The diagnosis of DN is considered in a diabetic patient that has undergone a routine urinalysis (UA) that includes screening for microalbuminuria and has physical exam findings that are associated with diabetes mellitus. These can be:

•  Hypertension
•  Fourth heart sound
•  PVD
•  Diminished deep tendon reflexes and sensations such as fine touch (signs of diabetic neuropathy)
•  Non-healing skin ulcers or osteomyelitis

Type 2 DM cases with retinopathy and severe proteinuria usually have DN, but the patients who have not yet developed retinopathy are more likely to be having non-diabetic glomerular disease.

Signs and symptoms

In diabetic patients, early signs and symptoms for kidney disease are non-specific and rare. The more common presentation of kidney disease is after it has progressed significantly [50]. Clinical features include:

•  Albuminuria/proteinuria
•  Ankle and/or pedal edema
•  Elevated blood pressure
•  Elevated blood urea nitrogen (BUN) and serum creatinine
•  Nocturia
•  Polyuria
•  Nausea/vomiting
•  Fatigue, pallor, anemia
•  Pruritus
•  Reduction in dose/frequency of insulin or other anti-diabetic medication

The differential diagnosis for DN in a patient with diabetes mellitus includes:

•  Primary or secondary glomerular disease
•  Chronic obstruction
•  Renovascular hypertension 
•  Renal vein thrombosis
•  Nephrosclerosis
•  Cholesterol embolization
•  Renal artery stenosis
•  Interstitial nephritis
•  Multiple myeloma
•  Amyloidosis

Urinalysis

A 24-hour urine collection is used for estimating glomerular filtration rate (GFR) and analysis of protein, creatinine and urea levels in the urine. UA of a DN patient usually shows glycosuria and proteinuria (150 to >300mg/dl). Though uncommon, but hyaline casts may also be found.

Blood tests

Estimating the GFR (by using equations like the MDRD formula), are useful to monitor the progression of kidney disease.

Serum and urinary electrophoresis

These are useful for excluding multiple myeloma as the cause for DN in suitable case scenarios. They also help in the classification of proteinuria (usually glomerular type in DN).

Renal ultrasonography

In the initial course of the disease, the kidney is either slightly enlarged or normal in size. With chronic renal disease, the kidney shrinks in size. Ultrasound sound is helpful in excluding obstruction. It is preferrable to have echogenicity studies in chronic renal disease.

Renal biopsy

A renal biopsy is indicated only if the diagnosis of DN is in doubt or an alternative diagnosis is more likely. A renal biopsy is not required to diagnose DN in a case presenting with typical history, physical exam and lab findings suggestive of a progressive renal disease.

Glycemic control

A strict glycemic control is essential in DN since evidence indicates that in patients with diabetes mellitus (type 1 and type 2, both), hyperglycemia plays a major role in contributing to the progression of the disease. There is strong evidence supporting the aforementioned recommendation, especially for type 1 diabetes.

Control of hypertension

An effective control of blood pressure delays the progression of diabetic glomerulopathy. It has been demonstrated that rate of decline in renal function is retarded by effective control of hypertension in cases with type 1 DM, proteinuria and hypertension [51], especially when a fall in SBP occurs together with a reduction in glomerular capillary pressure. The appropriate lower limit for SBP is yet to be ascertained [52].

Angiotensin-converting enzyme (ACE) inhibitors

Evidence indicates that ACE inhibition can significantly delay the progression and development of DN.

Angiotensin receptor blockers (ARBs) for renin-angiotensin system (RAS) inhibition

There is evidence suggesting that ARBs are a good option for treating DN [53].

Renal replacement therapy

Renal replacement can be presented as an option for diabetic patients with ESRD, especially those who are chronically ill. The details pertaining to renal replacement therapy should preferably be discussed with the patient at an early stage of the disease. It is advisable to initiate treatment at a creatinine clearance / estimated GFR(eGFR) of 10-15 ml/min for cases diagnosed with DN. Treatment can be initiated at an early stage for diabetics in the following circumstances:

• Uncontrollable blood pressure secondary to hypervolemia
• Presence of uremic symptoms as anorexia and cachexia
• Severe vomiting due to presence of uremia in addition to gastroparesis

Dietary changes

Several recommendations that focus on providing an outline of a diet for different caloric requirements, suited to various case scenarios have been made available by the American Diabetic Association. Protein restricted diet (0.8-1 g/kg/day) may be helpful in delaying the progression of DN in advanced cases. Phosphorus and potassium restriction is recommended for cases with advanced nephropathy, which may require the use of agents like phosphate binders.

DN is associated with significant morbidity and mortality. A reliable predictor for the morbidity and mortality associated with DN for both type 1 and type 2 DM is proteinuria. The prevalence of albuminuria in DM is 30-35%. In patients diagnosed with diabetes mellitus, microalbuminuria and macroalbuminuria, both increase the all cause mortality.  Cardiovascular morbidity can be predicted by Microalbuminuria is known to be associated with cardiovascular morbidity and mortality. It is also known to increase the risk of coronary artery disease (CAD) and peripheral vascular disease (PVD).

ESRD accounts for 59-66% of mortalities in type 1 DM patients that have concurrent nephropathy. A prospective study from Germany reported a survival rate of <40% in the younger age group diagnosed with type 1 DM and <10% in the elderly with type 2 DM. ESRD can be caused by type 1 and type 2 DM, both. However, majority of the cases are the ones diagnosed with type 2 DM. Although an approximate 20-40% of type 1 DM cases develop ESRD, there has been a steady decline in the fraction of cases that developed ESRD due to type 1 DM. Comparing it with statistics for type 2 DM, in spite of having only 10-20% cases that develop uremia secondary to diabetes, they almost equate the total number of diabetics developing ESRD due to 5-10 fold greater prevalence of type 2 diabetes. In patients with type 1 DM and DN, cardiovascular disease is a significant cause of mortality (15-25%).

Hyperglycemia

In patients diagnosed with either type 1 or type 2 diabetes mellitus (DM), one of the major risk factors for developing microalbuminuria is hyperglycemia [1] [2] [3]. A 37% reduction in microvascular endpoints has been associated with 1% decrease in HbA1c [11]. A recently published trial also emphasized on aggressive treatment of DM to decrease microvascular sequelae [7]. It has also been shown that mild to moderate renal injury secondary to DN in cases with type 1 DM was reversed after pancreatic transplantation [6]. Although there are a few studies that have demonstrated a reduction in GFR with high glucose levels [4] [5], the role of metabolic control in presence of albuminuria needs to be further investigated to define any significance. 

Arterial hypertension

Arterial hypertension is known to be correlated with the progression of DN, in addition to being a major risk factor [8] [9] for the same. Upon analysis of UKPDS, it was observed that for every 10 mmHg decrease in systolic blood pressure (SBP), the risk of microvascular complications was reduced by 13%. Also, patients having a SBP<120 mmHg in the same group had the smallest risk for microvascular complications [10].

Smoking

Smoking is a known risk factor for DN [8] [11]. Although the speculation of smoking being a contributing factor in the progression of DN is unconfirmed [2] [5] [12], patients are advised to quit smoking irrespective of the phase of DN. This intervention aims at decreasing the associated cancer and cardiovascular risk as well.

Dyslipidemia

High serum cholesterol level is a known risk factor for developing DN in patients diagnosed with type 2 DM [2] [8]. Albuminuria in type 1 DM cases has been asociated with elevated serum triglycerides, LDL cholesterol and total cholesterol [13] [14]. In type 1 DM cases with macroalbuminuria, an elevated serum cholesterol level may likely be a risk factor for developing loss of GFR [15].

Proteinuria

Proteinuria can itself cause DN to progress. A proteinuria greater than 2 g/24 hrs has been associated with an increased risk of ESRD [16]. The leakage of albumin may activate inflammatory cascades, which in-turn can lead to glomerular damage [17]. Therefore, decreasing urinary albumin excretion may well be a reasonable approach for the treatment of DN.

Glomerular hyperfiltration

Glomerular hyperfiltration has a minor role, if any, as a causative of DN [26]. In approximately one-third of patients diagnosed with type 2 DM, GFR is elevated [18] [19]. Theoretically, this may lead to glomerular damage, which in-turn can result in DN [28]. Presently, the evidence for classifying glomerular hyperfiltration as a risk factor of DN is controversial [20] [21] [22]. Elevated urine albumin excretion (UAE) is frequently observed in type 2 DM cases with one kidney [23] [24], whereas aggressive disease has not been observed in patients with type 1 DM with a single kidney [25].

Dietary factors

In patients with type 1 DM, it has been found that high UAE values are associated with an increased dietary protein consumption [27]. There is no evidence for the same association in cases with type 2 DM. It has also been found that in cases with type 1 DM, consuming fish protein in higher amounts is associated with a smaller risk of microalbuminuria [28]. The presence of microalbuminuria has also been associated with a high consumption of saturated fats in cases with type 1 DM [30]. It is speculated that the underlying mechanism for these effects may be related to hemodynamic factors [29]. 

Genetic risk factors

It has been theorized that the interaction of certain genes with the environment may cause DN [31] [32] [33]. So far, there is no known gene that could exert a major effect for causation of DN. A better understanding of the genes that act as predisposing factors to DN may allow development of screening techniques and preventive measures to benefit the high risk cases.

United States 

It is rare to find DN in patients who incurred type 1 DM (insulin dependent diabetes mellitus, IDDM) for a period that is less than ten years. Concurrent overt nephropathy is found in nearly 3% of cases newly diagnosed with type 2 DM (non-insulin dependent diabetes mellitus, NIDDM). The highest incidence of 3% per year is most often found in patients with a history of diabetes for approximately 10 to 20 years, beyond which there is a progressive decline in the incidence.

International 

There is considerable variation in the epidemiological data on DN from various European countries. The proportion of cases for renal replacement therapy in Germany is higher than United States. In the year 1995, a study conducted in Heidelberg, Germany, reported that among the admission cases for renal replacement therapy, 59% had diabetes and of these, 90% had type 2 DM. The incidence of ESRD from type 2 DM was reported to be increasing in Denmark and Australia, countries which have been known to have a low incidence of type 2 DM. The data from Asian countries has been difficult to retrieve. 

Sex distribution 

Males and females are equally affected from DN.

Age distribution 

It is rare to find DN in patients who incurred type 1 DM for a period that is less than ten years. The highest incidence of 3% per year is most often found in patients with a history of diabetes for approximately 10 to 20 years. Patients that are diagnosed with end-stage kidney disease have a mean age of approximately 60 years.

Prevalence by race

The incidence and severity of DN is higher in blacks (3-6 times greater than whites), Pima Indians and Mexican Americans who have type 2 DM. It may be possible that the higher incidence of DN reported in these races could be associated with multiple factors that are influenced by socioeconomic considerations like diet, hypertension, poor control of hyperglycemia and obesity. This may also be an indication of familial clustering of the disease in these particular populations.

From 1997-2002, the incidence of ESRD-DM did not decrease in men, Hipanics, blacks and people in the age group of 65-74 years. Another study evaluating the period 1990-2002 reported that the incidence of ESRD-DM increased in people over the age of 75 years. The goal of decreasing the incidence of ESRD-DM in persons over the age of 75 years can be challenging since the survival of diabetic patients is increasing and ESRD typically occurs in cases having a 15-20 years long history of diabetes [34]. Additionally, as the number of diabetics in the United States increases along with continued ageing of the population, the number of cases for ESRD will continue to rise. The present trend of a decline in the incidence of ESRD in diabetics may change if the mean age for developing diabetes decreases, or those diagnosed with diabetes live for a longer period of time.

There are three significant changes that are observed on histological examination of a kidney tissue sample obtained from a patient having diabetic nephropathy. These include glomerular basement membrane (GBM) thickening, mesangial expansion (secondary to hyperglycemia, possibly through glycosylation or increase in matrix protein production) and glomerular sclerosis (secondary to intraglomerular hypertension, caused by afferent renal artery dilatation or ischemic injury due to narrowing of glomerular vasculature by hyaline deposition). There is no major difference in the prognostic significance with any of these histological patterns.

There are several mechanisms that contribute to the pathogenesis of DN, which include polyol pathway activation, effect of high glucose, activation of renin-angiotensin system, formation of reactive oxygen species (ROS), glomerular hyperfiltration, protein kinase C pathway activation and increase in advanced glycation end-products (AGEs) [35] [36]. These mechanisms bring about various downstream changes at the cellular level that eventually lead to disruption of the glomerular filtration barrier, visualized on histologocal examination as mesangial expansion, tubulointerstitial fibrosis and nodualr glomerular sclerosis [37].

Glomerular endothelial cells

These are highly fenestrated cells that have minute pores (50-80 nm in size) through their cytoplasm [38]. Glycocalyx (consisting proteoglycans [PG] like versican, glypican, syndecan and perlecan), glycosaminoglycans (GAG), chondroitin sulfate and heparan sulfate cover the luminal surface of endothelial cells [39].

Endothelial cells

They form an important component of the glomerular filtration barrier. As the size of the pores is larger than the circulating proteins like albumin, the glomerular endothelial cells are considered non-contributory for macromolecule filtration. Recent studies, however, have demonstrated that these cells play an important role in glomerular filtration barrier. GAG digestion by chondroitinase, hyaluronidase, and heparanase damage the glycocalyx layer and decrease the density of negative charge at the glomerular filtration barrier, thus increasing fractional clearance of albumin [40] [41]. It has been observed that the fractional clearance of albumin increases 12 folds without any changes in the ultrastructure when non-covalently bounds components of endothelial glycocalyx are eluded by infusing hypersonic sodium chloride in the renal artery [42].

Tubulointerstitial cells

The tubulointersitium consists of interstitial cells, tubular system and the vascular system of the kidney [45]. There is significant amount of evidence indicating that tubulointerstitial changes are associated with progression of DN [43] [44]. 

Morphology of podocytes

Loss of podocytes within the glomeruli occurs early in the the progression of DN. Pagtalunan et al., using renal biopsies obtained from Pima Indian patients diagnosed with type 2 diabetes with macroproteinuria, demonstrated a decrease in the number of podocytes per glomeruli [46]. The flattening of podocyte foot processes was found to be associated with the loss of podocytes [46]. A reduction in the number of podocytes has been found to be a good predictor for the progression of albuminuria [47]. The nephropathy found in type 1 DM patients has been shown to have similar changes [48] [49].

The measures to prevent or retard the progression of diabetic nephropathy include:

• Control of blood pressure with a target SBP of <130 mmHg and diastolic blood pressure of <80 mmHg using ACE inhibitors (preferred for type 1 DM) or ARBs (preferred in type 2 DM patients)
• Restrict salt intake to <6 grams per day
• Dietary protein restriction (0.8 - 1.0 g/kg body weight)
• Tight control of hyperglycemia, with a target HbA1c <7.0
• Smoking cessation
• Consider initiating the patient on statins  
• Weight loss in obese patients 
• Avoid minor analgesics
• Avoid use of nephrotoxic drugs such as NSAIDs, certain antibiotics and contrast media

Diabetic nephropathy (DN) is a clinical syndrome, characterized by the presence of persistent albuminuria (>300 mg/day or >200 μg/min confirmed by testing at least twice, 3-6 months apart), elevated arterial blood pressure and progressive decline in glomerular filtration rate (GFR). Approximately 20-40% of diabetic patients are eventually diagnosed with DN. It is the most common etiology for end-stage renal disease (ESRD) and the most frequent indication for chronic dialysis. The major risk factors include hypertension, hyperglycemia, glomerular hyperfiltration, proteinuria, disorders of renal renin-angiotension system, genetic predisposition and presence of advanced glycation end-products. Other possible risk factors include dyslipidemia and numeric depletion of nephrons.

Diabetes can lead to kidney disease by causing injury to the nephrons due to excess glucose (a type of sugar). Diabetes does not allow the body to use the glucose present in blood. When the glucose builds up in the blood, it starts damaging the nephrons. Nephrons are a part of the kidney that filter out the waste and fluid from blood to make urine. Diabetes is a major cause of kidney disease. Controlling the blood sugar levels is important in order to prevent and treat kidney disease.

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