Diabetic kidney disease in pediatric patients: A current review

Table 1 Risk factors for diabetic kidney disease development

Non-modifiable	Modifiable
Small/young age at DM onset	Poor glycemic control
Diabetes duration	Glucose variability: Hypo/hyperglycemia
Puberty	Overweight/obesity
Family history of diabetic complications and insulin resistance	Dyslipidemia
Genetic factors	High blood pressure
Race/ethnicity	Microalbuminuria
	Smoking, alcohol
	Intrauterine exposure (maternal diabetes, obesity)
	Low birth weight

DM: Diabetes mellitus.

Table 2 Diabetic kidney disease stages

Stage	Estimated period	Characteristics	GFR	BP	Biomarker-albuminuria	Biomarker UACR mg/mmoL
1 = hyperfiltration	From diabetes onset to 5 yr	Glomerular hyperfiltration and hypertrophy. No ultrastructure abnormality. A 20% increase in renal size. ↑Renal plasma flow	N/increased	N	Normoalbuminuria < 30 mg/g	< 2
2 = silent	From 2 yr after onset	Mild GBM thickening and interstitial expansion	N	N	Normoalbuminuria < 30 mg/g	< 3
3 = incipient	5–10 yr after onset	More significant changes vs stage 2. Moderate tubular and GBM thickening and variable focal mesangial sclerosis	GFR–N or mild decreased	Increasing BP; +/- hypertension	Microalbuminuria appears Albuminuria 30-300 mg/g	2-20
4 = overt	10-15 yr after onset	Marked GBM thickening and variable focal mesangial sclerosis	GFR-decreased < 60 mL/min/1.73 m2	BP↑	Macroalbuminuria > 300 mg/g	> 20
5 = uremic		Diffuse glomerulosclerosis, ESRD	GFR-marked decreased < 15 mL/min/1.73 m2	BP↑	Decreasing albuminuria

UACR: Urinary albumin to creatinine ratio; GBM: Glomerular basement membrane; GFR: Glomerular filtration rate; BP: Blood pressure; ESRD: End-stage renal disease; ↑: Increase; N: Normal.

Table 3 Normal glomerular filtration rate limit at different ages according to KDOQI Guidelines[66] and Hogg et al[67]

Age	Gender	Normal GFR
1 wk	Males and females	41 ± 15 mL/min/1.73 m2
2–8 wk	Males and females	66 ± 25 mL/min/1.73m2
> 8 wk	Males and females	96 ± 22 mL/min/1.73 m2
2–12 yr	Males and females	133 ± 27 mL/min/1.73 m2
13–21 yr	Males	140 ± 30 mL/min/1.73m2
13–21 yr	Females	126 ± 22 mL/min/1.73m2

GFR: Glomerular filtration rate.

Table 4 Renal biomarkers of diabetic kidney injury[21,43]

Biomarkers
Traditional biomarkers	Traditional biomarkers of glomerular injury	Albumin/creatinine ratio eGFR	Lack of specificity and sensitivity	(1) Predict the late stages of DKD; (2) Daily variation in urine albumin/creatinine ratio; and (3) eGFR values may be affected by the patient’s hemodynamics, diet and hydration status
Novel biomarkers	Glomerular biomarkers	NF-α, transferrin, Type IV collagen, L-PGDS, IgG, ceruloplasmin, laminin, GAGs, fibronectin, podocalyxin, VEGF	Appear before microalbuminuria	Early predictor of DKD
	Tubular biomarkers	α-1-microglobulin CysC; KIM-1; NGAL; nephrin; NAG; L-FABP; VDBP; CypA; s-Klotho	Appear before/precede microalbuminuria	(1) Are more sensitive vs new glomerular biomarkers; (2) Early predictors of DKD; and (3) Predictor of DKD progression
	Biomarkers of inflammation	Cytokines: TNF-α, IL-1β, IL-18, interferon gamma-IP-10, MCP-1, adiponectin, G-CSF, eotaxins, RANTES or CCL-5, orosomucoid	(1) Precede a significantly increased albuminuria; (2) Correlate positively with albumin excretion rate and intima-media thickness; and (3) May trigger direct renal injury	Predictor of DKD progression
	Biomarkers of oxidative stress	Urinary 8oHdG Pentosidine		Predict the development of DKD

L-PGDS: Lipocalin-type prostaglandin D synthase; IgG: Immunoglobulin G; GAGs: Glycosaminoglycans; CysC: Cystatin C; KIM-1: Kidney injury molecule 1; 8oHdG: 8-oxo-7,8-dihydro-2-deoxyguanosine; RANTES: Regulated on activation, normal T cell expressed and secreted; G-CSF: Granulocyte colony-stimulating factor; MCP-1: Monocyte chemoattractant protein 1; IP-10: Induced protein-10; TNF-α: Tumor necrosis factor α; IL: Interleukin; CypA: Cyclophilin A; VDBP: Vitamin D-binding protein; L-FABP: Liver-type fatty-acid binding protein; NAG: N-acetyl-β-D-glucosaminidase; NGAL: Neutrophil gelatinase-associated lipocalin; DKD: Diabetic kidney disease; eGFR: Estimated glomerular filtration rate; VEGF: Vascular endothelial growth factor; CCL-5: Chemokine ligand 5T.

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.