Diabetic kidney disease in pediatric patients: A current review

Table 5 Common and new therapeutic strategies in diabetic kidney disease

Therapy	Drug class	Aim	Mechanism of action	DKD result/effect	Dose adjustment to eGFR (mL/min/1.73 m2)
Conventional therapies
Strict glycemic control (Insulin)	-	HbA1c < 7%	(1) Reduces the risk of microalbuminuria; and (2) Reduces progression of microalbuminuria to macroalbuminuria	Delay DKD progression/risk	GFR = 10–50: Reduce the dose to 75%; GFR < 10: Reduce dose to 50%
Dietary protein/phosphate restriction	-	↓High protein intake	(1) Reduces hyperfiltration; and (2) Slows down/delays the loss of function or progression of diabetic nephropathy in T1DM and T2DM	Lower DKD risk	No restriction. CKD stage 3: 100%-140% of the DRI. CKD stage 4-5: 100%-120% of the DRI
Weight loss, increased physical activity	-		(1) Reduces hyperfiltration; and (2) Reduces albuminuria, especially in moderate/severe obesity	Lower DKD risk	No
Antihypertensive therapy	(1) ACEI/ARB/calcium-channel blockers; and (2) ACEI/ARB + calcium-channel blockers	Control of BP	(1) Reduces albuminuria and delays the onset of DN; (2) Prevents progression of DN in microalbuminuric patients; and (3) Reduces the frequency of microalbuminuria in hypertensive normoalbuminuric cases	Delay DKD progression	ARB, calcium channel blockers: No adjustment ACEI: GFR 30-60: Reduce dose to 50%; GFR < 30: Stop
Treatment of Dyslipidaemia	(1) Atorvastatin; (2) Fluvastatin; and (3) Osuvastatin	Reduce LDL-C	Reduce albuminuria in patients with DKD receiving RAAS blockers	Reduces CV disease/risk	No
Psychological Intervention	(1) Family therapy; (2) Cognitive behavioral therapy; (3) Motivational interviewing; (4) Counselling; (5) Mentoring; and (6) Peer support	Reduce depression	Follow lifestyle adjustment regimens and achieve optimal glucose levels	Delay DKD progression	No
Novel therapies
Vitamin D analogues	Paricalcitol. Calcitriol		(1) Ameliorates nephropathy by reducing the albuminuria; and (2) Prevent glomerulosclerosis	Delay DKD progression	No
Vitamin D metabolites			Inhibit RAAS and prevent glomerulosclerosis	Delay DKD progression/risk	No
Uric acid antagonist	Allopurinol	Uric acid antagonist/xanthine oxidase inhibitor	(1) Reduces urinary TGF-β1 in diabetic nephropathy; (2) Reduces albuminuria in T2DM; and (3) Improves endothelial dysfunction	Delay DKD risk/progression	GFR > 50: No adjustment. GFR 30-50: Reduce dose by 50%. GFR < 10: Reduce dose to 30%, longer interval
Renin inhibitor	Aliskiren	Block RAAS cascade	Reduces albuminuria and serves as an antihypertensive in T2DM	Delay DKD progression	No
Endothelin antagonist or I inhibitor ETA receptor antagonist	Atransetan, avosentan, sparsentan (irbesartan + ETA)		(1) Reduces residual albuminuria in type 2 diabetic nephropathy; (2) Reduces proteinuria in T2DM patients and nephropathy; and (3) Significant proteinuria reduction	Delay/slow DKD progression	Yes
MRA Mineralocorticoid Receptor Antagonists	Spironolactone = nonselective MRA. Eplerenone	↑Natriuresis	Reduce albuminuria and blood pressure in patients with DN when added to a RAAS inhibitor	Delay DKD risk/progression	GFR > 50: No dose adjustment. GFR 30-50: Reduce dose to 25%, once daily. GFR < 10: No use
SGLT2 inhibitors	Empagliflozin, canagliflozin	Glucose-lowering	(1) Improves glycaemic control, reduces fasting blood glucose and HbA1c by increasing urinary glucose excretion; and (2) Reduces the reabsorption of sodium	Delay DKD progression, reduces blood pressure	No
GLP-1 agonist	Liraglutide, semaglutide	Stimulates insulin secretion, ↑satiety	Improves glycaemic control	Delay DKD risk/progression	No
	Exenatide, lixisenatide	Stimulates insulin secretion	Improves glycaemic control	Delay DKD risk/progression	Caution in CrCl < 50 mL/min
DDP-4 inhibitors	Linagliptin, saxagliptin, vildagliptin	Glucose-lowering-preserve the glucagon-like peptide effect	Reduce albuminuria in macroalbuminuric T2DM patients	Delay DKD risk/progression	eGFR < 50 mL/min: Reduce dose by 50%; eGFR < 30 mL/min: Reduce dose by 75%
TZD Thiazolidinediones	Rosiglitazone. Pioglitazone	↓Hepatic glucose production activate peroxisome proliferator-activated receptor-γ to increase tissue insulin sensitivity	(1) Reduce albuminuria in macroalbuminuric T2DM patients; and (2) Lower microalbuminuria and proteinuria	Delay DKD risk/progression	No
Aldosterone synthase (CYP11B2) inhibition		Decrease in plasma aldosterone levels		Delay DKD risk/progression	NL
Anti-inflammatory Compounds
CCR2 Antagonists		Emapticap pegol (NOX-E36), CCX-140	Reduces UACR and HbA1c	In T2DM-delay DKD, DN risk/progression	NL
VAP-1 inhibitors	An adhesion molecule for lymphocytes, regulating leukocyte migration into inflamed tissue	ASP-8232	Reduces albuminuria in T2DM in CKD	Delay DKD risk/progression	NL

ETA: Endothelin type A; T2DM: Type 2 diabetes mellitus; DKD: Diabetic kidney disease; UACR: Urine microalbumin to creatinine ratio; HbA1c: Glycated hemoglobin; GFR: Glomerular filtration rate; RAAS: Renin-angiotensin-aldosterone system; eGFR: Estimated glomerular filtration rate; ↓: Decreased; T1DM: Type 1 diabetes mellitus; CKD: Chronic kidney disease; DRI: Dietary reference intake; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; BP: Blood pressure; DN: Diabetic nephropathy; LDL-C: Low-density lipoprotein cholesterol; CV: Cardiovascular; TGF-1: Transforming growth factor 1; MRA: Mineralocorticoid receptor antagonists; SGLT-2: Sodium-glucose cotransporter-2; GLP-1: Glucagon-like peptide 1; CrCl: Creatinine clearance; DPP-4: Dipeptidyl peptidase 4; TZD: Thiazolidinediones; NL: Not listed; CCR2: Chemokine receptor 2; VAP-1: Vascular adhesion protein 1.