Nephropathy in Diabetes

Preliminary note

People with diabetes who are affected by kidney damage have a significantly increased cardiovascular risk. This requires early diagnosis, consistent and target-oriented therapy of diabetes, arterial hypertension and all concomitant diseases, as well as early, close and patient-centered cooperation between general medicine, diabetology, nephrology and cardiology.

Definition

Nephropathy in diabetes is understood to represent all forms of kidney damage that may occur in temporal or causal relation to diabetes mellitus. In the course of the disease, there may be changes in the excretion of protein (primarily albumin but also other proteins) in the urine, a decrease in kidney function, recognizable by a reduction in the glomerular filtration rate (eGFR), and the development and/or worsening of concomitant diseases associated with diabetes, such as arterial hypertension and lipid metabolism disorders.

The development of kidney damage in type 1 diabetes mellitus typically occurs in 5 stages [1]. In people with type 2 diabetes mellitus, the development of kidney damage may be different and renal biopsy studies have demonstrated a high rate of non-diabetes-associated changes. Therefore, the extent of kidney damage is classified independently of the underlying disease according to Kidney Disease: Improving Global Outcomes (KDIGO) ([Fig. 1]) by determining the estimated glomerular filtration rate (eGFR) and the extent of albuminuria, measured by the ratio of albumin to creatinine (albumin-to-creatinine-ratio, ACR) [2]. Albuminuria is an important prognostic parameter for the progression of renal function impairment and is divided into 3 “A” stages; the extent of renal function impairment is divided into 6 “G” stages as eGFR ([Fig. 1]). Determination of ACR, also to assess the effectiveness of therapy,

Fig. 1 Stages of chronic renal failure according to Kidney Disease: Improving Global Outcomes (KDIGO) [2]. The risk of an unfavorable course is marked in color (green: low risk [if no markers of chronic kidney disease are present, no CKD]; light orange: moderately increased risk; orange: high risk; dark red: very high risk). CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate.

Screening, examination and diagnosis

The eGFR and albuminuria should be determined at least once a year in people with diabetes mellitus. The determination of ACR in morning urine is recommended. The ratio of urine albumin to urine creatinine (ACR), which allows a standardized and urine concentration-independent determination of the extent of albuminuria, is important. Before doing so, it is recommended to perform a urine multi-field strip test to exclude interfering factors, such as a urinary tract infection. If the result is unclear or pathological, repeated determination at 3-month intervals is recommended for validation. Today, the determination of eGFR is usually performed according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or alternatively according to the Modification of Diet in Renal Disease (MDRD) formula. The determination of cystatin in serum can also be used. Limitations of these estimation formulas include considerable excess weight or low weight, advanced age, but also rapidly changing kidney function.

Differential diagnosis

Not everyone affected by diabetes has kidney damage caused by diabetes in the presence of impaired kidney function and/or albuminuria. Close monitoring of the findings and the initiation of further diagnostic measures and/or an appointment with a nephrologist are necessary in the case of

• In case of suddenly-occurring high proteinuria

• With rapidly-increasing proteinuria,

• In case of rapid decrease in eGFR or increase in creatinine or cystatin C in serum,

• For a pathological urine strip test, in particular the detection of erythrocytes and/or leucocytes

• For diabetes duration≤5 years for people with type 1 diabetes

• In case of conspicuous sonographic changes of the kidneys, asymmetrical kidney size, unilateral reduction in size, etc.

• Patients without albuminuria/proteinuria: they may have a hypertensive nephropathy;

  • if arterial hypertension is present, further diagnostic measures may be necessary (see section on Blood pressure).

Supplementary diagnostics

• Examination of the pulse status, especially in the area of the feet, determination of the ankle-brachial index, if necessary vascular Doppler examination

• Long-term blood pressure measurement

• Electrocardiogram (ECG) and/or stress test

• Fundoscopy

• Determination of lipid status, especially low-density lipoprotein (LDL) cholesterol (measured), non-high-density lipoprotein (HDL) cholesterol and one-time Lipoprotein (a) (Lp(a))

Prophylaxis and delay of the progression of kidney damage

Lifestyle modification can have a beneficial effect on the development of kidney damage, for example, by

• Not smoking,

• Reducing salt consumption to a maximum of 5 g NaCl/day (corresponds to 2 g sodium/day),

• Performing regular physical activity, target 150 minutes/week [11],

• Losing weight,

• If necessary, normalizing an increased protein intake (target 0.8 g protein/kg body target weight/day),

General measures in everyday diagnostics and/or therapy:

• Differentiated indication for the use of contrast media in radiology,

• Avoiding the administration of non-steroidal antirheumatic drugs,

• Antibiotic therapy of symptomatic urinary tract infections,

• Dose adjustment of medications to the reduced renal function and consideration of the risk of accumulation and interaction of medications in case of reduced renal function.

Early and consistent therapeutic measures can positively influence the development and/or deterioration of kidney damage through

• Target value-oriented blood pressure therapy (see “Blood pressure therapy” section),

• Target value-oriented diabetes therapy (see “Therapy of diabetes mellitus” section),

• Target-oriented lipid therapy (see “Therapy of dyslipidemia” section).

In close coordination with the nephrologist, the therapy of renal disorders of the acid-base balance and the calcium-phosphate balance, possibly anemia, or the reduction of protein intake is carried out.

Therapy

Blood pressure therapy

Patients with type 1 and type 2 diabetes mellitus without manifest arterial hypertension

• In normotensive patients with type 1 and type 2 diabetes mellitus with persistent elevated albuminuria (stage A2 KDIGO), therapy with angiotensin-converting enzyme (ACE) inhibitors may be considered; this treatment should be performed for patients with macroalbuminuria (stage A3 KDIGO). In the case of intolerance to ACE inhibitors, an angiotensin II receptor type 1 (AT1) blocker can be used as a substitute in both patient groups.

Patients with type 1 and type 2 diabetes mellitus and arterial hypertension

• The European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines [3] recommend antihypertensive therapy for all patients with blood pressure≥140/90 mmHg. Blood pressure should be reduced to target values≤130/80 mmHg in patients with hypertension and diabetes. In patients with chronic renal insufficiency (CKD), a systolic target blood pressure of 130–139 mmHg is recommended. The new KDIGO guidelines for managing blood pressure in chronic kidney disease [12] recommend a systolic blood pressure target of<120 mmHg, including in people with diabetes and CKD. However, the target blood pressure can be adjusted individually depending on the extent of proteinuria, concomitant diseases and therapeutic safety.

• For primary use in drug therapy: ACE inhibitors – AT1 blockers in case of intolerance – in combination with calcium antagonists as well as other substances, if necessary. Beta-blockers and diuretics are recommended as additional combination medications for the prevention of coronary complications and for blood pressure control; data on the possible deterioration of glycemic control with the use of these substances is mixed. The combined therapy of ACE inhibitors and AT1 blockers is not recommended because of the dangerous risk of hyperkalemia.

Therapy of diabetes mellitus

• To prevent kidney damage, an HbA1c value between 6.5% (48 mmol/mol) and 7.5% (58 mmol/mol) is recommended. The upper target range between 7.0 and 7.5% (53–58 mmol/mol) is recommended for patients with macroangiopathy and/or hypoglycemia perception disorder.

• To prevent the progression of diabetic kidney damage, an HbA1c value of approximately 7% (53 mmol/mol) is recommended.

For patients with type 2 diabetes mellitus and a clinically-predominant chronic renal insufficiency, a sodium/glucose co-transporter-2 (SGLT-2) inhibitor therapy is recommended in addition to lifestyle and metformin therapy in the absence of contraindications. If this is not possible, glucagon-like peptide-1 (GLP-1) receptor agonists with proven cardiovascular benefit should be used [4] [5].

As of stage G3b/G4 KDIGO, the HbA1c value is no longer a reliable parameter for the quality of metabolic control, as it can be unreliable, especially in the presence and/or treatment of renal anemia.

The use of continuous glucose monitoring (CGM) is not formally approved for chronic renal failure and dialysis, but numerous publications and case reports indicate safe use.

For people with type 2 diabetes mellitus, [Fig. 2] shows an overview of the selection and possible dose adjustment of some antidiabetic drugs in patients with impaired kidney function. It should be noted that people with diabetes and impaired renal function have a massively increased risk of hypoglycemia; this is due to a slower breakdown of insulin (especially exogenously-supplied insulin), reduced gluconeogenesis of the kidney, and prolonged renal elimination of oral antidiabetics with consecutively extended half-life. Therefore, renal function should be checked every 3/6/12 months depending on the stage of the disease, and the dose of antidiabetic drugs used should be adjusted in accordance with the concomitant medication.

Fig. 2 Overview: Approval of antidiabetic drugs in chronic renal insufficiency in Germany as well as hypoglycemia risk of the individual substances. The information refers exclusively to the approval as an antidiabetic drug. eGFR = estimated glomerular filtration rate; Inh = Inhibitor; GLP-1 = glucagon-like peptide-1; RA = receptor agonist); DPP-4 = dipeptidylpeptidase 4; SGLT-2 = sodium-glucose cotransporter-2. Data source: respective package leaflet for experts, version dated June 2022.

For people with diabetes and CKD up to dialysis, sensor-based insulin pump therapy, possibly with automatic insulin delivery (so-called AID or hybrid closed-loop systems), can achieve better metabolic control than by subcutaneous insulin administration [15 ] [16], although there is no formal approval from the manufacturer. Care should currently be provided by specialized centers because of the particular requirements for insulin therapy in dialysis patients.

Therapy of dyslipidemia

According to the ESC/EAS guidelines [6], the cardiovascular risk of patients in eGFR stages G3-G5 should be classified as high or very high. The presence of diabetes also increases the cardiovascular risk. For patients with chronic renal insufficiency not requiring dialysis, a statin or statin/zetimib combination oriented to the current target values [6] is indicated. Therapy with atorvastatin or fluvastatin is preferable, as dose adjustment is not necessary if the eGFR changes. For dialysis patients without atherosclerotic cardiovascular disease, statin therapy should not be restarted. However, if lipid-lowering therapy was in place before the start of dialysis, it can be continued.

Inhibition of progression

The risk of progression of renal failure is significantly determined by the extent of ACR and the limitation of renal function. The diabetes-related changes in the glomeruli are at least partially reversible, in principle, with optimally-controlled parameters for blood glucose and blood pressure, especially when the renin-angiotensin-aldosterone system (RAAS) is blocked. Blockage of the RAAS has also been shown to be cardioprotective. It is possible that newer substances, which specifically influence the aldosterone effect, are similarly effective.

Antidiabetic therapy with specific incretin mimetics [7] and SGLT-2 inhibitors [8] was shown to be effective in large cardiovascular endpoint studies (Liraglutide: Leader, Dulaglutide: Rewind; Empagliflozin: EmpaReg-Outcome, Canagliflozin: Canvas, Dapagliflozin: Declare-TIMI-58) show a reduction in cardiovascular mortality and a consistent positive effect on albuminuria and eGFR loss over the study period, thus demonstrating a nephroprotective effect.

The Credence and Dapa-CKD studies, which were specifically designed to reduce renal endpoints, impressively demonstrated the nephroprotective effect of canagliflozin and dapagliflozin [9] [10]. In almost all studies and meta-analyses, the nephroprotective effects for Dapagliflozin and Empagliflozin were also shown in patients with impaired renal function. Therefore, SGLT-2 inhibitors should be used not only in people with diabetes but also in people without the presence of diabetes in other approved indications. This also applies to impaired renal function up to stage G4. Recent data on the non-steroidal mineralocorticoid receptor antagonist finerenone also exhibits nephroprotective and cardioprotective effects The substance is approved in the EU and will probably be available in Germany in 2022.

Follow-up

Depending on the stage of nephropathy, the following parameters should be checked 2–4 times a year:

• Determination of the eGFR,

• Determination of ACR, also to assess the effectiveness of therapy,

• Blood pressure therapy including self-monitoring and possibly long-term blood pressure measurement,

• Determination of the HbA1c value,

• Determination of lipids (especially LDL cholesterol, possibly triglycerides).

It is recommended for patients with diabetes to consult a nephrologist in the case of renal insufficiency as of stage G3a (see [Fig. 1]). As renal function decreases with age for physiological reasons, the appointment with the nephrologist for diabetics older than 75 years should be made at the latest at stage G3b. Any more severe kidney function impairment or findings indicating non-diabetic kidney disease require an immediate appointment with a nephrologist.

German Diabetes Association: Clinical Practice Guidelines
This is a translation of the DDG clinical practice guideline published in Diabetologie 2022; 17 (Suppl 2): S327–S331 DOI 10.1055/a-1908-0801

Conflicts of Interest

LM has received fees and/or reimbursements from the following companies/institutions over the last 3 years: Abbott, AstraZeneca, Bayer, Boehringer Ingelheim Pharma, Diaplan, DDG, DGfN, Eli Lilly Pharma, Esanum, MedLearning, Merck Inc., MSD Sharp&Dohme. He declares that he sees no conflict of interest with the article he has created.; TE has received fees/cost reimbursements from Lilly, Novo Nordisk CME-Verlag, Santis, and Sanofi over the last 3 years. Within the scope of a consulting activity he received a fee from Sanofi. He is also supported by a Novo Nordisk Postdoctoral Fellowship, which is carried out in cooperation with the Karolinska Institutet, and by a mentorship program of the European Foundation for the Study of Diabetes (EFSD), which is supported by an educational grant from AstraZeneca.; MG received fees/cost reimbursements/study grants from the following companies: Alexion, Astellas, AstraZeneca, Baxter, Bayer, Boehringer/Lilly, Chiesi, Novartis. BI declares having no potential conflicts of interest.

Acknowledgment

We are grateful to Dr. Bautsch for the editorial corrections to the manuscript.

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Publication History

Article published online:
23 January 2023