Complications in Diabetes Mellitus: Bench to Bedside Manoj Chadha
INDEX
Page numbers followed by f refer to figure, fc refer to flowchart, and t refer to table.
A
Acute kidney injury 3, 11
history of 18
Advanced glycation end products 12, 13, 43, 44
Afferent arteriolar hyalinization 14
Albumin
excretion rate 21
to-creatinine ratio 17, 21
twenty-hour urine collection for 30
Albuminuria 1, 2, 4, 7, 20, 23, 40, 44
Alpha-glucosidase inhibitor 26, 27
American Diabetes Association 20, 25, 35
American Society of Nephrology 35
Amlodipine 30, 31
Anemia 2
Angiotensin
converting enzyme inhibitor 22, 41
receptor blockers 22
Ankle, swelling of 1
Antidiabetic drugs 28, 28t
Apararenone 42
Atherosclerotic cardiovascular disease 26
high risk of 27
Atrasentan 42
Avosentan 42
B
Bardoxolone methyl 42
Baricitinib 42
Blood
glucose control 18
pressure 12, 30, 41
control 29
goal 29
high 2, 33
measurement of 15
systolic 29
sugar, uncontrolled 33
vessels disease 33
Body
mass index 30
weight 35, 41
C
Canagliflozin 42
Carbohydrate 33, 35, 36
Cardiovascular disease 6, 33
Cell injury, progression of 12
Chemokine
cytokine inhibitors 43
ligand 2 inhibitor 44
Chronic high blood glucose 24
Chronic kidney disease 2, 10, 17, 21, 25, 26, 34, 41
classification of 8f
nutritional management of 35
screening for 20
stages of 7t
D
Dapagliflozin 42
Diabetes Control and Complications Trial 12
Diabetes mellitus 4, 14, 17, 18, 22, 24, 34, 35, 39, 40
family history of 18
gestational 18
global prevalence of 1
long duration of 18
natural history of 21t
prevalence of 1
type 1 4, 10, 14, 16, 20, 41
type 2 4, 10, 14, 16, 17, 26, 30, 40, 43
vascular complications of 15
worldwide prevalence of 10
Diabetic kidney disease 4, 5t, 10, 11, 15, 17, 18, 18t, 20, 22, 24, 3436, 3941, 42t, 43
biomarkers of 19f, 41f
classification of 7
development of 2
diagnosis of 17, 19
dietary management in 33t
evolution of 21f
family history of 11, 18
food pyramid of 34f
glycemic management in 24, 25, 26fc
management of 32
natural history of 14, 5f
new drugs in 29t
pathology of 13fc, 40
pathophysiology of 10
prevalence of 32
progression of 1
risk factors of 3t, 11t
screening of 15, 20, 20fc
sodium intake in 36
treatment 43
newly approved drugs for 41
Diabetic nephropathy 10, 15fc, 22, 22t, 43
future therapies of 43
management of 39
manifestation of 15
progression of 6, 6f
Dietary
management 35t
protein intake 33, 35
sodium intake 37
Dipeptidyl peptidase-4 26
inhibitor 27, 43
Dipstick proteinuria 15
Dyslipidemia 2, 4, 18
E
Empagliflozin 31, 42
Endoplasmic reticulum 44
Endothelial cell dysfunction 12
Endothelin receptor antagonists 29, 42
Energy 36
Estimated glomerular filtration rate 17, 19, 20, 22, 2528, 30, 34, 41, 43
Ethnicity 18
Excess sodium retention 12
Extracellular matrix 13
deposition of 13
F
Fat 35, 36
Fatty acid 34
Febrile conditions 23
Fibrin cap 14
Fibroblast growth factors 19
Fibrosis, tubulointerstitial 40
Finerenone 42
G
Glimepiride 30, 31
Glomerular basement membrane 5, 14, 40, 41
thickening of 13
Glomerular filtration rate 4, 5, 7, 7t, 8f, 15, 21, 25, 34, 40
Glomerular hyperfiltration 13, 15, 18
progression 1
Glomerular lesions, diffuse 14
Glomerulosclerosis 10
Glucagon-like peptide-1 28, 42, 43
analog 42
receptor agonist 26, 27
Glycemic control 26
Growth factors 12
H
Heart
disease 33
failure 26, 27
decompensated congestive 23
Hematuria 22
Hemoglobin, glycated 3, 12, 19, 25
Hepatitis, viral 22
High protein intake 3, 11
High sodium intake 3
Hyperglycemia 13, 11, 15, 24
severe 23
sudden 23
Hypertension 24, 11, 12, 15, 18, 24, 30, 34
accelerates 6
family history of 18
glomerular 13
management of 31
severe 23
sudden 23
Hypertrophy, renal 13
Hypoglycemia 27
I
Incretins 28
Insulin 27
resistance 18
Intensive glycemic control 12
International Diabetes Federation 35
Interstitial fibrosis 10, 14
Intrauterine growth retardation 18
J
Janus kinase 44
signal transducer and activator of transcription 43
K
Kidney
biopsy 45
cells of 24
disease 33
chronic 2, 10, 17, 21, 25, 26, 34, 41
diabetic 4, 5t, 10, 11, 15, 17, 18, 18t, 20, 22, 24, 3436, 3941, 42t, 43
end-stage 25
family history of 18, 33
genetic 3, 11
improving global outcomes 25
nondiabetic 22
outcomes quality initiative 25
injury 3, 25
acute 3, 11
molecule 19, 41
protection 28
structure, abnormal 33
vasculature of 24
Kimmelstiel–Wilson nodules 14, 40
Korean Diabetic Association 25
L
Legs, swelling of 1
Lipid nephrotoxicity hypothesis 4
Lipoprotein, high-density 19
Liraglutide 42
Liver-type fatty acid-binding protein 19
Low-protein diet 37
M
Macroalbuminuria 6
Menstruation 23
Mesangial expansion 12, 40
Mesangiolysis, segmental 4
Mesenchymal stem cells 45
Metabolic syndrome 1, 18
Metformin 30
Microalbuminuria 4, 6, 14, 15, 18
Mineralocorticoid receptor antagonists 29, 43
Molecular biology discoveries, application of 44
Monounsaturated fatty acid 34, 36
Morning sickness 2
Myeloma 22
N
National Kidney Foundation 7, 7t, 8, 35
Nephropathy
diabetic 10, 15fc, 22, 22t, 43
ischemic 22
nondiabetic 22, 22t
stages of 7f
Nephrosclerosis, hypertensive 22
Nephrotic syndrome 6
Neuropathy, peripheral 30
Neutrophil gelatinase-associated lipocalin 19
Nicotinamide adenine dinucleotide phosphate oxidases 43
Nodular glomerulosclerosis 14
N-terminal pro-B-type natriuretic peptide 19
Nuclear factor-2 erythroid related factor 44
Nutritional therapy 37
O
Obesity 14, 11, 18, 33
Oral contraceptives, use of 18
Oxidative stress 12
triggering of 12
P
Periodic acid-Schiff stain 14
Pharmacotherapy 27
Pigment epithelium-derived factor 19
Pirfenidone 42
Polyunsaturated fatty acid 34, 36
Pro-adrenomedullin, mid-regional fragment of 19
Protein 35
kinase C 25
urine dipstick for 30
Proteinuria 6, 15, 18, 22
Pyridoxamine 42
R
Renal artery stenosis 22
Renal disease, end-stage 1, 5, 10, 15, 21, 34, 35, 39
Renal failure 6, 22
Renal replacement therapy 10
Renin–angiotensin–aldosterone system activation 12
S
Saturated fatty acid 34
Sclerosis, glomerular 14
Semaglutide 42
Serum uric acids 41
Sodium 35
glucose cotransporter-2 26, 28, 43
inhibitors 27, 28, 41, 42
Soluble tumor necrosis factor receptors 19
Stem cell therapy 44
Sulfonylurea 26, 27
Sympathetic nervous system activation 12
Systemic lupus erythematosus 22
T
Telmisartan 30, 31
Thiazolidinedione 2628
Toxins 3, 11
Tubular atrophy 13
Tubule-interstitium 40
Tumor necrosis factor receptor 1 41
U
Urinary tract infection 23
Urine albumin-to-creatinine ratio 30
V
Vitamin D, deficiency of 18
W
Weight gain 1
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Burden, Risk Factors, Challenges, and Natural History1

Bibin Jose,
Ashpak Patel,
Amit Atul Kothari
 
SUMMARY
There has been a significant rise in the global prevalence of diabetes mellitus (DM). It is important to diagnose and manage DM early as it could result in progression of diabetic kidney disease (DKD). DM is responsible for >50% cases of end-stage renal disease (ESRD). ESRD is associated with high mortality rates.1
In India, the prevalence of DKD is increasing and is around 34.4%.2 It is important that the risk factors are monitored and kept in control, to control the increasing numbers of DKD. Various risk factors have been attributed to the development of DKD. However, increased albuminuria and hyperglycemia are the most significant of the risk factors. The understanding of DKD has changed over the years owing to new studies which points toward the structural changes. To guide the diagnosis better, the international pathological classification of glomerular changes in DKD places a significant role on diagnosis as DKD as all patients do not show the same classic pattern of glomerular hyperfiltration progression.
 
INTRODUCTION
The prevalence of DM is increasing globally because of increased rates of obesity, metabolic syndrome, and lifestyle changes.1 One of the microvascular complications of DM is DKD. Early diagnosis and management of DM could slow progression of DKD.1 The condition is also known as diabetic nephropathy. It is characterized by albuminuria, weight gain, swelling of ankle and legs, frequent 2urination in the night, morning sickness, anemia, and high blood pressure.2 Often, DKD could advance to ESRD, which is associated with high mortality rates in comparison to non-DKD ESRD patients.3 The condition often remains undiagnosed until the manifestations of serious complications.2
 
GLOBAL BURDEN
Globally, DKD is highly prevalent. Nearly 40% of patients with DM develop DKD which is the leading cause of chronic kidney disease (CKD) globally.2 The increasing DKD prevalence parallels that with the global increase in the prevalence of DM.3
The global prevalence of DKD is increasing and some of the reports across the globe show the following trends:2
  • Prevalence of CKD in patients with DM in China was 38.8%.
  • About 34.4% prevalence of DKD in India.
  • Composite prevalence of diabetic-CKD of around 62.3%.
  • Up to 11.4% incidence of CKD was reported in UAE after 9 years of follow-up.
  • Elderly patients from the eastern Mediterranean region reported the highest prevalence rates of DM and CKD-DM.
  • The UK prospective diabetes study (UKPDS) group reported 28% patients developing renal impairment.
 
RISK FACTORS
Despite various measures toward management of DKD, after the onset of nephropathy in DM, globally it has been observed that kidney disease is progressive and is a major cause of ESRD.4 Table 1 depicts the risk factors associated with DKD.3
Various risk factors have been attributed to the development of DKD:2
  • (Increased) albuminuria
  • Hyperglycemia
  • Hypertension
  • Dyslipidemia
  • Obesity
  • Smoking
 
Albuminuria
The major risk factor for the development and progression of kidney disease in patients with DM is increased albumin excretion.2 Normal albuminuria is an albumin-to-creatinine ratio of <30 mg/g creatinine, moderate albuminuria 3is an albumin-to-creatinine ratio of 30–300 mg/g creatinine, and severely increased albuminuria is an albumin-to-creatinine ratio of >300 mg albumin/g creatinine.5
TABLE 1   Risk factors for diabetic kidney disease (DKD).
Risk factor
Susceptibility
Initiation
Progression
  • Demographic
  • Older age
+
  • Sex (men)
+
  • Race/ethnicity (black, American Indian, Hispanic, Asian/Pacific Islanders)
+
+
  • Hereditary
  • Family history of DKD
+
  • Genetic kidney disease
+
  • Systemic conditions
  • Hyperglycemia
+
+
+
  • Obesity
+
+
+
  • Hypertension
+
+
  • Kidney injuries
  • Acute kidney injury (AKI)
+
+
  • Toxins
+
+
  • Smoking
+
+
  • Dietary factors
+
+
  • High protein intake
+
+
  • High fat dairy products
+
+
  • High intake of saturated and trans fats
+
+
  • High sodium intake
+
+
 
Hyperglycemia
The most prominent risk factor of DKD is hyperglycemia. Hyperglycemia further worsens renal function by altering the antioxidant system and results into formation of glycated end products. Progression of nephropathy in patients with DM is associated with variations in glycated hemoglobin (HbA1c).2
 
Hypertension
A recent meta-analysis reported association between hypertension and DKD.2 When compared with nonhypertensives, hypertensives are at a higher risk of 4developing DKD. The association between hypertension and DKD was further established by a study conducted in China which reported that hypertension control was associated with 23% reduction in the incidence of ESRD.2
 
Dyslipidemia
Lipid nephrotoxicity hypothesis described the impact of dyslipidemia on renal function. Dyslipidemia is one of the contributors in the progression of DKD. It results in apoptosis of podocytes and macrophage infiltration which leads to the development of DKD. Hyperglycemia and insulin resistance could further aggravate dyslipidemia in DKD patients. Lipoprotein levels were found to be directly correlated with the prevalence of DKD. The low-density lipoprotein/high-density lipoprotein (LDL/HDL) ratio was an independent predictor of microalbuminuria (MAU).2
 
Obesity
A strong association has been observed between DKD and obesity. It is assumed that obesity could result in glomerular injury, glomerular hypertrophy, and proteinuria, thereby eventually resulting in DKD. However, substantial evidence to confirm this association between obesity and DKD2 does not exist.
 
Smoking
Smoking is an independent risk factor for DKD development. It is a result of oxidative stress, hyperlipidemia, deposition of advanced end glycation products, and glomerulosclerosis.2
 
STRUCTURAL CHANGES
Diabetic kidney disease is associated with various structural changes in kidney. Within the first year, the glomerular basement membrane thickens which is paralleled by capillary and tubular basement membrane thickening. Other changes include loss of endothelial fenestrations, mesangial matrix expansion, and loss of podocytes with effacement of foot processes. Within 5–7 years after the diagnosis of type 1 diabetes mellitus (T1DM), mesangial volume expansion is detectable. With further progression of diabetes mellitus (DM), segmental mesangiolysis is observed. The exudative lesions result from the subendothelial deposits of plasma proteins, which form periodic acid–Schiff-positive and electron-dense deposits and accumulate in small arterial branches, arterioles, and glomerular capillaries as well as microaneurysms. These deposits can result in luminal compromise. Glomerular filtration rate (GFR), albuminuria, and hypertension are strongly correlated with mesangial expansion and somewhat less strongly associated with the glomerular basement membrane width in DM patients. Similar renal structural changes are observed in T1DM and T2DM patients. The international pathologic classification of glomerular changes in DKD is given in Table 2.35
TABLE 2   International pathologic classification of glomerular changes in diabetic kidney disease.
Class
Description
Inclusion criteria
1
Mild or nonspecific light microscopy changes and electron microscopy-proven GBM thickening
GBM > 395 nm in women and >430 nm in men 9 years of age and older; biopsy does not meet any of the criteria mentioned below for classes 2–4
2a
Mesangial expansion, mild
Mild mesangial expansion in >25% of the observed mesangium; biopsy does not meet criteria for class 3 or 4
2b
Mesangial expansion, severe
Severe mesangial expansion in >25% of the observed mesangium; biopsy does not meet criteria for class 3 or 4
3
Nodular sclerosis (Kimmelstiel–Wilson lesion)
At least one convincing Kimmelstiel–Wilson lesion; biopsy does not meet criteria for class 4
4
Advanced diabetic glomerulosclerosis
Global glomerular sclerosis in >50% of glomeruli; lesions from classes 1–3
(GBM: glomerular basement membrane)
 
NATURAL HISTORY
The natural history of DKD continues to evolve. It has been observed in clinical settings that many DKD patients do not show the classic pattern of glomerular hyperfiltration progressing to persistent albuminuria associated with hypertension and declining GFR (Fig. 1).3
zoom view
FIG. 1: Conceptual model of the natural history of diabetic kidney disease.
6
zoom view
FIG. 2: Progression of diabetic nephropathy.
Figure 2 demonstrates the progression of diabetic nephropathy, which can be divided as follows:6
  • Microalbuminuria: Albumin excretion rate, 30–300 mg/24 h
  • Macroalbuminuria or proteinuria (>300 mg/24 h)
  • Nephrotic syndrome
  • ESRD/chronic renal failure
Hypertension accelerates both the onset of MAU and the progression of renal disease after the onset of macroalbuminuria. Macroalbuminuria denotes significant diabetic nephropathy and is followed by a decline in GFR. Elevated systolic blood pressure accelerates the progression of type 2 diabetic nephropathy.6
A major goal of treatment for patients with type 2 diabetic nephropathy is to prevent or slow the progression to ESRD. Effective antihypertensive treatment reduces MAU in hypertensive patients with DM and helps slow the progression of diabetic nephropathy. Early intervention can affect outcome.6
Data from the UKPDS showed the annual transition rates to stages of nephropathy versus mortality for patients with T2DM (Fig. 3). Mortality was predominantly due to cardiovascular disease (CVD). In patients without evidence of albuminuria, the number of individuals dying versus those developing MAU was similar (1.4% vs. 2.0%). Once patients had MAU, their mortality rate increased to 3% and was close to the rate of developing albuminuria (2.8%). Patients with albuminuria had 4.6% mortality, a twofold increased risk of death compared with the progression to elevated serum creatinine or kidney failure (2.3%). Once creatinine was elevated or patients required renal replacement therapy, their risk of dying was very high—more than 19%. Clearly, many patients with DM and CKD are dying before reaching CKD stage 5 or ESRD.7
The clinical presentation of DKD is altering. A comparison of cases from the time periods of 1988–1994 and 2009–2014 shows that the prevalence of albuminuria as a manifestation of DKD decreased from 21 to 16%, low 7estimated GFR (eGFR) increased from 9 to 14%, and severely reduced eGFR (<30 mL/min/1.73 m2) increased from 1 to 3%.
zoom view
FIG. 3: Stages of nephropathy versus mortality for patients with T2DM.
Additionally, an autopsy study found absence of albuminuria or low eGFR in some patients throughout their life.3 During the later stages of DKD, with a decline in GFR, both kidney and nonkidney-related DKD complications develop. Anemia and bone and mineral metabolism disorders often develop earlier in DKD than in other types of CKD. Predominant tubulointerstitial disease is associated with damage to the peritubular interstitial cells that produce erythropoietin. As a result, patients with DM may be prone to erythropoietin deficiency and are nearly twice as likely to have anemia compared with patients with nondiabetic CKD and comparable eGFR.3
 
Classification of Diabetic Kidney Disease Based on Glomerular Filtration Rate and Albuminuria
The National Kidney Foundation has classified various stages of CKD based on GFR levels and therefore differs from other systems, in which staging is based primarily on urinary albumin excretion (Table 3).8
TABLE 3   Stages of chronic kidney disease based on glomerular filtration rate (GFR) by the National Kidney Foundation.
Stage
Description
GFR (mL/min/1.73 m2 body surface area)
1
Kidney damage* with normal or increased GFR
≥90
2
Kidney damage* with mildly decreased GFR
60–89
3
Moderately decreased GFR
30–59
4
Severely decreased GFR
15–29
5
Kidney failure
<15 or dialysis
* Kidney damage defined as abnormalities on pathologic, urine, blood, or imaging tests.
8The National Kidney Foundation has classified CKD on cause (C), GFR (G), and albuminuria (A). This is further depicted as a heat map (Fig. 4).
zoom view
FIG. 4: Classification of chronic kidney disease (CKD) based on cause, glomerular filtration rate (GFR), and albuminuria categories: “Heat Map”.
 
CONCLUSION
  • Prevalence of DM is increasing globally with increased rates of obesity, metabolic syndrome and lifestyle changes.
  • DKD is one of the microvascular complication of DM.
  • Prevalence of DKD in India is reported to be 34.4%.
  • Increased albuminuria is one of the major risk factors contributing to progression of kidney disease among DM patients.
  • The pathology of DKD is altering and over the years understanding of DKD has changed. It is important, to utilize international pathological classiffication to diagnose patients correctly.9
REFERENCES
  1. Thomas B. The global burden of diabetic kidney disease: Time trends and gender gaps. Curr Diab Rep. 2019;19(4):18.
  1. Hussain S, Jamali MC, Habib A, Hussain MS, Akhtar M, Najmi K. Diabetic kidney disease: An overview of prevalence, risk factors, and biomarkers. Clin Epidemiol Glob Health. 2021;9:2–6.
  1. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032–45.
  1. Jamale T. Progression of diabetic kidney disease: Who is at risk? J Postgrad Med. 2020;66(4):182–3.
  1. National Kidney Foundation. CKDinform: A PCP's Guide to CKD Detection and Delaying Progression. [online] Available from https://www.kidney.org/sites/default/files/CKDinform%20-%20Module%202%20-%20core%20slides%2011.16.16.v2.pdf [Last accessed July, 2021].
  1. Pylypchuk GB, Beaubien E. Diabetic nephropathy. Prevention and early referral. Can Fam Physician. 2000;46:636–42.
  1. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; for the UKPDS Group. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63:225–32.
  1. Standards of Medical Care in Diabetes—2011. American Diabetes Association Diabetes Care. 2011;34(Suppl 1):S11–61.