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
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
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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
- 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%.
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
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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).
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.
REFERENCES
- Thomas B. The global burden of diabetic kidney disease: Time trends and gender gaps. Curr Diab Rep. 2019;19(4):18.
- 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.
- Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032–45.
- Jamale T. Progression of diabetic kidney disease: Who is at risk? J Postgrad Med. 2020;66(4):182–3.
- 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].
- Pylypchuk GB, Beaubien E. Diabetic nephropathy. Prevention and early referral. Can Fam Physician. 2000;46:636–42.
- 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.
- Standards of Medical Care in Diabetes—2011. American Diabetes Association Diabetes Care. 2011;34(Suppl 1):S11–61.