Diabetic Kidney Disease (Diabetic Nephropathy)

Essentials

• Diabetic kidney disease (DKD, also diabetic nephropathy) is a chronic kidney disease causing albuminuria and/or impaired kidney function.
• Albuminuria may be reversible in both type 1 and type 2 diabetes.
• Treatment of hypertension, good glycaemic control and not smoking are important for preventing and treating the disease.
• Patients with kidney disease should be screened for albuminuria (urine albumin/creatinine ratio) and estimated glomerular filtration rate (eGFR) and have their blood pressure checked at least annually. Hypertension should be treated effectively.
• Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the first-line drugs in the prevention and treatment of diabetic kidney disease.
• SGLT2 inhibitors and GLP-1 agonists are the first-line antidiabetic drugs. SGLT2 inhibitors also preserve renal function and are the primary choice.
  • These groups of drugs reduce cardiovascular morbidity and mortality, which is one of the main problems with diabetic kidney disease.
  • GLP-1 agonists and nowadays also SGLT2 inhibitors can be used even at low eGFR levels.
  • SGLT2 inhibitors decrease the risk of hyperkalaemia without causing hypokalaemia.

Definitions

• Diabetic kidney disease is a chronic kidney disease causing albuminuria and/or impaired kidney function.
• The term used in the past, ‘diabetic nephropathy', refers to the structural changes due to hyperglycaemia that can be seen in renal biopsy.
• The definition of albuminuria is given in table T2 and that of chronic kidney disease in table T3.

Epidemiology

• Albuminuria may remain stable for a long time or it may be reversible. This depends essentially on the therapeutic control of plasma glucose levels and blood pressure.
• GFR may be reduced even where no albuminuria has been detected.
• Albuminuria and decreased eGFR are cardiovascular risk factors that potentiate each other's effects.
• Type 1 diabetes
  • Albuminuria very rarely develops within the first 5 years.
  • Approximately 25% of patients will develop albuminuria and less than 10% severely increased albuminuria (proteinuria) or end-stage renal failure when they have had the diabetes for 40 years 1.
  • A small share of the patients will end up requiring renal replacement therapy (in Finland, 2.2% or 7.0% of patients after having had the diabetes for approx. 20 or 30 years, respectively).
• Type 2 diabetes
  • Albuminuria is present in approximately 20% of patients at presentation.
  • The progression of renal damage is likely to be quite similar to that in type 1 diabetes.
  • Up to about 40% of patients with type 2 diabetes develop an impairment of renal function during their disease. In only a part of the patients is the renal failure caused by classic diabetic nephropathy.
  • As cardiovascular mortality is particularly high in patients with diabetic kidney disease, only a small proportion of patients will progress to end-stage renal failure. Due to the high prevalence of type 2 diabetes, the number of patients with type 2 diabetes starting dialysis annually is equal to that of patients with type 1 diabetes.

PreventionChoice of Antihypertensive Drug in the Diabetic Patient from Prognostic Point of View, Glycaemic Control for Slowing the Progression of Microvascular Complications in Diabetes Mellitus, Protein Restriction in Diabetic Renal Disease, Statins for Improving Renal Outcomes, Reducing Cardiovascular Events by Multifactorial Intervention in Patients with Type 2 Diabetes, , ACE Inhibitors and Angiotensin II Receptor Blockers for Diabetics with Microalbuminuria, Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease

• The appearance of albuminuria is also a warning signal for the risk of heart disease - it calls for intensifying the lifestyle treatment and in most cases also the pharmacotherapy.
• Risk factors for increased albuminuria include:
  • hypertension
  • poor glycaemic control
  • smoking
  • high dietary protein intake
  • dyslipidaemia
  • obesity and a sedentary lifestyle.
• Impacting these risk factors and using ACE inhibitors or ARBs or certain antidiabetic medications (SGLT2 inhibitors or GLP-1 analogues) can slow down the course of kidney disease and reduce cardiovascular morbidity and mortality.

Diagnosis of diabetic kidney disease

• Increased albuminuria is the most common, early finding.
• Urine albumin/creatinine ratio levels exceeding 3 mg/mmol are usually defined as showing increased albuminuria T2.
• Albumin excretion in urine should be measured when diagnosing type 1 diabetes (after the correction of acute hyperglycaemia) and screened for annually after 5 years have elapsed from diagnosis. In people with type 2 diabetes, screening should be done annually starting immediately after diagnosis.
• In children, kidney disease is hardly ever diagnosed before puberty.
• In diabetes, renal function may be impaired even if albumin excretion in urine is normal. Therefore, the estimated glomerular filtration rate (eGFR) should be determined annually Gfr Calculator.

Measuring albuminuria

• Urinary albumin can be screened for in a variety of ways Proteinuria.
• The albumin/creatinine ratio, measured preferably from a single morning urine sample, is normally used.
  • False positive results may be obtained in elderly people, as creatinine excretion in urine decreases with advancing age.
• The reference values are presented in table T2.
• Albumin excretion is subject to daily variation, and it may be increased in urinary tract infection or acute febrile illness, after physical exercise, during menstruation as well as in heart failure. Diagnosis must therefore be based on two positive results out of three measurements carried out during a 3-6-month period.
• Albuminuria is a significant finding at any eGFR level.
• The estimated glomerular filtration (eGFR) should be determined annually Increased Blood Creatinine Concentration, Egfr and Renal Function Tests Gfr Calculator. The classification of chronic kidney disease is presented in table T3.
  • Chronic kidney disease can be diagnosed if eGFR stays below 60 ml/min/1.73 m² for at least 3 months.
• Chemical screening of urine is recommended at least when diagnosing the kidney disease. Microscopic haematuria may also be present in patients with diabetic kidney disease.
• Renal ultrasonography may be needed for differential diagnosis.
• When albuminuria has been detected and the treatment of all risk factors has been intensified, response to treatment should be confirmed after 3-6 months.
• If albuminuria or reduced eGFR has been detected, the level of albuminuria and eGFR should be followed regularly, at least once a year. The frequency of follow-up depends on the rate of progression and the severity of the kidney disease.

Treatment of hyperglycaemia

• Good glycaemic control reduces the incidence of early diabetic kidney disease in all patients with diabetes.
• The aim is to reach the recommended individually set target value for Hb_A1c, which is higher in elderly patients and in patients with multiple diseases than in patients who have had diabetes for only a short time Comprehensive Treatment and Follow-Up of Type 2 Diabetes.
• Very intensive treatment of hyperglycaemia will slow down the development of albuminuria but its effect on the progression of kidney disease is uncertain, and it may predispose the patient to hypoglycaemias, particularly if they have progressive renal failure.

Treatment of hypertensionACE Inhibitors and Angiotensin II Receptor Blockers for Diabetics with Microalbuminuria, Antihypertensive Agents for Preventing Diabetic Kidney Disease, Choice of Antihypertensive Drug in the Diabetic Patient from Prognostic Point of View

• In diabetic kidney disease, the target blood pressure is below 130/80 mmHg. Very low levels (< 120/70 mmHg) should not be aimed for with pharmacotherapy.
• If increased albuminuria is detected in a normotensive patient, consideration should be given to starting an ACE inhibitor since ACE inhibitors have been shown to reduce albuminuria regardless of blood pressure.
• ACE inhibitors are always the first-line drug for patients with type 1 diabetes. ARBs are a good alternative if the patient cannot tolerate ACE inhibitors, and either can be used equally well in patients with type 2 diabetes. Low-dose thiazide diuretics (12.5-25 mg hydrochlorothiazide), calcium-channel blockers and selective beta blockers may also be considered. In most cases, a combination of these drugs is needed in order to reach treatment goals.
• Renal artery stenosis is common, which must be borne in mind when an ACE inhibitor or ARB is started for the treatment of diabetic kidney disease (risk of sudden deterioration in renal function; measurement of plasma creatinine).
• If overt proteinuria leads to oedema, a loop diuretic should be given (e.g. furosemide). In patients with type 1 diabetes and normal renal function, also a low dose of a thiazide diuretic may be used combined with other antihypertensive drugs.
• In combined use of drugs affecting the renin-angiotensin system (ACE inhibitors, ARBs and renin inhibitors) the risks usually outweigh the benefits; therefore, the use of such combinations should be limited to special cases in specialized care.
• In the majority of patients with type 2 diabetes, hypertension is associated with obesity and lifestyle changes are the primary form of intervention. The treatment should emphasize weight loss, moderate salt intake, limiting the consumption of alcohol and increasing the amount of physical exercise.
• Of the antidiabetic drugs, those that facilitate glucose excretion by the kidneys (SGLT2 inhibitors) and GLP-1 analogues have a clinically significant blood pressure lowering effect as well as established renal protective and arterial disease event reducing effects.
  • The renal and cardiovascular protective effect is not explained merely by the effect on blood pressure or glycaemia.
• Autonomic neuropathy is common in patients with chronic renal failure, and measures should be taken to avoid orthostatic hypotension.

Diet

• For the basis of dietary recommendations, see also local recommendations.
• Diet has an impact on many factors which are important as far as nephropathy is concerned. These include:
  • glycaemic control
  • blood pressure
  • plasma lipids
  • obesity
  • renal function and the degree of proteinuria.

Indications for a specialist consultation

• The available resources determine the structure of local treatment chains.
• A consultation with a specialist in internal medicine or a nephrologist is warranted if nephropathy is progressing rapidly (increasing albuminuria or decreasing GFR) regardless of intensified treatment or if there are problems relating to differential diagnosis or significant treatment problems.
• Due to the presence of multiorgan damage, patients with diabetic kidney disease should receive early active treatment for uraemia.
• Renal transplantation is usually the treatment of choice for uraemia in suitable patients. If coronary artery surgery or angioplasty is needed, it should be performed before the transplantation.

Drug therapy in diabetic kidney diseaseSglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease

• For drug doses in patients with renal failure, see locally available, relevant pharmaceutical source(s) and summaries of product characteristics (SPCs).
• The dose of statins usually needs no adjustment. Atorvastatin and fluvastatin are considered the safest of statins in renal insufficiency, because the role of the kidneys in their elimination is the smallest. In patients on cyclosporin, the manufacturer's instructions are to be followed. Concomitant use of rosuvastatin and cyclosporin is contraindicated.
• NSAIDs may have an adverse effect on glomerular filtration.

• In patients with diabetic kidney disease, SGLT2 inhibitors are the first choice, taking into account the eGFR limits allowed by the summary of product characteristics. They are seen to belong to the treatment (if they are otherwise suitable) regardless of the balance of diabetes and other antidiabetic drugs.
• SGLT2 inhibitors reduce albuminuria and slow down the decrease of eGFR Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease. They have a favourable effect on cardiovascular mortality and reduce the need for hospital treatment of heart failure Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease. Chronic kidney disease (with or without type 2 diabetes) is nowadays an indication for dapagliflozin.
• GLP-1 agonists may be used up to an eGFR level of 15 ml/min/1.73 m² . They, too, have a favourable effect on cardiovascular morbidity and mortality.
• Long-acting GLP-1 agonists prevent the aggravation of albuminuria in patients with cardiovascular disease, particularly.
• Of DPP-4 inhibitors, the dose of saxagliptin, sitagliptin and vildagliptin must be reduced if eGFR falls below 50-60 ml/min. There is no need to change the dose of linagliptin. If GLP-1 agonists are to be started, DPP-4 inhibitors must be withdrawn.
• Sulphonylureas should not be used in patients with renal failure.
• Starting metformin should be avoided in renal insufficiency (GFR < 60 ml/min/1.73 m² ) because the accumulation of metformin carries an increased risk of lactic acidosis.
  • If a patient with an eGFR of 45-60 ml/min/1.73 m² is on metformin, the dose should be reduced (not more than 2 g/day) and the patient should be carefully followed up. The dose should be further halved, if eGFR is between 30-44. If the eGFR is below 30 ml/min/1.73 m² , metformin must not be used.
  • Administration of metformin should be discontinued before major surgery and before interventions involving the use of an intravenous contrast medium because of the risk of exacerbation of renal insufficiency and of lactic acidosis.
  • During acute illnesses that alter the haemodynamics or fluid balance, metformin should be discontinued (patient guidance) and hyperglycaemia treated with insulin.
• An insulin sensitizer (pioglitazone) can be used at the physician's discretion in mild to moderate renal insufficiency but adverse effects such as fluid retention and anaemia render its use problematic.
• Switching over to insulin therapy is often appropriate in renal insufficiency. Exogenous insulin is eliminated via the kidneys, and the prolonged duration of action of insulins should, therefore, be kept in mind.
• Use of antidiabetic drugs in patients with renal failure: see table T4.

Other renal problems in people with diabetes

• Clinical features suggestive of other renal pathologies:
  • development of proteinuria before 5 years have elapsed from diagnosis (in type 2 diabetes, it is often difficult to determine the time of disease onset)
  • acute presentation of renal disease
  • haematuria
  • absence of retinopathy and neuropathy in a patient with type 1 diabetes.
• Diabetes increases the risk of asymptomatic bacteriuria and symptomatic UTI but looking for and treating asymptomatic bacteriuria is of no benefit.
• Cystitis and pyelonephritis should be treated normally. Imaging should be performed with lower treshold than normally if the disease does not respond to treatment chosen by antimicrobial sensitivity.
• UTIs are associated with more complications, such as renal-level infections, intra- or perirenal abscesses and sepsis.
  • Pyelonephritis in elderly patients with diabetes more often involves bacteraemia, and mortality is increased.
  • Pyelonephritis requires hospital treatment more often than in patients without diabetes.
• Neurogenic bladder and increased residual urine predispose the patient to urinary tract infections and may cause incontinence.
• Diabetic patients are at increased risk of developing acute renal failure in association with surgery, trauma or systemic infections Acute Kidney Injury.
• Contrast media may cause acute renal failure. If an investigation requiring the use of a contrast medium is necessary, the dose of the contrast medium should be as small as possible, and adequate hydration must be ensured .