Diabetic kidney disease (DKD) occurs in approximately 30% of patients with type 1 diabetes (T1DM) and 40% of patients with type 2 diabetes (T2DM). It is the leading cause of end-stage kidney disease (ESKD) in the Western populations, contributing to almost 50% of all cases. But there have been advances in the diagnosis and treatment of diabetic kidney disease, especially related to glycemic monitoring and targets and the use of antihyperglycemic therapies.
Diabetic kidney disease encompasses all forms of kidney disease in a patient with diabetes and not necessarily just the classic diabetic nephropathy. DKD is defined as any decline in glomerular filtration rate (GFR) or presence of albuminuria or both, whereas the classical diabetic nephropathy is defined by the presence of albuminuria (traditionally with concomitant diabetic retinopathy). We no longer use the term micoralbuminuria, but moderately increased albuminuria for albumin creatinine ratio 30-300 mg/g or albumin excretion rate 30-300 mg/day, to stress the importance of albuminuria as a predictor of adverse renal and cardiovascular events and to not diminish its significance by using the term ”micro.” Macroalbuminuria has been replaced by severely increased albuminuria – >300 mg/g.
Glycemic control in diabetics can be assessed by the HbA1c measurement, self-monitoring of blood glucose (SMBG) and/or continuous glucose monitoring (CGM). Early intensive diabetes control is associated with a lower risk of long-term diabetic microvascular complications (microalbuminuria), decrease in the development of impaired GFR and hypertension, and mortality.
An HbA1c goal of <7% is recommended by the American Diabetes Association (ADA) for most patients, with lower goals (<6.5%) based on provider judgment and patient preference. Higher targets (<8%) are recommended for those with advanced CKD, established macrovascular complications, limited life expectancy, hypoglycemic unawareness and risk of medication-induced hypoglycemia. HbA1c assessment may be inaccurate in certain conditions, such as in the presence of hemoglobin variants and use of erythropoietin stimulating agents as in advanced CKD.
SMBG and CGM should be implemented in patients with markedly labile blood glucose values who are more prone to hypoglycemic events and in patients who require intensive insulin regimens to optimize glucose control while minimizing hypoglycemia. CGM metrics like Time-In-Range (TIR), Time-Below-Range (TBR) and Time-Above-Range (TAR) may be used in place of HbA1c as glycemic targets. With the use of CGM, the ADA recommends a goal TIR of >70% as a parallel goal to HbA1c. Another new measure is the glucose management indicator (GMI), which estimates A1C from mean CGM glucose using at least 10 days of data.
While several classes of antihyperglycemic agents are available, there are two newer agents that have cardiorenal benefit.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i)
The most important of the newer classes of antihyperglycemic drugs are the sodium-glucose cotransporter-2 inhibitors (SGLT2i). SGLT2i work on the sodium-glucose cotransporter-2 in the proximal tubule and inhibit renal tubular glucose and sodium reabsorption, thereby inducing euglycemia. It reduces intraglomerular pressure albuminuria, oxidative stress and inflammation in the kidney, and ultimately decreases the risk of CKD progression and CVD events. Additionally, they cause modest volume contraction, systemic blood pressure reduction and weight loss.
Major adverse effects are diabetic ketoacidosis, lower extremity amputations, recurrent urinary tract infections and genital mycotic infections. They can cause an initial decrease in GFR due to hemodynamic effects, but this is usually reversible and rarely needs therapy discontinuation. Several large cardiovascular outcomes trials such as EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 that examined renal effects as secondary outcomes and recent trials like CREDENCE and DAPA-CKD that focused on primary renal outcomes, have shown that long-term use of SGLT2i is associated with the preservation of GFR. Canagliflozin can be used in patients with reduced GFR (above 30 ml/min/1.73m2). Dapagliflozin has been studied in populations with eGFR down to 25 ml/min/1.73m2 and has also shown efficacy in non-diabetic CKD.
The use of an SGLT2i is recommended by KDIGO, the ADA the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) for patients with T2DM and DKD with eGFR >30 ml/min/1.73m2 and urinary albumin/creatinine of >300 mg/g. ADA guidelines recommend that when an additional agent is required to be added to metformin or metformin cannot be used or tolerated, an SGLT2i or GLP-1RA should be considered. Unless contraindicated, KDIGO recommends using metformin along with an SGLT2i as the first-line therapy in patients with T2DM and CKD.
For patients not meeting their glycemic targets despite using other antihyperglycemic agents and who can tolerate further lowering of HbA1c, KDIGO suggests adding an SGLT2i. For patients meeting their glycemic target or who are at risk of hypoglycemia with further lowering of A1c, agents other than metformin can be reduced to allow the addition of SGLT2i.
Glucagon-like peptide-1 receptor agonists (GLP-1RA)
Glucagon-like peptide-1 receptor agonists (GLP-1RA) stimulate the incretin hormone pathway and thereby enhance the glucose-dependent insulin secretion, suppress post-prandial glucagon release, slow the gastric emptying and improve satiety through effects on the central regulation of feeding. Independent of the glucose-lowering effects, GLP-1RAs also have direct reno-protective effects. These agents inactivate sodium-hydrogen exchanger 3 in the brush border of the renal proximal tubular cells and promote secretion of atrial natriuretic peptide, thereby inducing natriuresis and diuresis and thus improving blood pressure.
In large cardiovascular outcomes trials like ELIXA, LEADER, SUSTAIN-6 and REWIND, GLP1-RAs have shown beneficial renal effects including preservation of eGFR and prevention of worsening albuminuria. The ADA recommends using an SGLT2i or GLP-1RA with cardiovascular benefit in patients with established atherosclerotic CVD, established kidney disease or heart failure. KDIGO also recommends using a long-acting GLP-1RA as an agent of choice in patients who cannot achieve their glycemic target despite the use of metformin and SGLT2i.
Efficacy of SGLT2i in improving glycemic control is reduced at eGFR <45 ml/min/1.73m2. To achieve additional glycemic control at that level, a long-acting GLP-1RA should be considered. The medications, liraglutide, semaglutide and dulaglutide are minimally cleared by kidneys and, therefore, do not require any dose adjustment even with eGFR as low as 15 ml/min/1.73m2. For T2DM patients who need the addition of an injectable agent on top of oral agents to achieve their glycemic target, the ADA recommends preferred use of GLP-1RA over insulin.
Intensive blood pressure lowering in patients with DKD reduces mortality and prevents cardiovascular morbidity; in addition, more intensive blood pressure lowering may prevent end-stage kidney disease (ESKD) in patients with severely increased albuminuria (measured or estimated urine albumin excretion >300 mg/day). Target BP is <120-125/80.
Spironolactone, a steroidal mineralocorticoid receptor antagonist and a newer nonsteroidal selective mineralocorticoid receptor antagonist, Finerenone, reduced the progression of kidney function impairment and cardiovascular events in patients with type 2 diabetes and DKD by reducing inflammation and fibrosis. As of February 2021, Finerenone has not been FDA approved.
A Note on Hyperkalemia
Two new medications have become available for the treatment of hyperkalemia that have allowed for the continued use and titration of angiotensin-converting enzyme inhibitor (ACEi)/Angiotensin receptor blocker (ARB) and mineralocorticoid receptor antagonist (MRA) for the management of albuminuria in DKD. Gastrointestinal cation exchangers – patiromer (Veltassa) and sodium zirconium cyclosilicate (Lokelma) are nonabsorbable compounds that exchange calcium or sodium and hydrogen, respectively. Sodium polystyrene sulfonate is no longer recommended as chronic therapy. In fact, sodium polystyrene sulfonate (Kayexalate) is discouraged due to risk of intestinal necrosis. Sodium zirconium cylosilicate (Lokelma) is in fact more rapid acting and works within the first 4 hours of ingestion.