Diabetic nephropathyE14.20; N08.3

Diabetes-associated kidney diseases include all forms of renal damage that can occur in patients with diabetes mellitus, such as (diffuse or nodular) glomerulosclerosis, chronic interstitial nephritis, papillary necrosis and various tubular lesions. In their early form, they can be avoided or reversed in the long term by consistent blood sugar and blood pressure controls. Clinically, the symptoms of type 1 and type 2 diabetes are defined by persistent (micro) albuminuria (Papadopoulou-Marketou N et al. 2017), decrease in glomerular filtration, development or worsening of arterial hypertension, dyslipoproteinemia and other diabetes-typical complications (Schlosser M et al. 2017; Bhattacharjee N et al. 2016). Diffuse diabetic glomerulosclerosis" is the most common lesion and is found in most diabetics with nephropathy, regardless of the clinical manifestations of renal involvement. Nodular glomerulosclerosis (Kimmelstiel-Wilson type)" is specific for diabetes mellitus.

Classification of diabetic nephropathy with associated concomitant diseases (varied according to Schlosser 2017)

• Stage 1a (renal impairment with normal renal function): microalbuminuria; glomerular filtration rate (ml/min): >90; urinary albumin-creatinine quotient (mg/g): m = 20-200mg albumin/g creatinine; w: 30-300mg albumin/g creatinine; blood pressure within normal range, rising or hypertensive.
• Stage 1b (renal impairment with normal renal function): microalbuminuria; glomerular filtration rate (ml/min): >90; urinary albumin-creatinine ratio (mg/g): m = 20-200mg albumin/g creatinine; w: 30-300mg albumin/g creatinine; dyslipidemia, rapid progression of CHD, AVK, retinopathy, and neuropathy.
• Stage 2: Mild renal insufficiency: Glomerular filtration rate (ml/min): 60-89; urinary albumin-creatinine ratio (mg/g): m = >200mg albumin/g creatinine; w: >300mg albumin/g creatinine; S-creatinine borderline or elevated, hypertension, dyslipidemia, hypoglycemic tendency, rapid progression of CHD, AVK, retinopathy and neuropathy; anemia development; bone metabolism disorder.
• Stage 3: Moderate renal insufficiency: Glomerular filtration rate (ml/min): 30-59; urinary albumin-creatinine ratio (mg/g): decreasing; S-creatinine borderline or elevated, hypertension, dyslipidemia, hypoglycemic tendency, rapid progression of CHD, AVK, retinopathy and neuropathy; anemia development; disorder of bone metabolism.
• Stage 4: High-grade renal insufficiency: Glomerular filtration rate (ml/min): 15-29; urinary albumin-creatinine ratio (mg/g): decreasing; S-creatinine borderline or elevated, hypertension, dyslipidemia, hypoglycemic tendency, rapid progression of CHD, AVK, retinopathy, and neuropathy; anemia development; disorder of bone metabolism.
• Stage 5: Terminal renal insufficiency: Glomerular filtration rate (ml/min): <15; urinary albumin-creatinine quotient (mg/g): decreasing; S-creatinine borderline or elevated, hypertension, dyslipidemia, hypoglycemic tendency, rapid progression of CHD, AVK, retinopathy , and neuropathy; anemia development; disorder of bone metabolism.

Not all patients with diabetes mellitus develop diabetic nephropathy. Family studies prove a genetic predisposition (Papadopoulou-Marketou N et al. 2017). Furthermore, men have a higher risk of developing diabetic nephropathy than women. The average progression to diabetic nephropathy in type 1 and type 2 diabetes is about 2.5% per year; after 10 years 20-30% of people with diabetes mellitus develop diabetic nephropathy. At around 30%, diabetic nephropathy is the most common cause of renal failure requiring dialysis in Central Europe (Tesch GH 2017). The risk of nephropathy is now considered to be the same for type 2 diabetes as for type 1 diabetes.

The pathophysiology of diabetic nephropathy is determined by changes in metabolic and hemodynamic processes. For example, the enhancement of glucogenic pathological metabolic processes leads to increased oxidative stress, to increased formation and accumulation of advanced glycation end products (AGEs) and to changes in polyol and hexosamine metabolism. Pathogenetically significant is intraglomerular hypertension which induces glomerular hyperfiltration (Wada J et all. 2013). Furthermore, signal transduction pathways such as protein kinase C (PKC), mitogen activated protein (MAP) kinases, nuclear transcription factors such as NF-κB and profibrotic cytokines such as TGF beta are activated at the molecular level. These complex molecular pathomechanisms lead to proteinuria, glomerulosclerosis, interstitial fibrosis and tubule atrophy.

Hyperglycaemia inhibits the expression of thrombomodulin in the endothelial cells of the glomeruli. Thrombomodulin activates protein C. Activated protein C in turn prevents the apoptosis of endothelial cells and podocytes of the glomeruli triggered by hyperglycaemia. If the expression of thrombomodulin decreases, this leads to an increased loss of glomeruli.

Furthermore, the immune response in patients with diabetic nephropathy differs from that of other nephrogenic diseases (Tesch GH 2017. The role of the complement system in the pathogenesis of the disease is still largely unexplained (Flyvbjerg A 2017). The role of glomerular inflammatory processes is also unclear (Wada J et all. 2013).

The damage to the glomeruli is primarily caused by non-immunological mechanisms and is histopathologically characterized by nodular glomerulosclerosis (Kimmelstiel-Wilson).

Classification of diabetic nephropathy according to the severity of histologically detectable tissue changes

• Class I: Thickening of the glomerular basement membrane (>395 nm in women, >430 nm in men).
• Class IIa: Mild widening in more than 25% of the mesangium observed (connective tissue between the capillary loops of the glomerulus: the mesangium is not wider than the lumen of the capillary loops.
• Class IIb: Severe widening in > 25% of the observed mesangium: the mesangium is wider than the lumen of the capillary loops.
• Class III: Nodular sclerosis: At least one typical nodular sclerosis of the capillary loops with hyaline accumulation.
• Class IV: Advanced diabetic glomerulosclerosis: More than 50% of the glomeruli are completely sclerosed.

The diagnosis "diabetic nephropathy" can be assumed with high probability if a persistent albuminuria exists, i.e. the albumin-creatinine quotient in urine is >20mg/g in men and >30mg/g in women, measured in 2 samples within 3 months in each case. Otherwise, the necessary screening is carried out at least once a year by determining the albumin-creatinine quotient in the first morning urine and calculating the eGFR, since patients with diabetes can already have limited kidney function even without albuminuria. Further diagnostics:

• Evaluation of the ocular fundus
• ECG, possibly with load
• Long-term blood pressure measurement
• lipids (total, HDL and LDL cholesterol, triglycerides)
• Foot status (pulses, peripheral arterial pressure measurements, tuning fork test)
• In case of renal insufficiency: exclusion of:
  • secondary renal hyperparathyroidism (measurement of serum calcium and phosphate, parathormone)
  • Anemia (Hb in men: <13g/dl; in women <12g/dl)

Already at the stage of microalbuminuria, the risk of life-threatening complications of the cardiovascular system is increased and rises significantly with increasing renal function impairment. A uremic syndrome manifests itself in decreasing performance, general malaise, fatigue, pruritus, loss of appetite, nausea and vomiting. Diabetic nephropathy is accompanied by diabetogenic disorders of other organs such as.

Skin(pruritus, mycotic and bacterial infections, facial erythema(rubeosis diabeticorum), necrobiosis lipoidica s.a. diabetes mellitus, skin lesions).

Potency disorders, amenorrhea

Macro-microangiopathy (early arteriosclerosis, arterial occlusive disease of the cerebral vessels, PAVK, coronary heart disease)

Diabeticretinopathy ( E14.30 + H36.0)

Diabetic neuropathy (E14.40)

Diabeticfoot syndrome (E14.74)

Diabeticcardiomyopathy (E14.20+I125.-)

Patients with diabetic nephropathy should moderate their daily protein intake (recommended intake is 0.8 g -1.0 g protein per kg body weight).

A normal body weight is desirable (body mass index: 18.5 - 24.9 kg/m²).

Appropriate lifestyle change

Furthermore:

• Smoking ban
• regular physical activity
• Consistent taking of the medication

Therapy of diabetic nephropathy (the correct selection and dose adjustment of oral antidiabetic drugs in renal insufficiency is important. This reduces the risk of cardiovascular complications such as heart attack or stroke. Further inhibiting the progression (progression) of renal impairment):

• Biguanides: Metformin (possible up to a GFR of 30 (45) ml/min/1.73sqmKO under close monitoring in stable patients). Metformin has a nephroprotective effect in addition to its antidiabetic effect (Eisenreich A et al.2017).
• Sulfonylureas: glimeprod/gliquidone dose reduction, contraindicated if GFR <30.
• Sodium-glucose cotransporter 2 inhibitors(SGTL2 inhibitors): Empagliflozin dose reduction to 10mg/day if GR<60ml/min. Drug to be preferred in presence of cardiovascular risks.
• Insulin: Dose adjustments usually necessary during course.
• Therapy of hypertension:

Medicinal reduction of blood pressure to values below 130/80 mmHg.

• ACE inhibitors or AT1 antagonists are recommended as first-line agents, usually in combination with a diuretic.
• The effect of ACE inhib itors and AT1 antagonists is explained by inhibition of hyperfiltration and sclerosis in the glomeruli. If protein excretion is > 1.0 g/24 h, the goal is to lower blood pressure to <125/75 mmHg. Another treatment goal is to reduce protein excretion <0.5-1 g/24h. In the presence of macroalbuminuria: even with normal blood pressure, therapy with an ACE inhibitoror an AT1 antagonist is recommended.

Other:

• In stage 1-4 diabetic kidney disease, LDL cholesterol should be reduced to levels <100 mg/dl (optionally <70 mg/dl) with statin monotherapy (statins = first-line agents).
• Antiplatelet agents: their use is recommended when there is evidence of cardiovascular complications (e.g. Ass 100mg/day).
• Renal function < 15% requires renal replacement procedures such as hemodialysis, peritoneal dialysis or renal transplantation. In patients with type 2 diabetes, kidney transplantation may be considered. In patients with type 1 diabetes, combined kidney and pancreas transplantation may be possible.
• Phosphate-calcium metabolism: compensation of a disturbed phosphate-calcium metabolism by phosphate-lowering agents or vitamin D or corresponding analogues.

With poor adjustment of blood sugar, the risk of disease increases significantly. An increase in protein excretion in the urine indicates the progression of the disease.

Halving protein excretion through drug therapy halves the risk of kidney failure!

Other risk factors include elevated blood lipids and nicotine abuse. In most cases, diabetic nephropathy is accompanied by other complications such as retinopathy, neuropathy or macroangiopathy (see classification below). In the presence of nephropathy with proteinuria, the ten-year survival rate is estimated to be 25% to 50%, with non-renal causes of death such as coronary heart disease or stroke also contributing to the high mortality. In manifest diabetic nephropathy, 75% of type 1 diabetics and about 20% of type 2 diabetics develop terminal renal failure within 20 years. In Europe and the USA, about 50% of all dialysis patients are diabetics.

The following measures are recommended for the prevention of diabetic nephropathy:

• Strict adjustment of blood sugar levels, if necessary adjustment to intensified insulin therapy. For therapy control, the HbA1c value is determined in the blood (<6.5-7.5%, depending on the age and concomitant diseases of the patient).

Addresses on the Internet: http:// www. German Diabetes Society. en

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3. Flyvbjerg A (2017) The role of the complement system in diabetic nephropathy. Nat Rev Nephrol 13:311-318.
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