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An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines

Diabetic nephropathy (DN) is a major healthcare challenge. It occurs in up to 50% of those living with diabetes, is a major cause of end‐stage kidney disease (ESKD) that requires treatment with dialysis or renal transplantation, and is associated with significantly increased cardiovascular morbidity and mortality. DN is a clinical syndrome characterized by persistent albuminuria and a progressive decline in renal function, but it is increasingly recognized that the presentation and clinical course of kidney disease in diabetes is heterogeneous. The term diabetic kidney disease (DKD) is now commonly used to encompass the spectrum of people with diabetes who have either albuminuria or reductions in renal function. In this article, the clinical presentation and approach to diagnosis of DKD will be discussed, as will its prognosis. The general principles of management of DKD will also be reviewed with reference to current international guidelines.


| INTRODUCTION
Diabetic nephropathy (DN) is a clinical syndrome characterized by persistent albuminuria and a progressive decline in renal function, and the term infers the presence of a typical pattern of glomerular disease.
DN is reported to occur in 20% to 50% of those living with diabetes and is the single commonest cause of end-stage kidney disease (ESKD) in many populations, accounting for 28% of those commencing renal replacement therapy (RRT) in the United Kingdom, 1 with corresponding figures of 44% in the United States and 38% in Australia. 2 DN is typically associated with arterial hypertension and increased cardiovascular morbidity and mortality; outcomes for people with type 1 (T1DM) or type 2 (T2DM) diabetes who develop DN are significantly worse than those who do not. Despite the large and increasing number of people affected by these sometimes devastating consequences, DN is also an area that has seen significant therapeutic advances. Well-evidenced interventions, such as inhibition of the renin-angiotensin-aldosterone-system (RAAS), have contributed to sustained improvements in patient outcomes over the last four decades. 3,4 There is increasing awareness that DN is not always relentlessly progressive, that there is significant variation in individual rates of chronic kidney disease (CKD) progression and that regression of albuminuria is not uncommon. 5 The emergence of newer therapeutic agents, such as the sodium-glucose cotransporter 2 inhibitors (SGLT2i), provide further optimism.
As the first in this series of articles, this article will provide an overview of the diagnosis, prognosis and treatment goals for DN. This will include a discussion of the heterogeneity of kidney disease that can occur in people with diabetes, particularly in T2DM, and how the classical paradigm of DN is not always observed in clinical practice.
Indeed, the term diabetic kidney disease (DKD) is increasingly used to refer to persistent albuminuria or a reduction in eGFR in the setting of diabetes and moves away from connotations of specific underlying renal pathology. When discussing albuminuria, we will follow the recommendations of the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines for CKD, which suggested the use of three categories to describe severity of albuminuria and that the terms micro-and macro-albuminuria should no longer be used. 6 These categories are summarized in Table 1, with urinary albumin-to-creatinine ratio (ACR) values of 3 to 30 mg/mmol or 30 to 300 mg/g (corresponding to micro-albuminuria) referred to as "moderately increased" (A2); and ACR values of >30 mg/mmol (>300 mg/g), corresponding to macro-albuminuria, referred to as "severely increased" (A3).

| Clinical features of DN
The hallmark of established DN is persistent albuminuria (category A3, severely increased), with co-existing retinopathy and no evidence of alternative kidney disease. In T1DM, this definition is highly specific, that is, if these features are present then the histological picture will almost certainly be that of diabetic glomerulopathy. 7 It is rare for DN to manifest in people with T1DM in the first 10 years following diagnosis, but between 10 and 20 years the incidence of DN is approximately 3% per year. Overall, approximately 15% of people with T1DM have severe (A3) albuminuria and a further 15% display moderate (A2) albuminuria. 2 After 20 years, the incidence rate declines so that people with normal renal function and normal urinary albumin excretion after 30 years of T1DM are at lower risk of developing DN. 8 Therefore, the risk of developing DN varies between individuals and is dependent not only on duration of T1DM, but it is also influenced by other factors, such as glycaemic control, blood pressure and genetic susceptibility.
T2DM accounts for 90% of diabetes globally, so the majority of people who develop DN do so because of T2DM. 9 The epidemiology of DN in T2DM shows more variation than in T1DM, with a wider range of reported prevalence rates across different countries and ethnic groups. 2 For example, a cross-sectional study that randomly screened 28 538 people from 33 countries who had T2DM but without known kidney disease reported that the prevalence rates of albuminuria were a third higher in Asian and Hispanic groups (55%) as compared to Caucasians (40.6%). 10 There is likely to be a polygenic component that explains some of this variation between ethnic groups. This is supported by observations of familial clustering of DN and genome-wide association studies that have identified genetic susceptibility loci. 11 There is also greater heterogeneity in T2DM in clinical presentation and in the underlying pathological lesions of DKD. This includes greater variation in the timing between diagnosis of diabetes and development of DN, with up to 3% of those with T2DM having already developed albuminuria at time of diagnosis. This usually results from a period of preceding undiagnosed diabetes or prediabetes, 12 although it can occasionally signify alternative renal pathology. Furthermore, DN occurs without co-existing retinopathy in as many as a third of cases, a scenario that is much more common in T2DM as compared to T1DM. 13,14 Additionally, while the presence of persistent albuminuria with co-existing retinopathy in T2DM indicates DN in the majority of cases, 14 this is not always so. Prospective biopsy studies of T2DM in which kidney biopsies were taken for research (as opposed to clinical reasons that introduce selection bias and increase the risk of finding alternative diagnoses 15 ) have reported that a small proportion (<10%) of those with both severe (A3) albuminuria and retinopathy had non-diabetic forms of kidney disease. 13,16 However, this has not been a universal finding, with other studies reporting 100% specificity for the combination of severe (A3) albuminuria and retinopathy to predict the classical histological appearance of DN. 14 Some of this variation may reflect differences in the epidemiology of DN in T2DM in different populations, but study design, biopsy practice and the generally small sample sizes of studies in which renal biopsy is performed may also contribute. Of greater importance is the growing appreciation of the wider spectrum of renal pathology that underlies DKD in T2DM. In one study of 52 patients with T2DM and clinical features of DN (urine protein excretion 900-9200 mg/24 h, serum creatinine 80-796 μmoL/L [0.9-9 mg/dL], no data on retinopathy), renal biopsy findings varied between those with classical diabetic glomerulopathy (36.5%), predominantly ischaemic changes (30.8%) and another glomerular disease superimposed on DN (32.7%). 17 Similar findings were reported in 34 people with T2DM and moderate (A2) albuminuria, in whom diabetic changes were seen in 10 biopsies (29.4%), ischaemic/fibrotic changes in 14 (41.2%) and minimal pathology reported in the remaining 10 (29.4%). 18

| Histological features of DN
Kidney biopsy is used to make the diagnosis in only a minority of cases of DN, but the typical histological features are described in an international classification system. Classes I to IV are characterized by thickening of the glomerular basement membrane, mesangial expansion, nodular sclerosis (Kimmelstiel-Wilson lesion) and severe glomerulosclerosis, respectively. 19 In addition to these characteristic glomerular features, interstitial fibrosis and tubular atrophy (IFTA), interstitial fibrosis, arteriolar hyalinosis and arteriosclerosis are frequently also present. The pathophysiology of DKD is discussed further elsewhere in this issue of Diabetes, Obesity and Metabolism. which without intervention will progress to more advanced and less reversible stages of kidney disease in a significant proportion of affected individuals. This is also supported by the development of histological lesions of diabetic glomerulopathy by the time that moderate albuminuria is detected (and sometimes even before any clinical manifestations are apparent). 28 However, other data challenge this concept and suggest that the traditional paradigm of an inexorable progression from moderate albuminuria through severe albuminuria to progressive fall in eGFR is not seen in all people with DN. In particular, the rates of regression of albuminuria may be greater than previously appreciated in both T1DM and T2DM. Perkins et al reported regression of albuminuria in 386 people with T1DM and moderate (A2) albuminuria who were evaluated over a 6-year follow-up period. 5 After 6 years, the cumulative incidence of progression to severe (A3) albuminuria was 19% (95% CI 14-23%). Over the same time period, the cumulative proportion of those that regressed to normo-albuminuria was 59% (95% CI 54-64%), an observation that was not explained by RAAS inhibition. In a separate study, regression from moderate (A2) albuminuria to normo-albuminuria in a cohort of T2DM was reported to occur in 23.6% of cases. 29

| Methodological aspects of assessing albuminuria
In addition to varying clinical trajectories, the assessment of albuminuria is made more complex due to marked intra-individual variation in albumin excretion. In a cohort of proteinuric CKD patients who submitted three separate urine samples, the coefficient of variation for ACR was 29.7% (in random samples) and 32.5% (in early morning samples). 30 This variability is also seen with measurements of urine albumin excretion rate, where it is further exaggerated by the challenges of accurate collection of timed or 24-hour urine samples. 31

| Non-albuminuric DKD
It is increasingly recognized that reductions in eGFR can occur in the setting of normal urinary albumin excretion in both T1DM and T2DM. 36,37 In general, non-proteinuric CKD often points towards aetiologies that are ischaemic in nature or in which tubulo-interstitial pathologies predominate. 38,39 However, non-proteinuric DN has also been described in association with the typical histopathological changes of diabetic glomerulopathy. 40 41 The lower risk of CKD progression or the development of ESKD in non-albuminuric DKD vs DN with significant albuminuria has been reported in a number of other studies. 43,44 However, this should not mask that the development of non-albuminuric DKD is a significant risk factor for death and major cardiovascular events compared to those without kidney disease; again risks are even greater when albuminuria is also present. 45 There are several possibilities that may explain the occurrence of non-proteinuric DN. These include co-existing vascular disease or tubulo-interstitial fibrosis that in fact are the dominant processes, that eGFR decline has resulted from previous episodes of AKI (either recognized or subclinical) or that albuminuria has been reduced by RAAS inhibitors. 46 The challenge of diagnosing DN is F I G U R E 1 Schematic of a clinical approach for the diagnosis of diabetic kidney disease (DKD). * indicates ACR = urinary albumin creatinine ratio, albumin excretion rate is also appropriate. AKI, acute kidney injury; RAAS, reninangiotensin-aldosterone system further illustrated by an autopsy study in which 20 of 106 (19%)  uncertainty. This approach to diagnosis is summarized in Figure 1.

| Features that may indicate alternative forms of kidney disease
Non-diabetic forms of kidney disease may be suggested by the following: • Atypical trajectory of eGFR decline or onset of albuminuria. Rapid declines in eGFR (>5 mL/min/year) or sudden onset of albuminuria are not typical of DN, nor is severe albuminuria in the first 5 years of T1DM. Looking at serial eGFR trends will help to identify previous episodes of AKI, which are increasingly recognized to be associated with CKD onset and progression. [49][50][51] • Very severe albuminuria (ACR > 300 mg/mmol or > 3000 mg/g) or nephrotic syndrome. Although DN is a well-recognized cause of nephrotic syndrome, primary glomerular disease is more likely in this setting, particularly when the nephrotic syndrome has an acute onset.
• Active urinary sediment. Non-visible haematuria is not a classical finding in DN but can occur. The presence of haematuria on urinalysis is not particularly helpful and has poor ability to discriminate between diabetic and non-diabetic kidney disease with a c-statistic of only 0.59 (0.54-0.63). 52 However, the presence of red cell casts or dysmorphic red cells on urine microscopy is much more likely to signify an alternative pathology, typically a glomerulonephritis.
• Diagnosis of or clinical features that are suspicious for another systemic disease that commonly causes kidney disease (e.g., connective tissue disorders, HIV).
• Family history of non-diabetic forms of kidney disease.

| Differential diagnoses to consider in the setting of non-albuminuric DKD
Although non-albuminuric DN is well described, this presentation should prompt evaluation for the following: • Ischaemic nephropathy. Suggested by vascular disease elsewhere, smoking history, hypertension, aortic disease or asymmetric kidneys on renal ultrasound. Sometimes, this scenario is incorporated under the umbrella term of DKD (ie, without renal biopsy), and several of the risk factors for ischaemic nephropathy are very common in people with diabetes. Renovascular disease can also be suggested by large (>30%) declines in eGFR after initiation of RAAS inhibitors.
• Dysproteinaemia-related renal disease. There are a variety of renal diseases associated with dysproteinaemias that are initially screened for with serum electrophoresis and assay of serum free light chains. This includes monoglonal gammopathy of renal significance, defined as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin, but does not meet the treatment criteria for a specific haematological malignancy. 53 • Previous episodes of AKI. reported incidence rates of ESKD of between 2.2 and 4.1 events/100 person-years. 63 In T2DM, variation in reported rates of CKD progression and incidence of ESKD is also seen. In a prospective observational study, Rossing et al followed 227 people with T2DM and severe (A3) albuminuria for an average of 6.5 years (minimum follow up 3 years), in whom GFR was measured annually with Chromium-EDTA clearance. 64 The mean decline in eGFR was −5.2 mL/min/ year, but a standard deviation of 4.1 mL/min/year suggests that the distribution of eGFR change encompassed declines of as much as  Table 2.

| Lifestyle measures
Non-pharmacological interventions are an essential component of any strategy to improve outcomes in patients with DKD and should include weight loss, increased physical activity, reduction in dietary sodium intake and smoking cessation. Unfortunately, these goals are notoriously difficult to achieve; it is essential for patients to be encouraged to be actively involved in their own management and to receive support in achieving mutually agreed treatment goals.

| Lipid lowering and CV risk reduction
The onset of kidney disease in people with diabetes portends a significant increase in the risk of cardiovascular mortality, and as such aggressive risk factor modification is warranted in all patients. This includes smoking cessation and lipid lowering; the importance of blood pressure lowering is discussed later. There is ongoing debate as to whether lipid lowering therapy has a direct benefit in slowing the progression of DN. In CKD, it has been suggested that hyperlipidaemia may contribute to glomerulosclerosis, and while some studies have suggested that lipid lowering may help to preserve eGFR or reduce albuminuria this has not been conclusively proven. [73][74][75] In reality, the point may be slightly academic as patients should receive lipid lowering therapy for cardiovascular risk reduction, and it is a component of combination therapy that has been shown to improve outcomes in the Steno-2 trial (discussed later). 76-78

| Glycaemic control
Improving glycaemic control has beneficial effects upon the development and progression DN. The DCCT randomized 1441 people with T1DM to intensive insulin therapy (target HbA1c <6.05%, achieved 7.3%) or standard therapy (achieved HbA1c 9.1%). 79  for an additional 4 years. 80 Long-term outcome assessment has also shown that intensive insulin treatment slowed eGFR decline and reduced the proportion of people who developed a persistent reduction in eGFR to <60 mL/min/1.73 m 2 (50% risk reduction with intensive therapy). 81  Albuminuria is defined as urine albumin excretion >30 mg/day or equivalent (urine albumin-to-creatinine ratio > 3 mg/mmol or > 30 mg/g).
In T2DM, the evidence is a little more mixed. The United Kingdom Prospective Diabetes Study (UKPDS) randomized 3867 people to intensive control (using oral agents or insulin), or to diet control only. There was a smaller separation in HbA1c levels between the study arms (7.0% vs 7.9%), and while overall events were improved in the intensive arm, differences were not observed in development of moderate or severe albuminuria or doubling of serum creatinine. 83 More positive results were reported from the ADVANCE trial, which randomized 11 140 people with T2DM to intensive (HbA1c 6.5%) or standard (HbA1c 7.3%) glycaemic control. 84  including worsening of renal function, ESKD, cardiovascular events or mortality. 85 Conversely the ACCORD trial, which randomized 10 251 people to intensive or standard glycaemic control, was discontinued early due to higher mortality in the intensive therapy arm and no evidence of benefit elsewhere. 86 In summary, intensive glycaemic control can reduce the risk of the onset of DN and slows its progression when it has occurred, although does so at the expense of more hypoglycaemic events.
This appears true for both types of diabetes although the evidence is clearer in T1DM, and the benefit of more intense glycaemic control seems to decrease at more advanced stages of DKD. receiving RAAS inhibitors, 87 and are now recommended in ADA Guidelines, "SGLT2i should be considered for patients with type 2 diabetes and CKD who require another drug added to metformin to attain target A1C or cannot use or tolerate metformin" 32 and the EASD Guidelines. 33 It should be noted that the renoprotective effects of SGLT2i are largely independent of their hypoglycaemic effects.
These agents will not be discussed in more detail here as they are the focus of specific editorials elsewhere in this edition of Diabetes, Obesity and Metabolism.  66 The composite endpoint of a doubling of serum creatinine, ESKD or death was reduced by 16% in the losartan group, who also had significantly lower incidence of doubling of serum creatinine and ESKD when these endpoints were assessed individually. The risk of hospitalization with heart failure was also reduced.
Similar results have been replicated in Asian populations, 95  However, it has not been shown that reductions in albuminuria with diltiazem or verapamil result in improved outcomes. There is broad consensus between guidelines that in people with diabetes and albuminuria, BP should be lowered to <130/80 mmHg to achieve optimal renal and cardiovascular protection (Table 2), though in those prone to postural hypotension a less stringent target should be considered.
Dietary salt restriction can also be an effective component of blood pressure treatment, and the ADA guidelines suggest daily sodium intake of <2300 mg. 32

| Combined interventions
In clinical practice, people with diabetes should be assessed and man- There are few data examining similar approaches in T1DM. 105 A final consideration is implementation of interventions that have been shown to be effective in trials into "real-life" clinical practice. A number of observational studies have reported how this can be challenging, how there are differences between individuals in how easily treatment targets can be attained, and that failure to achieve treatment goals is associated with higher rates of DKD progression. 106,107

| SUMMARY
Diabetic kidney disease is a major healthcare challenge, complicating the course of many people who live with diabetes, and is a major cause of ESKD. The presence of DKD is also strongly associated with CV events and has a major influence on survival. Its presentation and prognosis are heterogeneous and vary between individuals, with nonalbuminuric DKD and high rates of regression of albuminuria examples of this, while the severity of albuminuria, particularly when combined with elevated blood pressure, remains an important marker of those at higher risk of progression. Management of DKD requires a holistic approach that combines cardiovascular risk reduction with elements to slow the progression of kidney disease, namely glycaemic control, RAAS inhibition and blood pressure lowering. Effective delivery of these interventions in combination reduces the risks of DKD progression, as well as other microvascular complications, cardiovascular events and mortality. Several international groups have issued clinical guidelines that largely agree on recommended targets, and in clinical practice these should be tailored for each individual patient.