A Project work on Recent approches in the Treatment of Diabetic Nepheropathy
Purushottam Ravindra Patil1, Nikhil Kailas Patil2, Vinit Khairnar3
1,2Dr. Babasaheb Ambedkar Technological University, Lonere, Maharashtra, India.
3Asst. Professor, Ahinsa Institute of Pharmacy, Dondaicha 425408, Dist. Dhule, M.S., India.
*Corresponding Author E-mail: nitingosavi2000@gmail.com
ABSTRACT:
Renal failure is a common long-torm complication of diabetes mellitus. Stages of diabetic nephropathy have been described that characterize its clinical course. Diabetic nephropathy develops secondary to long- changes that damage the glomeruli’s. Therapy that focuses on the control of glomerular pressures and systemic hypertension can slow the progression of proteinuria and deterioration of renal function. Angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers have been demonstrated to be effective in the management of diabetic nephropathy. A systematic approach to the patient with diabetes with help identify those individuals early in the course of disease when proper therapy may be most helpful. Diabetic nephropathy is the leading cause of chronic renal disease and a major cause of cardiovascular mortality. Diabetic nephropathy has been categorized into stages: micro albuminuria and macro albuminuria. The cut-off values of micro- and macro albuminuria are arbitrary and their values have been questioned. Subjects in the upper-normal range of albuminuria seem to be at high risk of progression to micro- or macro albuminuria and they also had a higher blood pressure than normoalbuminuric subjects in the lower norm albuminuria range. Diabetic nephropathy screening is made by measuring albumin in spot urine. If abnormal, it should be confirmed in two out three samples collected in a three to six-months interval. Additionally, it is recommended that glomerular filtration rate be routinely estimated for appropriate screening of nephropathy, because some patients present a decreased glomerular filtration rate when urine albumin values are in the normal range. The two main risk factors for diabetic nephropathy are hyperglycemia and arterial hypertension, but the genetic susceptibility in both type 1 and type 2 diabetes is of great importance. Other risk factors are smoking, dyslipidemia, proteinuria, glomerular hyper filtration and dietary factors. Nephropathy is pathologically characterized in individuals with type 1 diabetes by thickening of glomerular and tubular basal membranes, with progressive meningeal expansion (diffuse or nodular) leading to progressive reduction of glomerular filtration surface. Concurrent interstitial morphological alterations and hyalinization of afferent and efferent glomerular arterioles also occur. Podocytes abnormalities also appear to be involved in the glomerulosclerosis process. In patients with type 2 diabetes, renal lesions are heterogeneous and more complex than in individuals with type 1 diabetes. Treatment of diabetic nephropathy is based on a multiple risk factor approach, and the goal is retarding the development or progression of the disease and to decrease the subject's increased risk of cardiovascular disease. Achieving the best metabolic control, treating hypertension (<130/80 mmHg) and dyslipidemia (LDL cholesterol <100 mg/dl), using drugs that block the renin-angiotensin-aldosterone system, are effective strategies for preventing the development of micro albuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with diabetes.
KEYWORDS: Recent Aproches, Treatment, Diabetic Nepheropathy.
INTRODUCTION:
Diabetic nephropathy (DN) affects approximately one-third of individuals with diabetes mellitus individuals with diabetes mellitus (DM) and carries with it considerable cardiovascular morbidity and mortality. Despite modern management of DM, the prevalence of this clinical entity continues to increase in association with an escalating diabetic population and, surprisingly, the excess of mortality risk of DM.
Diabetic nephropathy is characterized by excessive amassing of extracellular matrix (ECM) with thickening of glomerular and tubular basement membranes and increased amount of meningeal matrix, which ultimately progress to glomerulosclerosis and tubule-interstitial fibrosis. In view of this outcome, it would mean that all the kidney cellular elements, i.e., glomerular endothelia, meningeal cells, podocytes, and tubular epithelia, are targets of hyperglycemic injury. Conceivably, high glucose activates various pathways via similar mechanisms in different cell types of the kidney except for minor exceptions that are related to the selective expression of a given molecule in a particular renal compartment.
To begin with, there is an obligatory excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced gyration products (AGEs), activation of protein kinas C (PKC), increased expression of transforming growth factor-β (TGF-β), GTP-binding proteins, and generation of reactive oxygen species (ROS). The ROS seem to be the common denominator in various pathways and are central to the pathogenesis of hyperglycemic injury. In addition, there are marked alterations in intraglomerular hemodynamic, i.e., hyper filtration, and this along with metabolic derangements adversely compounds the hyperglycemia-induced injury. Here, the information compiled under various subtitles of this article is derived from an enormous amount of data summarized in several excellent literature reviews, and thus their further reading is suggested to gain in-depth knowledge of each of the subject matter.
Screening for diabetic nephropathy must be initiated at the time of diagnosis in patients with type 2 diabetes, since 7% of them already have micro albuminuria at that time. For patients with type 1 diabetes, the first screening has been recommended at 5 years after diagnosis.
However, the prevalence of micro albuminuria before 5 years in this group can reach 18%, especially in patients with poor glycemic and lipid control and high normal blood pressure levels. Furthermore, puberty is an independent risk factor for micro albuminuria. Therefore, in type 1 diabetes, screening for micro albuminuria might be performed 1 year after diabetes diagnosis, especially in patients with poor metabolic control and after the onset of puberty. If micro albuminuria is absent, the screening must be repeated annually for both type 1 and 2 diabetic patients. The first step in the screening and diagnosis of diabetic nephropathy is to measure albumin in a spot urine sample, collected either as the first urine in the morning or at random, for example, at the medical visit. This method is accurate, easy to perform, and recommended by American Diabetes Association guidelines. Twenty-four– hour and timed urine collections are cumbersome and prone to errors related to collecting samples or recording of time.
The results of albumin measurements in spot collections may be expressed as urinary albumin concentration (mg/l) (26, 27) or as urinary albumin to-creatinine ratio (mg/g or mg/mol) (14, 27, and 28). Although expressing the results as albumin concentration might be influenced by dilution/concentration of the urine sample, this option is still accurate and cheaper than expression as albumin-to-Creatinine ratio. The cutoff value of 17 mg/l in a random urine specimen had a sensitivity of 100% and a specificity of 80% for the diagnosis of micro albuminuria when 24-h timed urine collection was the reference standard. This value is similar to the cutoff value of 20mg/l recommended by the European Diabetes Policy Group. All abnormal tests must be confirmed in two out of three samples collected over a 3- to 6-month period (14,28), due to the known day-to-day variability in UAE. Screening should not be performed in the presence of conditions that increase UAE, such as urinary tract infection, hematuria, acute febrile illness, vigorous exercise, short-term pronounced hyperglycemia, uncontrolled hypertension, and heart failure. Samples must be refrigerated if they are to be used the same day or the next day, and one freeze is acceptable before measurements. Immunoassays routinely used for albumin measurements present adequate diagnostic sensitivity for detection of diabetic nephropathy. However, it was recently demonstrated that conventional immunochemical-based assays did not detect an uncreative fraction of albuminuria, underestimating UAE.
High-performance liquid chromatography measures total albumin, including immunoreactive and immunounreactive forms, and may allow early detection of incipient diabetic nephropathy.
Diabetes causes unique changes in kidney structure. Classic glomerulosclerosis is characterized by increased glomerular basement membrane width, diffuse meningeal sclerosis, halitosis, micro aneurysm, and hyaline arteriosclerosis. Tubular and interstitial changes are also present. Areas of extreme meningeal expansion called Kimmelstiel-Wilson nodules or nodular meningeal 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 meningeal expansion and glomerular basement membrane thickening among normoalbuminuric, microalbuminuric, and protein uric type 1 and type 2 diabetic patients, with no clear cutoff to distinguish the groups.
Many epidemiological studies demonstrate that ethnicity family history, gestational diabetes, elevated blood pressure, dyslipidemia, obesity and insulin resistance are the major risk factors of diabetic nephropathy other putative risk factors include elevated glycosylated systolic pressure, proteinuria and smoking.
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 subsets of patients have an increased susceptibility to 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 hyper filtration, smoking, dyslipidemia, proteinuria levels, and dietary factors, such as the amount and source of protein and fat in the diet.
In the early stages of diabetic’s nephropathy, you may not notice any sign or symptoms .in later stages, the sign and symptoms include.
1. Worsening blood pressure control
2. Swelling of feet, ankles, hand or eye
3. Increased need of urinate
4. Less need of insulin or diabetic medicine
5. Confusion or difficulty to concentration
6. Nausea and vomiting
7. Fatigue
8. Persistent itching
A) Prevention:
The basis for the prevention of diabetic nephropathy is the treatment of its known risk factors: hypertension, hyperglycemia, smoking, and dyslipidemia. These are also risk factors for cardiovascular disease and should be vigorously treated.
Clinical trials have consistently demonstrated that A1C levels 7% are associated with decreased risk for clinical and structural manifestations of diabetic nephropathy in type 1 and type 2 diabetic patients. In the Diabetes Control and Complications Trial (DCCT), intensive treatment of diabetes reduced the incidence of micro albuminuria by 39%. It is interesting to note that patients randomized to strict glycemic control had a long-lasting reduction of 40% in the risk for development of micro albuminuria and hypertension 7– 8 years after the end of the DCCT. In the UKPDS, a 30% risk reduction for the development of micro albuminuria was observed in the group intensively treated for hyperglycemia. Moreover, in the Kumamoto Study, intensive glycemic control also reduced the rate of development of micro and macro albuminuria. Therefore, intensive treatment of glycemic aiming at A1C7% should be pursued as early as possible to prevent the development of micro albuminuria.
Treatment of hypertension dramatically reduces the risk of cardiovascular and micro vascular events in patients with diabetes. Hypertension is common in diabetic patients, even when renal involvement is not present. About 40% of type 1 and 70% of type 2 diabetic patients with norm albuminuria have blood pressure levels 140/90mmHg. In the UKPDS, a reduction from 154 to 144mmHg on systolic blood pressure reduced the risk for the development of microalbuminuria by 29%. Blood pressure targets for patients with diabetes are lower (130/80mmHg) than those for patients without diabetes. In the HOT (Hypertension Optimal Treatment) study, a reduction of diastolic blood pressure from 85 to 81 mmHg resulted in a 50% reduction in the risk of cardiovascular events in diabetic but not no diabetic patients.
The role of ACE inhibitors in the prevention of diabetic nephropathy in patients with type 1 diabetes has not been defined. The use of perindopril during 3 years in normotensive normoalbuminuric type 1 diabetic patients delayed the increase in albuminuria. In patients with type 2 diabetes, ACE inhibitors and ARBs both diminish the risk for diabetic nephropathy and reduce the occurrence of cardiovascular events. In the MICRO-HOPE (Heart Outcomes Prevention Evaluation) study (106), ramipril (10mg/day) decreased the risk of overt nephropathy by 24% and the risk of cardiovascular death in patients with type 2 diabetes who were 55 years of age with one additional cardiovascular risk factor by 37%. Moreover, ramipril reduced UAE at 1 year and at the end of the study (106). Therefore, ACE inhibitors have been shown to be beneficial for Reno- and cardio protection in patients with type 2 diabetes.
B) Treatment:
The goal of treatment is to prevent the progression from micro- to macro albuminuria, the decline of renal function in patients with macro albuminuria, and the occurrence of cardiovascular events. The treatment principles are the same as those adopted for the prevention of diabetic nephropathy, although in this case multiple and more intensive strategies must be used.
The effect of strict glycemic control on the progression from micro- to macro albuminuria and on the rate of renal function decline in macroalbuminuric patients is still controversial. In the DCCT study, intensified glycemic control did not decrease the rate of progression to macro albuminuria in patients with type 1 diabetes who were microalbuminuric at the beginning of the study. The Microalbuminuria Collaborative Study Group reported similar findings. However, these studies were underpowered to detect an effect of intensified glycemic control on the progression from micro- to macro albuminuria. Moreover, improvement of glycemic control, especially if associated with lower blood pressure levels, reduced the renal function decline in protein uric type 1 diabetic patients. In patients with type 2 diabetes, very few studies analyzed the role of blood glucose control on the progression of diabetic nephropathy. In the Kumamoto Study, a reduction in the conversion from micro- to macro albuminuria was observed with intensive treatment. Although the effects of strict glycemic control on the progression of diabetic nephropathy are not firmly established, it should be pursued in all these patients.
In microalbuminuric type 1 and type 2 diabetic patients, numerous studies have demonstrated that treatment of hypertension, irrespective of the agent used, produced a beneficial effect on albuminuria. Renin-angiotensin system (RAS) blockade with ACE inhibitors or ARBs confers an additional benefit on renal function. This Reno protective effect is independent of blood pressure reduction and may be related to decreased intraglomerular pressure and passage of proteins into the proximal tubule. These drugs decrease UAE and the rate of progression from microalbuminuria to more advanced stages of diabetic nephropathy. A meta-analysis of 12 trials evaluating 698 no hypertensive microalbuminuric type 1 diabetic patients showed that treatment with ACE inhibitors decreased the risk of progression to macro albuminuria by 60% and increased the chances of regression to norm albuminuria. ARBs were also effective in reducing the development of macro albuminuria in microalbuminuric type 2 diabetic patients. Irbesarta (300mg/day) reduced the risk of progression to overt diabetic nephropathy by 70% in a 2-year follow-up study of 590 hypertensive microalbuminuric type 2 diabetic patients. Additionally, a 38% reduction in UAE was observed, with 34% of patients reversing to norm albuminuria. It is also interesting to note that UAE was still reduced 1 month after the withdrawal of irbesartanin another trial, valsartan 80mg/day produced a greater reduction in UAE than amlodipine (44 vs. 8%) with the same degree of blood pressure reduction. These data reinforce the idea that the antiproteinuric effect of ARBs is blood pressure independent. Although there is no long-term study comparing the effects of ACE inhibitors and ARBs on the progression from microalbuminuria to overt diabetic nephropathy, both agents led to a similar reduction in albuminuria in a 12-week study and a 1-year study. Therefore, the use of either ACE inhibitors or ARBs is recommended as a first-line therapy for type 1 and type 2 diabetic patients with microalbuminuria, even if they are normotensive.
A detailed discussion of the agents used to treat hypertension in patients with diabetic nephropathy is beyond the scope of this article, and recent guidelines and reviews on this subject are available Therefore, only general guidelines will be discussed here, taking into account the special characteristics of these patients. To reach the blood pressure goal of 130/80 mmHg in diabetic patients in general or 125/75 mmHg in patients with proteinuria 1.0 g/24 h and increased serum Creatinine, three to four antihypertensive agents are usually necessary. It is more important to reach the blood pressure goals than to use a particular agent, since most patients will require several agents. However, due to the known Reno protective effect of ACE inhibitors and ARBs, treatment should start with either of these agents. Patients with systolic blood pressure 20 mmHg or diastolic blood pressure 10 mmHg above the goal should start treatment with two agents.
C) Strategies of blood pressure regulation:
1. Glycemic optimization Extended observations from the EDIC (Epidemiology of Diabetes interventions and complications) study on the original Diabetes Control and Complication Trial cohort of type 1 diabetics clearly demonstrated legacy effect of early intensive diabetic control
2. These include glycemic control, management of hypertension, and reducing dietary salt intake and phosphorus and potassium restriction advanced cases.
3. A meta-analysis from the Cochrane Database shows a large fall in blood pressure with salt restriction, similar to that of single-drug therapy.
4. All diabetic patients should consider reducing salt intake at least to less than 56 g/d, in keeping with current recommendations for the general population, and may benefit from lowering salt intake to even lower levels.
5. Management of lifestyle and proper and regulate diet.
6. Cardiovascular risk reduction, glycemic control, BP control, and inhibition of the RAS.
7. Pretreat and Diamicron Modified Release Controlled Evaluation), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and VADT (VA Diabetes Trial).
8. A RAS-blocking medication
9. cardiovascular risk reduction is of paramount importance in these patients 9) Lipid-lowering therapy is crucial for cardiovascular risk reduction.
Despite improved understanding of the pathophysiology of DN over the last 2 decades, an effective and specific treatment for this inexorable condition remains limited as the incidence of type 2 DM is predicted to continue an exponential upward trajectory, particularly in the developing world. The clinician is still equipped with no more then merely RAS blockers for control of blood pressure, various hypoglycemic agents for optimizing blood glucose and perhaps statins for controlling hyperlipidemia. Large- scale clinical trial that rode on the identification.
We have witnessed enormous progress in the understanding of the risk factors and mechanisms of diabetic nephropathy, the stages of renal involvement in diabetes, and the treatment strategies to prevent or interrupt the progression of diabetic nephropathy. Early detection of diabetic nephropathy, adoption of multifactorial interventions targeting the main risk factors (hyperglycemia, hypertension, dyslipidemia, and smoking), and use of agents with a Reno protective effect (ACE inhibitors and/or ARBs) do indeed reduce the progression of renal disease. Treatment of hypertension is a priority. Attention to these procedures will also ensure the reduction of cardiovascular mort
The writing of this dissertation has been one of toughest part of the curriculum. It has been kept on track and seen through to completion with the support and encouragement of numerous people including our friends, colleagues and from the bottom of their heart. Penning down this part of acknowledgement peoples give us a chance to express our gratitude to them who directly or age to bear and them occurring splashes of confusion, queries problem and things which cannot be expressed in words.
Words seem to be insufficient to express our deep sense gratitude, to be loved and respected guided Prof.Mr.Vinit Khairnar, at Ahinsa institute of pharmacy Dondaicha, we are our privileged to have work with an individual who constantly offered wise suggestion and informed the way to tackle the challenge. His valuable guidance, keen interest, inspiration unflinching encouragement and moral support throughout my dissertation work make our task successful and complete.
We would like to express our obligation to Mr. Dipesh karnawat sir, principal of Ahinsa institute of Pharmacy Dondaicha for providing us all the facilities for our dissertation work. It would not be forgivable to humble nature of Prof. Mr. Vinit Khairnar sir constantly support in ourevery needful movement.
I am immensely thankful to all Teachers, Ahinsa institute of Pharmacy Dondaicha for their valuable guidance through my work.
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Received on 23.04.2022 Modified on 10.05.2022
Accepted on 20.05.2022 ©A&V Publications All right reserved
Res. J. Pharmacology and Pharmacodynamics.2022;14(4):257-262.
DOI: 10.52711/2321-5836.2022.00044