DIABETIC KIDNEY DISEASE

Hector Castro, MD

No conflicts of interest

Diabetic kidney disease

• Definition and terminology

• Epidemiology

• Risk factors

• Natural history

• Pathophysiology

• Diagnosis

• Management

Definition and terminology

• Definition: Clinical diagnosis based on the presence of albuminuria, decreased eGFR or both in diabetic patients

• Diabetic nephropathy (DN) or diabetic kidney disease (DKD): Classic diabetic glomerulopathy versus various other forms of kidney disease in diabetes including nonclassical glomerular lesions and tubulointerstitial disease. There is no uniform criteria or accepted definitions to differentiate DN from DKD

• Moderately increased albuminuria (microalbuminuria): 30-300 mg/g or mg/day

• Severely increased albuminuria (macroalbuminuria): >300 mg/g or mg/day

• Decreased eGFR: <60 mL/min (CKD-EPI or MDRD formulas)

Epidemiology

• Since the 1950s, kidney disease has been clearly recognized as a common complication of DM

• Leading cause of CKD and ESRD worldwide (30-50% of ESRD population). In the United States, more than 58,000 people have ESRD attributed diabetes (50%)

• DKD develops in approximately 30% of patients with DM1 and 40% of patients with DM2

Epidemiology

• The increasing prevalence of DKD parallels the worldwide rising prevalence of DM2. In 2015, the International Diabetes Federation estimated that approximately 440 million people had diabetes (8.8% of world's adult population); by 2035, the prevalence is projected to increase to over 550 million

• In the US, the prevalence of DM has increased over the last 20 years from 6 to 10%

• DM2 in the youth is now and well-recognized result of the global pandemic of obesity. It leads to earlier renal complications and with a more rapid rate of progression than in DM1

Epidemiology

• The severity and incidence of diabetic nephropathy are especially great in African-Americans, Native Americans, and Mexican Americans

• Nephropathy is the strongest mortality predictor in patients with DM. The majority of patients actually die from CV disease and infections before reaching ESRD

• The incidence of ESRD among patients with DKD is relatively uncommon because most die before requiring RRT

Risk factors

• Complex disease with a polygenetic component and multiple phenotypes

• Susceptibility factors: Age, sex, race/ethnicity, family history

• Initiation factors: Hyperglycemia, AKI

• Progression factors: Hypertension, dietary factors, obesity

• Familial studies have demonstrated clustering of DKD. Patients with DM with a first-degree relative with diabetic nephropathy have substantially more risk for developing DKD than those without an affected relative

Risk factors

• Hyperglycemia

In normoalbuminuric patients with DM, poor glycemic control is an independent predictor of development of proteinuria and/or ESRD

• Hypertension

Studies have linked high blood pressure to the development of microalbuminuria, overt proteinuria, and declining kidney function, with higher BP associated with worse outcomes in a continuous fashion

Pathophysiology

Structural changes

Natural history

• Classic pattern of glomerular hyperfiltration progressing to microalbuminuria and later overt proteinuria associated with hypertension and declining eGFR

• The paradigm of the natural history of DKD continues to evolve. In many patients DKD does not follow the classic pattern

• Recent reports have noted that up to 25% of patients with DM2 and low kidney function have little or no proteinuria

• Some patients develop functional impairment without havingpreceding albuminuria

Natural history

Natural history

• Rarely develops before 5 years of duration of DM1

• Peak incidence in persons who have had diabetes for 10-20 years

• Diabetic patients with no proteinuria after 20-25 years have low risk of developing overt renal disease later in life (1% per year)

• Approximately 3% of newly diagnosed patients with DM2 have overt nephropathy

• The single stronger predictor of kidney function deterioration and DKD progression is proteinuria

Natural history

Diagnosis

• The clinical diagnosis of DKD is made on the basis of measurement of eGFR and albuminuria along with clinical features, such as diabetes duration and presence of retinopathy

• Screening for DKD should be performed annually for patients with DM1 beginning 5 years after diagnosis and annually for all patients with DM2 beginning at the time of diagnosis

• The preferred test for albuminuria is a urinary albumin-to-creatinine ratio performed on a spot sample, preferably in the morning

Diagnosis

• In patients with albuminuria, the presence of diabetic retinopathy is strongly suggestive of DKD

• Retinopathy is concordant with DKD in 95% of patients with DM1 and 60-65% of patients with DM2

• The development of significant albuminuria before 5 years or after 25 years of duration of DM1 decreases the likelihood of DKD

Diagnosis

• The approach to a patient with DM and kidney disease must center on the determination of whether the patient’s kidney disease is DKD or another condition

• Atypical features of DKD include sudden onset of low eGFR or rapidly decreasing eGFR (greater than 5-7 mL/min/year), abrupt increase in albuminuria or development of nephrotic or nephritic syndrome (dysmorphic RBCs or cellular casts), refractory HTN, signs or symptoms of another systemic disease, and >30% eGFR decline after initiation of a RAS inhibitor

• Kidney biopsy is rarely done to confirm the diagnosis; most commonly used to rule out an alternative diagnosis

Diagnosis – Potential serum biomarkers

• Albuminuria, especially within the moderately increased range, although an important risk marker, lacks the specificity and sensitivity to optimize the stratification of patients at risk for the development and progression of DKD

• Serum neutrophil gelatinase-associated lipocalin (NGAL) and beta-trace protein (βTP) as tubular and glomerular markers respectively, may be independent biomarkers for early detection of DKD

• Circulating microRNA-130b (miR-130b) has been implicated in the development of DKD and may serve as a potential biomarker for the identification of patients at risk of developing DKD

Management

Management

• Glycemic control

• Blood pressure control

• RAS inhibition

• Cardiovascular risk reduction

Management – Glycemic control

• Intensive blood glucose control early in the course of disease results in a long-lasting favorable effect on the risk of developing DKD (“legacy effect” or “metabolic memory”) for DM1 and newly diagnosed DM2 patients

• The beneficial effects of glycemic control on microvascular complications are significant and durable in patients with DM1

• For DM2 patients with established DKD fewer supportive data is available. Based on large trials with an aggregate enrollment of nearly 25,000 participants it is unclear if intensive glucose control (A1c target ~6%) offers additional renal benefit

Management – Glycemic control

• The risk of hypoglycemia with intensive glucose control is greater in patients with decreased eGFR

• Both the KDIGO and KDOQI guidelines recommend an A1c target of about 7.0% to prevent or delay progression of the microvascular complications of diabetes

• Individuals with multiple co-morbidities, limited life expectancy, and at risk for hypoglycemia should not be treated to an A1c target of <7.0%

Management – Blood pressure control

• Based on the current evidence, it is clear that BP reduction is important in the management of patients with DKD

• Cardiovascular and kidney event rates are higher with increasing BP and are reduced progressively with therapy to lower BP

• In general, antihypertensive therapy, irrespective of the agent used, slows the progression of DKD, particularly when lowering of systemic blood pressure is accompanied with concomitant lessening of glomerular capillary pressure

Management – Blood pressure control

• Use of ACEi or ARB is recommended for patients with DKD and increased albuminuria. ACEi and ARBs are considered to have similar effects on lowering blood pressure and decreasing albuminuria

• Initial antihypertensive therapy should be with either ACEi or ARB, but not both simultaneously. Combination antihypertensive therapy will be needed for most patients, a non-dihydropyridine CCB may be preferred for patients with severely increased albuminuria

• Antihypertensive agents, including RAS blockers, are not indicated for primary prevention of DKD in normotensive normoalbuminuric patients

Management – Blood pressure control

• Intensive blood pressure control is recommended. KDIGO guideline suggests a target blood pressure of 140/90 mm Hg or less for all for all diabetic patients, and 130/80 mm Hg or less for patients with moderately or severely increased albuminuria and DM

• There may be a point beyond which further BP reduction may not be helpful or even be harmful despite a reduction in proteinuria. Some trials have shown that kidney benefit reaches a plateau at SBP <130 mm Hg, whereas all-cause mortality increases at SBP <120 mm Hg

Management – RAS inhibition

• RAS inhibition has proven to be the single best evidence-based therapy for slowing the progression of DKD

• RAS blockade using various agents, including ACEi, ARBs, direct renin inhibitors, and MRAs has shown efficacy in animal models of DN across the full spectrum of DM-related injury

• Early therapy in patients with DM1 is ineffective in preventing the development of moderately increased albuminuria

• RAS blockade may prevent the development of moderately increased albuminuria in patients with DM2

Management – RAS inhibition

• RAS blockers have shown to reduce the risk of progression of DKD from microalbuminuria to overt proteinuria, and also from overt proteinuria to doubling of SCr, RRT, or death

• In general, treatment with RAS inhibitors reduces the rate of eGFR decline from 7-12 mL/min per year to 3-6 mL/min per year

• It is well established that the efficacy of RAS blockers is independent of BP control in slowing the progression of DKD

• Although RAS blockade with more than 1 agent may be more effective in reducing proteinuria, the adverse even profile (hyperkalemia, AKI, and increased CV events) and the lack of benefit in preventing ESRD preclude its use for the treatment of DKD

Management – SGLT2 inhibitors

• In 2001, the IDNT and RENAAL trials confirmed the kidney benefits ofRAS inhibition, leading to the FDA approval of ARBs for the treatment ofDKD

• Subsequent clinical trials have been modeled on the idea of a RAS blocker as standard of cafre plus an additional agent to forestall the progression ofDKD

• Multiple therapies targeting various proposed molecular mechanisms ofinjury, including glomerular hyperfiltration, inflammation, fibrosis, and extracellular matrix deposition, have been attempted with only marginal success

Management – SGLT2 inhibitors

• Since 2008, the FDA has mandated that all new glucose-loweringagents undergo long-term CV outcome trials to demonstrate safety

• Of the newer classes of glucose-lowering agents, the sodium-glucosecotransporter 2 inhibitors (SGLT2i) have shown in large RCTs toconsistently reduce the risk of CV outcomes, including atheroscleroticCV events and hospitalization for heart failure

• Secondary analyses of these CV outcome trials unexpectedly reportedbenefits on albuminuria, eGFR decline and ESRD

Management – SGLT2 inhibitors

• Most participants in these CV safety trials were at low risk of ESRD and thus the effect of SGLT2i on the most important kidney outcome(the need for RRT) was uncertain

• The Canagliflozin and Renal Events in Diabetes with EstablishedNephropathy Clinical Evaluation (CREDENCE) trial was designed tospecifically address this evidence gap

• The CREDENCE trial enrolled 4401 DM2 patients with eGFR 30-90 mL/min and albuminuria >300 mg/g despite treatment with an ACEi or ARB

Management – SGLT2 inhibitors

Management – SGLT2 inhibitors

• Canagliflozin reduced the risk of the primary outcome (doubling of serum creatinine, ESRD, or death from kidney or CV causes) by 30% compared with placebo

• Adverse events were similar overall in the 2 groups, with no significant differences in the risk of lower limb amputation or the rates of fracture

• CREDENCE demonstrated that addition of canagliflozin to standard of care provided substantial kidney and CV protection in DKD

• Two other trials to address the kidney effects of other SGLT2i on DM patients with overt DKD are undergoing (DAPA-CKD and EMPA-KIDNEY)

Management – SGLT2 inhibitors

• Indicated for DN patients with severely increased albuminuria despite angiotensin inhibition, and independently from glycemic control

• Typically added to the patient’s existing hypoglycemic regimen since these drugs have weak glucose-lowering effect, particularly in patients with reduced kidney function

• Avoid start in patients with eGFR <30 mL/min

• Avoid in patients with prior amputation or current threat of amputation

• Monitor fluid status with concomitant use of loop diuretics

• Not appropriate for use in DM1 patients with DN

Management – Other interventions

• Patients with DKD are at particularly high risk of CV events, and most have a higher risk of CV death than developing ESRD

• It is important to ensure aggressive CV risk factor modification

• Components of this therapeutic approach include tobacco cessation, lipid-lowering therapy, and diet

• Dietary sodium (<2.4 g/day) and protein restriction (0.6 to 0.8 g/kg/day) is recommended for DKD patients, with a target of around 1,600 kcal per day in which 60% comes from carbohydrates and 40% from proteins

Management – Key recent advances

• A SGLT2i is now indicated to preserve kidney function and to prevent ESRD, hospitalization for CHF and CV death in DKD

• GLP1 receptor agonists are emerging as effective agents for glycemic control, ASCVD risk reduction and eGFR preservation, even in patients with advanced stages of DKD

• Endothelin blockade is another promising therapeutic approach for DKD when applied after safety assessment for volume retention, irrespective of initial albuminuria reduction

• Vitamin D and omega-3 fatty acids are ineffective in preventing loss of kidney function or ESRD in patients with DKD

• Allopurinol did not slow eGFR decline despite effective uric acid lowering in patients with DM1 and DKD

Management – Novel treatment approaches

• Low-intensity shockwave therapy (LI-SWT)

• Suggested as a therapy for promoting tissue regeneration

• Phase 1 prospective, single-arm study using LI-SWT in 14 patients with stage III CKD and DM. Each patient received 6 sessions over 3 weeks. Follow up visits at 1, 3 and 6 months

• Overall the treatment was well tolerated with transient microscopic hematuria in 3 patients and non-sustained flank pain in most subjects

• At 6-month follow up there was a trend of improvement in eGFR and a reduction of albuminuria, although not statistically significant

Additional therapeutic considerations

• 30-45% of insulin is metabolized and cleared by the kidneys. As kidney function drops, insulin lasts longer, putting patient at risk for hypoglycemia

• Metformin does not cause kidney disease or kidney falure, but it is contraindicated in patients with eGFR <30 mL/min due to riskof severe lactic acidosis

• RAS blockers have a robust indication in the treatment of proteinuric CKD, including DKD. However, monitoring of eGFR and potassium should be done upon initiation or up-titration of RAS blockers; and dose reduction, temporarly withholding, or discontinuation should be considered in most cases of AKI and/or hyperkalemia

Take-home points for clinical practice

• Screen for DKD with eGFR and UACR yearly starting at time of diagnosis of DM2 and 5 years after diagnosis of DM1

• Focus management on control of BP, proteinuria, and glycemia along with lifestyle modification to prevent CV disease

• BP target 130/80 or less in the presence of albuminuria. Use ACEi or ARB but avoid combination of RAS blockers

• A1c target 7%. Watch for hypoglycemia. Discontinue metformin if GFR <30 mL/min

• Use SGLT2i for DM2 patients with DKD with eGFR >30 and severely increased albuminuria despite RAS inhibition

• Early preparation for renal replacement therapy with dialysis access planning. High risk of primary AVF failure

Thank you