Natural Treatment to get rid of Kidney Problems

The Kidney Disease Solution

The ebook teaches you how to beat kidney disease in a way that no big pharm company wants you to know. The biggest companies make their money when people like you, with kidney disease come in and wonder if there is any way that they can be cured. The medical industry profits off of these sorts of people, because most people do not know that there is a way around the mass-produced medical industry. With the information in this ebook guide you will be able to restore your help without using drugs that end up hurting your kidneys even more. You will be able to avoid surgery, or having to use dialysis just to survive. You can also improve your quality of life if you are already on dialysis or end stage renal failure. This book was born of years of research from Duncan Capicchiano, ND. All of his research, findings, and suggestions are available to you! More here...

The Kidney Disease Solution Overview

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The writer presents a well detailed summery of the major headings. As a professional in this field, I must say that the points shared in this manual are precise.

This ebook does what it says, and you can read all the claims at his official website. I highly recommend getting this book.

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Protection Of Diabetic Nephropathy By Blockade Of

In most Western countries, diabetic nephropathy (DN) is now the single most common condition (25-45 ) found in patients (15) with end-stage renal disease (ESRD). This is to some extent due to better survival of diabetic patients with renal failure, but mostly due to the dramatic global diabetes epidemic. Alarming data were recently reported also from Asia indicating a dramatic increase in the prevalence of T2DM in this region (41) and that most patients in this region who have ESRD have T2DM (42). About 70 percent of T2DM patients with renal failure suffer from nodular glomerulosclerosis (Kimmelstiel-Wilson). Classical DN evolves in a sequence of stages after a period of glomerular hyperfiltration, increased urinary albumin excretion (AER microalbuminuria i.e. 30-300 mg day) indicates the onset of overt DN. Poor glycemic control and elevated SBP (> 135 mm Hg) interact in enhancing the risk of DN proteinuria and smoking are major promoters of progression. The risk of onset of...

The impact of diabetes on your kidneys

Chronic kidney disease is more prevalent now than it has been in the past. The major source of all these new cases is diabetes. This section tells you what you need to know to prevent and manage diabetic kidney disease. Your kidneys consist of about a million units called nephrons. Each nephron contains a structure called the glomerulous (the plural is glomeruli) (see Figure 5-1). Glomeruli cleanse your blood through the following process When you first get diabetes, your kidneys are enlarged and seem to function abnormally well, judging by how fast they clear wastes from your body. Your kidneys seem to function so well because you have a large amount of glucose entering your kidneys, which draws a lot of water with it and causes an increase in the pressure inside each glomerulous. This more rapid transit of blood through the kidneys is known as an increased glomerular filtration rate (GFR). Early in the development of your diabetes, the membrane surrounding your glomeruli, called the...

How blood pressure affects the development of kidney damage

This is most important for people with Type 2 diabetes because, in their case, the blood pressure is often already high when the diabetes is diagnosed. A large trial has recently shown a significant relationship between the value of the systolic blood pressure and the onset of kidney disease the lower the systolic pressure, the less frequent is the occurrence of kidney disease (Figure 4.7). But, as with blood sugar, there is no threshold for blood pressure below which one is definitely protected from kidney failure.

Monitoring Kidney Function

Screening for kidney disease is very important because there are treatments that prevent the kidney disease from getting worse (see Chapter 3). The screening usually starts five years after diagnosis in people with type 1 diabetes, and at diagnosis in people with type 2 diabetes. The ADA recommends that people with diabetes be screened annually for kidney disease by measuring blood creatinine levels and urine albumin level in the first morning urine. It is not necessary to do a twenty-four-hour or an overnight urine collection the spot urine first thing in the morning is just as good. Your doctor will give you a small urine cup, and you will collect the first morning urine and take it to the lab. A urine albumin of less than 30 (milligrams per gram creatinine) is normal, 30 to 300 indicates early diabetic kidney disease (microalbuminuria), and greater than 300 indicates more significant disease (macroalbuminuria).

When nephropathy already exists

The more developed the kidney disease is, the more relevant is the degree of high blood pressure for the progression of the disease. If appropriate treatment can keep the blood pressure in the normal range at the stage of micro- or macroalbuminuria, the chances are good that the kidney damage will not proceed or will at least be delayed. This has been demonstrated in several studies. Figure 4.8 shows, as an example, the course of kidney disease in a patient who already had macroalbuminuria as a sign of advanced kidney damage and in whom the blood pressure was at first not well managed. At this time, the kidney function deteriorated fairly rapidly. However, it was possible, through good management of the blood pressure, to arrest the downwards trend after several months and to stabilize kidney function at a lower level. Management of high blood pressure stabilizes kidney function Management of high blood pressure stabilizes kidney function Figure 4.8 The course of kidney failure in a...

Treatment And Prevention Of Diabetic Nephropathy

Diabetic nephropathy is the most common cause of ESRD in the Western world and is responsible for almost a third of all the patients with ESRD in the United States. Approximately 20-30 of diabetic patients will develop kidney disease over their lifetime. However, possibly as a result of improvements in glycemic control and blood pressure therapy, the incidence of diabetic nephropathy seems to be declining (145-147). Therapies to prevent or delay the progression of diabetic nephropathy are thus critical and the various strategies effective at various stages are discussed below.

Coping with Kidney Disease

Kidney disease due to diabetes is known as diabetic nephropathy, and it develops in less than half of the people at risk to get it. Some important factors contribute to kidney disease (some of which you can't change and some of which you can) I Certain ethnic groups, especially African Americans, Native Americans, and Mexican Americans, tend to have nephropathy more often. You can't change this. In the following sections, I explain the impact of uncontrolled diabetes on the kidneys and tell you how to prevent and treat kidney damage. Uncontrolled diabetes can affect the kidneys in many ways, depending on the stage of the disease. Luckily, with regular testing for an important indicator (microalbuminuria), anyone can lessen the impact of kidney disease before it progresses.

Early indications of kidney disease

If your kidneys are on their way to being damaged by diabetic nephropathy (kidney disease caused by diabetes), doctors can detect microalbuminuria in your urine. A healthy kidney permits only a tiny amount of albumin, a protein in the blood, to enter the urine. However, a kidney being damaged by nephropathy is unable to hold back as much albumin, and the level in the urine increases, causing microalbuminuria. Recent evidence suggests, however, that an abnormal amount of albumin in the urine is not always present when diabetic neuropathy is developing. A study in Diabetes Care in January 2004 showed that as many as 25 percent of people with diabetes have kidney disease even though there is no increase in the albumin in their urine. Blood tests for kidney function show some loss of function, yet the test for increased albumin is negative. In other words, the absence of microalbuminuria does not always indicate that no kidney damage is taking place. Rather, this finding suggests that...

ACE Inhibitor or ARBs in Early Nephropathy

DETAIL was a much-needed, long-term study comparing an ACE inhibitor with an ARB in a diabetic population. The 5-yr, prospective, multicenter, double-blind study directly compared the ACE inhibitor, enalapril, with the ARB, telmisartan, in patients with type 2 diabetes, hypertension and evidence of early nephropathy, and in many cases microalbuminuria. DETAIL was also the first study of its kind to monitor the progression of kidney disease by directly measuring the GFR, now recognized as the best indicator of overall kidney function and ESRD. Thus, with the latest results from DETAIL in mind, the clinician may choose either an ACE inhibitor or an ARB, or even the two in combination (23). However, questions remain regarding the longer term in advanced nephropathy. The strong endpoint studies, namely the Reduction of endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan type 2 Diabetic Nephropathy Trial (IDNT) study, in patients with type 2...

Evidence for a role of AGEs in diabetic kidney disease

Activity,16,17 more specifically that of PKCpII.17 When carried out under physiological glucose conditions, in vitro studies provide evidence that early glycation products may contribute to the pathogenesis of diabetic glomerulopathy independently of glucose.16 Furthermore, hyperglycaemia and glycated albumin exert an additive effect.16 In cultured kidney epithelial cells, CML reduces proteoglycan expression,18 suggesting that AGEs might be involved in changes in the glomerular basement membrane (GBM) filter in diabetes. Crosslink formation, induced by AGEs such as pentosidine, leads to increased stiffness of the protein matrix in advanced diabetes, and is potentially linked to vascular leakiness and hyperpermeability.19 In vivo evidence for a role of AGEs in the development and progression of diabetic kidney disease comes mainly from studies in streptozotocin (STZ)-induced diabetic rats. AGEs react with mesangial matrix and GBM, and do this in a more intense way in renal tissue from...

Kidney Disease As A Window To The Circulation

Development of kidney disease in diabetes reflects processes operative at distant sites that have a major impact on risks of adverse outcomes. In the chapters by Sowers et al. and Stehouwer et al., hypertension, CVD, and endothelial dysfunction in diabetes are reviewed in depth. This section will address how early and late indicators of CKD provide insight into global circulatory dysfunction. Albuminuria is the earliest clinical indicator of CKD in diabetes. However, albuminuria also increases risk of CVD events and death independent of traditional risk factors (32,33). Although this relationship is particularly apparent in diabetes, albuminuria also appears to increase CVD risk in other groups, including those with essential hypertension and the general population (34,35). In a study of persons undergoing elective coronary angiography, we found a direct correlation between albuminuria levels and severity of coronary artery disease (36). This relationship was most pronounced in the...

Rationale For Early Screening For Diabetic Kidney Disease

University of Minnesota, Director, National Kidney Disease Education Program, Senior Scientific Advisor, National Institutes of Health, National Institute of Diabetes, Digestive, and Kidney Diseases, 6707 Democracy Blvd, Room 625, Bethesda, MD 20892, fax +1 301-480-3510 Primary prevention of diabetic nephropathy is probably possible with rigorous glucose and blood pressure control 1-3 . Indeed, many people at risk for type 2 diabetes could even prevent the development of diabetes 4, 5 . However, screening for diabetic renal disease falls within the scope of secondary prevention. The goal of such screening is not to prevent the appearance of renal damage but to detect it early enough that its course can be favorably deflected. Thus, at first approximation such screening has the same general goals as mammography for breast cancer or fecal occult blood detection for colon cancer. Several principles guide the decision for any screening of this type 6 . First, the disease should be serious...

Preventing kidney disease

The best treatment for kidney disease is preventative. If you can't prevent it with the following measures, you can at least slow it down if you t Avoid other kidney damage. People with diabetes tend to have urinary tract infections that can further damage the kidneys, so your child needs to drink plenty of fluids and acidify the urine with cranberry juice (the bugs don't like an acid urine) to avoid these infections. Nerve damage is also a risk, resulting in a neurogenic bladder with poor emptying of urine and a tendency to develop more urinary tract infections. (I discuss nerve damage later in this chapter.)

Evidence for a role of GHIGFs in diabetic kidney disease

In mesangial cells, IGF-I stimulates cell growth,123 and proteoglycan production,124 and contributes to altered ECM accumulation.125 These data provide in vitro evidence for IGF-I being an important player in the development of diabetic glomerulopathy. Experimental evidence concerning the role of GH IGFs in development of diabetic kidney disease is quite extended.111 It is well known that serum GHBP concentrations are decreased in experimental diabetes.126,127 Renal GHBP mRNA expression, on the contrary, is increased in both short-term and long-term diabetic rats, but is not accompanied by a change in GHR mRNA expression.118 STZ-diabetic dwarf rats with isolated GH and IGF-I deficiency show less renal and glomerular hypertrophy than diabetic control rats with intact pituitary.128 In addition, long-term diabetic dwarf rats display a smaller rise in UAE, indicating that GH and IGF-I may be involved in the development of specific diabetic renal changes.129 The initial increase in renal...

Evidence for a role of RAS in diabetic kidney disease

In vitro blockade of the RAS in PTCs inhibits the stimulatory effects of hyperglycaemia on angiotensinogen expression, Ang II production, and cellular hypertrophy, supporting the notion that intrarenal Ang II formation may play a role in the development of renal hypertrophy in early diabetes.224 It has previously been shown that ET and Ang II enhance protein tyrosine phosphorylation by PKC-dependent and -independent pathways in glomerular mesangial cells, and it was suggested that these vasoactive peptides share in the signalling pathways of growth factors.225 Ang II-stimulated ET-1 production in glomerular mesangial cells is partially PKC-dependent226 and plays a role in the mitogenic effect of Ang II.227 Although the role of RAS in diabetic nephropathy is indisputable,207 data concerning the influence of diabetes on systemic and intrarenal RAS have been conflicting. In experimental diabetes, plasma levels of RAS components have generally shown suppression of the system, and the...

How does diabetes affect your kidneys

One-third of people with type 1 diabetes and 10-20 per cent of people with type 2 diabetes develop kidney disease after living with diabetes for 15 years or more. To understand how this complication develops, you need to know a little bit about the structure and function of the kidneys. The kidneys maintain the body's internal environment by controlling its fluid and electrolyte levels, and by removing its waste products. Each kidney contains approximately one million microscopic units called nephrons, which filter out waste products from the blood. Over long periods of time, high blood sugar levels damage the tiny blood vessels in the kidneys, making them thicker and clogged, and impairing the filtering ability of the nephrons. As a result, they are less able to filter wastes and impurities from the blood properly. Waste products in the bloodstream then build up to harmful levels. At the same time, some of the nutrients and proteins that should remain in the blood leak out of the...

Evidence For A Role Of Gh In Diabetic Kidney Disease

Decreased serum GHBP concentrations and low hepatic GHR number are well described features in experimental diabetes 16,17,23,24 . In contrast only few data have been published on the renal expression of GHR and GHBP in experimental diabetes. In a recent study including both short- and long-term diabetic rats, differential changes in kidney GHR and GHBP mRNA were observed 16 . In the cortex, no change was seen in the GHR mRNA throughout the observation period of six months, while a significant increase in the GHBP mRNA was observed 1 month after induction of diabetes and sustained for the rest of the study period 16 . No changes were seen in GHR or GHBP mRNA in the medullary regions 16 . These data indicate that although the GHR and GHBP mRNAs originate from the same gene, they are differentially regulated during the development of experimental diabetic kidney disease and furthermore imply a specific functional role for GHBP. Whether the increase in renal GHBP mRNA actually enhances...

Gene Expression Profiling in Diabetic Nephropathy With Structure Function Correlation

Isotype 4, and osteopontin as lead classifier genes in relation to the mesangial matrix expansion phenotype. We used the expression levels of these genes in the kidney to classify a separate group of animals for the absence or presence of diabetic glomeru-lopathy with a high degree of precision. Immunohistochemical analysis of murine and human diabetic kidney samples showed that both markers were expressed in podocytes in the glomeruli and followed regulation similar to that observed in the microarray. A similar type of analysis led to the identification of CD36 as a lead classifier in relation to hyperglycemia and albuminuria. CD36 was recently found to be increased in proximal tubular cells in human DN and mediate tubular cell apoptosis advanced glycosylation endproducts and free fatty acids (29). Thus, the application of phenotype-based statistical modeling approaches with microarray may lead to the identification of new markers for the development of diabetic kidney disease.

How is kidney function measured

Blood, for example, creatine and urea accumulate. Creatine is a waste product of muscle metabolism that is normally excreted through the kidneys. Healthy people (Table 2.1) have a creatine serum concentration of between 0.6 and 1.2 mg 100 ml. The normal value in an individual depends on the muscle mass. In someone with less muscle, it is lower in 'muscle men', it is higher. If kidney function fails, the creatine concentration in the blood gradually rises. Generally, though, mild kidney impairment does not lead to a noticeable change in serum creatine concentration. It rises only when kidney function has decreased by more than half. In people with little musculature, the low starting point for the creatine concentration can mean that it stays within the normal range for a long time, even when kidney function is seriously compromised. A more exact picture of kidney function is given by the so-called creatine clearance rate. To measure this, the urine must be collected for 24 hours or...

With nephropathy is there a point of no return

Another important question is whether there is any benefit of good blood sugar control once the signs of kidney failure, either micro- or even macroalbuminuria, have appeared. This was disputed for a long time. The opinion was that there was a point of no return, after which there could be no reversing the course of the disease - it would progress inexorably until dialysis was necessary, regardless of how well controlled the blood sugar level was. But the studies of recent years have shown clearly that good blood sugar control brings benefits, even at this stage. The progression of the nephropathy can be prevented, or at least delayed, by good management. This is true for both Type 1 and Type 2 diabetes.

Kidney Transplantation

Kidney transplantation is considered the most desirable form of RRT, but rates of kidney transplant are limited worldwide by organ availability. Many studies find that transitional and disadvantaged populations have less access to kidney transplantation than the majority population (147,148). In the United States, African Americans undergo renal transplantation less often than whites, in part because they are less likely to want a kidney transplant, but also because African Americans who do want a kidney transplant are less likely to be referred to transplant centers, even after adjusting for coexisting morbidity (149). Moreover, once referred, African Americans are less likely than whites to complete the evaluation necessary before being listed for transplant (150,151). Barriers to completion include limited access to transportation, child-care responsibilities, and lack of available time away from work factors that affect transitional and disadvantaged populations...

Treating kidney disease if prevention fails

When the kidneys reach the stage of uremia (see the earlier section Progressive changes), there's no alternative to dialysis, a mechanical cleansing of the blood, or transplantation of a healthy kidney. Two techniques are currently in use for dialysis t Peritoneal dialysis may be done at home. A tube is inserted into the peritoneal cavity, the body cavity containing the stomach, liver, and intestines. A large quantity of fluid is dripped into the peritoneal cavity, and the body wastes are drawn out into the peritoneal cavity. After several hours, the fluid is drained out with its wastes. Glucose must be placed in the fluid, and this complicates control of the patient's diabetes. Peritoneal dialysis usually must be done daily, and it's possible to travel while undergoing this type of dialysis. Peritoneal dialysis may be associated with infection of the tube, just like hemodialysis. There's little difference between these two forms of dialysis in terms of long-term survival. The...

Dietary Salt Intake And Diabetic Nephropathy

Systemic blood pressure elevation accelerates the progression of diabetic nephropathy in both type 1 and type 2 diabetic patients 93 , and effective antihypertensive treatment reduces albuminuria and the rate of decline in GFR in these patients. Extracellular fluid volume expansion due to impaired renal sodium excretion is the most clinically important mechanism that leads to the development of secondary hypertension in diabetic and non-diabetic patients with chronic renal disease 94 95 . Regardless of which specific antihypertensive agent is used, sodium restriction and treatment with loop diuretics is of major importance for the management of hypertension in these patients 95 . Recent short-term studies have demonstrated that the antiproteinuric effect of blockers of the renin-angiotensin-system RAS and nondihydropyridine calcium channel blockers is enhanced during dietary salt restriction independently of the blood pressure reduction in both diabetic and non-diabetic renal diseases...

Progression of diabetic nephropathy

A valid determination of the rate of decline in GFR in patients with chronic renal disease requires a reliable method for the determination of GFR, repeated measurements of the GFR, and a follow-up of at least 2 years 59 . However, when short-term effects of intervention are likely, rate of decline in GFR is slow, and the hypothesised benefit of the intervention is proportional to the rate of decline in GFR without intervention, a time-to-event (ESRD death) approach is favoured compared to a slope-based analysis 60 . If not accounted for in the design of the study, it would be expected that patients receiving a low protein diet would start dialysis later than patients with higher protein intake 61 . An ideal marker for the determination of GFR should be freely filtered through the glomerular capillary wall, biological inert, and neither secreted nor reabsorbed by the kidney tubules. 51Cr-EDTA or 125I-iothalamate has proved to be valid markers for the determination of the GFR 62 ,...

Magnitude Of Diabetic Nephropathy

In 2000 in the United States, 42,000 people developed end stage renal disease due to diabetic nephropathy for an incidence rate of 146 per million population 12 . This leads to a prevalence of 131,000 people receiving ESRD care due to diabetes. All of these numbers had more than doubled over the prior ten years 12 . Diabetes was the leading cause of ESRD accounting for about 43 of prevalent cases. These trends have begun to be recognized worldwide 13 . With an annual mortality of 23 during renal replacement therapy in the United States, 31,000 people with diabetic nephropathy and ESRD died in 2000 despite dialysis or transplantation 12 . These data compare with the death rates for the third and fourth leading causes of cancer death in the United States, breast and prostate, which accounted for 42,000 and 31,000 deaths respectively. Unlike ESRD due to diabetes, the death rates for these two cancers have been essentially stable for more than a decade 14 . Thus, the disease burden...

The Use Of Antihypertensive Agents In Dm Subjects With Established Diabetic Nephropathy

The impact of angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB) and conventional antihypertensive agents on renal function has been evaluated in both normotensive and hypertensive DM2 subjects with persistent proteinuria and variable degrees of renal impairment. In hypertensive DM2 subjects with persistent proteinuria studied for periods of greater than 6 months, ACEI 1321 , ARB 4, 6 and certain CCB 19, 21-23 reduced albuminuria. In general, the earlier reports showed that ACEI were very effective in reducing blood pressure and urinary albumin excretion 13-15, 17-21 . The decrease in blood pressure and albuminuria was usually associated with a slowing of the progression of renal failure. Parving's group has reported a disparity in effects on albuminuria and renal function 15 . Whereas lisinopril was more effective than atenolol in reducing albuminuria, both agents were similar in efficacy in terms of rate of decline...

Course Of Nephropathy During Pregnancy

Studies in pregnant women and rat models indicate that increased GFR is due to elevated RPF and vasodilation of afferent and efferent arterioles without evidence of increased glomerular capillary pressure (Pgc) 86 , with some contribution from both decreased afferent and efferent osmotic pressure and increased Kf 84,90 . Based on studies in chronically instrumented rats, it is unlikely that vasodilatory prostaglandins mediate the renal hemodynamic changes of pregnancy 86,91 . Nitric oxide is the prime candidate for causing glomerular vasodilation in pregnancy 92 , as acute selective blockade of both iNO and nNO reduce the gestational levels of RPF and GFR without effect on systemic arterial pressure 93,94 . Extensive studies in various pregnant rat models of experimental nephropathy never showed increased Pgc 86 , which is With DN in pregnancy, the expected rise in CrCl is seen in only about one-third of patients, as summarized in table 2 38,95,96 . In another one-third of DN...

Therapeutic Effects of HGF in Acute Renal Failure

Based on the renotrophic actions of HGF, the potential application of HGF for the treatment of renal diseases has been tested in various experimental models. In a clinical setting, acute renal failure is often caused by nephrotoxic drug administration (e.g., cisplatin, cyclosporine A, tacrolimus, and antibiotics) and renal ischemia. Administration of cisplatin caused acute renal failure in mice, whereas HGF administration prevented

What is the natural history of diabetic nephropathy

From the time of microalbuminuria appearance, progression of the disease is gradual and without warning signs or symptoms, until the patient ends up at an advanced stage (clinically overt nephropathy or diabetic nephropathy are described in Type 1 DM 3. Stage of incipient nephropathy This stage is divided into two phases, depending on albumin excretion in the urine, and lasts for 1020 years. At the initial phase, microalbuminuria excretion rate is 20-70 mg min and blood pressure is normal or minimally elevated. At the late phase of this stage, albumin excretion rate has increased (70200 mg min) and hypertension is persistent. Optimal control of diabetes, and even more important of arterial hypertension, while aiming at controlling intraglomerular pressure as well, is essential for the deceleration of renal function decline in this stage. 4. Stage of clinically overt nephropathy (clinical proteinuria) The main characteristic of this stage is macroalbuminuria or proteinuria (that is, an...

Mechanisms of Diabetic Complications Nephropathy as Related to Perspectives of Treatment

Diabetic nephropathy (DN) is characterized by a number of functional and structural abnormalitites. Functional changes include initial renal hyper-filtration hyperperfusion with subsequent development of microalbuminuria which is a modest increase in the urinary excretion of albumin and is not detected by conventional dipstick methods. At this stage, ultrastructural changes including glomerular basement membrane thickening, glomerular hypertrophy and mesangial expansion are present. This is followed by the subsequent development of glomerulosclerosis and tubulointerstitial fibrosis. Overt proteinuria supervenes followed by the development of renal impairment and ultimately renal failure. Although the renal complications of diabetes had already been described in the 18th century, it is only over the last 20 years that the mechanisms linking chronic hyperglycemia to the development of DN have begun to be unravelled (fig. 1). It is likely that DN occurs at least partly as a result of a...

AGEs and Diabetic Kidney Disease

A number of key consequences ensue from elevated levels of glucose one of these, the generation of AGEs, is linked to the development of diabetic complications (1,2). AGEs are a heterogeneous class of compounds formed by a number of mechanisms in the tissues, including nonenzymatic glycation and oxidation of proteins and lipids. Examples of AGEs that have been found in diabetic tissues, including in the diabetic kidney, include pentosidine, carboxymethyl lysine (CML) AGEs, and pyrallines (3-10). In addition to measurement of tissue AGEs in the kidney, many researchers have reported the utility of measurement of serum plasma AGEs as markers of the presence and or degree of DN (11-16). Certainly, examination of peripheral blood provides a more readily available source of material for initial determination of AGEs, particularly for serial assessments. It is important to note that confounding factors in at least some of these studies are the following. First, these studies support the...

Prevention of Diabetic Nephropathy General Considerations Glycemic Control

Because the causative event in diabetic nephropathy is hyperglycemia, the ideal preventive approach would be achievement of normal or near-normal glycemia. Both the DCCT and UKPDS studies clearly showed that intensive blood glucose control reduces the risk of development of nephropathy (28,29). Although such results are intuitive, the intensive insulin therapy used in the DCCT (28) was associated with a fourfold increase in the incidence of severe hypoglycemic episodes (defined as coma or need for medical assistance) and an average gain of 4.6 kg in weight after 5 yr of intensive therapy. However, despite these concerns in the DCCT study, a 33 reduction in the development of nephropathy occurred in type 1 diabetics. Also, both the DCCT Research Group and the UKPDS concluded that there was not a minimal glycemic threshold above normal for the development of the microvascular complications of diabetes and, thus, recommended that patients attempt to achieve as tight glucose control as...

Factors Influencing Nutritional Status In Dialysis Patients

Approximately 40 of dialysis patients exhibit some degree of protein and energy malnutrition and this is associated with an increased risk of morbidity and mortality. In the Modification in Renal Disease Feasibility Study (MDRD) in which 840 patients were prospectively studied, 42 of CAPD patients and 30 of HD patients were considered to be malnourished (15). Contributing factors to protein energy malnutrition occurring in dialysed patients are shown in Table 15.1. Table 15.1 Factors implicated in protein-energy malnutrition in dialysis patients Uraemic symptoms can continue for upto three months after starting dialysis Dialysis-related effects Nutritional intake deteriorates with inadequate dialysis IHD and episodes of hypotension limiting dialysis time PVD can limit vascular access for HD Infections of vascular access in HD patients and peritonitis in PD

Factors Affecting The Clinical Outcomes Of Diabetic Patients On Dialysis

The presence of a variety of comorbid conditions at the initiation of dialysis (Table 2) may adversely affect the clinical outcome and thus the success of any chronic dialysis program on RRT, by increasing the morbidity and mortality of the dialysis population with the DN. Factors Affecting Outcome of Diabetic Patients With ESRD on Dialysis Comorbidity at initiation of dialysis Volume status Residual renal function Dialysis complications (peritonitis) Adequacy of dialysis dose Ultrafiltration (UF failure) Dialysis characteristics

Dialysis in Remote Locations

The difficulties of providing dialysis to patients who live in remote locations are considerable (128). The Australian Remote Area Dialysis Program was established in 1989 by the Royal Perth Hospital and oversees many patients on home hemodialysis. Because nearly half of indigenous patients with ESRD come from regions without dialysis facilities (129), practitioners have had to develop other novel approaches to dialysis. Community hemodialysis is used in some areas a dialysis machine is located at a community center in a small village and shared by two or more patients. Patients use the dialysis machine with the assistance of a paid caregiver who has undergone basic training in its set-up and use (130). Continuous ambulatory peritoneal dialysis is another dialysis modality that can be used in remote locations (131). However, long-term continuous ambulatory peritoneal dialysis is limited in both indigenous Australians and indigenous Canadians by high rates of infection (132,133)....

Hemodialysisrelated Complications In Diabetic Dialysis Patients

Factors Contributing to Dialysis-Associated Hypotension in Diabetic Patients Consequence of myocardial infarction Diabetic cardiomyopathy Reduced blood viscosity Peripheral vascular resistance May precipitate dialysis-related angina Malnutrition Increase dialysis time No antihypertensive medications on morning of dialysis Prime dialysis circuit with hypertonic albumin Decrease dialysate temperature (particularly near end of dialysis)

Vascular Access in Diabetic Hemodialysis Patients

In older, mainly type 2 diabetics, calcifications may hinder the maturation of distal (wrist) vascular access, preventing the hypertrophy of the feeding artery, and thus it has been suggested (41) that the primary choice of an elbow AVF in general avoids frustrating attempts at the wrist, especially when late referral requires dialysis to be started rapidly. Also, many skilled surgical technical variations are possible in these patients because the increasing use of CVC for dialysis is a matter of concern. Rodriguez et al. (42) reported a prevalence of 79.6 of native vascular access in diabetics, with an 11 prevalence of CVC. Careful preoperative planning should allow examining the presence of adequate peripheral vessels and detection of suitable diabetic patients for a successful AVF and those at high risk of distal ischemia and steal syndrome.

The pros and cons of a kidney transplant

The biggest advantage of having a kidney transplant is that your quality of life is much improved compared to dialysis. For one thing, you no longer need dialysis if it has been started. For another, you're likely to be able to resume your regular life activities, even becoming pregnant if you're female. (I explain the precautions for women with T1DM to take when they're trying to conceive in Chapter 16.) The success rate of a kidney transplant is quite high, too. Ninety percent of transplanted kidneys are working well after one year, 80 percent after four years, and 50 percent after ten years. Some transplants have lasted as long as 40 years. Now that's something to cheer about It's important to continue to monitor your kidney function after the transplant to make sure that your body isn't rejecting the kidney. The best test for this is the creatinine. If it starts to rise, you have to temporarily increase the dosage of your immunosuppressive drugs. (See the later section Following...

Outcome of Kidney Transplantation

There is consensus that medical rehabilitation of the diabetic patient with uremia is best after transplantation (87). Although survival of the diabetic patient with a kidney graft is worse compared with a grafted nondiabetic patient, the gain in life expectancy of the diabetic patient with a graft, compared with the dialyzed diabetic patient on the waiting list, is proportionally much greater than in the nondiabetic patients, because on dialysis survival of the diabetic patient is poor. The higher mortality of the diabetic compared with the nondiabetic patient with a kidney graft is mainly explained by pre-existing vascular disease (28), LVH, and post-transplant hypertension. Woolfe (87) calculated the adjusted relative risk of death of transplant recipients as compared with patients on the waiting list. It was 0.27 for diabetic patients compared with 0.39 in nondiabetic patients with glomerulonephritis. Obviously, the perioperative risk is higher in diabetic than in nondiabetic...

How failing kidney function affects diabetes management

To achieve good blood sugar control in the presence of failing kidney function is a difficult task for patient and doctor. There are various reasons for this. Someone who has advanced nephropathy often also suffers from other complications of diabetes. These may include damage to the nerves that regulate the gastrointestinal tract. Then food is no longer digested and absorbed properly. Typical signs are bloating, feeling full, irregular bowel movements, diarrhoea, nausea and vomiting. The irregular absorption of food can cause the blood sugar levels to swing violently. Additionally, remember that many drugs, including those that reduce blood pressure, are excreted via the kidneys. If kidney function deteriorates and excretion does not occur properly, these drugs may persist in the circulation. This means that their effects are heightened and prolonged, which can lead to hypoglycaemia or other complications. Therefore, not all drugs are suitable for the treatment of people with...

Are retinopathy and nephropathy in a woman with DM contraindications for her pregnancy

Pregnancy does not seem to increase future risk of nephropathy. However, possible preexistent nephropathy or microalbuminuria are associated with increased rates of premature delivery, due mainly to pre-eclampsia occurrence, which can lead to intrauterine growth retardation and more rarely to death of the infant or even of the mother. During diabetic pregnancy the glomerular filtration rate is reduced, even with strict glycaemic control. When there is established proteinuria, urinary protein excretion can increase significantly and decrease after delivery, without permanently affecting the kidney function, unless there is concomitant hypertension. Pre-eclampsia and premature labour are observed at rates above 60 percent in women with creatinine clearance less than 80 ml min or urinary protein excretion more than 1 g 24 hs. Women, however, with plasma creatinine levels more than 2 mg dl (176.8 mmol L) are at increased risk for these complications and so this creatinine level, as well...

Definition Of Diabetic Nephropathy Dn

Figure 3.1 Renal ultrastructure in patients with type 2 diabetes (data from Fioretto et al,204 Gambara et al,205 Ruggenenti et al16 and Schwartz et al206). Note that the rate of decline in renal function correlated with degree of proteinuria rather than the histological type in the study by Ruggenenti et al.16 Typical refers to the classical glomerular changes described for diabetic nephropathy. Figure 3.1 Renal ultrastructure in patients with type 2 diabetes (data from Fioretto et al,204 Gambara et al,205 Ruggenenti et al16 and Schwartz et al206). Note that the rate of decline in renal function correlated with degree of proteinuria rather than the histological type in the study by Ruggenenti et al.16 Typical refers to the classical glomerular changes described for diabetic nephropathy. The five studies summarized in Figure 3.1 emphasize the heterogeneity of renal ultrastructural morphology in type 2 diabetes and demonstrate differences in classification of renal disease among...

Factors that influence the development of nephropathy

Whether nephropathy ever develops and how rapidly it progresses vary immensely from patient to patient. For some, the risk of kidney damage increases with the duration of diabetes, but the risk does fall when the diabetes is continuously well controlled. For others, however, hereditary factors are also important. Even among those who have high blood sugar levels for years, there are some people who never develop nephropathy. On the other hand, there are people with fairly good diabetes control who nevertheless develop kidney damage. We know that children from families with diabetes in which one member already has a renal problem have a much higher risk, from the onset, of developing nephropathy. Unfortunately, there is as yet no definite known marker in the blood or the urine that can predict the risk of developing nephropathy for an individual patient. This would naturally be a great help, as patients at higher risk could then be managed much more intensively.

Treatment for diabetic nephropathy

If the information in the previous section is making your blood pressure rise, take a deep breath. I'm happy to report that all the inconvenience and discomfort associated with diabetic nephropathy can be avoided. Following are a few key treatments that you can do to prevent the disease or significantly slow it down after it begins I Control your blood glucose This crucial step has been shown to avoid the onset of nephropathy and to slow it down once it starts. Both the Diabetes Control and Complications Trial (DCCT) in the United States, which studied glucose control in type 1 diabetes, and the United Kingdom Prospective Diabetes Study Groups in type 2 diabetes have proved this point. If you keep your blood glucose close to normal, you will not develop diabetic nephropathy. (For information on controlling your blood glucose, see Part III.) One of the best findings from the DCCT is that even eight years after the trial ended, participants experienced persistent benefits of reduced...

Strength Of Screening Tests For Diabetic Nephropathy

At present only two general classes of tests are used to detect diabetic nephropathy. First, GFR can be assessed. This is done most conveniently by measuring serum creatinine and entering that value in an estimating equation. Current equations have been incompletely validated for patients with diabetes and serum creatinine measurements are not so true as desirable especially in the near normal range 20, 21 . However, these deficiencies are not the major reason that GFR based screening has not been favored as a screening tool. Indeed, despite these weaknesses estimation of GFR is still a useful and needed adjunct to usual screening. As described above, when GFR has descended into the clearly abnormal range, much of the course of nephropathy has been run and the opportunity for intervention has diminished. Thus, GFR decline is a late index of kidney damage Albuminuria precedes the decline in GFR and testing for microalbuminuria is the commonly recommended screening test for diabetic...

Testing for Kidney Damage Microalbuminuria

The finding of very small but abnormal amounts of protein in the urine, called microalbuminuria, is the earliest sign that high glucose may be damaging your kidneys (see Chapter 5). When microalbuminuria is found, you still have time to reverse any damage. Doing this simple little test can protect your kidneys from damage. Ask your doctor about it if you think it has never been done. Show him or her this page if the doctor is unclear as to why it is performed. Up to 25 percent of patients with diabetes can have ongoing kidney damage without showing an elevated microalbumin. For this reason, the idea that all patients with diabetes should receive an ACE inhibitor may not be far-fetched.

Genetic Factors in the Development of Diabetic Nephropathy

There appears to be a genetic susceptibility to the development of nephropathy in diabetes (see Table 3). It has been observed that some persons with diabetes progress rapidly to develop nephropathy, whereas in others, normal or near-normal renal function is maintained even after 30 or more years of diabetes. In fact, about 65 of patients with type 1 diabetes will not develop nephropathy, despite suboptimal glycemic control (145,146). Hence, it appears that genetic factors are important in the genesis of diabetic nephropathy (145-148). The DCCT studies showed that although a tight control of hyperglycemia can reduce the incidence of nephropathy, it did not completely eliminate this complication (149). The genetic risk of developing nephropathy contrasts sharply with diabetic retinopathy, where the prevalence rates increase linearly with duration of diabetes (150). There are several family-based studies that further allude to the genetic risk of nephropa-thy. In families with two or...

Familial Aggregation Of Diabetic Nephropathy

The strongest evidence for an inherited susceptibility to diabetic nephropathy comes from studies showing that some families in particular have an increased risk of renal disease. A family history of nephropathy (or premature cardiovascular disease as its surrogate) continues to be the most accurate and available marker for identifying patients most at risk, with familial aggregation now described for nephropathy in both type 17-8 and type 2 diabetes.9,10 The diabetic offspring of parents with diabetes and proteinuria have three to four times the prevalence of nephropathy compared to the siblings of diabetic parents without renal disease.7,8 The risk appears to be further increased if both parents have diabetic nephropathy, as opposed to only one parent with albuminuria (Figure 4.1).9 This has led to the suggestion that the predisposition to diabetic nephropathy may be inherited as a dominant trait.7,11 In addition to proteinuria, familial aggregation has also been demonstrated in the...

Which other conditions except diabetic nephropathy may be accompanied by microalbuminuria

Transient increase in albumin excretion in the urine or even proteinuria can be due to poorly controlled diabetes, urine infections, uncontrolled hypertension, heart failure, febrile illnesses, physical activity, pregnancy and increased intake of protein with the food. Furthermore, variation of albumin excretion can be observed not only during a 24-hour period, but from day to day as well. Nephropathy from other causes also - albeit rare - should be considered, especially in cases of acute deterioration of renal function and proteinuria, without an obvious cause (vasculitides, collagen vascular diseases, glomerulonephritides, multiple myeloma, monoclonal gammopathies accompanying other diseases, etc.). This is particularly likely when nephropathy is not accompanied by retinopathy. When there is pyuria, urine culture is necessary for exclusion of urinary tract infection. Other recommended tests are erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and immunologic...

Role of Early Pancreas or Islet Cell Transplantation in the Prevention or Reversal of Diabetic Nephropathy

Pancreas transplantation provides essentially euglycemic control in type 1 diabetes patients. The glycosylated hemoglobin levels usually average 5.5 with almost no hypoglycemic episodes (212). Conversely, the glycosylated hemoglobin levels achieved on intensive insulin regimen in the DCCT study were only 7 and two-thirds of such patients had progression of nephropathy (190). As there appears to be no minimum threshold for glycemia that prevents progression of diabetic nephropathy, the near-normal glycemic control achievable with pancreas or islet cell transplantation may be necessary to prevent or reverse diabetic nephropathy. Indeed, pancreas transplantation has been shown to prevent or reverse the development of diabetic nephropathy (212-214). It can also reverse more advanced and established diabetic nephropathy in native kidneys, although it took up to 10 yr to see such effects in one study (214). In this study, eight patients with type 1 diabetes, but without uremia, who had...

Insulin And Nephropathy

Insulin sensitivity, while contributing to glycaemic control, is also a strong independent predictor of the development of diabetic nephropathy. This effect is not confined to patients with type 2 diabetes. There are now data describing the role of insulin sensitivity in the development of complications in type 1 diabetes.59 An association between insulin sensitivity and diabetic nephropathy may be inferred from the strong link between insulin sensitivity and cardiovascular mortality. In addition, markers of insulin resistance, such as triglyceride levels and waist to hip ratio, are also risk factors for albuminuria. Insulin sensitivity may also be genetically determined. Yip et al59 described familial clustering of insulin sensitivity in type 1 diabetes. Insulin resistance is also more common in the relatives of patients with nephropathy than in the relatives of patients with diabetes and normoalbuminuria. Similar findings have been reported in type 2 diabetes.60 In this context,...

What is the frequency of nephropathy in DM

The cumulative incidence of diabetic nephropathy for both types of diabetes is around 30-35 percent. In Type 1 DM, microalbuminuria can often occur more than 10 years after disease onset, whereas its prevalence is associated with the duration of diabetes and can reach 40-50 percent after 30 years of the disease. Unless certain therapeutic interventions are applied at the stage of persistent microalbuminuria, proteinuria develops in 80 percent of the patients with Type 1 DM after another 10-15 years, so that 25 percent of patients ultimately develop proteinuria after 25 years of the disease. Around 50 percent of Type 1 diabetic patients with overt nephropathy develop end stage renal disease within 10 years, and 75 percent within 20 years. In Caucasians with Type 2 DM, the course of diabetic nephropathy is similar to that in Type 1 DM, with the exception that persistent microalbuminuria can already be present at the time of diagnosis of the diabetes in 10-48 percent of the patients this...

Possible Role Of Hyperfiltration As A Risk Marker For Diabetic Nephropathy

In certain IDDM patients, glomerular hyperfiltration is especially marked and sustained during many years, and it has been suggested that such hyperfiltration represents a pathogenetic factor for later development of diabetic nephropathy. This suspicion is supported by the apparent analogy between the characteristic early renal hemodynamic changes in human IDDM and in animal models of diabetes. Thus, in experimental diabetes a normalisation of the high GFR or the high intraglomerular hydraulic pressure by pharmacological or dietary means, has attenuated progression of renal disease 71 . In human diabetes retrospective data has suggested that marked hyperfiltration is associated with later nephropathy 12,72 . Two studies later questioned these early observations (75,76), but long-term prospective studies have confirmed an associations between glomerular hyperfiltration and later development of nephropathy. In a swedish cohort of normoalbuminuric adolescent patients multiple regression...

Lipids And Diabetic Nephropathy

Dyslipidaemia is also an important component of the development of diabetic complications such as nephropathy.45 Triglycerides, intermediate-density lipoproteins, remnant-like particles and postprandial lipaemia are all increased in patients with albuminuria.46 In addition, low-density lipoprotein size is decreased in diabetic nephropathy. These changes may be apparent before the development of albuminuria.47 Several studies have correlated the presence of an abnormal lipid profile with the onset and progression of diabetic nephropathy.4849 Research in atherosclerosis disease has long established the importance of the genetic influences on lipid metabolism. It is therefore plausible that some of these modifiers may also contribute to the development and progression of diabetic renal disease. An example of the risk associated with inherited dyslipidaemia may be demonstrated in experimental studies using mice in whom the gene for apolipopro tein E (Apo E) has been 'knocked out'. These...

Diabetic Nephropathy And Pregnancy

The potential problems of diabetic nephropathy (DN) and pregnancy require the anticipation of preconception care. Clinicians who care for adolescent and adult diabetic women need to recognize that they may become pregnant, that most of the risks to mother and offspring are related to poor control of hyperglycemia and hypertension, and that the risks may be reduced through intensified multifactorial interventions before conception and throughout pregnancy. In the past, women with DN were generally advised to avoid pregnancy because there was a low probability of a healthy infant and a chance that nephropathy would worsen. Although advances in obstetrical and neonatal care have improved the outlook, nephropathy in pregnancy still presents a challenging situation requiring coordination between the patient and providers from many specialties. As reviewed in this chapter, women with nephropathy remain at high risk for many pregnancy complications, including superimposed

Future Perspectives For The Study Of Genetics Of Diabetic Nephropathy

Numerous association studies have been carried out in a large number of small patient populations with predictable conflicting results. The D-allele of the ACE ID polymorphism is suggested to be a new risk factor, although the effect is modest and prospective data are sparse. The M235T polymorphism in the angiotensinogen gene and the AGT1R1166 polymorphism are unlikely to contribute, whereas the promoter variant in the aldose reductase gene might turn out to contribute to the genetic susceptibility of diabetic nephropathy. In the mean time, the human genome project has identified and sequenced 50 to 100 000 human genes, including numerous new candidate genes for diabetic nephropathy. Large collaborative and prospective studies are required to determine which associations may be of relevance. Though cumbersome, family-based studies for linkage analyses are complementary and require multi-national collaborations for the collection of large enough numbers of families to allow confident...

Nephropathy screening and treatment

Diabetic nephropathy occurs in almost 40 of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30-299 mg 24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk 11, 12 . Patients with microalbuminuria who progress to macroalbuminu-ria (> 300 mg 24 h) are likely to progress to ESRD. Several interventions have been demonstrated to reduce the risk and slow the progression of renal disease. Key points diabetic nephropathy Limit protein intake to the recommended daily allowance (0.8 g kg) in those with chronic kidney disease In patients with type 1 diabetes, with hypertension and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. In patients with type 2 diabetes, hypertension,...

The Reninangiotensin System Ras And Diabetic Nephropathy

The pivotal role of the RAS in the pathogenesis of diabetic nephropathy has long been recognized. This is perhaps best manifested by the unique protective effects conferred by inhibitors of the RAS in diabetic renal disease.68 In experimental models, upregulation of the RAS in the setting of diabetes is associated with accelerated nephropathy. In the transgenic (mRen-2)27 rat, a mouse Ren-2 gene is inserted into the genome of a Sprague-Dawley rat, resulting in the overexpression of renin at sites of normal physiological expression69 and activation of the intrarenal RAS.70 The induction of diabetes in this model results in progressive renal pathology with features similar to human diabetic nephropathy (Figure 4.4). Similarly, insertion of multiple copies of the human angiotensin-converting enzyme (ACE) gene into transgenic mice results in increased proteinuria in response to diabetes, correlating with plasma ACE activity.71 These studies suggest that genetic modifications in the RAS...

Ambulatory Blood Pressure And Diabetic Nephropathy

The implementation of 24-h ambulatory BP (24-h AMBP) in the study of diabetic nephropathy has underscored the role of blood pressure elevation even in the earliest phases of diabetic nephropathy. Higher 24-AMBP characterizes type 1 diabetic patients with high normal urinary albumin excretion 65 and a close association between increases in UAE and blood pressure was found in the transition from normo- to microalbuminuria 66 . In the above mentioned study of patients with low-grade microalbuminuria 41 differences in BP were undetectable with clinic BP (mean of three random zero measurements) but using 24-h AMBP, statistically highly significant differences between the two groups were demonstrated. Likewise, in a substudy of the HOPE study, highly significant reductions in night blood pressure were detected by 24-h AMBP 67 , - reductions that could account for a substantial part of the beneficial effects obtained. A critical appraisal of the insensitivity of clinical BP

The Effect of ACE Inhibitor and ARBs on Renal Outcomes and Mortality Studies in Diabetic Nephropathy

During the oral presentation in San Francisco of the important studies on ARBs and overt diabetic nephropathy (type 2 diabetes) (25), one of the dedicated physicians in the audience asked one of the principal investigators Why did you not compare ACE inhibitors with ARBs, because we know that ACE inhibitors are quite effective in type 1 and 2 diabetes according to many studies The principal investigators became slightly disturbed, but clearly this question was very relevant, and an important review article on this issue was recently published in the British Medical Journal (26). It is an interesting meta-analysis conducted in a very systematic way. The question put forward in this chapter was relevant and clear when considering all papers dealing with ACE inhibitor and ARBs on renal outcomes and all-cause mortality in patients with diabetic nephropathy is there a difference The data sources were solid Medline, EM-base, and Cochrane Central Register for controlled clinical and contacts...

Combination Therapies in Diabetic Nephropathy

The finding that RAGE antagonism in diabetic animals does not impact on levels of glucose or lipids strongly supports that optimal strategies to attenuate the course of nephropathy will include agents targeting multiple key axes. For example, Davis and colleagues have shown superior protective effects of combination therapy with ACE inhibitors (perindopril) and aminoguanidine in STZ-induced spontaneously hypertensive rats (77). Interestingly, other studies have suggested that there is interplay between ACE and AGE pathways. Administration of ACE inhibition (ramipril) or aminoguanidine attenuated AGE formation in the kidney of STZ diabetic animals to the same degree, thereby suggesting that accumulation of AGEs in experimental DN may be linked through oxidative stress (77). Other studies confirmed this relationship STZ-treated diabetic rats receiving the AT1 receptor antagonist valsartan displayed reduction of tissue and plasma CML-AGEs (78). Thus, it would not be surprising that...

Genetic Approaches To Diabetic Nephropathy

Diabetic nephropathy is likely to be a complex genetic trait, i.e. a phenotype that does not exhibit classic Mendelian recessive or dominant inheritance attributable to a single locus. Thus a combination of susceptibility alleles at several genes provides a risk of developing the disease. The relative high cumulative incidence (25-35 ) of the disease can be accounted for if predisposing alleles with modest effects are common at several independent loci, since then their combination in a given person is expected to occur In candidate gene analysis one tests the association between a particular genetic variant and a trait, e.g. diabetic nephropathy, with the hope of identifying a variant that is more frequent among individuals with than those without the trait due to a causal relationship between the variant and the trait. The choice of candidate genes and variants should make biological sense and be physiological meaningful. A problem with this approach is that there are numerous...

Sodiumhydrogen Exchanger Nhe Activity And Nephropathy

Overactivity of the amiloride-sensitive Na+ H+ exchanger (NHE) has been described in patients with type 1 diabetes who develop nephropathy. As its name suggests, the NHE mediates excretion of intracellular H+ in exchange for extracellular sodium. It is therefore important in the regulation of intracellular pH and cell volume, and stimulus-response coupling, as well as matrix synthesis and cell proliferation. Exchanger activity and expression are modulated by a large variety of stimuli, including growth promoters, hormones, changes in cell volume and extracellular pH. In addition, some NHE activity may be genetically determined. For example, Trevisan et al97 demonstrated concordance for NHE activity in cultured skin fibroblasts from siblings with type 1 diabetes. Matteucci and Giampietro98 demonstrated that NHE activity was also altered in non-diabetic siblings of patients with nephropathy. There is evidence that the traits that determine NHE activity may segregate with the...

Development Of Susceptibility Genes To Nephropathy

If an inherited susceptibility to diabetic nephropathy exists, it raises a number of questions about how such a trait came to be and why it should continue to be present in at least a third of patients with diabetes. Since the trait is so commonplace, it suggests primeval origins. Moreover, it must have been propagated widely because, in the absence of hyperglycaemia, it is not deleterious. It may even be that a theoretical survival advantage exists in a predisposition to diabetic nephropathy in the absence of hyperglycaemia.11 For example, genes which benefited preagriculturalist hunter-gatherers, adapted to life in a variety of habitats, may be counterproductive in sedentary people whose Westernized diet is characterized by high amounts of fat, refined carbohydrates, and salt, as well as being poor in fibre, nutrients and vitamins. It is also worth considering that genes which protect against perinatal mortality (the main cause of prereproductive death) also predispose to...

Management Of Advanced Renal Failure

Although normalizing blood pressure, optimizing glycemic control, and adhering to low protein diet may slow the development and progression of diabetic nephropathy many patients still progress to ESRD. Patients with diabetic nephropathy and declining renal function should be referred to nephrologists at an early stage and certainly by the time serum creatinine levels have raised to 2-3 mg dL. This helps to optimize treatment and early consideration for renal replacement therapy. Reports from both Europe and the United States showed that a high proportion of patients with diabetic nephropathy were referred to nephrologists late in the course of their disease, and resulting in suboptimal care (90,91).

The Role Of The Biopsy In Assessing Diabetic Kidney Disease

This is an issue that has prompted much discussion in the literature with some authors arguing in favour of an increasing use of biopsy. There is certainly a role for renal biopsy in clinical studies of diabetic nephropathy. However, the routine clinical use of biopsy in these patients is less clear and may vary according to the stage of the disease. We have not differentiated between type 1 and type 2 diabetes as the same issues apply to both groups. Once overt nephropathy has developed histological lesions are predictably advanced. In contrast, patients with lower levels of microalbuminuria can have very variable light microscopic appearances, from normal structure to well established diabetic lesions 33 . Structural changes can also be apparent even in the absence of functional changes. The lack of correlation between functional measurements and histological changes has been suggested as a reason to biopsy patients with low levels of microalbuminuria 34,35 . This is justifiable...

What do we call diabetic nephropathy

Diabetic nephropathy is the decline in renal function due to DM and manifests clinically with proteinuria, usually several years after the onset of hyperglycaemia. The earliest clinical indication of diabetic nephropathy is the appearance of a small quantity of albumin in the urine (albumin excretion rate > 30mg 24h or > 20 mg min in a 4-hour or 8-hour urine collection or > 30 mg g creatinine in a spot urine sample). Specifically, microalbuminuria is defined as the excretion of 30-300 mg of albumin in a 24-hour period or 20-200 mg min or 30-300 mg g creatinine in a spot urine sample. When albumin excretion rate is higher than these cut-offs, we talk about macroalbuminuria or more precisely overt proteinuria (which corresponds to a total protein excretion rate of > 500 mg 24 hours).

Transforming Growth Factor And Other Cytokines In Experimental And Human Diabetic Nephropathy

Penn Center for Molecular Studies of Kidney Diseases, Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania Philadelphia, PA, USA Genetic, hemodynamic, and metabolic factors are important in the pathogenesis of diabetic nephropathy. This chapter, complementing the coverage of related chapters in this book, will focus on some of the metabolic mediators, especially the various cytokines and growth factors, with particular focus on the transforming growth factor- (TGF-P) system. Various mediator factors and signal transduction pathways interact in an intricate circuitry of autocrine, paracrine, or even endocrine mechanisms when the kidney is chronically exposed to high ambient glucose concentrations. The effects of high glucose on renal cells may arise as a consequence of increased flux of glucose metabolism through the polyol pathway 1 , increased de novo synthesis of diacylglycerol (DAG) with subsequent activation of protein kinase C (PKC) 2, 3...

Studies On The Genetics Of Diabetic Nephropathy

Putative candidate genes for diabetic nephropathy. Table 1. Putative candidate genes for diabetic nephropathy. Among the candidate genes suggested for nephropathy, genes of the renin-angiotensin system and especially the gene coding for ACE, have attracted most interest. In addition to the circulating renin-angiotensin system, recent studies have demonstrated local gene expression of both renin, angiotensinogen, and ACE genes in the kidneys, adrenals, heart and blood vessels. Although vascular ACE activity is regulated at a considerably slower rate than that of renin, the enzyme is nevertheless a determinant of local angiotensin II production 13 . Thus, locally generated components of the renin-angiotensin system may play important roles in the function of these target organs, and may even reach the circulating blood and thus contribute to the levels found in plasma. In diabetes, the initial report from Marre et al in 1994 proposed a protective effect of the II genotype...

Vegf In Experimental Diabetic Kidney Disease

The possible role of VEGF in diabetic nephropathy has been investigated in several animal models of diabetes mellitus, initially in essentially descriptive studies but more recently in experiments in which the effects of VEGF have been blocked. Cooper et al. (21) demonstrated an early and sustained increase in VEGF gene and protein expression in the visceral epithelial cells of the glomerulus from rats with streptozotocin-induced diabetes. On the other hand, the expression of VEGFR-2, mainly in the glomeruli was increased at the earlier 3-wk time-point but not at 32 wk, suggesting a more important role for VEGF in the earlier stages of diabetic renal disease. A similar increased expression of VEGF mRNA and protein has been reported at early timepoints in the development of nephropathy in spontaneously diabetic rats. These investigators suggested that hypoxia and cAMP played a regulatory role in the expression of VEGF at the onset of diabetes (29). Changes in VEGF expression have been...

How is diabetic nephropathy treated Glycaemic control

In Type 2 diabetic patients with incipientl nephropathy, it is wise to use sulfonylureas carefully, discontinue metformin administration and use insulin if needed. The risk of prolonged hypoglycaemias from sulfonylurea administration when CRF occurs is high. Specifically, metformin administration is interrupted when creatinine is higher than 1.5 mg dl (132.6 mmol L) in men and > 1.4 mg dl (123.8 mmol L) in women, due to the heightened risk of lactic acidosis.

Evidence for a role of VEGF in diabetic kidney disease

In vitro mesangial cells, glomerular endothelial cells, VSMCs, and proximal and distal tubular cells are capable of producing VEGF.189-191Ang II can stimulate VEGF production in mesangial cells,189-191 and high glucose-induced VEGF production in VSMCs seems to be PKC-dependent.192 Further, various growth factors and cytokines have been shown to stimulate VEGF production in non-renal cells.111 Finally, VEGF stimulates NF-kB concentrations in endothelial cells in vitro.193 The recent study in OLETF rats described above reported renal VEGF mRNA and glomerular immunoreactivity to be increased.179 Changes in renal VEGF and VEGF receptor concentrations have also been described in STZ-diabetic rats.186 In a clinical study in children and adolescents with type 1 diabetes, serum VEGF levels are similar to the levels in non-diabetic controls.194 However, another clinical study, describing VEGF expression in renal biopsy specimens from patients with different kidney diseases, included a small...

Familial Factors In Diabetic Nephropathy

Reports of nephropathy developing in some patients with apparently well controlled diabetes and not developing in some patients even after years of severe hyperglycemia lead to the conclusion, expressed by several researchers 1-5 , that some, but not all, individuals are predisposed to the development of diabetic renal disease. This chapter reviews some of the data, which indicate that there are familial differences in the predisposition to diabetic renal disease. If this familial predisposition is genetic, there must be an interaction between the genes and the environment, and it is often difficult to differentiate between genetic inheritance and the effect of a common environment shared by family members.

Protein Bioinformatics In The Investigation Of Diabetic Nephropathy

Bioinformatic analysis is of substantial assistance in characterizing hypothetical proteins identified by mass spectrometric analysis. It can unmask those unknown proteins, which may turn out to be common or well-known proteins. Using data mining, the unnamed protein (gil12841975 BAB25424) that is upregulated in diabetic mouse kidney has been finally unmasked (51). The data indicate that this unknown protein is, indeed, phosphatidylethanolamine-binding protein. Additionally, motif scanning shows that this unknown protein contains several kinase motifs, especially protein kinase C that plays an important role in the pathogenesis of diabetic nephropathy. Therefore, this protein phosphatidylethanolamine-binding protein should have a potential functional role in protein kinase C-dependent pathogenic mechanisms of diabetic nephropathy. Fig. 7. The model of renal protein trafficking in type 1 diabetic nephropathy. This model has been created by extensive bioinformatic analysis and...

Anti Fibrotic Function of HGF in Chronic Renal Diseases

Obstructive Nephropathy Obstructive nephropathy occurs as a result of urinary retention, caused by obstructive causes (such as congenital hypoplasia, and urinary calculi) (70). Ureteral obstruction and tubulo-interstitial fibrosis is one of the most frequent causes of end-stage CRD in children (70). Unilateral ureter-ligation obstruction (UUO) in rodents mimics human obstructive nephropathy. Using this UUO model, we found that HGF supplementation suppressed renal TGF-P1 expression, associated with repressed infiltration of macrophages, a source of TGF-Pj (71). This was followed by inhibition of interstitial fibrosis (i.e., myofibroblast hyperplasia and ECM overdeposition). In this process, HGF Fig. 3. Anti-fibrotic effect of HGF in chronic renal diseases. (A) Anti-fibrotic and therapeutic effects of HGF on nephrotic syndrome. Administration of rh-HGF into nephrotic ICGN mice enhanced tubular regeneration (as evidenced by BrdU intake) (left), whereas interstitial fibrosis was markedly...

Genetic Models of RAGE Modification and Diabetic Nephropathy

In order to definitively address the role of RAGE in the pathogenesis of DN, genetic models have been employed in experimental systems. In the first studies, Yamamoto and colleagues (52) generated transgenic mice that overexpress RAGE in vascular cells (and to some degree on mononuclear phagocytes) and cross-bred these mice with animals that develop insulin-dependent diabetes shortly after birth. The double-transgenic diabetic mice displayed increased enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with the diabetic litter-mates that lacked the RAGE transgene. In those studies, consistent with roles for advanced glycation in amplifying RAGE-mediated perturbation in this setting, these authors found that administration of OPB-9195, an inhibitor of AGEs, prevented the nephropathy phenotype in the double-transgenic mice (52).

Evidence for a role of endothelin in diabetic kidney disease

And urine flow260 have been shown to stimulate ET-1 synthesis or release. Studies examining systemic and intrarenal ET-1 in diabetes are rare and have yielded conflicting results. Plasma ET-1 levels have been described as either undetectable,261 unchanged,198 enhanced260-263 or suppressed,264 and renal ET-1 levels have been shown to be unchanged,261 enhanced,256 or reduced.198 Accordingly, it is suggested that these changes are caused by the diabetic state, and differences may be due to the degree of hyperglycaemia, the renal localization, or varying duration of diabetes.198 Glomerular ET-1 mRNA levels increase with progression of diabetic nephropathy in STZ-diabetic rats, whereas the mRNA levels for ET receptor A and B do not change in diabetes.256 On the contrary, early after the induc-tion of diabetes, renal ET-1 mRNA and protein expression have been reported to be reduced and plasma ET-1 levels unchanged, implying that the intrarenal ET-1 system may be affected independently of...

Structuralfunctional Relationships In Diabetic Nephropathy

Mesangial expansion is the major hallmark of nephropathy in type 1 diabetic patients (42) and is, more or less, related to all other renal structural or functional alterations of the disease. Increased Vv(Mes glom) closely correlates with a decrease in peripheral GBM filtration surface density Sv(PGBM glom) . On the other hand, total filtration surface per glomerulus S(PGBM glom) is highly correlated with GFR across the spectrum from hyperfiltration to renal insufficiency in type 1 diabetes (42-45). Vv(Mes glom) is also related to the AER (42,46) and high blood pressure (20,42). Similarly, but less strongly than for Vv(Mes glom), GBM width is directly correlated with blood pressure and AER and inversely correlated with GFR (42,46). In fact, the rate of development of mesangial expansion and GBM thickening varies among patients (42,46). For example, relatively marked GBM thickening can be seen without remarkable mesangial expansion and vice versa, preventing a precise correlation...

Glomerulonephritis And Other Complicating Diseases

Glomerulonephritis has been thought to occur more frequently in patients with diabetic renal disease than could be explained by mere coincidence 39, 40 . Autopsy studies have, however, shown that complicating glomerular disease is rare and probably not exceeding prevalence in the general population 41 . In biopsy studies of patients with IDDM glomerulonephritis seems to be comparatively rare 42, 43 , probably around 2-3 in unselected cases with proteinuria and duration of diabetes of more than 10 years. It has recently been reported that it may be more common in NIDDM for literature see ref 44 , but data from different series are conflicting. The rates of glomulonephritis in these studies vary between 0 and 69 and those of other complicating renal diseases between 0 and 20 . Geographical differences and variable criteria for histopathological diagnosis may be partly responsible, but the main cause of the diverging results is probably selection of patients for renal biopsy. Most of the...

Energy Requirements for Dialysis Patients

Energy requirements to achieve neutral nitrogen balance in stable diabetic dialysis patients are similar to those of healthy non-diabetic adults (35kcal kg body weight), with lower requirements for subjects over 65 years of age (30-35kcal kg body weight) (19). Patients on CAPD receive part of their energy requirements from dialysate glucose (see below) (20). Table 15.3 A checklist for interpreting blood results of dialysis patients Table 15.3 A checklist for interpreting blood results of dialysis patients

Nephropathy and Hypertension in Diabetic Patients

Strict and steady near normoglycemia over many years is of paramount importance for the prevention and postponement of renal disease, as well as other complications in most patients with type 1 and type 2 diabetes. Later, several other factors appear to affect progression in renal disease of which blood pressure (BP) elevation seems most important. This seems also to be the case for macrovascular complications along with dyslipidemia, smoking and, as mentioned, hyperglycemia. Incipient renal disease in diabetes, as judged by the occurrence of microalbuminuria, is frequently characterized by hypertension starting with increase in BP from a normal level. The increase, however, is often subtle and may only be detectable by careful and continuous monitoring, e.g. by 24-hour ambulatory recordings. Elevation of BP is found in both types of diabetes, but there appear to be several distinctions between type 1 and type 2 diabetes some of these variations are clearly explained by the different...

Impaired Autoregulation Of Gfr In Patients With Diabetic Nephropathy

Animal studies have demonstrated impaired renal autoregulation in models of glomerulosclerosis 81 , glomerulonephritis 74 , nephrosclerosis 82,83 and nephrosis 84,85 . In humans Parving et al 68 demonstrated a wide variation in response to clonidine induced acute BP reduction ranging from normal to severely impaired GFR autoregulation in long-term Type 1 diabetic patients with nephropathy. A similar clonidine induced reduction in MABP had no impact on autoregulation in short-term normoalbuminuric Type 1 diabetic patients and in the nondiabetic control group. The reduction in arterial BP induced a reduction in albuminuria in the Type 1 diabetic patients with nephropathy, suggesting diminished glomerular capillary pressure. Fig. 2. Relative change in glomerular filtration rate (GFR) (percentage change of control GFR) and relative change in MABP (percentage change of control MABP) induced by intravenous injection of clonidine. (A). Fourteen Type 2 diabetic patients with nephropathy ( ),...

Familial Aggregation Of Phenotypes Of Diabetic Nephropathy

Proteinuria and kidney function impairment are two phenotypes that are the major hallmarks of DN. Several studies demonstrated that both aggregate in families of diabetic as well as nondiabetic individuals as heritable traits. Before we discuss these results, a few comments are necessary about the ways the studies were designed. The relative contributions of heredity and shared environment to the familial aggregation of a disease have been tested historically by comparing the occurrence of the disease in monozygotic and dizygotic twin pairs (9), an impractical approach in T2DM patients with nephropathy. Alternatively, the hereditary and environmental components of familial aggregation can be partitioned on the basis of the pattern of covariance between pairs of relatives within families. Recent developments in statistical genetic analysis now enable the assessment of heritability (h2) (the proportion of total pheno-typic variance owing to additive genetic effects) and the genetic...

Dalla V.m. Masiero A. Roiter A.m. Et Al Is Podocyte Injury Relevant In Diabetic Nephropathy Studies In Patients With

In early stages of overt diabetic nephropathy Kidney Int 58, 2129-2137 Annet L, Hermoye L, Peeters F, Jamar F, Dehoux JP, Van beers BE (2004) Glomerular filtration rate, an assessment with dynamic contrast-enhanced MRI and a cortical-compartment model in the rabbit kidney J Magn Reson Imaging 20, 843-849 development of diabetic nephropathy Diabetes 38, 1142-1147 Bjornson A, Moses J, Ingemansson A, Haraldsson B, Sorensson J (2005) Primary human glomerular endothelial cells produce proteoglycans, and puromycin affects their posttranslational modification Am J Physiol Renal Physiol 288, F748-756 Blouch K, Deen WM, Fauvel JP, Bialek J, Derby G, Myers BD (1997) Molecular configuration and membranes Macromolecules 17, 1170-1173 Brenner BM, Meyer TW, Hostetter TH (1982) Dietary protein intake and the progression of kidney disease, the role of haemodynamically mediated glomerular injury and the pathogenesis of progressive glomerular sclerosis in aging, renal ablation and intrinsic renal...

Effect Of Pregnancy On The Subsequent Progression Of Diabetic Nephropathy

For years, there has been concern that the hyperfiltration, hypertension, or heavy proteinuria of pregnancy might damage glomeruli, tubules, and interstitium and accelerate the postpartum progression of DN to end-stage renal disease. In a pooled series of 195 women experiencing pregnancies with DN and having renal function assessed 1-10 years afterwards, 23 were in renal failure and 5.6 had died (table 4). Not surprisingly, the frequency of progression to renal failure after pregnancy was 49 in the group of women with impaired renal function in early pregnancy, compared to 7 if Cr was < 134 uM or CrCl was > 80 ml min in early gestation (table 5) 38,95,96, 98,100,101,148,189-192 . A similar risk of post-pregnancy decline of renal function based on pre- or early pregnancy CrCl was also reported by Biesenbach, and he speculated that inadequate antihypertensive therapy may have contributed to the original and further decline in renal function 104 . Table 5. Course of diabetic...

Minimally Invasive Cgm Dialysis Cathetertype Isf Glucose Sensor

Dialysis catheter-type glucose sensors consist of a flexible catheter that the patient inserts through the skin into the sc tissue. The small pore dialysis catheter is connected to a fluidics system that transports a salt solution (dialysate) into and out of the body. Glucose-free dialysate is infused into the dialysis catheter previously inserted into the sc tissue, and allowed to equilibrate with ISF glucose. Glucose containing dialysate is pumped out of the body to an external electrochemical glucose sensor at a slow rate (5-10 L min) to optimize equilibration and recovery of glucose from tissue fluids. The glucose sensor is automatically calibrated and recalibrated using liquid glucose standards obtained from the manufacturer. Sensor drift is less of a problem because the enzyme and electrodes are not in direct contact with the body tissues. Limitations include large size, long sample acquisition time (10-15 min), inaccuracy due to incomplete glucose equilibration, infection and...

Ethnic Variability In Diabetic Nephropathy

Figure 4.2 Increased prevalence of nephropathy in Polynesian patients with a family history of end-stage renal disease (ESRD) rather than diabetes. D+ESRD people with a first-degree relative with ESRD and diabetes N+ESRD people with a relative having non-diabetic ESRD D people with a relative with diabetes but no known nephropathy C people with no known relatives with either diabetes or nephropathy (*D-ESRD vs D, p 0.01, D vs C, p 0.2). Adapted from Diabetic Medicine with permission.17 Figure 4.2 Increased prevalence of nephropathy in Polynesian patients with a family history of end-stage renal disease (ESRD) rather than diabetes. D+ESRD people with a first-degree relative with ESRD and diabetes N+ESRD people with a relative having non-diabetic ESRD D people with a relative with diabetes but no known nephropathy C people with no known relatives with either diabetes or nephropathy (*D-ESRD vs D, p 0.01, D vs C, p 0.2). Adapted from Diabetic Medicine with permission.17 Like familial...

Hyperglycaemia And The Pathogenesis Of Diabetic Nephropathy

Diabetic Nephropathy Pathogenesis

The main metabolic disorder occuring in diabetes is hyperglycaemia. Two landmark studies, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive blood glucose control clearly reduces the development or progression of diabetic nephropathy 43,44 . Thus, the impact of extracellular high glucose concentrations on renal cell gene expression was investigated in detail The involvement of PKC in diabetic nephropathy is in accordance with several reports, which provide evidence for a role of glucose-induced activation of PKC in the elevated synthesis of matrix components 62,63 . Application of a PKC P isoform specific inhibitor ameliorated the changes in glomerular filtration rate, albumin excretion rate and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities 64 . Moreover, inhibition of PKC activities abrogated the high glucose-induced TGF-P1 promoter...

Heparin And Gags Renoprotection In Diabetic Nephropathy Does It Support The Steno Hypothesis

A number of reports showed that heparin and more generally GAGs prevent and cure experimental diabetic nephropathy 16,64-67 and decrease albuminuria in type 1 and 2 diabetic patients 68,69 . Because defects in HS-GAG synthesis are believed to be so striking in diabetic nephropathy, the treatment of diabetic nephropathy with HS-GAG like substances can be viewed as an experiment to test the Steno hypothesis. However, the activity of these drugs cannot be explained, by the Steno hypothesis, only in terms of recovery of the diabetes-induced abnormalities in HS-PG metabolism, restoration of anionic-HS charges in glomerular and other basement membranes, and recovery of derangement in basement membrane permeability. Indeed, Oturai 70 has shown that heparin treatment does not correct the diabetes-induced vascular hyperpermeability although heparin and GAGs are known to be curative in arteriosclerosis 71,72 . However, this effect on permselectivity depends on the complex activity of heparin on...

Interaction Of Proteins And Other Plasma Factors With Podocytes And Tubules In Diabetic Nephropathy

Lysosome Ros

Interventions in experimental diabetes have shown that agents that reduce proteinuria also induce parallel changes in the renal tubules. For instance, in experimental diabetes, ramipril and aminoguanidine both prevent diabetes-related increases in albumin excretion rate and restore renal tubular lysosomal processing to normal levels (30). Intervention with an angiotensin receptor blocker as well as an angiotensin-converting enzyme inhibitor also ameliorates the endocytosis of urinary albumin and restores renal tubular megalin expression to normal while preventing increases in diabetes-related albuminuria (70). It is likely that receptor-mediated endocytosis also occurs in the podocyte because podocytes also contain megalin receptors (71). Megalin is a 600-kDa transmembrane protein belonging to the low-density lipoprotein receptor gene family and is identified in rat podocytes as the target for immune deposit-forming antibodies in Heymann nephritis (72). Studies in isolated rat...

Renal Failure and Macular Edema

There are anecdotal reports that treatment of renal failure will reduce macular edema in patients who have both (125). However, hemodialysis failed to reduce fluorescein leakage in the eyes of type 2 diabetic patients with renal failure and macular edema (126). There are no epidemiological studies or clinical trials that have demonstrated that reduction of microalbuminuria and prevention of overt diabetic nephropathy manifest by clinical proteinuria will result in reduction of risk of retinopathy. This may be a moot point because most treatments aimed at poor

Evolution Of Diabetic Nephropathy

Diabetic Nephropathy Evolution

Diabetic renal disease is characterised by changes in both AER and GFR in predisposed patients. The usual sequence starts with an increase in GFR (hyperfiltration), followed by an increase in AER leading to microalbuminuria. Hyperfiltration may persist through the phase of microalbuminuria or it may normalise prior to the onset of overt nephropathy (macroalbuminuria), which is accompanied by further increases in AER and a declining GFR. In parallel with these changes, there is a rise in blood pressure which may begin before the development of microalbuminuria in type 2 diabetes but usually occurs during the early microalbuminuric phase in type 1 diabetes. The major clinically identifiable initiators are hyperglycaemia and blood pressure control. Increases in AER into the microalbuminuric range may occur transiently with exercise, urinary tract infection, uncontrolled hyperglycaemia and cardiac failure, and on a long-term basis with hypertension, non-diabetic renal disease, and in...

37zehrer Cl Gross Cr Comparison Of Quality Of Life Between Pancreas Kidney And Kidney Transplant Recipients One-year

Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz FC. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 1967 61 827-837. 26. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998 339 69-75. 31. Gaber AO, Cardoso S, Pearson S, Abell T, Gaber L, Hathaway D, et al. Improvement in autonomic function following combined pancreas-kidney transplantation. Transplant Proc 1991 23 1660-1662. 37. Zehrer CL, Gross CR. Comparison of quality of life between pancreas kidney and kidney transplant recipients 1-year follow-up. Transplant Proc 1994 26 508-509. 38. Piehlmeier W, Bullinger M, Nusser J, Konig A, Illner WD, Abendroth D, et al. Quality of life in type 1 (insulin-dependent) diabetic patients prior to and after pancreas and kidney transplantation in relation to organ function. Diabetologia 1991 34(Suppl 1) S150-157.

Aldose Reductase And Diabetic Nephropathy

Aldose reductase is a key enzyme of the polyol pathway, involved in the metabolism of glucose and the NADPH-dependent reduction of a broad range of carbonyl compounds. In particular, the downstream accumulation of sorbitol and activation of the hexose kinase pathway have been implicated in the pathogenesis of a number of diabetic complications, including nephropathy.86,87 Recent studies have shown that polymorphisms in the aldose reductase gene may be associated with susceptibility to nephropathy in patients with both type 188 and type 2 diabetes.89 In particular, the polymorphism in the (A-C)n microsatellite repeat sequence (located upstream of the transcription start site) may modulate expression of the aldose reductase gene. Among the eight different alleles at this site, the Z-2 allele is associated with upregulated expression of the aldose reductase gene in the presence of hyperglycaemia90 and increased prevalence of the nephropathy.91 Segregation of the Z-2 allele has also been...

Diabetic Nephropathy and Superimposed Preeclampsia

Women with diabetes and microalbuminuria or nephropathy are at an increased risk for preeclampsia compared to women with diabetes and no renal disease. In a Danish study (110) of 203 women with type 1 diabetes, 85 had normal albumin excretion, 11 had microalbuminuria, and 5 had diabetic nephropathy. Of those with normal albumin excretion 6 developed preeclampsia, and there was pre-term delivery in 35 . In those with microalbuminuria, 42 developed preeclampsia and 62 with preterm delivery, and in those with diabetic nephropathy, 64 developed preeclampsia and 91 with preterm delivery. This study illustrated for the first time that urinary albumin excretion rate (AER) was associated with preterm delivery, in addition to preeclampsia, which had been shown in prior studies (6, 111-113). A study comparing women with type 2 (DM2) and type 1 (DM1) diabetes (114) found that though the overall rate of hypertension in pregnancy was similar between women with DM2 and women with DM1 (41 vs. 45 )...

Antiproteinuric Therapies in Diabetic Nephropathy

Mechanistic experimental studies support that proteinuria is a risk factor but growth factor cytokines that are present in proteinuric glomerular ultrafiltrate are culprits in entertaining tubulo-interstitial fibrogenesis. Thus, the goal is to reduce glomerular macromolecule filtration. To this end angiotensin-converting enzyme (ACE) inhibitors have become the standard of care in DN. Substantial reductions in proteinuria can also be achieved with angiotensin receptor blockers (ARBs). In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, the level of proteinuria in type 2 diabetic patients with nephropathy who were treated with losartan decreased, on an average by 35 (58). Losartan has also been shown to reduce urinary TGF-P excretion without affecting TGF-P serum levels (59). With irbesartan, proteinuria can be reduced by approx 60 in type 2 diabetics with nephropathy and microalbuminuria as demonstrated in the Irbesartan in...

Pharmacological Blockade of RAGE and Its Impact in Diabetic Nephropathy

Studies demonstrating the enhanced expression of RAGE in the diabetic kidney did not shed light on whether this observation was linked mechanistically to the pathogenesis of nephropathy. To approach this question, pharmacological approaches have been taken to test the role of the RAGE axis in diabetes-associated nephropathy. In the first experiments, we employed the soluble form of the receptor. Soluble RAGE (sRAGE) was produced and purified from a baculovirus expression system and administered to animals once daily based on the pharmacokinetic profile of distribution and elimination (43). To extend these studies to a chronic model in which early changes of nephropathy of diabetes develop, we employed db db mice, a murine model of insulin resistance and type 2 diabetes. Mice were treated once daily with sRAGE or vehicle, phosphate-buffered saline from age 8 wk. db db Mice displayed increased expression of RAGE and S100 calgranulins in the kidney, particularly in podocytes and in...

Prevention And Reversal Of Diabetic Nephropathy Lesions

Patients (71), but also reduces GBM thickening (72), and, in patients who have renal allografts, results in less accumulation of mesangial matrix (73). Pancreas transplantation 2-4 yr after renal transplantation is associated 4-6 yr later with less mesangial expansion than after kidney transplantation alone (74). Simultaneous kidney pancreas transplantation prevents DN lesions (75). We documented that although DN lesions do not change 5 yr after pancreas transplantation (76), significant improvement or preventing diabetic glomerulopathy lesions including reduction in the thickness of GBM and TBM and mesangial matrix, disappearance of K-W nodular lesions representing substantial remodeling of the glomerular architecture, was seen 10 yr after pancreas transplantation alone (77). Possible explanations for this delayed healing could be relative insusceptibility of heavily glycosylated and cross-linked ECM molecules to degradation (78) or phenotypical alterations in renal cells that...

Vegf In Diabetic Nephropathy In Humans

In spite of the large amount of experimental evidence implicating VEGF in the development of experimental diabetic nephropathy, there is a lack of convincing evidence of a pivotal role for VEGF in human diabetic nephropathy. Of interest is a patient described by Baba et al. (56). This patient had a syndrome known as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and type 2 diabetes for 30 yr, when he died from cardiac failure. Plasma levels of VEGF had been markedly elevated, yet before death renal function was not severely impaired and at autopsy there were only slight glomerular changes. Thus, it is possible that rather than VEGF playing a pathophysiological role in the diabetic kidney, it acts as a survival factor protecting the kidney from ongoing injury. A recent report has described various VEGF gene polymorphisms in a large group of diabetic patients with retinopathy and nephropa-thy (57). The VEGF-460 polymorphism was associated...

Erythropoietin And The Anemia Of Diabetic Nephropathy

Renal injury also causes a transformation of peritubular fibroblasts into myofibrob-lasts. One hypothesis is that myofibroblasts can still generate erythropoietin but less well than fibroblasts (11). This is of interest in relation to diabetic nephropathy, as advanced glycation endproducts (AGEs) have been shown to modulate myofibroblast transformation (15). This may be one explanation for the occurrence of anemia in DN at an earlier stage than in nondiabetic renal disease with a similar degree of renal impairment. a strong correlation between polyneuropathy and the development of anemia in patients with type 1 diabetes (17). However, these patients also had coexisting nephropathy making it difficult to distinguish cause from association. In addition, denervated kidneys are still able to produce erythropoietin in response to anemia. Nonetheless, a key role for the sympathetic nervous system in impaired erythropoietin responsiveness should not be discounted. In our study of 722...

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