What is Diabetic Nephropathy/Diabetic Nephropathy (DN) or diabetic kidney disease is a syndrome characterized by the presence of pathological quantities of urine albumin excretion, diabetic glomerular lesions, and loss of glomerular filtration rate (GFR) in diabetics. Diabetes may be classified as type 1 (autoimmune β-cell destruction and absolute insulin deficiency), type 2 (relative insulin deficiency and resistance), and other types (eg, pancreatic disease).
Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hr, or 300 mg/g creatinine), a progressive decline in glomerular filtration rate (GFR), arterial hypertension, and increased cardiovascular morbidity and mortality.
Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months or years.[rx][rx] Early on there are typically no symptoms.[rx] Later, leg swelling, feeling tired, vomiting, loss of appetite, or confusion may develop. Complications may include heart disease, high blood pressure, bone disease, or anemia.[rx][rx]
Pathophysiology of Diabetic Nephropathy
DN is a clinical syndrome characterised by the insistent albuminuria that should be confirmed on at least two occasions separated by 3-6 months, by continuous decline in the glomerular filtration rate (GFR), and by increased arterial blood pressure. DN is characterised by different events. The characteristic occurrence is thickening of the glomerular basement membrane (GBM). After renal damage, the thickening of the basement membrane starts, which leads to pathologic modifications in mesangial and vascular cells. It includes formation of AGEs, accumulation of polyols, and activation of protein kinase C [rx,rx]. It leads to activation of the inflammatory pathway playing a significant role in the damage of GBM [rx].
Secondly, the renal hemodynamic anomaly is similar in both types of diabetes [rx]. An initial physiologic abnormality is glomerular hyper-filtration related to intra-glomerular hypertension [rx]. This is complemented by the onset of microalbuminuria. Microalbuminuria is considered the first sign indicating the onset of DN [rx].
The exact pattern observed in the pathophysiology of DN is:
Thickening of GBM
Impaired endothelial integrity
Onset of microalbuminuria
Impairment of nitric oxide transport
Loss of afferent/efferent auto-regulatory control
Continued loss of glomerular filtration capabilities
Causes of Diabetic Nephropathy
- Hyperglycemia – Hyperglycemia is a significant risk factor for the development of microalbuminuria, both in type 1 and in type 2 DM [rx,rx,rx]. A reduction of 1% in HbA1c is associated with a 37% decrease in microvascular endpoints . In the presence of micro- and macroalbuminuria the role of metabolic control is less defined, even though some studies showed a deleterious effect of high glucose levels on GFR [rx,rx].
- Arterial Hypertension – Arterial hypertension is a main risk factor for the development of DN [rx,rx], and probably the best known relevant factor related to its progression. Analysis of UKPDS showed that every 10 mmHg reduction in systolic BP is associated with a 13% reduction in the risk of microvascular complications, with the smallest risk among those patients with systolic BP <120 mm Hg [rx].
- Smoking – Smoking is a risk factor for DN [rx,rx] and might contribute to its progression [rx]. Although some studies did not confirm these observations [rx,rx], it is strongly recommended to quit smoking in any phase of DN, also aiming to reduce the associated cardiovascular and cancer risk.
- Dyslipidemia – In type 2 DM, elevated serum cholesterol is a risk factor for the development of DN [rx,rx]. In type 1 DM patients increased serum triglycerides, total and LDL-cholesterol were associated with micro- and macroalbuminuria [rx,rx]. High serum cholesterol also seems to be a risk factor for GFR loss in macroalbuminuric type 1 diabetic subjects [rx].
- Proteinuria – Proteinuria itself could lead to progression of DN. Proteinuria >2 g/24 h is associated with a greater risk of ESRD [rx]. Increased leakage of albumin may induce glomerular damage probably through activation of inflammatory cascades [rx]. This would be a reason to target decreased urinary albumin excretion in DN treatment.
- Glomerular hyperfiltration – Elevated GFR values are present in about one third of type 2 DM patients [rx,rx] and theoretically it could cause DN due to glomerular damage [rx]. Studies led to controversial findings regarding its role as a risk factor for the development of DN [rx,rx]. Type 2 DM patients with a single-kidney more often present increased UAE levels [rx,rx]. On the other hand, type 1 DM patients with only one kidney do not have a more aggressive disease [rx]. Glomerular hyperfiltration probably plays a small role, if any, in the development of DN [rx].
- Dietary factors – Increased dietary protein intake seems to be associated with the presence of higher UAE values, at least in patients with type 1 DM [rx]. In patients with type 2 DM this association has not been documented. The source of proteins in the diet also seems to be related to the presence of DN. A higher intake of fish protein is related to a lower risk of microalbuminuria in type 1 DM patients [rx]. The mechanisms involved in these findings are unknown but probably related to hemodynamic factors [rx].
- Vascular disease – includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome, and vasculitis.
- Glomerular disease – comprises a diverse group and is classified into:
- Primary glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
- Secondary glomerular disease such as diabetic nephropathy and lupus nephritis
- Congenital disease such as polycystic kidney disease.
- Tubulointerstitial disease – includes drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy.
- Obstructive nephropathy – is exemplified by bilateral kidney stones and diseases of the prostate such as benign prostatic hyperplasia.
- On rare cases – pinworms infecting the kidney can also cause nephropathy.
- Nontraditional causes of CKD (CKDu) – are denoted if the common causes of CKD are not present:
- Autoimmune disease, such as lupus erythematosus
- Infection with hepatitis B, hepatitis C or syphilis
- Certain medications, such as gold salts and nonsteroidal anti-inflammatory drugs
- Solid cancerous tumors or blood cancers
Symptoms of Diabetic Nephropathy
CKD is initially without specific symptoms and is generally only detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases:
- Blood pressure – is increased due to fluid overload and production of vasoactive hormones created by the kidney via the renin–angiotensin system, increasing one’s risk of developing hypertension and/or suffering from congestive heart failure.
- Urea accumulates – leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Due to its high systemic circulation, urea is excreted in eccrine sweat at high concentrations and crystallizes on skin as the sweat evaporates (“uremic frost”).
- Potassium accumulates – in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20–25 ml/min/1.73 m2, at which point the kidneys have decreased ability to excrete potassium.[rx]
- Erythropoietin synthesis is decreased causing anemia.
- Fluid volume overload – symptoms may range from mild edema to life-threatening pulmonary edema.
- Hyperphosphatemia – due to reduced phosphate excretion, follows the decrease in glomerular filtration. Hyperphosphatemia is associated with increased cardiovascular risk, being a direct stimulus to vascular calcification.[rx] Moreover, circulating concentrations of fibroblast growth factor-23 (FGF-23) increase progressively as the renal capacity for phosphate excretion declines, but this adaptative response may also contribute to left ventricular hypertrophy and increased mortality in CKD patients.[rx][rx]
- Hypocalcemia – due to 1,25 dihydroxyvitamin D3 deficiency (caused by stimulation of FGF-23 and reduction of renal mass),[rx] and resistance to the calcemic action of parathyroid hormone.[rx] Osteocytes are responsible for the increased production of FGF-23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D3).[rx] Later, this progresses to secondary hyperparathyroidism, renal osteodystrophy, and vascular calcification that further impairs cardiac function. An extreme consequence is the occurrence of the rare condition named calciphylaxis.[rx]
- The concept of chronic kidney disease-mineral bone disorder (CKD-MBD)– [rx][rx] currently describes a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of: (1) abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (renal osteodystrophy); and( 3) vascular or other soft-tissue calcification.[rx] CKD-MBD has been associated to poor hard outcomes.[rx]
- Metabolic acidosis – (due to accumulation of sulfates, phosphates, uric acid etc.) may cause altered enzyme activity by excess acid acting on enzymes; and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia).[rx] Acidosis is also due to decreased capacity to generate enough ammonia from the cells of the proximal tubule.[rx]
- Iron deficiency anemia – which increases in prevalence as kidney function decreases, is especially prevalent in those requiring haemodialysis. It is multifactoral in cause, but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression.
- People with CKD – suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with CKD and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.[rx]
- Sexual dysfunction – is very common in both men and women with CKD. A majority of men have a reduced sex drive, difficulty obtaining an erection, and reaching orgasm, and the problems get worse with age. A majority of women have trouble with sexual arousal, and painful menstruation and problems with performing and enjoying sex are common.[rx]
- A usual first symptom – is frequent urination at night: nocturia. Other symptoms include tiredness, headaches, a general feeling of illness, nausea, vomiting, frequent daytime urination, lack of appetite, itchy skin, and leg swelling.[rx]
- swollen ankles, feet, lower legs, or hands caused by water retention
- darker urine, due to blood in the urine
- shortness of breath
- fatigue, caused by lack of oxygen in the blood
- nausea or vomiting
- metallic taste
- Weight gain
- Poor appetite
- Urine that looks foamy
- High cholesterol
- Increased protein in the urine (proteinuria)
- Decreased protein in the blood, particularly albumin
Natural clinical course of diabetic kidney disease
The natural history of DN is divided into five stages [rx]
- Stage 1 – Renal pathology develops at the onset of diabetes. The growth of the kidney increases by several centimetres. By the time of diagnosis, the GFR and urinary albumin excretion (UAE) have been increased. It can be controlled at this level by onset of insulin.
- Stage 2 – The second phase typically lasts for 5-15 years after diagnosis of diabetes. The characteristics of the second phase include: (1)GFR remains elevated due to hyperfiltration. (2)Kidneys remain hypertrophied and UAE rate stays normal.
- Stage 3 – The characteristics of stage three are:
Microalbuminuria is present. It occurs in 30-50% of patients after diabetes onset, 80% of whom go on to develop overt nephropathy over 10-15 years.
GFR remains elevated or returns to normal range
Blood pressure starts to rise in 60% of patients
Histological changes-progression is as seen in stage two.
- Stage 4 – This stage is also known as clinical nephropathy or overt nephropathy. The characteristic histological features of stage four are formation of the Kimmelstiel-Wilson nodule (focal glomerular sclerosis) and macroproteinuria. It can progress to nephrotic in 30% of patients or may decline in 80% depending on deterioration of GFR.
- Stage 5 – As the GFR continues to decline, ESRD may develop. DN is considered the most common cause of ESRD because of associated autoimmune neuropathy and cardiac disease.
The stages of chronic kidney disease (CKD) are mainly based on measured or estimated GFR. There are five stages but kidney function is normal in stage 1 and minimally reduced in stage 2.
Categories of Diabetic Nephropathy
Category C I: Normal or near normal renal structure
- These patients (35% of MA and 15% of proteinuria) had normal renal biopsies or showed very mild glomerular, tubular, interstitial and/or vascular changes.
Category C II: Typical diabetic nephropathology
- These patients (30% of MA and 50% of proteinuria) had established diabetic lesions with an approximately balanced severity of glomerular, tubulo-interstitial and arteriolar changes, a picture typical of that seen in most T1DM patients with obvious light microscopic DN changes.
Category C III: Atypical patterns of renal injury
- These patients (35% of MA and proteinuria) had relatively mild diabetic glomerular changes considering disproportionately severe: (a) Tubular atrophy, TBM thickening and reduplication and interstitial fibrosis (tubulo-interstitial lesions). (b) Advanced glomerular arteriolar hyalinosis commonly associated with atherosclerosis of larger vessels. (c) Global glomerular sclerosis. In C III group these patterns were present in all possible combinations.
Diagnosis of Diabetic Nephropathy
1)Enough time: At least 10 years past the onset of diabetes, but this criterion is often not verifiable in type 2.
2)Persistent albuminuria more than 300 mg in 24 hours
3)Diabetic retinopathy at the same time: Given that almost all patients with type 1 diabetes with diabetic nephropathy have retinopathy, retinopathy in patients with first and second criteria, prove the diagnosis, and lack of it virtually excluded diagnosis.
Renal disease less than 5 years or after 30 years of diabetes onset
- Puria, RBC or WBC cast
- Serum creatinine test
- Microscopic examination of urine
- Progressive proteinuria
- Progressive renal failure
- Acute nephrotic syndrome
- Acute renal failure
- Macroscopic hematuria
Diagnosis is based on the measurement of abnormal levels of urinary albumin in a diabetic[rx] coupled with exclusion of other causes of albuminuria. Albumin measurements are defined as follows:[rx]
- Normal albuminuria – urinary albumin excretion <30 mg/24h;
- Microalbuminuria – urinary albumin excretion in the range of 30–299 mg/24h;
- Macroalbuminuria – urinary albumin excretion ≥300 mg/24h.
Incipient nephropathy is the initial presence of low but abnormal amounts of urine albumin, referred to as microalbuminuria (persistent albuminuria at level 30–299 mg/24 hours). Overt nephropathy or macroalbuminuria (persistent albuminuria at level ≥300 mg/24 hours) develops after many years in type 1 diabetes but may be present at the time of diagnosis of type 2 diabetes.
Screening for DN
- Most guidelines recommend screening with a spot urine albumin/creatinine ratio (ACR; normal >30 mg/g creatinine), from either first morning (preferred) or random specimens. An abnormal result is repeated once or twice over a few months for consistency.
- The routine use of renal biopsy to confirm DN is much debated. Many nephrologists do not biopsy patients with classic features such as retinopathy, duration of diabetes <10 years, slow decline in GFR, gradual progression of proteinuria, and lack of active urinary sediment
- There are limitations in using albuminuria as a marker of DN as many patients experience GFR loss without deterioration in albuminuria and even normoalbuminuria.[rx] In fact, histologically proven advanced diabetic glomerular lesions can develop despite normoalbuminuria.[rx] Furthermore, low-grade albuminuria is a lesser predictor of disease progression than macroalbuminuria.[rx]
According to NICE guidelines, the following patients should be referred early to the specialist [rx]:
1) Stage 4 and 5 CKD (with or without diabetes)
2) Proteinuria together with hematuria
3) Rapidly declining GFR
4) Hypertension that remains poorly controlled despite use of at least four antihypertensive drugs at therapeutic doses
5) People with, or suspected of having, rare or genetic causes of CKD.
- A series of circulating markers of inflammation such as C reactive protein and interleukin 1, 6 and 18, and tumor necrosis factor are increased in DN and their levels correlate with albuminuria and progression to ESRD. In addition, hyperglycemia, TGF-β1 and angiotensin II stimulate the secretion of VEGF, causing the production of endothelial nitric oxide, vasodilation and glomerular hyperfiltration [rx].
Treatment of Diabetic Nephropathy
Treatment of diabetic nephropathy is based on some principle:
1)Tight control of hyperglycemia
2)control of blood and glomerular pressure
3)Control of dyslipidemia
4)Restriction of protein intake
However, there are some clinical features that help in making the decision to do renal biopsy, summarised as:
1) Short-duration type 1 diabetes
2) Autoimmune disease
3) Mild or absent retinopathy
4) Red cell casts in urine
5) Significant and persistent proteinuria
Optimal blood glucose control
Control of blood pressure at 120/70 mmHg
Avoidance of potential use of nephrotoxic drugs such as nonsteroidal Antiinflammatory Drugs (NSAIDs), aminoglycosides, etc.
Early detection and management of diabetes, especially in setting of family history.
Potential New Therapies
There is a lot of research ongoing regarding the treatment of DN
- High doses of thiamine and its derivative benfotiamine have been shown to reduce the rate of microalbuminuria in experimental diabetes nephropathy, probably due to the decrease in activation of protein kinase C, protein glycation and oxidative stress [rx].
- Treatment with a protein kinase C beta inhibitor normalises GFR, decreases albumin excretion rate, and ameliorates glomerular lesions in diabetic rodents [rx].
- Pimagedine, a second-generation inhibitor of advanced glycation end product, reduced urinary protein excretion and the decline in GFR in proteinuric type 1 diabetic patients in a randomized, placebo-controlled study [rx].