stage:That is, the end-stage renal stage (abbreviated as ESRD), which requires dialysis or kidney transplantation to maintain life.

　　How should children with diabetic nephropathy be prevented?

　　1. Predictive indicators

　　Research on the prevention of type 1 diabetes began in the 1970s, and the method of measuring ICA was calibrated with JDF units in 1989 as reported by Swedes. A total of 405 newly diagnosed type 1 diabetes patients and 321 normal controls were measured for ICA in blood, with a positive rate of 96% (389/405) in patients and 2.8% (9/321) in controls. Follow-up for 2 years showed that 2 out of 9 controls developed diabetes, while the ICA levels of the other 7 were all less than 40 JDF units, and they all turned negative later. Joslin-Sacramento began measuring ICA and (or) IAA in the first-degree relatives of 8000 type 1 diabetes patients in 1983, with 16 out of 1723 (0.9%) relatives positive. Follow-up for 2 years showed that two of them developed diabetes. Later, standardized intravenous glucose tolerance tests (IVGTT) were performed for those with positive ICA and (or) IAA, measuring insulin levels at 1 minute and 3 minutes after injection of glucose. If the insulin level is less than 5% of the normal value, it indicates that diabetes will occur within 3 years. In recent years, the measurement of GAD has also become an indicator for prediction.

　　2. Preventive treatment

　　For people in high-risk populations (first-degree relatives) who are ICA and/or GAD positive, large-scale preventive treatment research with niacin or insulin has already begun in Europe and the United States. Germany has an international trial using niacin to prevent type 1 diabetes in children under 12 years old, called the DENIS plan is being carried out. Due to animal experiments showing that insulin can delay the onset of diabetes, the United States has launched a research study called DPI-Ⅰ, which studies the prevention of diabetes in people with a high risk of developing type 1 diabetes by dividing them into two groups to use oral or injectable insulin for prevention. The results are still waiting. In summary, due to the progress in the study of the pathogenesis of type 1 diabetes, it is possible that the methods for predicting and preventing type 1 diabetes will have greater progress, and it is expected to achieve good results.

　　1. Urinary microalbumin measurement:Also known as urinary albumin excretion rate (urinary albumin excretion, UAE), it is mostly measured by radioimmunoassay and enzyme-linked immunosorbent assay. Under a state of rest, normal people should have less than 20μg/min (30mg/d). Urinary albumin excretion rate between 20～200μg/min is considered as microalbuminuria, which can be considered as DN stage III. The standard for diagnosing early diabetic nephropathy is three examinations within 6 months, with an interval of more than 1 month between each examination, and twice the urinary albumin excretion rate is between 20～200μg/min. Some people believe that taking morning urine for microalbumin measurement, with urine creatinine as the base, 30～300mg/g is considered as stage III DN. In addition, the author believes that urinary β2-microglobulin is significantly increased in the early stage of DN (before the routine urine protein is positive), which can also be used as one of the auxiliary diagnostic methods, but most scholars believe that its accuracy is not as good as UAE.

　　2. Urinary transferrin:Transferrin and albumin have similar molecular weights, and the mechanical barrier of the glomerular filtration membrane does not play a role in them. In the early stage of diabetic nephropathy, due to the defect in the electrostatic barrier of the filtration membrane, an increase in urinary albumin excretion can occur. However, the negative charge carried by urinary transferrin is significantly less than that of albumin, so it is easier to pass through the negatively charged glomerular filtration membrane. Therefore, some scholars believe that urinary transferrin can be used as an early diagnostic standard for diabetic nephropathy and is superior to urinary albumin.

　　3. Retinol-binding protein:It is a low molecular weight protein (molecular weight 21,000), and the free retinol-binding protein is quickly filtered by the glomerulus and decomposed in the proximal tubules of the kidney. The content in normal human urine is very low, and it is considered as a sensitive indicator of tubular damage, which can reflect the early damage of the renal tubules. Some scholars have observed that in diabetic patients, when the urinary albumin excretion rate is normal, the excretion of urinary retinol-binding protein is higher than that of normal people, which can be used as an early diagnostic indicator of diabetic nephropathy. Routine examinations include B-ultrasound, electrocardiogram, X-ray examination, and fundus examination. DM retinopathy and renal lesions belong to microvascular lesions and often occur simultaneously. Therefore, if a patient has DM retinopathy, it is necessary to consider DN.

　　The dietary suggestions for pediatric diabetic nephropathy patients mainly include the following points: 1. Pay attention to light food as the main diet, and pay attention to dietary regularity. 2. Reasonable diet according to the doctor's advice. 3. Eat less spicy and irritating foods.

　　I. Treatment

　　1. Conservative Medical Treatment:The key is to control diabetes early, which is helpful for preventing the progression of renal lesions.

　　(1) The application of antihypertensive drugs: β-blockers, calcium antagonists, enzyme inhibitors (such as captopril) can be selected, and there are reports that thiazide diuretics have adverse effects on the treatment of this disease.

　　(2) Symptomatic and supportive therapy: Including the supply of sufficient calories, the application of essential amino acids, etc.

　　(3) Insulin: Due to the reduction in dosage, mainly due to the deterioration of renal function, the excretion and inactivation are both reduced, so the dosage should be appropriately reduced.

　　(4) Anticoagulation therapy: For the coagulation mechanism of diabetics, anticoagulants (such as heparin) are used for treatment.

　　2. Dialysis Therapy:It can improve the survival rate of patients, and some authors have compared continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis, believing that the former is superior to the latter for this disease.

　　3. Renal Transplantation:Since 1969, there have been reports, but some authors have found that the urinary system complications after renal transplantation in this disease are frequent, including ureteral necrosis, bladder urine leakage, neurogenic bladder, etc.

　　II. Prognosis

　　The prognosis of this disease is poor. If there is a large amount of proteinuria (>3gm/d), more than 6 years of death; intermittent proteinuria, survival can exceed 10 years; without proteinuria, renal failure does not occur, and hypertension can accelerate the progression of renal failure.