Diabetic Nephropathy and Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and world-wide. Alterations in glomerular hemodynamics, inflammation, and fibrosis are primary mediators of kidney tissue damage, although the relative contribution of these mechanisms likely varies between individuals and over the course of the natural history of diabetic kidney disease. The presence of DKD is also strongly associated with cardiovascular morbidity/mortality and has a major influence on survival. Clinical presentation and prognosis of DKD are heterogeneous and vary between individuals, although 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 glycemic 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 tai-lored for each individual patient. SGLT2 inhibitors are exciting new options now available to slow the progression of diabetic nephropathy.


Introduction
Diabetic kidney disease and diabetic nephropathy are the leading cause of chronic kidney disease (CKD) end-stage kidney disease (ESKD) in the United States and

Diabetic Nephropathys vs. Diabetic Kidney Disease
"Diabetic nephropathy" is a diagnosis that refers to specific pathologic structural and functional changes seen in the kidneys of patients with DM (both type 1 and type 2 Diabetes Mellitus [T1/T2DM]) that result from the effects of DM on the kidney. Clinically it is characterized by persistent albuminuria and a progressive decline in renal function, and the term infers the presence of a typical pattern of glomerular disease.
"Diabetic kidney disease" (DKD) is a clinical diagnosis based upon the presence of proteinuria, decrease estimated glomerular filtration rate (eGFR), or both in diabetes. It does not indicate a specific pathological type. It can be from many diverse causes, including hypertensive nephrosclerosis and unresolved acute kidney failure. The likelihood that "diabetic nephropathy" is the cause of diabetic kidney disease varies widely depending upon the clinical circumstances. It is highly likely that diabetic nephropathy is the cause of diabetic kidney disease in type 1 diabetes of five or more years duration with albuminuria, but the frequency can range widely in type 2 diabetes.

Epidemiology
The risk for the development of diabetic nephropathy has a genetic component that is likely polygenetic. The prevalence of diabetic nephropathy varies among racial and ethnic groups such that African Americans, Native Americans, and Mexican Americans have increased risk as compared with European Americans.
The disparity in DKD disease among minority populations could also be explained in large part by socioeconomic status, which is tightly intertwined with educational attainment. Albuminuria and decreased eGFR (<60 mL/min/1.72m 2 ) is more common among individuals with lower education level, even after controlling for sociodemographic and clinical factors [3]. Although an argument can be made that barriers to care are a major contributor to this discrepancy in prevalence, it is likely not the sole factor, and genetic differences potentially also play a role. The apolipoprotein 1 (APOL1) gene has been found to explain some of the racial disparity in nondiabetic ESKD but it has not born out as a causative factor for diabetic kidney disease among African Americans. However, APOL1 variants are associated with an increased risk for progression of diabetic kidney disease in African Americans [4]. Familial studies have also demonstrated clus- with T1/T2DM and diabetic nephropathy have substantially more risk for developing diabetic nephropathy than those without an affected relative. This familial clustering has also been well documented in the Pima Indian population [5]. Ongoing efforts to identify specific genetic factors and genes associated with the development of diabetic nephropathy are ongoing. Several candidate genes, including glucose transporter 2, transforming growth factor β, and endothelial nitric oxide synthase, have been identified, isolating a definitive causal pathway has proved to be elusive because there is no simple mendelian inheritance, and the interplay of several genes is likely involved and may differ between populations.

Pathophysiology
Hyperglycemia results in production of advanced glycation end-products (AGE) and reactive oxygen species [6]. While hyperglycemia undoubtedly plays a central role, hyperinsulinemia and insulin resistance also may incite pathogenic mechanisms, possibly accounting for variation in histopathology between type 1 and type 2 diabetes. Ultimately, alterations in glomerular hemodynamics, inflammation, and fibrosis are primary mediators of kidney tissue damage, although the relative contribution of these mechanisms likely varies between individuals and over the course of the natural history of diabetic kidney disease [7] [8].
The pathophysiology leading to the development of diabetic nephropathy and resultant end-stage kidney disease follows from the diabetic milieu leading to the generation and circulation of advanced glycation end products, elaboration of growth factors, and hemodynamic and hormonal changes. These lead to the release of reactive oxygen species and inflammatory mediators. Collectively, these changes result in glomerular hyperfiltration, glomerular hypertension, renal hypertrophy, and altered glomerular composition, which is manifested clinically as albuminuria and hypertension [9]. Pathologically, the kidneys undergo several changes, including deposition (in primarily the mycangium) of extracellular matrix, glomerular basement membrane thickening, proliferative changes, and tubular atrophy, ultimately resulting in interstitial fibrosis and glomerulosclerosis (the final common pathway of many kidney diseases).
With the onset of DM, kidney size and weight increase by an average of 15%, and this size increase remains even after progressive reductions in kidney function occur. An examination of kidney tissue reveals thickening of the glomerular basement membrane and expansion of the mesangium. The classic pathologic lesion of diabetic nephropathy is nodular in nature and was first described by

Natural History of Diabetic Nephropathy
The natural history of diabetic nephropathy in patients with T1DM was initially characterized in patients with juvenile-onset DM in the late 1970s by examining death records of patients who were classified as having died of kidney failure.
This study helped us understand the true untreated natural history of diabetic nephropathy due to T1DM as it was before the advent of therapy for diabetic nephropathy [11]. Based on this study, proteinuria appears 11 to 23 years after the T1DM diagnosis, serum creatinine concentration begins to increase after 13 to 25 years, and ESKD develops after 18 to 30 years. With the subsequent development of more sensitive assays to detect urinary albumin excretion, small amounts of albumin in the urine were noted to precede the development of overt proteinuria in most patients, occurring 5 to 10 years after the diagnosis of DM [12].
Presently, microalbuminuria and macroalbuminuria are referred to as A2 and A3, respectively (Table 1), by the KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease (CKD) guideline [13]. The natural history of diabetic nephropathy in patients in longitudinally studied populations with T2DM is essentially identical to that in patients with T1DM, though the timing of diabetes onset in patients with T2DM is difficult to assess. Therefore, a patient may even present with proteinuria and on kidney biopsy have diabetic nephropathy before T2DM is diagnosed. Another important difference in the natural history of patients with T1 versus T2DM is that the major macrovascular complication, namely cardiac disease and death due to cardiac disease, can occur at any point along the course of a patient with T2DM from the onset of DM and early diabetic nephropathy, whereas the elevated risk for cardiovascular disease is not apparent until advanced kidney disease has developed in patients with T1DM [14].
The classic study by Kussman et al in patients with T1DM allows one to picture a timeline of kidney disease progression that starts with microalbuminuria and proceeds sequentially through stages of overt proteinuria, kidney function decline, and ultimately end-stage kidney disease [11]. Multiple studies of diabetic nephropathy progression over the years have confirmed this timeline and the critical role of proteinuria assessment both as a diagnostic criterion for the presence of diabetic nephropathy and for the assessment of disease severity and likelihood of progression. The single biggest predictor of kidney function deterioration and diabetic nephropathy progression is proteinuria [15]. When the loss of kidney function has begun, as evidenced by an increasing serum creatinine concentration or a declining estimated glomerular filtration rate (eGFR), the

Clinical Approach to Diagnosis of Diabetic Nephropathy
In many cases, Nephropathy is a clinical diagnosis. A kidney biopsy is the gold standard test for diagnostic and prognostic information, but in most centers is usually only performed when an alternative renal pathology is suspected.

Screening
DKD usually does not cause symptoms, so guidelines from the ADA and KDIGO group recommend that kidney function and albuminuria should be measured at diagnosis and annually thereafter in T2DM and in type 1 DM recommendation is to start screening from 5 years after diagnosis [13] [17]. Albuminuria is best assessed using ACR measurements on spot urine samples (ideally early morning samples); timed or 24-hour urine collections to measure albumin excretion are also appropriate although less convenient and more prone to collection errors.
Renal function should be assessed using a serum-creatinine based eGFR calculation (CKD-EPI equation recommended due to its superior performance in the eGFR range 60 -90 mL/min/1.73m 2 ).

Confirmation of Persistent Abnormalities
If a reduction in eGFR or an increase in albuminuria is detected, this should be confirmed on repeat testing over 3 to 6 months; a minimum of two elevated ACR levels more than 3 months apart are required before an individual is con-  [13]. This is to differentiate from transient changes as well as to account for the intra-individual variation that is seen in ACR. Similarly, two eGFR values below 60 mL/min/1.73m 2 at least 90 days apart are required to make a diagnosis of CKD.

Diagnosis of Diabetic Nephropathy
The approach to a patient with DM and evidence of kidney disease must center on the determination of whether the patient's kidney disease is diabetic nephropathy or another kidney disease. The natural history and progression timeline discussed earlier will greatly aid the clinician in determining the likelihood that a given patient's disease is diabetic nephropathy in individuals with T1DM [10].
The development of significant albuminuria before 5 years' or after 25 years' duration of T1DM decreases the likelihood of diabetic nephropathy [11]. Additionally, 95% of patients with T1DM and diabetic nephropathy also have diabetic retinopathy, so the absence of retinopathy may imply a diagnosis other than diabetic nephropathy [18]. Seven-field fundus photos must be obtained to eliminate the presence of retinopathy and prompt kidney biopsy because a dilated ophthalmologic examination is insensitive. In T1DM, a clinical diagnosis of DKD can be made when there is persistent moderate (A2) or severe (A3) albuminuria or a persistent reduction in eGFR to <60 mL/min/1.73m 2 , occurring at least 5 years after onset of diabetes. In over 95% of cases, diabetic retinopathy will also be present, and there should be no clinical suggestions of alternative kidney disease. Albuminuria is not required to make a diagnosis of DKD in the setting of a persistently reduced eGFR, but this clinical scenario should prompt consideration of other forms of non-albuminuric kidney disease, as should albuminuria in the absence of retinopathy.
Diagnosis of DN in patients with T2DM is more challenging because these epidemiologic clues are not as helpful. Diabetic retinopathy is concordant with diabetic nephropathy in only about 60% to 65% of cases; thus, its absence does not generate a high negative predictive value for the diagnosis of diabetic nephropathy [19]. Also, because the onset of T2DM is generally unknown, one cannot as reliably use the natural history timeline to assist in diagnosis [20]. Thus, it is really important to assess whether something other than DM is the cause of kidney disease. This evaluation will typically involve a thorough history and physical examination and selected laboratory and imaging tests to determine whether a kidney biopsy would be of benefit. There is no formal practice guideline on when to pursue kidney biopsy in patients with DM. Prospective kidney biopsy studies have illustrated that if a patient with DM has retinopathy (T1DM), onset of proteinuria in the usual timeframe (T1DM), and no evidence to support another disease (T1/T2DM), an alternative diagnosis that would substantially alter therapy is unlikely to be found [18]. Therefore, it is not surprising that most patients with DM and reduced kidney function do not undergo kidney biopsy. In T2DM, the clinical diagnosis can be more challenging due to the in-

Features That May Indicate Alternative Forms of Kidney Disease
Non-diabetic forms of kidney disease may be suggested by the following: 1) 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 [21] [22].
2) 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.
3) Active urinary sediment. Microscopic hematuria is not a classical finding in DN but can occur. The presence of hematuria on urinalysis is not particularly helpful and has poor ability to discriminate between diabetic and non-diabetic kidney disease [23]. 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.

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: 2) Dysproteinemia-related renal disease. There are a variety of renal diseases associated with dysproteinemias that are initially screened for with serum electrophoresis and assay of serum free light chains. This includes monoclonal 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 hematological malignancy [24].
4) Tubulointerstitial nephritis (TIN), classically associated with eosinophilia and urinary leukocytes but can present with normal urinary sediment. TIN is often due to medications (e.g., non-steroidal anti-inflammatory drugs, proton-pump inhibitors, antibiotics, diuretics), and a careful medication history to establish temporal links between initiation of culprit medications and onset of eGFR decline can be useful. Diagnosis requires kidney biopsy.

Treatment of Diabetic Nephropathy
Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, BP control, and inhibition of the RAS and emerging therapies including SGLT-2 inhibitors. Each of these arenas will be discussed with a focus on an optimal evidence-based approach to care of patients with diabetic nephropathy.

Cardiovascular Risk Reduction
Patients with diabetic nephropathy necessarily have DM and thus cardiovascular disease risk is significant and a competing risk for kidney failure. Therefore, it is important to ensure that aggressive risk factor modification is undertaken, usually in partnership with the patient's primary care physician. Components of this therapeutic approach include tobacco cessation and lipid-lowering therapy. Evidence of cardiovascular disease risk reduction for both tobacco cessation and lipid lowering is abundant though, it is outside the scope of this review.

Glycemic Control
The effect of improved glycemic control on clinical outcomes, including pro-  [26]. Given the benefits seen with the intensive control arm in the DCCT, all participants were advised to remain or convert to intensive control.
Thus, glycemic control as measured by HbA 1c concentration converged to 7.8% and 7.9% for the former conventional and former intensive control groups, respectively. Despite this convergence, the development of microalbuminuria and overt proteinuria was reduced (53% and 86%, respectively) by intensive control over 4 additional years of follow-up. Thus, the beneficial effects of glycemic control on microvascular complications are significant and durable in patients with T1DM.
The available data for patients with T2DM are more ambiguous. In the United Kingdom Prospective Diabetes Study (UKPDS), participants were randomly assigned to intensive glycemic control using oral agents and/or insulin or to conventional therapy (diet control) [27]. The achieved mean HbA 1c concentration was 7.0% in the intensive control arm compared to 7.9% in the conventional arm. Participants in the intensive control arm saw a reduction in any DM-related end point, but a reduction was not seen for specific kidney events of interest, namely the development of microalbuminuria, overt proteinuria, or doubling of serum creatinine concentration. Three more recent large trials with an aggregate enrollment of nearly 25,000 participants were conducted to assess any potential benefit of intensive glucose control in T2DM: ADVANCE (Action in Diabetes and Vascular Disease), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and VADT (VA Diabetes Trial) [28] [29] [30]. These studies targeted and achieved HbA 1c concentrations of ~6.0% relative to a control arm of ~7.0%. Results of these studies are decidedly mixed, with either no benefits on cardiovascular effects ranging to cardiovascular risk in the intensive group and no kidney benefit, with the exception of 1 trial showing a reduction in albuminuria but no benefit on the preservation of kidney function. All 3 trials established increased risk for hypoglycemic events related to intensive glycemic control to HbA 1c concentrations of near 6.0%. Intensive glycemic control to an HbA 1c concentration of 7.0% prevents microvascular (not macrovascular) complications (UKPDS). However, it is unclear whether any further HbA 1c concentration reduction is of utility, particularly for preventing kidney disease outcomes.
Based on the available evidence (Table 2), target goal HbA 1c concentration should be close to 7.0% to reduce microvascular complications and diabetic nephropathy progression. Any further reduction is of unproven benefit and would likely put the patient at risk for hypoglycemic events. This is congruent with current American Diabetes Association and KDOQI clinical practice guidelines.

Blood Pressure Control
Hypertension has been linked to the development of microalbuminuria, overt  The study noted a decrease in the development of microalbuminuria and overt proteinuria in the intensive BP group, but was unable to demonstrate a benefit on creatinine clearance, the primary outcome of the trial [33]. The ACCORD trial tested the hypothesis that more intensive BP control (systolic BP < 120 mm Hg) would be of benefit relative to standard BP therapy (systolic BP < 140 mm Hg), with 4733 patients participating in this randomized trial [34]. The achieved systolic BPs at 1 year of follow-up were widely separated, at 119.3-and 133.5-mm Hg in the 2 groups. It took on average 3.5 BP medications to achieve this BP goal in the intensive therapy group versus 2.3 BP medications in the standard therapy group. The study found no reduction in the rate of the primary composite cardiovascular outcome associated with either BP goal. Intensive BP control was associated with a reduction in albuminuria, but no reduction was seen in end-stage kidney disease events. ACCORD trial was not powered to detect renal events because the trial population was a more general cohort with DM rather than one selected for diabetic kidney disease. Increased risk for acute kidney injury events requiring dialysis therapy along with other adverse events attributed to antihypertensive therapy were also seen in the intensive BP control arm.
Based on the current evidence, it is clear that BP reduction is important in the management of patients with diabetic nephropathy [35]. Cardiovascular and kidney event rates are higher with increasing BP and are reduced progressively with therapy to lower BP. There may be a point beyond which further BP reduction may not be helpful or even be harmful despite a reduction in proteinuria [36].

RAS Inhibition
RAS blockade using various drugs, including ACE inhibitors, ARBs, direct renin inhibitors, and mineralocorticoid antagonists have shown efficacy in animal models of diabetic nephropathy across the full spectrum of DM-related injury. In humans, RAS inhibition has proved to be the single most effective therapy for slowing the progression of diabetic nephropathy. These agents have been studied at each clinical stage of diabetic nephropathy, and we review those data here. IDNT randomly assigned 1715 participants to irbesartan, amlodipine, or placebo with follow-up for a mean of 2.6 years. BP was targeted at <135/85mm Hg and was achieved with agents in classes other than those under study [41]. Independent of BP control, irbesartan reduced the risk for the composite outcome of doubling of serum creatinine concentration, end-stage kidney disease, or death as compared to amlodipine or placebo. The RENAAL trial followed up 1513 patients with T2DM and overt proteinuria for a mean of 3.4 years and demon-  [40]. Taken together, these studies provide robust evidence supporting the benefit independent of BP control of RAS-blocking medication on slowing the progression of diabetic nephropathy.
Although these trials showed a dramatic benefit with ARB therapy, many participants on ARB therapy still had renal events, which raised the question for trials to assess further therapy and drug development to derive further benefit.
The question of therapy with multiple agents that block the RAS was addressed in 3 large clinical trials. The first was ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint), a cardiovascular outcomes trial that randomly assigned 25,620 patients with cardiovascular disease risk to ramipril, telmisartan, or both. There was no difference among the 3 arms in the composite cardiovascular outcome [42]. mg, daily or losartan, 100 mg, daily plus placebo. This trial was terminated early due to an increase in adverse events (acute kidney injury and hyperkalemia) in the combination therapy arm [43]. ALTITUDE (Aliskiren Trial in T2DM Using Cardio-Renal Endpoints) tested whether dual RAS blockade with Aliskiren and either an ACE inhibitor or an ARB reduced cardiovascular and kidney events.
This trial was also terminated early due to an increase in adverse events and no apparent benefit in the dual-therapy group [44].
The current evidence (Table 3) strongly supports the use of RAS-blocking agents in the treatment of patients with diabetic nephropathy. Although RAS blockade with more than 1 agent may be effective in reducing proteinuria, the adverse-event profile (hyperkalemia, acute kidney injury, and increased cardiovascular events) and the lack of benefit in preventing end-stage kidney disease preclude its general use for the treatment of diabetic nephropathy.

Emerging Therapies
Sodium glucose cotransporter 2 (SGLT2) inhibitors are relatively new medications that have been approved for the treatment of diabetes. Their mechanism of action is to block glucose and sodium uptake in the proximal tubule, thereby generating natriuresis and glucosuria [45].   [47]. In these cardiovascular outcome trials, the SGLT2 inhibitors had positive effects on kidney outcomes, namely albuminuria reduction and a reduction in the occurrence of a composite renal outcome. In the EMPA-REG Outcome trial, the HR in the empagliflozin arm for incident or worsening nephropathy (a composite of the development of albuminuria with albumin excretion > 300 mg/g creatinine, doubling of serum creatinine accompanied by eGFR ≤ 45 mL/min, initiation of renal replacement therapy, or death from renal causes) was 0.61 (P < 0.001) [46]. CANVAS demonstrated a benefit of similar magnitude (HR, 0.60) on a composite outcome of a sustained 40% reduction in eGFR, need for renal replacement therapy, or death from renal causes [47].

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.