Diabetes: Current and Future Developments

Chronic Kidney Disease or CKD is defined as a persistent reduction in renal function over 3 months period along with biochemical or structural abnormalities or an absolute estimated glomerular filtration (eGFR) rate < 60 ml/min/1.73 m2 over 3 months with or without abnormalities. In practice, precise knowledge of the GFR is not required and CKD can be adequately monitored by eGFR using estimating equations. CKD is an important confounder in the outcomes of several diseases, particularly Diabetes Mellitus (DM), Cardiovascular Diseases (CVD) and Obesity. There is paucity of data using CKD as a primary outcome variable in randomized clinical trials, as a result most guidelines in this area are based on secondary analysis, observational studies or have inadequate sample sizes. The prevalence of CKD is important not only at an individual level to guide clinicians for proper management of their other illnesses but also at a population level for the purposes of all-inclusiveness in the design of clinical trials. The inclusion of individuals with CKD in emerging studies will allow us to address whether or not CKD plays a vital confounding role on many disease outcomes.

In order to get a good grasp on the epidemiology of CKD, an epidemiology collaborative equation called CKD-EPI equation is most widely utilized. This equation has its strength in being validated in several populations and estimates glomerular filtration rate (GFR) based on several demographic factors and serum creatinine. The National Health and Nutrition Examination Survey (NHANES) conducted by the National Center for Health Statistics (NCHS) collects health data on noninstitutionalized individuals in the United States via interviews, laboratory tests and examinations [1] has given us the needed information on the Epidemiology of CKD in the US. These surveys utilize CKD-EPI equation to quantify the statistical data on CKD trends.

Chronic Kidney Disease (CKD) is becoming a global health concern. The high percentage of people living with obesity and diabetes mellitus are part of the reason for the high prevalence of CKD. In the United States, the obesity epidemic disproportionally affects minority populations. In this chapter, we will review the epidemiology of obesity and diabetes and explore their link to CKD. We will also define CKD, and examine the increasing global burden of obesity, diabetes and CKD. We will discuss ethnic and gender disparities in these conditions and in the care received by minority patients. Finally, we will suggest management strategies to slow the progression to end stage renal disease particularly in vulnerable populations.

There is a rise in the number of elderly people and those with chronic kidney disease (CKD) in the United States. Despite the high prevalence of CKD in the elderly, most will die before renal replacement therapy (RRT), as CKD itself, is an independent risk for death. Control of modifiable risk factors such as proteinuria and hypertension may retard disease progression in this population, however, in those who do progress to stage 5, options for RRT include hemodialysis (HD), peritoneal dialysis (PD), kidney transplantation and conservative (medical) management. Special problems in the elderly with CKD include those inherent to the patient and those related to limited resources. Inherent to the elderly patient with CKD is the problem of accurately measuring estimated glomerular filtration rate (eGFR), frailty, depression, cognitive decline, limited autonomy, heart failure and arterio-venous fistula maturation issues. Problems with resources include but are not limited to: a paucity of evidencebased literature due to exclusion of the elderly from large clinical trials and scarce resources like kidney transplantation. Best clinical practices are personalized to the individual patient and should balance risk factors, patient autonomy and available resources

Diabetes mellitus affects up to 50% of renal transplant recipients. The incidence of hyperglycemia is high in the early transplant period due to surgery and the exposure to immunosuppressant medications. Patients who develop post-transplant diabetes mellitus (PTDM) are at increased risk of cardiovascular events, infections, graft loss, and mortality. Pre- and post-transplant screening is essential for early detection and management of individuals at high risk for PTDM. This chapter aims to review the latest evidence on the epidemiology, risk factors, guidance on screening, management of the disease and its complications. New international consensus guidelines on diagnosis, current research, as well as quality improvement options will be discussed.

The prevalence of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) varies depending on the presence of traditional coronary artery disease (CAD) risk factors, and is as high as 85% in the long-standing diabetic patient on hemodialysis that is over the age of 45. This highly elevated risk necessitates timely assessment and therapeutic interventions to mitigate the complications of CAD that remain the most common cause of mortality in the patient with CKD. With the overlapping risk factors and multifactorial causes of CAD seen in patients with CKD such as diabetes, hyperlipidemia, and obesity, clinicians need to maintain a high index of awareness of the proper evaluation and management tools and principles in their armamentarium of care for these patients. In this chapter, we examine the current evaluations and management principles and discuss their therapeutic implications.

Diabetic kidney disease (DKD) is a growing health burden globally. Obesity levels continue to increase in developed and developing nations. Obesity represents a chronic inflammatory state that alters glucose metabolism and insulin function, leading to Diabetes Mellitus. Diabetes mellitus initiates a cascade of metabolic and hemodynamic changes in the nephron. Interaction of metabolic and hemodynamic pathways lead to inflammation and fibrosis of the glomerus, a hallmark of DKD. Early control of hyperglycemia and the use of angiotensin converting enzymes inhibitors (ACEi) or angiotensin receptor blockers (ARB) are the cornerstone of management, aiming to slow down the progression of DKD. Better understanding of the pathogenesis involved in development of DKD, has resulted in an exploration for novel therapeutic modalities. These new modalities promise to not only slow down progression of DKD, but also potentially reverse DKD.

The presence of moderately increased albuminuria and/or proteinuria are associated with increased incidence of progressive kidney disease, cardiovascular events and death. Urine albumin-to-creatinine ratio is the preferred method of screening for albuminuria and protein-to-creatinine ratio is preferred for proteinuria. A random urine sample is accurate for diagnosis.

The presence of moderately increased albuminuria in type 1 diabetes is associated with increased risk of all-cause mortality (relative risk 1.8) and also increased risk of cardiovascular mortality (relative risk 1.8) compared with patients with type 1 diabetes but normal albumin excretion. In type 2 diabetes, the relative risk for all-cause mortality in patients with moderately increased albuminuria versus normal albumin excretion was 1.9, while the relative risk for cardiovascular and coronary heart disease mortality was 2.0 and 2.3 respectively.

Albuminuria is a robust, independent and continuous marker, with no lower limit, for increased risk of cardiovascular disease and cardiovascular mortality in diabetes and CKD patients as well as in the general population. The presence of moderately increased albuminuria can signal the beginning of diabetic nephropathy and also signals the presence of endothelial dysfunction.

In type 1 and type 2 diabetes, intensive glycemic control and blood pressure treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) decrease the prevalence of moderately increased albuminuria and prevent its progression to overt proteinuria.

The most effective treatment to prevent cardiovascular complications in diabetes and CKD seems to be a comprehensive multifactorial risk factor reduction: glycemic control, aggressive blood pressure control, management of albuminuria with angiotensin blockade, treatment of dyslipidemia, daily aspirin, exercise, weight loss and smoking cessation.

Diabetic kidney disease is a serious complication of uncontrolled diabetes. In this context, more than 50% of the patients on dialysis have diabetes as their primary cause of kidney failure. Diagnostic markers to detect diabetic kidney disease even before the onset of albuminuria is important to guide early intervention to slow the progression of diabetic kidney disease. Both serum and urinary biomarkers may be elevated before the appearance of albuminuria in the diabetic population and they can be used for detection of early diabetic kidney disease. As diabetes effect glomeruli, tubules and vessels in the kidney, the biomarkers can broadly be divided into those derived from glomerular or tubular injury. Further, inflammatory biomarkers are also useful in the early detection of diabetic kidney disease. Detection of these biomarkers can identify the diabetic kidney disease even before the onset of albuminuria. Further response of these biomarkers to our treatment can govern the management strategies in this complicated group of patients. Despite the identification of various useful markers, further large, multicenter prospective trials are still needed to confirm their clinical usefulness. This chapter will discuss novel biomarkers of diabetic kidney disease and new applications of these markers for early detection and progression of disease.

Nearly a quarter of the diabetic population has comorbid chronic kidney disease (CKD) and this number is increasing worldwide due to the increasing prevalence of obesity. More advanced stages of CKD present us with the twin competing challenges of both insulin resistance and an increased risk for hypoglycemia. Glycemic control is essential to delay or prevent the onset of CKD. However, the management of hyperglycemia in patients with CKD is complex and presents us with therapeutic challenges in terms of goals and monitoring of glycemic control. Although intensive glycemic control (hemoglobin A1c ≤ 7%) in patients without CKD reduces the development of microalbuminuria and the progression from microalbuminuria to macroalbuminuria, it does not stop the progression of kidney disease in patients with diabetes in whom the glomerular filtration rate is reduced, the serum creatinine is elevated or there is progression to end stage renal disease. Recent data indicate the intensive glucose control in CKD stages 1-3 may result in increased cardiovascular and all cause mortality. Patients with diabetes and CKD stages 3-5 have increased risk of hypoglycemia. These data reveal that glycemic goals for patients with diabetes and CKD must be individualized depending on the characteristics of the patient.

In this chapter we review the current views on the goals and methods of glycemic control, monitoring tools and risk of hypoglycemia in diabetic patients at various stages of CKD. We address the treatment options including the best lifestyle adjustments, nutrition, supplements, surgical interventions and pharmacologic agents. This chapter will provide clinical guidance in order to provide individualized glycemic goals and therapy for diabetic patients with CKD and end stage renal disease and will be an indicator of where additional research is needed.

Nutrition optimization can be a beneficial intervention in slowing down the progression of chronic kidney disease (CKD). Oftentimes, especially in obese patients with CKD, nutritional interventions are complex; involve carbohydrate and lipid restrictive strategies in addition to limitations in protein intake of poor biological value. Given the long time course CKD can take in individuals and given the unpredictable nature of CKD which varies between individuals, it is essential that periodic long term follow up with any nutritional intervention in any patient be rigorously monitored to assess adherence to dietary regimen and avoid ill consequences of too strict of a strategy. Unfortunately, long-term outcomes data of optimal dietary interventional strategies and intake of various nutrients for patients with CKD are lacking, especially for obese diabetic patients. Nevertheless, understanding the effects of adequate and inadequate nutrition in renal disease can help clinicians and patients work together to modify key risk factors that impact CKD progression. This chapter reviews the aberrancies and pathophysiological mechanisms that are associated with various microand macro-nutrient imbalances and how those imbalances can impact CKD and other comorbidities, especially in patients suffering from metabolic syndrome and obesity.

Diabetic glomerular disease is the leading cause of chronic kidney disease in the United States. Renin-angiotensin-aldosterone system (RAAS) activation pays a major role in the development of diabetic kidney disease. Microalbuminuria predicts the development of proteinuria and chronic kidney disease in diabetic patients. RAAS blockers are the first line of therapy for diabetic patients with hypertension. They are also used to treat microalbuminuria even in normotensive diabetics. Head to head trials have shown that angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have an equal effect in reducing blood pressure and microalbuminuria in diabetic patients. Direct renin inhibitors are the newest addition to RAAS blockers that block the rate-limiting step in the RAAS pathway. Dual blockage with ACE-Is and ARBs are not recommended. While there is better blood pressure reduction with the combination, there are no further beneficial effects on microalbuminuria and an increased incidence of hypotension, hyperkalemia, syncope and renal dysfunction. The progression of microalbuminuria to proteinuria has decreased significantly in the last 20 years as a result of better blood sugar and blood pressure control and the use of RAAS blockers.

While much progress has been made advancing our knowledge in the Pathogenetic mechanisms of diabetic kidney disease (DKD) including the role of oxidative stress, inflammation and fibrosis as eloquently presented (by N. Sharma, J. Lee and I.M. McFarlane) in chapter 6 of this volume, this progress has not been adequately translated into therapeutic modalities to aid clinicians handling the rapid rise of DKD that is associated with significant increase in morbidity and mortality in the USA and around the globe. For example, agents that block the renin angiotensin aldosterone system (RAAS) such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are only effective in halting the progress of DKD in a minority of patients.

In this chapter we discuss the major therapeutic targets that are currently under investigations in clinical trials, highlighting the pathogenetic mechanisms and the therapeutic rationale for these potential interventions as future preventive and therapeutic strategies in DKD, a rapidly growing epidemic.