INTRODUCTION:

Diabetis nephropathy is a kidney disease. In normal conditions the function of kidney help to regulate fluids and salts balance in the body, which is vital for control blood pressure (BP) and protect cardiovascular condition. In Diabetic condition increases blood sugar levels in high, this sugar level increase long time of the period then these high glucose levels can damage various regions of the body including the cardiac system and kidney. Damaging of kidney that results or this condition is termed as diabetes nephropathy.

The average incidence of diabetic nephropathy is high (3% per year) during the first 10 to 20 years after diabetes onset. Typically, it takes 15 years for small blood vessels in organs like kidney, eyes and nerves to get affected. It is estimated that more than 20 and up to 40% of diabetic patients will develop chronic kidney disease (CKD) depending upon the population, with a significant number that develop end stage kidney disease (ESKD) requiring renal replacement therapies such as kidney transplantation. Diabetes with no clinical sign of kidney damage during the initial 20 to 25 years is significantly less likely (1% a year) to cause major renal complications later in life. Diabetic nephropathy is a kind of chronic kidney disease. The kidneys help regulate the levels of fluids and salts in the body, which is vital for controlling blood pressure and protecting cardiovascular health.When a person has diabetes, whether type 1, type 2, or gestational diabetes, their body cannot use or produce insulin as it should.

Gestational diabetes occurs during pregnancy and may increase the risk of type 2 diabetes later in life. Diabetes results in high blood sugar levels. Over time, these high glucose levels can damage various areas of the body, including the cardiovascular system and kidneys. The kidney damage that results is known as diabetic nephropathy. Diabetic nephropathy is a major cause Trusted Source of long-term kidney disease and end-stage renal disease (ESRD). In ESRD, the kidneys no longer work well enough to meet the needs of daily life. ESRD can lead to kidney failure with potentially life-threatening consequences.

Diabetic nephropathy kidney disease that results from diabetes is the number one cause of kidney failure. Almost a third of people with diabetes develop diabetic nephropathy. People with diabetes and kidney disease do worse overall than people with kidney disease alone. This is because people with diabetes tend to have other long-standing medical conditions, like high blood pressure, high cholesterol, and blood vessel disease (atherosclerosis). People with diabetes also are more likely to have other kidney-related problems, such as bladder infections and nerve damage to the bladder. Kidney disease in type 1 diabetes is slightly different than in type 2 diabetes. In type 1 diabetes, kidney disease rarely begins in the first 10 years after diagnosis of diabetes. In type 2 diabetes, some patients already have kidney disease by the time they are diagnosed with diabetes.¹

Natural History of Diabetic Nephropathy:

The earliest clinical evidence of diabetis nephropathy is microalbuminuria termed as urinary albumin elimination of 30-299mg/24 hours in a twenty four hour urinary collection, 20-199, ug/min in a timed urine collection, or 30-299, ug/mg creatinine in a spot urine collection on at least two occasions within a three-to-six month period .In the absence of specific interventions, about 80% of patients with type-I diabetes with sustained microalbuminuria progress to the stage of overt nephropathy or clinical microalbuminuria Journal of the national medical association volume 96, no.11, November 2004 Diabetic Nephropathy current concepts (defined as urinary albumin excretion >300mg/24 hours, >200 mg/min in a timed collection, or >300 jig/mg creatinine in a spot urine) over a period of 10 to 15 years. However, in patients who develop microalbuminuria late in the course of the disease (i.e., after more than 15 to 29 years), the risk of developing overt renal disease is only about 1% per year. ESRD develops in 50% of type-I diabetes patients with overt nephropathy within 10 years and in more than 75% by 20 years in the absence of treatment.

A greater proportion of patients with type-2 diabetes compared with type-I diabetes have microalbuminuria and overt nephropathy at or shortly after diagnosis of diabetes. This is because the disease may have been present for several years before the diagnosis is made. In addition, concomitant presence of hypertension at the time of diagnosis also contributes to the high prevalence of microalbuminuria in type-2 diabetes. Progression from microalbuminuria to overt nephropathy occurs in 20-40% of Caucasians within a 10-year period, with approximately 20% of those with overt nephropathy progressing to ESRD over a period of 20 years.²

Risk Factors and Pathogenesis:

Diabetic nephropathy develops in, at most, 40% of patients with diabetes, even when high glucose levels are maintained for long periods of time. This observation raised the concept that a subset of patients have an increased susceptibility to diabetic nephropathy.

Fig-1: Pathogenesis of diabetic nephropathy

· Furthermore, epidemiological and familial studies have demonstrated that genetic susceptibility contributes to the development of diabetic nephropathy in patients with both type 1 and type 2 diabetes.

· The main potentially modifiable diabetic nephropathy initiation and progression factors in susceptible individuals are sustained hyperglycemia and hypertension.

· Other putative risk factors are glomerular hyperfiltration, smoking, dyslipidemia, proteinuria levels, and dietary factors, such as the amount and source of protein and fat in the diet.

Symptoms of Diabetic Nephropathy:

· Swelling of the hands, feet, and face

· Trouble sleeping or concentrating

· Poor appetite

· Nausea

· Weakness

· Itching (end-stage kidney disease) and extremely dry skin

· Drowsiness (end-stage kidney disease)

· Abnormalities in the hearts' regular rhythm, because of increased potassium in the blood

· Muscle twitching ^3,4

Etiology of Diabetic Nephropathy:

A variety of factors contribute to the renal damage seen in diabetes. By definition, hyperglycemia is a common etiologic factor in diabetic patients with nephropathy, but a genetic predisposition and smoking contribute as well. Most significant, however, is the presence of hypertension, not only before and after the onset of microalbuminuria but probably also as another familial marker of risk, since patients with diabetes and a positive family history of hypertension are at higher risk of nephropathy.

1. Genetics and Ethnicity:

Although a sizable percentage, only a minority of patients with diabetes are destined to develop ESRD. In addition to the risks of poor glycemic control and hypertension, a subset of patients may be at greater risk for nephropathy based on inherited factors.¹² Familial clustering of patients with nephropathy may result from similarly poor glycemic or blood pressure control or may have additional independent genetic bases.

Diabetic siblings of patients with diabetes and renal disease are five times more likely to develop nephropathy than diabetic siblings of diabetic patients without renal disease. There is a strong concordance of both nephropathy and renal histopathology in twins with type 1 diabetes. In a study of Brazilian families with two or more diabetic members, the presence of diabetic nephropathy in the probands was significantly associated with a 3.75-fold increased risk of diabetic nephropathy in the diabetic siblings.

Postulates have been advanced linking diabetic nephropathy as well as cardiovascular disease and hypertension with inherited abnormalities of sodium-lithium countertransport.In a study of 89 patients with type 1 diabetes, an increased maximal velocity of sodium-lithium countertransport and a parent with hypertension each significantly increased the risk of nephropathy in the study patients.¹⁷ Moreover, the parents of patients with type 1 diabetes complicated by nephropathy have decreased survival, notably a fourfold increased risk of strokes.

Familial clustering and the beneficial effects of angiotensin-converting enzyme (ACE) inhibition on diabetic nephropathy have also led to investigation of the genetics of the renin-angiotensin system. Increased levels of ACE have been found in patients with type 1 diabetes and nephropathy, particularly carriers of certain abnormal alleles of the ACE gene. In a study of type 1 patients with ESRD compared with type 1 patients with diabetes for at least 15 years and no microalbuminuria, the presence of the DD genotype at the ACE locus increased the risk of end-stage nephropathy twofold.

2. Hyperglycemia:

It is well established that poor metabolic control is critical in the etiology of diabetic nephropathy. Nephropathy is uncommon in patients with HbA_1c consistently <7.5 8.0 % The degree to which glucose toxicity itself is directly causative in the renal lesion is still debated. At the very least, glucose is a meaningful and clinically relevant marker for the metabolic abnormality that leads to nephropathy, as shown in the DCCTand other treatment trials that demonstrate decreased nephropathy with lowered serum glucose.

Other hyperglycemia-dependent metabolic abnormalities that may also play a role in the development of nephropathy include AGEs and polyols. AGEs are the result of nonenzymatic covalent attachment of glucose to proteins, which not only changes the tertiary structure of proteins but also results in intra- and intermolecular crosslinking. Proteins of many types are affected by this process, and levels of circulating and tissue AGEs have been shown to correlate with microalbuminuria in diabetic patients. In a study of low- and high-molecular-weight AGEs in subjects with and without diabetes, AGE content in arterial wall collagen was fourfold higher in diabetes. Diabetic patients with ESRD had twice as much tissue AGE as patients without renal disease. Circulating AGEs were elevated in patients with diabetes compared to those without diabetes, and the levels correlated directly with creatinine.

Flux through the polyol pathway beginning with the conversion of glucose to sorbitol by aldose reductase is enhanced in hyperglycemia. The resultant increase in tissue sorbitol has been postulated to contribute to the microvascular complications of diabetes. Clinical trials of aldose reductase inhibitors have not shown beneficial effects in reducing microalbuminuria in humans; however, research continues in this arena.

3. Hypertension:

Hypertension is probably both a cause and an effect of diabetic nephropathy. In the glomerulus, an early effect of systemic hypertension is dilatation of the afferent arteriole, contributing to intraglomerular hypertension, hyperfiltration, and hemodynamically mediated damage. Renal responsiveness to the renin-angiotensin system may be abnormal in the diabetic kidney. For these reasons, agents that help to correct the abnormal intraglomerular pressures are preferentially selected for treatment of hypertension in diabetes. ACE inhibitors specifically decrease the efferent arteriolar pressure, thereby decreasing intraglomerular pressure and helping to protect the glomerulus from further damage, as seen in their beneficial effect on microalbuminuria.

Particularly after microalbuminuria is present, metabolic control is only one factor in preventing the progression of renal disease. Hypertension at this stage predicts a more rapid downhill progression of the renal damage. Blood pressure control is increasingly important once the renal lesion is present and as renal damage progresses.

4. Smoking:

Several lines of evidence have shown that smoking increases the risk and progression of diabetic nephropathy. In the Appropriate Blood Pressure in Diabetes Trial, 61% of enrollees were smokers. Analysis of a number of risk factors showed a 1.6-fold increased risk of nephropathy among smokers.^5,6

Pathology of Diabetic Nephropathy:

Diabetes causes unique changes in kidney structure. Classic glomerulosclerosis is characterized by increased glomerular basement membrane width, diffuse mesangial sclerosis, hyalinosis, microaneurysm, and hyaline arteriosclerosis. Tubular and interstitial changes are also present. Areas of extreme mesangial expansion called Kimmelstiel-Wilson nodules or nodular mesangial expansion are observed in 40 – 50% of patients developing proteinuria. Micro- and macroalbuminuric patients with type 2 diabetes have more structural heterogeneity than patients with type 1 diabetes. Evaluated by electron microscopy, the severity of glomerular lesions is related to GFR and UAE and to diabetes duration, degree of glycemic control, and genetic factors. Nonetheless, there is an important overlap in mesangial expansion and glomerular basement membrane thickening among normoalbuminuric, microalbuminuric, and proteinuric type 1 and type 2 diabetic patients.

Fig-2: Pathology of Diabetic Nephropathy

Complications:

Complications of diabetic nephropathy may develop gradually over months or years. They may include:

· Fluid retention, which could lead to swelling in your arms and legs, high blood pressure, or fluid in your lungs (pulmonary edema)

· A rise in potassium levels in your blood (hyperkalemia)

· Heart and blood vessel disease (cardiovascular disease), possibly leading to stroke

· Damage to the blood vessels of the retina (diabetic retinopathy)

· Anemia

· Foot sores, erectile dysfunction, diarrhea and other problems related to damaged nerves and blood vessels

· Pregnancy complications that carry risks for the mother and the developing fetus

· Irreversible damage to your kidneys (end-stage kidney disease), eventually needing either dialysis or a kidney transplant for survival

Managing blood sugar levels can reduce the risk. Whether a person has type 1 or type 2 diabetes, they can reduce the risk of diabetic nephropathy by:

· Monitoring blood glucose levels and keeping them within the target range

· Having a healthful diet that is low in sugar and salt

· Getting regular exercise

· Following a treatment plan, which may include the use of insulin or other medications

· maintaining a healthy weight ^7,8,9

Diagnosis: To determine diabetic kidney disease, need certain tests and procedures, such as:

· Blood tests. If any person have diabetes, then will need blood tests to monitor their condition and determine how well their kidneys are working.

· Urine tests. Urine samples provide information about Patients kidney function and whether you have too much protein in the urine. High levels of a protein called microalbumin may indicate your kidneys are being affected by disease.

· Imaging tests. Diabetalogist may use X-rays and ultrasound to assess your kidneys' structure and size. You may also undergo CT scanning and magnetic resonance imaging (MRI) to determine how well blood is circulating within your kidneys. Other imaging tests may be used in some cases.

· Renal function testing: Physician can assess patients kidneys' filtering capacity using renal analysis testing.

· Kidney biopsy: Kidney biopsy to remove a sample of kidney tissue. be given a numbing medication (local anesthetic). Physician will use a thin needle to remove small pieces of kidney tissue for examination under a microscope.

Treatment of Diabetics Nephropathy:

In the diabetic nephropathy there are specific treatment of patients can be divided into four major areas.

In practical terms, this means adequate blood glucose lowering and control of hypertension. A description of all glucose lowering agents is beyond the scope of the review but certain agents have theoretical benefits beyond glucose lowering. In addition, people with DKD are also more likely to experience retinopathy, nephropathy and foot ulcers so increased vigilance for these complications important. Treatment guidelines have been developed by several international and national organizations are summarized below-

1]Cardiovascular risk reduction (CVD):

Diabetic kidney disease (DKD) is strongly associated with CVD. DKD may be a marker of cumulative vascular damage due to diabetes or may causally promote CVD through several mechanism, such as blood pressure dysregulation, retention of uremic toxins, anemia and altered mineral metabolism. In light of high mortality of patients with diabetic nephropathy primary prevention of its development and efforts to hinder its progression once it is established are the utmost importance. Unfortunately, CKD frequently goes recognized by both patients and providers. Furthermore, patients with diagnosed CKD have been found to be less likely than the general population to receive appropriate CVD risk factor modifications. A large opportunity to improve outcome in this vulnerable patient population lies in simply raising awareness of these issues and intervening as early as possible.

2] Glycemic control:

The effect of improved glycemic control on clinical outcomes, including progression of diabetics nephropathy, has been tested in multiple large clinical trails involving patients with T1/T2 DM. The principle evidence regarding the benefits of glycemic control in patients with T1 DM comes from the diabetes control and complications trails (DCCT)¹. The DCCT randomized 1441 people with T1DM to intensive insulin therapy or standard therapy. After mean follow up of 6.5 years, there was a significant reduction in the development of moderate (A2) and severe (A3) albuminaria in the intensive arm, as well benefits for other microvascular complications.

3] Blood Pressure control-

The current Joint National Committee (JNC) Guidelines recommend targeting a blood pressure of <140/90mmHg for diabetic’s patients, irrespective of CKD. The effect of achieved BP was analyzed in detail in IDNT and suggested the presence of a J-shaped curve such that kidney benefits reached a plateau at systolic BP < 130mmHg, and all cause mortality increased at systolic BP<120mmHg.

4] Renin Angiotensin System Inhibition:

In humans, RAS inhibition has proved to be the single most effective therapy for slowing the progression of diabetic nephropathy. These agents have been studied at each clinical stage of diabetic nephropathy. Blockade of RAS using either angiotensin converting enzyme inhibitor or angiotensin receptor blokers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in human with DKD.

5] Diuretics:

Similar to dietary sodium restriction, thiazide diuretics (eg, hydrochlorothiazide 50 mg) when combined with an ACE inhibitor (lisinopril 40 mg/day) reduced albuminuria in type 2 diabetics. However, the combination is associated with more frequent orthostatic symptoms. For advanced CKD, a loop diuretic may be more appropriate. Diuretics may increase the effectiveness of ACE inhibitors. ^10,11,12,13

Herbal Drug Used in the Management of Diabetic Nephropathy:

· Andrographis Paniculata (Family: Acanthaceae; Common name: Kalmegh) Chronic administration of A. paniculata to alloxan-induced diabetic rats for four weeks produced significant blood glucose reduction. Chloroform extract significantly inhibited the induction of albuminuria, proteinemia and uremia. The studies clearly indicated a significant anti-diabetic activity with the chloroform extract of A paniculata roots and supports the traditional usage of the plant by Ayurvedic physicians for the control of diabetes. Also the extract is useful in preventing the incidence of long-term complication of diabetic nephropathy.

· Astragalus propinquus (Family: Fabaceae; Common name: Milk Vetch) It improves the pathogenesis and development of diabetic nephropathy which is closely associated with the changes of plasma Endothelin I (ET-I) levels and platelet function.

· Benincasa cerifera (Family: Cucurbitaceae; Common name: Kusmanda) Fruits of Benincasa cerifera have free-radical scavenging property. They are widely used as a vegetable in India and other tropical countries. They are also used in urinary infections, epilepsy, peptic ulcer and haemorrhages from internal organs. Benincasa cerifera prevents lipid peroxidation and protects the kidneys from severe increase of reactive oxygen species and depletion of superoxide dismutase and reduced glutathione.

· Brassica oleracea (Family: Brassicaceae; Common name: Red Cabbage) It is mainly used as a vegetable. It has anti-oxidant and antihyperglycaemic activity. Main constituents are the isothiocyanates and anthocyanins, reduces oxidative diabetic nephropathy. It contains anthocyanin pigments that are described as free radical scavenging and antioxidant agents. Its extract contains vitamins A, B and C all of which have protective roles against oxidative damage.

It also contains substantial quantities of isothiocyanates some of which are very potent antioxidants. Daily ingestion of red cabbage polar extract (1gm/kg body weight) ameliorates oxidative stress and diabetic nephropathy.

· Camellia sinensis (Family: Theaceae; Common name: Green tea, Chaay) Green tea prevents diabetes and hypertension related renal oxidative stress, attenuating renal injury. Spontaneously hypertensive rats (SHR) with streptozotocin induced diabetes and nondiabetic SHR were treated daily with tap water or freshly prepared green tea. After 12 weeks, the systolic blood pressure did not differ between treated and untreated nondiabetic or diabetic rats. However body weight was less and glycemia was greater in diabetic SHR rats than in no diabetic rats. Renal oxidative stress variables were greater in diabetic rats. The oxidative stress parameters were significantly less in rats treated with green tea. These findings suggest that the consumption of green tea may reduce nephropathy in diabetic hypertensive patients.

· Cinnamomum zeylanicum (Family: Lauracaeae; Common name: Dalchini) The ameliorative effect of the cinnamon oil upon early stage diabetic nephropathy due to its antioxidant and antidiabetic effect has been studied against alloxan (150 mg/kg I.P) induced diabetic nephropathy. Histological studies of the kidney revealed the protective effect of cinnamon oil by reducing the glomerular expansion, eradicating hyaline casts and decreasing the tubular dilatations. The results indicated that the volatile oil from cinnamon contained more than 98% cinnamaldehyde and that it confers dose-dependent significant protection against alloxan induced renal damage. The maximum decrease in fasting blood glucose has been achieved at the dose of 20 mg/kg

· Curcuma longa (Family: Zingiberaceae; Common name: Turmeric) Chronic treatment with Curcumin obtained from Curcuma longa significantly attenuates both renal dysfunction and oxidative stress in streptozotocin induced diabetic rats. The results confirmed evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin. ^14,15,16

Prevention of Diabetic Nephropathy:

Efforts at preventing diabetic nephropathy should be at the primary, secondary, and tertiary levels. Primary prevention aims at preventing diabetes in the population.

Lifestyle modifications that have been shown to prevent or delay the development of diabetes include regular physical exercise and weight control.

Exercise also reduces percentage of total and abdominal fat, improves blood lipid levels and insulin sensitivity, decreases blood pressure, and improves endothelial vasodilator function and left ventricular diastolic function.

Pharmacologic interventions using glucose-lowering drugs in high-risk individuals have also been reported to cause a significant lowering of the incidence of diabetes.

However, when compared with lifestyle interventions, drug therapy was less efficacious and was associated with significant adverse side-effects.

Presently, there is insufficient evidence to support the routine use of drug therapy for primary prevention.

Secondary prevention entails strict control of blood glucose, lipids, and blood pressure levels. Tertiary prevention involves screening for proteinuria and instituting appropriate treatment.¹⁷

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Received on 26.09.2021 Modified on 08.12.2021

Asian J. Pharm. Res. 2022; 12(1):54-60.

DOI: 10.52711/2231-5691.2022.00009