19.11 Special conditions: kidney disease

Kidney disease is one of the most common and important consequences of microvascular damage in diabetes. Its occurrence largely determines the increased risk of cardiovascular events and remarkably shortens life expectancy. Therefore, protecting the kidney is one of the main aims of patient care in diabetes and should be based on implementation of the intensive treatment of risk factors that promote its progression to prevent renal failure, and even more importantly, cardiovascular events. Very recently, some new therapies with a beneficial effect on renal disease have emerged; however, there is still plenty of room for additional innovative treatment strategies to prevent, arrest, treat, and reverse kidney disease caused by diabetes and its devastating consequences.

Diabetes-induced kidney disease typically develops after a diabetes duration of 10 years, or at least 5 years in type 1 diabetes, but may be present at the time of diagnosis of type 2 diabetes (see Chapter 21.1). It is estimated that up to 40% of patients with diabetes will develop kidney disease during the course of their disease.¹ In addition, together with arterial hypertension, diabetes is the most frequent cause of end-stage renal disease in developed countries.²

The evolution, timing, histological presentation, and clinical presentation of kidney disease due to diabetes vary in type 1 and type 2 diabetes. This probably pertains to differences in age and co-morbidities, such as hypertension, dyslipidaemia, and vascular disease that may coexist in different combinations and are maintained by different mechanisms. Hence, histologically, glomerulopathy characterized by thickening of the glomerular basement membrane and mesangial expansion, leading to progressive reduction in the filtration surface of the glomerulus, is the most important structural change in type 1 diabetes,³ whereas non-specific, tubulointerstitial, and vascular changes are more common in type 2 diabetes.⁴

Clinically, these structural changes are reflected by the occurrence of albuminuria and glomerular filtration rate (GFR) reduction. Currently it is believed that both albuminuria and impaired GFR are complementary, overlapping manifestations of kidney disease due to diabetes,⁵ with type 1 diabetes predominantly presenting with a proteinuric phenotype⁶ and as many as 35–57% of patients with kidney disease and type 2 diabetes present with a non-proteinuric GFR loss.⁷ Taken together, albuminuria certainly increases the risk of GFR loss and there are common risk factors for both albuminuria and GFR loss, but these phenotypes may not always evolve together.

Accordingly, modern diabetes care involves annual screening of all patients for the presence of urinary albumin (protein) concentration and calculation of estimated GFR based on standardized serum creatinine measurement (see Chapter 19.5).² Screening is important not only for renal disease detection but also for cardiovascular risk assessment since evidence suggests that a person with a chronically reduced GFR below 60 mL/min/1.73m² is much more likely to die of a cardiovascular event than survive to end-stage renal disease.⁸ Moreover, a recent study demonstrated that patients with chronic kidney disease and type 2 diabetes have much higher death rates for the same level of GFR compared to patients without diabetes.⁹ The increase in cardiovascular event occurrence in kidney disease due to diabetes may be due to common pathophysiological mechanisms that both renal and cardiovascular disease share, including inflammation, oxidative stress, insulin resistance, endothelial dysfunction, arterial calcification, and activation of the renin–angiotensin–aldosterone system (RAAS), among others.

The key risk factors for the development of kidney disease due to diabetes are certainly long-term exposure to hyperglycaemia and increasing age. Interestingly, onset of type 1 diabetes before 10 years of age is associated with the lowest risk of developing end-stage renal disease, indicating the role of sex hormones in shaping the risk of kidney disease due to diabetes. Importantly, traditional risk factors, such as increased blood pressure, smoking, obesity, and dyslipidaemia also markedly increase the risk of kidney damage. Intrauterine growth retardation is also associated with an increased risk of kidney disease due to diabetes, possibly due to a low glomerular filtration area and/or reduced nephron number at birth.¹⁰ Other recently discovered modifiable risk factors include chronic low-grade inflammation, advanced glycation end products, and lack of physical activity.¹¹ Notwithstanding, huge efforts have been put into providing the genetic architecture of diabetic kidney disease, yet much of the inherited predisposition for it remains unexplained.^12,13,14

While usually not much discussed, the kidney is crucially implicated in different aspects of glucose homeostasis. Therefore, the presence of kidney disease can affect glucose levels profoundly (Table 19.11.1) and contributes to the increased risk of hypoglycaemia, even in the absence of diabetes.¹⁵ Hypoglycaemia is not only a very unpleasant experience that can lead to unconsciousness if left untreated: a wealth of evidence today strongly argues that severe hypoglycaemia is associated with an increased risk of cardiovascular events and overall mortality.¹⁶

Although the liver is traditionally seen as the main site for gluconeogenesis, kidneys were found to contribute as much as 40% to the total body glucose production.¹⁷ With renal function decline, renal gluconeogenesis is therefore reduced, which in turn impairs the main defence mechanism against hypoglycaemia.

Together with the liver, the kidney is the principal site also for insulin clearance. After its release from pancreatic beta-cells, insulin levels in the portal circulation are fourfold higher than those in the systemic circulation.¹⁸ The liver then removes about 50% of insulin during the first portal passage, whereas the kidney clears most of the insulin in the systemic circulation, mainly by glomerular filtration and proximal tubular reabsorption and degradation.¹⁹ In healthy individuals, it is estimated that 6–8 U of insulin are removed and degraded by the kidney every day. The role of the kidney in insulin degradation is even more important after exogenous insulin application as it occurs in diabetes, since then insulin concentration is disproportionally higher in the systemic circulation compared to the portal one.

As renal function declines, to maintain renal insulin clearance, peritubular insulin uptake increases first. However, when GFR falls below 15–20 mL/min, peritubular uptake cannot compensate for the reduced insulin filtration and reabsorption anymore and consequently the metabolic clearance rate of insulin falls precipitously.²⁰ Besides, uraemic toxins that start to accumulate during renal function decline, may cause inhibition of the insulin degradation in non-renal tissues, especially in the liver, thus prolonging insulin half-life.²¹

Diminishing kidney function in kidney disease due to diabetes does not play a key role only in insulin clearance but also in clearance of most of other drugs used for the treatment of hyperglycaemia, therefore making glucose control in these patients rather challenging. In the setting of increased hypoglycaemia risk in patients with impaired kidney function, choosing medications that do not increase the risk of hypoglycaemia, such as glucagon-like peptide 1 (GLP-1) agonists, sodium–glucose cotransporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors, is of particular importance.²²

Most chronic nephropathies progress relentlessly to end-stage kidney disease. Even though we are used to think about diabetic kidney disease as a progressive, non-curable disease, this might not exactly be the case. Most chronic nephropathies progress relentlessly to end-stage kidney disease (see chapter 21.1 and 21.2). Indeed, a study with pancreas transplantation in patients with diabetes-induced nephropathy lesions at baseline has shown that 10 years after the transplantation and long-term restoration of normoglycaemia, glomerular lesions had substantially improved, with most patients’ glomerular structure returning to normal.²³

In line with that, the seminal Diabetes Control and Complications Trial (DCCT) that randomized patients with newly diagnosed type 1 diabetes to an intensive insulin-based or conventional glycaemic control arm and followed them for 30 years, revealed that patients with microalbuminuria and even macroalbuminuria can revert to normoalbuminuria.²⁴ Surprisingly, however, regression from microalbuminuria was not associated with a decreased risk of cardiovascular events or estimated GFR reduction, but it may be important to note that most of the regression from microalbuminuria occurred spontaneously even without the use of RAAS inhibition.²⁵

The core of the prevention and management of kidney disease due to diabetes can be figuratively summarized by a ‘five-finger rule’, as outlined in Table 19.11.2.^26,27,28,29 The rationale for kidney disease prevention and treatment is similar and will be covered together, with any important distinction between both specifically highlighted (see also Chapter 21.5).

The fundamental abnormality in diabetes is abnormal glucose metabolism, and the degree of abnormality predicts development of nephropathy (see Chapters 5.10 and 19.5).^30,31 Hence, optimal glycaemic control is crucial for prevention of kidney damage and deterioration in GFR.^31,32 Importantly, seminal studies in both type 1³³ and type 2 diabetes^34,35 have demonstrated a durable positive effect of initial intensive glucose control on renal outcomes despite later loss of the glycaemic separation in the intensive and less-intensive glucose control study arms. Today, accumulating research findings highlight that even transient glucose spikes may suffice to elicit continuous changes in metabolic milieu perpetuating target organ damage.³⁶ Therefore, it is not only average blood glucose mirrored by glycated haemoglobin that affects renal outcomes, but also other parameters of glucose exposure, in particular glucose variability, that may be important in assessment of the role of glycaemic control for target organ damage.³⁷

Yet even though without pancreas transplantation normoglycaemia is not easy to achieve, therapeutic options for patients with diabetes have improved substantially over the last years, with better technology to deliver insulin and monitor glucose levels as well as with new glucose-lowering medications. Even more encouraging are the initial reports showing that besides glucose-lowering effects, some new glucose-lowering medications also have direct beneficial effects on the kidney not mediated through glycaemia. For example, SGLT2 inhibitors reduce intraglomerular pressure, albuminuria, and slow GFR loss through mechanisms that appear independent of glycaemia.^38,39 Some GLP-1 receptor agonists have also been reported to improve renal outcomes, mainly albuminuria, compared with placebo.⁴⁰

Altogether, available evidence suggests that in early diabetes maintaining glucose levels as normal as possible is of utmost importance; however, with advanced kidney disease, optimal glycaemic control level is less clear,⁴¹ with most guidelines recommending target glycated haemoglobin level of approximately 7% but not below 7%.²²

Elevated blood pressure is an important risk factor for the development of kidney disease due to diabetes in both type 1 and type 2 diabetes and the benefit of RAAS blockade for slowing kidney disease progression with or without diabetes is well established (see Chapter 44.7).^42,43,44 Although use of all classes of antihypertensive agents is recommended, RAAS inhibitors represent the standard care in diabetes, mainly due to their renoprotective effects.²⁷

It is well accepted that in hypertensive patients blood pressure lowering is of central importance for slowing GFR loss,⁴⁵ with the current blood pressure target set at below 140/85 mmHg for the majority of patients with diabetes.²⁷ In the case of proteinuria, an even lower blood pressure target may be pursued, with the systolic blood pressure value below 130 mmHg, provided that changes in estimated GFR are monitored regularly.²⁷

In addition, uncertainty still exists whether albuminuria reduction per se would be beneficial in normotensive patients with diabetes.⁴⁶ Even though treatment with an angiotensin-converting enzyme inhibitor prevented progression from normoalbuminuria to microalbuminuria in hypertensive patients effectively,⁴⁷ RAAS inhibition was not beneficial in preventing microalbuminuria in normotensive patients.⁴⁸

Recently, dual RAAS blockade was again receiving some attention, after some studies were advocating its biggest potential to prevent end-stage renal disease in proteinuric patients.⁴⁹ However, current data speak against its use in kidney disease due to diabetes, due to increased rates of hypotension, hyperkalaemia, and acute kidney injury.^50,51

Currently available data support the active role of lipids in the development of kidney disease. In particular, elevated triglycerides, non-low-density lipoprotein cholesterol, apolipoprotein-B-100, or low high-density lipoprotein cholesterol levels are independently associated with the development of diabetic kidney disease (see Chapters 5.9 and 18.6).⁵² However, conventional lipid measurements do not fully account for the complex lipid changes associated with diabetic kidney disease, such as triglyceride enrichment across the lipoprotein particles, increased sphingomyelin levels, and imbalance of different apoprotein levels.⁵³ Statin treatment with or without ezetimibe is the mainstay approach for complex lipid abnormalities present in kidney disease patients.⁵⁴ Statin treatment was also one of the mainstays of the integrated multifactorial treatment in patients with type 2 diabetes and microalbuminuria from the Steno-2 study, demonstrating the importance of early aggressive multifactorial treatment in reducing microvascular as well as macrovascular diabetes complications.⁵⁵ However, in end-stage kidney disease, statins appear to have little effect on major cardiovascular complications.⁵⁶ Additional lipid-lowering therapies and approaches, however, may be needed to fully address the complex lipid abnormalities in diabetes and to prevent their deleterious effects.

Obesity adversely affects the major risk factors associated with kidney disease due to diabetes, including lipid, blood pressure, and glucose control, as well as promoting insulin resistance (see Chapter 16.3). Obesity also has direct effects on the kidney, including changes in intraglomerular haemodynamics, increased sympathetic activity, inflammation, and altered expression of growth factors. Although epidemiological data on the association of body mass index with kidney disease in diabetes gave inconclusive messages, with the Mendelian randomization approach, genetic evidence was provided for a causal link between obesity and diabetic kidney disease in type 1 diabetes.⁵⁷ This finding has widespread and profound consequences as obesity prevalence rises, pointing towards a dramatic increase in the prevalence of diabetic kidney disease unless interventions occur.

On the other hand, physical activity may be an effective tool against obesity. Physical activity, specifically its intensity, may have an impact on the initiation and progression of nephropathy in type 1 diabetes⁵⁸; similarly, results point in the same direction in type 2 diabetes.⁵⁹

Several studies have highlighted that smoking is a risk factor for kidney disease progression and also, that the risk increases with the increasing dose of smoking.⁶⁰ In addition, smoking is strongly associated with an increased risk of cardiovascular disease. Therefore, smoking cessation should be encouraged in every encounter with patients who smoke.

Although chronic kidney disease is common in diabetes and its consequences are grim, large long-term clinical trials have demonstrated that strategies implementing improved blood glucose and blood pressure control retard the development and progression of kidney disease. Indeed, as a result of treatment improvements the natural history of kidney disease due to diabetes has changed over the last decades, prolonging time to end-stage renal disease, and possibly decreasing cardiovascular disease burden at the same time.