Nephropathy in Diabetes

Introduction

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-centred cooperation between general medicine, diabetology, nephrology and cardiology.

Definition

Nephropathy in diabetes is understood as 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 estimated glomerular filtration rate (eGFR), and the development and/or deterioration of concomitant diseases associated with diabetes, such as arterial hypertension and lipid metabolism disorders.

The development of kidney damage in type 4 diabetes mellitus typically occurs in 5 stages [4]. In people with type 2 diabetes mellitus, kidney damage may develop differently, 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 eGFR and the extent of albuminuria, as measured by the ratio of urine albumin to urine creatinine (albumin-creatinine ratio, ACR) Albuminuria is an important prognostic parameter for the progression of renal impairment and is divided into 3 “A” stages; renal impairment is divided into 6 “G” stages as eGFR ([Fig. 1]). Determination of ACR can also be used to assess the effectiveness of therapy.

Fig. 1 Stages of chronic renal failure according to KDIGO. Based on data by [2]. The risk of an unfavourable course is colour-coded (green: low risk [if no markers of chronic kidney disease are present, no CRI]; light orange: moderately increased risk; orange: high risk; dark red: very high risk). CRI: chronic renal insufficiency; eGFR: estimated glomerular filtration rate.

Screening, examination and diagnosis

For people with type 1 diabetes, screening should be done at least annually, starting 5 years after diagnosis, and for people with type 2 diabetes at least annually, starting at diagnosis. This screening is carried out by testing a random sample of urine (determination of ACR) and blood (determination of eGFR) [2], [5]. The ratio of urine albumin to urine creatinine (ACR) is important and enables a standardised determination of the extent of albuminuria independent of urine concentration. 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 (CKDEPI) formula or alternatively according to the Modification of Diet in Renal Disease (MDRD) formula. The determination of cystatin C in serum can also be used and is superior to a creatinine-based determination of eGFR, but more expensive [6]. Limitations of all 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 and/or albuminuria caused by diabetes in the presence of impaired kidney function. 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,

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

• For diabetes duration ≤5 years in people with type 1 diabetes,

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

• A hypertensive nephropathy may be present in patients without albuminuria/proteinuria,

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

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

The current guidelines place greater emphasis on lifestyle modification. A healthy lifestyle has a positive influence on the development and progression of kidney damage. The following measures are important [2] [5] [7]:

• Not smoking,

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

• Performing regular physical activity, target 150 minutes/week,

• Healthy, plant-based, Mediterranean diet,

• Weight reduction in the presence of obesity,

• Normalization of increased protein intake, if necessary (target 0.8 g protein/kg body target weight/day in people with chronic renal insufficiency (CRI) without dialysis therapy).

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.

In addition to the lifestyle changes and general measures mentioned above, 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 value-oriented lipid therapy (see “Therapy of dyslipidaemia” section).

• Targeted drug-based progression inhibition (see "Drug-based progression inhibition” section).

In close coordination with the nephrologist, and if recommended, the therapy of renal disorders of the acid-base balance and the calcium-phosphate balance, possibly anaemia, 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). If ACE inhibitors are not tolerated, an angiotensin-1 (AT-1) blocker can be used as a substitute in both groups.

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

• Both the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) guidelines [3] [8] recommend antihypertensive therapy for all patients with blood pressure≥140/90 mmHg. Blood pressure in patients with hypertension and diabetes should be reduced to target values≤130/80 mmHg. Contrary to the KDIGO guideline on the management of blood pressure in CRI [9], which recommends a target systolic blood pressure of < 120 mmHg also for people with diabetes and CRI, a blood pressure target of < 120 mmHg is no longer recommended in both guidelines [3] [8]. However, the target blood pressure can be adjusted individually depending on the extent of ACR, concomitant diseases and therapy safety.

• For primary use in drug therapy: ACE inhibitors (AT1 blockers, if not tolerated) – 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 glycaemic control with the use of these substances is mixed. The combined therapy of ACE inhibitors and AT-1 blockers is not recommended because of the dangerous risk of hyperkalaemia.

Therapy of diabetes mellitus

• To prevent kidney damage, an HbA1c value between 6.5% (48 mmol/mol) and 8% (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 hypoglycaemia perception disorder [5] [7].

• 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[10] [11].

As of stage G3b/G4 KDIGO, the HbA1c value is no longer a reliable parameter for the quality of metabolic control, as it can change due to influencing factors, especially in the presence and/or treatment of renal anaemia.

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 hypoglycaemia; 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 Antidiabetic drugs and renal function based on eGFR. Overview: Approval of antidiabetic drugs in chronic renal insufficiency in Germany as well as hypoglycaemia risk of the individual substances. The information refers exclusively to the approval as an antidiabetic drug. Based on data by respective package leaflet for experts (dated July 2023) and ifap app version 3.15.2 (dated June 15, 2023; ifap Service-Institut für Ärzte und Apotheker GmbH) * Certain SGLT-2 inhibitors can also be used in severely impaired renal function (dapgliflozin: eGFR <25 ml/min/1.73m²; empagliflozin: eGFR < 20 ml/min/1.73m²), but restarting is not recommended. Abbreviations: GLP-1, glucagon-like peptide-1 DPP-4, Dipeptidylpeptidase-4 SGLT-2, Sodium glucose linked transporter 2, eGFR, estimated glomerular filtration rate; inhibitor; RA, receptor agonist.

The use of continuous glucose monitoring (CGM) is not formally approved for CRI and dialysis therapy, but numerous publications and case reports indicate that these systems are safe to use even with impaired renal function.

For people with diabetes and CRI up to dialysis, sensor-based insulin pump therapy, sometimes with automatic insulin delivery (what is known as AID or hybrid closed-loop systems), can achieve better metabolic control than subcutaneous insulin administration [12] [13]; it should be noted that the manufacturers do not formally approve of this. The current recommendation is for care to be provided by specialised centres because of the particular requirements for insulin therapy in dialysis patients.

Therapy of dyslipidaemia and cardiovascular risk reduction

The ESC guideline for the management of cardiovascular risk in diabetes from 2023 lists a separate section for people with CRI and diabetes for the first time. In particular, it is emphasized that CRI is an independent cardiovascular risk factor that increases with a higher degree of renal insufficiency. In addition to general measures such as nicotine abstinence, a healthy diet and exercise, as well as statin therapy (see below) and blood pressure therapy, measures of drug-based progression inhibition (SGLT-2 inhibitors, inhibition of renin-angiotensin-aldosterone system (RAAS), finerenone) are recommended as IA recommendations from the outset, as they also reduce the cardiovascular risk.

According to the ESC/EAS guidelines on dyslipidaemia [14], the cardiovascular risk of people with CRI in the eGFR stages G3-G5 should also 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 [2] oriented to the current target values [14] 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.

Drug-based progression inhibition

The risk of progression of renal failure is significantly determined by the extent of ACR and the limitation of renal function. There are now positive renal outcome studies for four drug classes/substances that demonstrate a reduction in renal endpoints compared to placebo and should be used primarily in the corresponding indication areas.

1. Renin-angiotensin-aldosterone system (RAAS) inhibitors: Angiotensin-converting enzyme inhibitors (e. g., captopril) and angiotensin II receptor blockers (e. g., irbesartan, losartan) were able to reduce renal progression in people with diabetic kidney disease compared to placebo [2] [3]. A RAAS inhibitor is thus an integral part in inhibiting the progression of kidney damage.

2. SGLT-2 inhibitors: The studies, which were specifically aimed at reducing renal endpoints, were able to impressively demonstrate the nephroprotective effect of canagliflozin, dapagliflozin and empagliflozin [15] [16] [17]. 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 diabetes in other approved indications [2]. This also applies to impaired kidney function, taking into account the respective approval conditions up to stage G5. Currently, SGLT-2 inhibitors are explicitly not recommended for people with type 1 diabetes, due to the increased risk of ketoacidosis.

3. Finerenone: The nonsteroidal mineralocorticoid receptor antagonist finerenone also showed nephroprotective and cardioprotective effects in people with type 2 diabetes and CRI with albuminuria ≥A2 stage [18]. Therefore, finerenone is also recommended for this patient group by KDIGO (class IIA) [2] ADA[5] and ESC (class IA)[3] provided that hyperkalaemia is not present. For people with type 1 diabetes, a targeted renal outcomes study (FINE-ONE) is currently underway, which compares finerenone with placebo. However, finerenone has not yet been approved for people with type 1 diabetes.

4. Semaglutide: Recently, a reduction in the combined renal endpoint was demonstrated for the GLP-1 receptor agonist semaglutide in the FLOW study [1]. In addition, there were also significant benefits for all secondary endpoints with semaglutide vs. placebo. Although no guideline has yet recommended the specific use of semaglutide in renal insufficiency and type 2 diabetes due to the recent publication, the results of the FLOW study should be taken into account when selecting a therapy.

Follow-up

Depending on the stage of nephropathy, the following parameters should be checked 1–4 times a year:

• Determination of 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).

Nephrological-specialist care is recommended for people with diabetes in the presence of CRI 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 higher 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 2024; 19 (Suppl 2): S309–S314.DOI: 10.1055/a-2312-0591

Conflicts of interest

L. Merker has received fees and/or reimbursements from the following companies/institutions in the last 3 years: Amgen, ÄZQ, AstraZeneca, Bayer, Boehringer Ingelheim, Pharma, Diaplan, DDG, DGfN, Eli Lilly Pharma, Esanum, National Association of Statutory Health Insurance Physicians, MedLearning, Merck Inc., MSD Sharp&Dohme, Novartis, NovoNordisk, RG Ärztefortbildung, Uniklinik Essen. He declares that he sees no conflict of interest with the article he has created. In the last 3 years, T. Ebert has received fees/reimbursements from the companies Bayer Vital/Bayer AG/RG Ärztefortbildung, Boehringer Ingelheim, CME-Verlag, Fresenius Medical Care Deutschland/Renal Research Institute New York, Lilly, Novo Nordisk, Sanofi and Santis. As part of a consulting activity, he received a fee from the companies Bayer, Lilly and Sanofi. He was also supported by a Novo Nordisk Postdoctoral Fellowship, which is carried out in cooperation with the Karolinska Institutet, a mentorship program of the European Foundation for the Study of Diabetes (EFSD), which is funded by an “Educational grant” from AstraZeneca, and the Team Award Nephrology+2023, which is funded by Otsuka Pharma GmbH. M. Guthoff received fees/reimbursements/study grants from the following companies: Alexion, Astellas, AstraZeneca, Baxter, Bayer, Boehringer/Lilly, Chiesi, Novartis, Sanofi. B. Isermann is a member of the Scientific Advisory Board of Functional therapeutic and receives scientific funding from the European Foundation for the Study of Diabetes (EFSD), which is funded by Lilly. E. Schleicher declares that he has no potential conflicts of interest.

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Publication History

Article published online:
06 May 2025