Diabetic nephropathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3]

Diabetic kidney disease (Diabetic Nephropathy) is the most common cause of chronic kidney disease and end stage renal disease (ESRD) in the United States ^[1] . Due to the ongoing world wide increase in the incidence of diabetes mellitus, Diabetic nephropathy (DN) is increasingly a major cause of ESRD disease worldwide ^[2].

Diabetic Nephropathy affects male and female patients equally. The incidence of DN in African-Americans, Native Americans and people of Mexican origins is greater than the incidence in white Americans ^[3]. Currently, the main goal in the treatment of diabetic nephropathy is to slow the progression of chronic kidney disease. This is achieved by excellent control of hyperglycemia, dyslipidemia, and blood pressure. Antiproteinuric therapy through renin-angiotensin-aldosterone system Inhibitors is considered to be a major pillar of the treatment ^[4]. Renin-angiotensin-aldosterone system inhibition it thought to be beneficial in the early stages of diabetic nephropathy through decreasing proteinuria and progression ^[5]. Therefore, early diagnosis and institution of prompt treatment is very important in the management of diabetes nephropathy. Also, the role of diabetes prevention becomes paramount patients at high risk (e.g. metabolic syndrome, impaired glucose tolerance).

Diabetic nephropathy (DN) is characterized by the presence of proteinuria or decreased renal function in patients with diabetes mellitus^[6][7][8] however, diabetic nephropathy can also present in form of non-proteinuric decline in GFR. Nonetheless, proteinuria remains the hallmark of diagnosis for diabetic nephropathy, despite emerging trends suggestive of non proteinuric diabetic nephropathy. ^[9]

The range of proteinuria in early DN is shown below^[6][7][8]:

• Males: Microalbuminuria in the range of 30-300 mg/24 hrs or a spot urinary albumin/creatinine ratio of 30-300 mg/g
• Females: Microalbuminuria in the range of 30-300 mg/24 hrs or a spot urinary albumin/creatinine ratio of 20-200 mg/g

Overt DN is defined according to the presence of proteinuria or according to renal function. The following ranges in overt DN are shown below^[6][7][8]:

• Proteinuria > 500 mg/24 hrs or albuminuria > 300 mg/24 hrs.
• Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2

Diabetic nephropathy was first described by Clifford Wilson and Paul Kimmelstiel in 1936.

Diabetic nephropathy can be classified according to the type of underlying diabetes mellitus or the histopathological findings of the disease.

Diabetic nephropathy is a serious complication in patients with long standing Type 1 or Type 2 Diabetes Mellitus. It usually occurs in about 10 to 15 years following the onset of diabetes mellitus. Poor glycemic control, dyslipidemia, smoking, and environmental and genetic factors play important roles in the development of diabetic nephropathy.

The exact cause of diabetic nephropathy is unknown. However, it is thought that hyperfiltration through the renal glomeruli may be responsible for the manifestations of the disease.

Diabetic nephropathy should be differentiate from other causes of glomerular disease such as nephritic syndrome, nephrotic syndrome, Fabry’s disease, poststreptococcal glomerulonephritis, lupus nephritis, antiglomerular basement membrane disease (goodpasture’s syndrome), Cryoglobulinemia, Henoch-Schönlein purpura, amyloidosis, pulmonary-renal syndromes (vasculitis), thin basement membrane disease, Alport’s Syndrome, anti-GBM Disease, hypertensive nephrosclerosis, and subacute bacterial endocarditis. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hemeturia, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features.

In the United States, prevalence of diabetic nephropathy (DN) has increased from 7.4% to 9.6% within a 20 years period (1988 to 2008), and this trend will likely continue due to the increasing incidence of diabetes in the American populace . Studies by de Boer et al showed that DN accounts for 44% of new ESRD cases with 6% attributed to type 1 DM, 38% attributed to type 2 DM, and a projected increase of 3 million cases over the course of 20 years. This increased incidence and prevalence of DN is notably greater among African Americans, Asians, and Native Americans than it is among Caucasians.

Risk factors of diabetic nephropathy can be modifiable such as hypertension, dyslipidemia, and smoking or non-modifiable such as advanced age and positive family history.

Microalbuminuria is an excellent tool for the early detection of diabetic nephropathy.

Patients with diabetic nephropathy can develop the manifestations of renal failure such as edema and unintentional weight gain late in the course of the disease.

The majority of patients with diabetic nephropathy are asymptomatic. However, patients may present with other signs of diabetes mellitus or chronic renal failure.

Microalbuminuria, as defined by an urinary albumin-to-creatinine ratio of >30mg/g is an early diagnostic clue to diabetic nephropathy. Some patients may go on to develop high-grade nephrotic range proteinuria, while others may develop diabetic nephropathy without any measurable albuminuria.

The diagnosis of diabetic nephropathy is based on history, physical examination and laboratory investigations. Renal imaging, such as ultrasound, is often done to rule out other kidney and urinary tract pathologies. However, the ultrasound findings in diabetic nephropathy are highly non-specific and may be normal. Some of the findings in chronic kidney disease due to diabetic nephropathy or other causes include: reduced renal length, reduced renal cortical thickness, increased renal cortical echogenicity, poor visibility of the renal pyramids and the renal sinus, marginal irregularities, papillary calcifications.

The goals of treatment are to slow the progression of kidney damage and control related complications. The main treatment, once proteinuria is established, is ACE inhibitor drugs, which usually reduce glomerular hypertension, proteinuria levels, systemic hypertension and slow the progression of diabetic nephropathy.

Primary prevention of diabetic nephropathy is aimed at preventing diabetes in the first place.

Once diabetic nephropathy develops, secondary prevention to halt the progression of the disease is aimed at strict control of blood pressure, blood glucose levels, as well as lipids.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [2]

Diabetic nephropathy was first described by Clifford Wilson and Paul Kimmelstiel in 1936.

• Diabetic nephropathy was first described by Clifford Wilson and Paul Kimmelstiel in 1936.^[1]
• Diabetic nephropathy is often called Wilson-Kimmelstiel syndrome after the two scientists.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Diabetic nephropathy can be classified according to the type of underlying diabetes mellitus or the histopathological findings of the disease.

Diabetic nephropathy can be classified according to the type of diabetes which resulted in the disease process. Another method of classification is based on the histopathological findings in diabetic nephropathy.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

The hallmark of diabetic nephropathy is mesangial expansion. Nonetheless, diabetic nephropathy is characterized by the presence of abnormalities in the glomeruli, such as glomerular hypertrophy, in the tubules and interstitium, such as tubular atrophy and interstitial fibrosis, and in the blood vessels, such as arteriosclerosis in both the afferent and the efferent renal arterioles. Findings on histopathological analysis may be evident very early in diabetes, but are often clinically present approximately 15 years after the onset of metabolic abnormalities. Diabetic nephropathy (DN) is characterized by the presence of proteinuria or decreased renal function in patients with diabetes mellitus. Diabetic nephropathy may be early or overt.

The pathophysiology of diabetic nephropathy is related to chronic hyperglycemia. However, it is not completely understood. It is thought to be related to the effects of the following:

• Hemodynamic factors: the imbalance between the arteriolar resistance of the afferent and efferent arterioles results in increased glomerular hydrostatic pressure and hyperfiltration. These effects are mediated by:
  • Activation of the renin-angiotensin-aldosterone (RAS) system: results in efferent vasoconstriction. In addition, the high levels of ACE are associated with greater albuminuria and nephropathy.
  • Increased levels of endothelin I and urotensin II contribute to vasoconstriction.
  • Dysregulation of the amounts of nitric oxide (NO) and nitric oxide synthase (NOS).
• Metabolic factors: oxidative stress and the production of reactive oxygen species (ROS) contribute to the damage seen in diabetic nephropathy.
• Growth factors: TGF-ß and its downstream product, CTGF, induce extracellular matrix (ECM) formation. In addition, they mediate the fibrosis seen in the later stages of diabetic nephropathy.
• Inflammation: much of the pathogenesis of diabetic nephropathy is related to the production of proinflammatory cytokines and the recruitment of macrophages and T-lymphocytes.

The onset of diabetic nephropathy generally occurs at least 15 years after the onset of diabetes mellitus. The pathogenesis of diabetic nephropathy occurs in distinct stages. Early pathogenesis – which may start as early as 2 years after the onset of diabetes – may include no visible lesions with mild global and diffuse hypertrophy of the renal glomeruli only. This process is called “GBM thickening”, a linear process that is caused by the accumulation of extracellular matrix.^[1] These changes may not be detectable by light microscopy and require electron microscopy to identify. When the accumulation of the extracellular matrix becomes significant, pathological changes on light microscopy will be evident, typically first seen 5 years after onset of type 1 diabetes and usually occurs at a faster frequency after 15 years of onset. While an increase in cellularity is often observed early in the disease, mesangial expansion without hypercellularity is common as the disease further progresses. Disorganized mesangial expansion – the hallmark of diabetic nephropathy – is not a linear process and is in fact the result of a vicious circle that is characterized by the presence of frequently mesangiolysis followed by the formation of micro-aneurysms and balloon formation of glomeruli, hyaline accumulation, and mesangial repair with concomitant thickening of the GBM lamina densa.

Advanced diabetic nephropathy is typically seen approximately 15 years after the onset of diabetes type I. It is characterized by the abundant sclerosis of the mesangium and mesangial expansion in an irregular nodular (round/oval) pattern, called Kimmelstiel-Wilson nodules.^[2] These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain.^[2] They are a non-specific finding in diabetic nephropathy but are frequently found in glomerular tufts in up to 25% of patients with advanced diabetic nephropathy.^[2] Kimmelsteil-Wilson nodules may also be found in other disease entities, such as multiple myeloma and other gammopathies, membranoproliferative glomerulopathies, post-infectious glomerulonephritis, amyloidosis, as well as idiopathic nodular glomerulosclerosis in patients with no renal disease.

Hyalinosis, defined as the exudation of hyaline material (usually lipid particles) between the basement membrane of Bowman’s capsule and the parietal epithelium.^[2] Meanwhile, the irreversible loss of podocytes plays a crucial role in the disease pathogenesis and the clinical finding of proteinuria in patients with diabetic nephropathy. Podocyte injury first starts with widening of the podocyte foot processes with consequent detachment from the GBM.^[3] As podocytes are lost, glomerulotubular junctions are exposed to further injury and formation of atubular glomeruli. Typically, patients with diabetic nephropathy do not demonstrate any specific findings on immunofluorescence, but IgG deposition is common in these patients. The presence of IgG is not believed to be a cause of the disease, but rather as a by-product due to the presence of an abnormal sticky GBM.^[2]

In the early stages of diabetic nephropathy, there is renal hypertrophy, due to expansion of the glomeruli. The resultant increase in kidney size is due to enlargement of the mesangium, the glomerular basement membrane, as well as the afferent and efferent renal arterioles. However, in the later stages of diabetic nephropathy and ESRD, the kidneys become small and atrophic, with diffuse glomerulosclerosis.

• Glomerular hypertrophy and possible hypercellularity
• Thickened capillary basement membranes
• Diffuse irregular mesangial expansion and sclerosis
• Nodular mesangial sclerosis
• Mesangiolysis
• Capillary micro-aneurysms
• Hyaline deposition

• Linear staining of capillary basement membrane for IgG
• Linear staining of capillary basement membrane for albumin

• Thickened basement membranes
• Increased mesangial extracellular matrix and possible hypercellularity
• Non-amyloidotic extracellular matrix
• Podocyte loss

• Atrophy
• Thickened tubular basement membrane
• Interstitial fibrosis

• Linear staining of tubular basement membrane for IgG
• Linear staining of tubular basement membrane for albumin

• Thickened tubular basement membranes
• Increased presence of interstitial collagen
• Tubular atrophy

• Hyalinosis of afferent and efferent arterioles
• Intimal sclerosis

• No specific changes

• Subendothelial and transmural hyaline arterial deposition in small arteries and arterioles

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Diabetes mellitus both type1 and type 2 is the major cause. It is thought to be due to hyperfiltration through the renal glomeruli. The chances of developing diabetic nephropathy is markedly increased in patients with a diabetic sibling or parent who has diabetic nephropathy. these observations have been seen in both type 1 and type 2 diabetes. The genetic basis underlying the heritability of diabetic nephropathy is not known.

• Diabetes, type 1 or 2
• Persistent, uncontrolled hyperglycemia
• Hypertension in the presence of diabetes.
• Diabetes with smoking
• High blood cholesterol and diabetes
• Genetic factors

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Diabetic nephropathy should be differentiated from other causes of glomerular disease such as nephritic syndrome, nephrotic syndrome, Fabry’s disease, poststreptococcal glomerulonephritis, lupus nephritis, antiglomerular basement membrane disease (goodpasture’s syndrome), Cryoglobulinemia, Henoch-Schönlein purpura, amyloidosis, pulmonary-renal syndromes (vasculitis), thin basement membrane disease, Alport’s Syndrome, anti-GBM Disease, hypertensive nephrosclerosis, and subacute bacterial endocarditis. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features.

Diabetic nephropathy should be differentiated from other causes of glomerular disease. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glomerular diseases:

Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3]

In the United States, prevalence of diabetic nephropathy (DN) has increased from 7.4% to 9.6% within a 20 years period (1988 to 2008), and this trend will likely continue due to the increasing incidence of diabetes in the American populace ^[1]. Studies by de Boer et al showed that DN accounts for 44% of new ESRD cases with 6% attributed to type 1 DM, 38% attributed to type 2 DM, and a projected increase of 3 million cases over the course of 20 years^[1]. This increased incidence and prevalence of DN is notably greater among African Americans, Asians, and Native Americans than it is among Caucasians.

• It is estimated that half of the diabetic patients will develop diabetic nephropathy after 20 years of the onset of the disease.
• Diabetic nephropathy is the most common etiology of nephropathy and dialysis in the Western world.^[2]
• The worldwide burden of diabetic nephropathy seems to be on the rise, with an incidence rising by 150% per one decade in USA, Europe, and Japan and a prevalence increasing from 6.4% in 2010 and estimated to reach 7.7% in 2030.^[3][4]
• Costs due to diabetic nephropathy reach as high as 30-40 billion USD annually in the USA only.^[5][6]
• The burden of diabetic nephropathy from type II diabetes is far more significant than that of type I diabetes.^[7]
• Advanced age in type 2 diabetes and early diagnosis in type 1 diabetes are associated with higher risk of DN.^[8][9]

• Diabetic nephropathy has no sex predilection.

• Most of the cases of diabetic nephropathy develop after 10 years of the diagnosis with most of the cases are diagnosed between 10 and 20 years after the onset of the disease.
• Diabetic nephropathy tends to occur in elderly patients with type 2 DM who have the disease for a long period of time.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Risk factors of diabetic nephropathy can be modifiable such as hypertension, dyslipidemia, and smoking or non-modifiable such as advanced age and positive family history.

Risk factors of diabetic nephropathy can be subcategorized into modifiable and non-modifiable risk factors:

Modifiable risk factors include:^[1][2][3][4]

• Hypertension
• Dyslipidemia
• Smoking: smoking is associated with worsening renal function
• Inadequate glycemic control

Non-modifiable risk factors include:^[1][2][3][4]

• Age: advanced age is a risk factor for diabetic nephropathy.
• Race: African Americans, Native Americans and Hispanics are at higher risk of developing diabetic nephropathy.
• Family history: patients with a family history of diabetic nephropathy are more likely to develop diabetic nephropathy themselves.
• Genetic profile: genetic variants in ACE, ALR2, APOC1, APOE, EPO, eNOS, HSPG2, VEGF, FRMD3, CARS, UNC13B, CPVL/CHN2, and GREM1 have been implicated in the development of diabetic nephropathy.
• Obesity: obesity is associated with higher incidence of diabetic nephropathy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Dima Nimri, M.D. [3]

Microalbuminuria is an excellent tool for the early detection of diabetic nephropathy.

• Screening for nephropathy in diabetes should begin at the time of diagnosis of type II diabetes mellitus^[1] and after 5 years of the diagnosis of type I diabetes mellitus.^[2]
• Screening for albuminuria is done with a routine dipstick urinalysis. However, routine dipsticks do not rule out microalbuminuria. Hence, if the test is positive, a 24-hour urine sample for quantifying the amount of protein should be done and if the test is negative, a radioimmunoassay for albumin should be done and repeated every year if the initial result is negative.
• The albumin to creatinine ratio should also be measured in a morning urine sample, a 24-hour or an overnight sample.
  • In the case of an abnormal urine albumin to creatinine ratio (more than 30 mg/ g Cr), test should be repeated once or twice over a period of few months for consistency of the results.
• Estimated GFR (eGFR) is often calculated at the time of screening to document and/or stage chronic kidney disease (CKD).
• If retinopathy is present along with albuminuria, the albuminuria is highly attributed to diabetic nephropathy.^[1][2]
• New genetic markers are being studied for diabetic nephropathy. These markers are being determined in order to facilitate an early identification and management of patients at a high risk of developing diabetic nephropathy.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Dima Nimri, M.D. [3]

If left untreated, diabetic nephropathy (DN) can progress to develop ESRD (end stage renal disease). Diabetic nephropathy can be complicated with coronary artery disease, hypertension, and type IV RTA, The prognosis of DN is bad with continued disease progression even after proper glycemic control.

• It is estimated that 20-40% of patients with diabetes develop diabetic nephropathy.
• The main trigger of diabetic nephropathy is chronic hyperglycemia.^[1] While a strict glycemic control reduces the rate at which microalbuminura appears and progress in patients with both type I and type II diabetes mellitus, it is debatable as to whether or not an improved blood glucose control halts the progression of renal disease once microalbuminuria is present.^[2]
• The natural history of the disease begins with the development of microalbuminuria, which usually begins 5 years after the onset of diabetes. The range for microalbuminura is 30 to 300 mg of albumin per 24 hours.
• Over the next 5-10 years, patients are more likely to develop overt proteinuria.
• Finally, over the next decade, nephrotic syndrome is more likely to occur. If left without management, diabetic nephropathy is most likely to be associated with a declining GFR and ultimately, end-stage renal disease (ESRD).
• At the point of ESRD, dialysis and kidney transplantation are the viable options for treatment.^[2]

Possible complications include:^[1]

• Coronary artery disease (CAD): In patients with diabetes mellitus, the main risk factor for the development of CAD is nephropathy^[2]
• Chronic kidney disease (CKD)
• End-stage renal disease (ESRD)
• Development and/or worsening of hypertension
• Complications related to dialysis
• Complications related to renal transplantation
• Type IV RTA: may occur in both type I and type II diabetes mellitus

Diabetic nephropathy has become the most common cause of ESRD in most countries due to the increased prevalence of diabetes epidemic.^[3] Even with medical interventions to slow the progression of microalbuminuria, diabetic nephropathy can progress to chronic kidney disease (CKD) and end-stage renal disease (ESRD).

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