Overview
Diabetic Nephropathy (Diabetic Kidney Disease)
1. Topic Overview (Clinical Overview)
Summary
Diabetic Nephropathy (DN), now often termed Diabetic Kidney Disease (DKD), is the leading cause of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD) worldwide. It is a microvascular complication of diabetes characterised by progressive albuminuria (Microalbuminuria -> Macroalbuminuria) and declining GFR. The pathognomonic histological finding is Kimmelstiel-Wilson nodules (Nodular glomerulosclerosis). Risk factors include poor glycaemic control, hypertension, and duration of diabetes. Early detection is via annual Albumin:Creatinine Ratio (ACR) screening. Management focuses on glycaemic control, blood pressure control (ACE inhibitors/ARBs), and SGLT-2 inhibitors (e.g., Dapagliflozin, Empagliflozin), which have revolutionised care by significantly slowing progression independent of glycaemic control. Diabetic nephropathy almost always co-exists with Diabetic Retinopathy – its absence should prompt consideration of alternative diagnoses.
Key Facts
- Epidemiology: ~40% of T1DM and ~20-40% of T2DM develop DKD. Leading cause of ESRD.
- Pathology: Hyperfiltration -> Microalbuminuria -> Macroalbuminuria -> Declining GFR -> ESRD.
- Kimmelstiel-Wilson Nodules: Pathognomonic on biopsy. Nodular glomerulosclerosis.
- Screening: Annual ACR (Urine Albumin:Creatinine Ratio).
- Key Drugs: ACEi/ARB (Renoprotective). SGLT-2 Inhibitors (Dapagliflozin – Major breakthrough).
- Co-Exists with Retinopathy: If retinopathy absent, reconsider diagnosis.
Clinical Pearls
"Retinopathy is the Partner of Nephropathy": If a diabetic has nephropathy but no retinopathy, look for another cause of renal disease.
"SGLT-2 Inhibitors are Game-Changers": Dapagliflozin, Empagliflozin slow DKD progression independent of glucose control. Prescribe early.
"ACEi/ARB for ALL Diabetics with Albuminuria": Even if blood pressure is normal, these drugs are renoprotective.
"Screen Annually": ACR + eGFR every year. Early detection = Early intervention.
Why This Matters Clinically
DKD is preventable and treatable if caught early. SGLT-2 inhibitors have transformed outcomes. Every diabetic needs annual kidney screening.
2. Epidemiology
Incidence
- T1DM: ~40% develop DKD over 15-25 years.
- T2DM: ~20-40% develop DKD.
- Leading Cause of ESRD: Globally.
- Increased CV Risk: DKD patients have markedly elevated cardiovascular mortality.
Risk Factors
| Factor | Notes |
|---|---|
| Poor Glycaemic Control | Higher HbA1c = Higher risk. |
| Hypertension | Accelerates progression. |
| Duration of Diabetes | Risk increases with time. |
| Smoking | |
| Dyslipidaemia | |
| Obesity | |
| Ethnicity | South Asian, African-Caribbean, Indigenous at higher risk. |
| Genetic Susceptibility | Family history. |
3. Pathophysiology
Stages of Diabetic Nephropathy (Mogensen Classification – T1DM Model)
| Stage | Description | GFR | Albuminuria |
|---|---|---|---|
| 1 | Hyperfiltration | Increased (>30) | Normal |
| 2 | Silent Phase | Normal | Normal (Structural changes on biopsy) |
| 3 | Incipient Nephropathy | Normal | Microalbuminuria (ACR 3-30 mg/mmol) |
| 4 | Overt Nephropathy | Declining | Macroalbuminuria (ACR >0 mg/mmol) |
| 5 | ESRD | <15 | Heavy Proteinuria, Uraemia |
Mechanism
| Step | Detail |
|---|---|
| Hyperglycaemia | Increases glomerular blood flow and pressure. |
| Hyperfiltration | Glomerular hypertension. Stretches mesangium. |
| Mesangial Expansion | Extracellular matrix accumulation. |
| GBM Thickening | Basement membrane thickening. |
| Nodular Sclerosis | Kimmelstiel-Wilson Nodules. |
| Glomerulosclerosis | Progressive fibrosis. Loss of nephrons. |
| Declining GFR | CKD progression. |
Pathways
- AGE Formation: Advanced Glycation End-products.
- PKC Activation: Protein Kinase C.
- TGF-β Pathway: Fibrosis.
- Renin-Angiotensin System: Intraglomerular hypertension.
4. Clinical Presentation
Early Stages
| Feature | Notes |
|---|---|
| Asymptomatic | Detected on screening (ACR, eGFR). |
| Microalbuminuria | ACR 3-30 mg/mmol. |
Later Stages
| Feature | Notes |
|---|---|
| Frothy Urine | Proteinuria. |
| Oedema | Peripheral, Periorbital (Nephrotic syndrome in severe). |
| Hypertension | Often worsening. |
| Declining Renal Function | Fatigue, Nausea, Anorexia. |
| Co-existing Complications | Retinopathy (Almost always present), Neuropathy, CVD. |
Nephrotic Syndrome (Severe Cases)
Heavy proteinuria (ACR >300 or >3.5g/day).
Common presentation.
Hypoalbuminaemia.
Common presentation.
Oedema.
Common presentation.
Hyperlipidaemia.
Common presentation.
5. Investigations
Screening (Annual in All Diabetics)
| Test | Target |
|---|---|
| Urine ACR (Albumin:Creatinine Ratio) | Normal <3 mg/mmol. Microalbuminuria 3-30. Macroalbuminuria >0. |
| eGFR | Calculate from Creatinine. Stage CKD. |
Staging of Albuminuria (KDIGO)
| Category | ACR (mg/mmol) | ACR (mg/g) |
|---|---|---|
| A1 (Normal) | <3 | <30 |
| A2 (Moderately Increased / Microalbuminuria) | 3-30 | 30-300 |
| A3 (Severely Increased / Macroalbuminuria) | >0 | >00 |
Other
| Test | Purpose |
|---|---|
| U&E | Creatinine, eGFR, Electrolytes. |
| HbA1c | Glycaemic control. |
| Lipid Profile | CV risk. |
| Retinal Screening | Confirm co-existing retinopathy. |
| BP | Hypertension assessment. |
| Urine Protein:Creatinine Ratio (PCR) | If ACR very high, PCR may be used. |
Renal Biopsy (Rarely Needed)
| Indication | Notes |
|---|---|
| Atypical Features | No retinopathy, Rapid decline, Active urine sediment (Haematuria), Short diabetes duration. |
| Findings in DKD | Kimmelstiel-Wilson Nodules (Nodular glomerulosclerosis). Diffuse mesangial expansion. GBM thickening. |
6. Management
Principles (Multi-Factorial)
- Glycaemic Control.
- Blood Pressure Control (ACEi/ARB).
- SGLT-2 Inhibitors.
- Cardiovascular Risk Reduction.
- Avoid Nephrotoxins.
- Renal Replacement Therapy (If ESRD).
Glycaemic Control
| Target | Notes |
|---|---|
| HbA1c <53 mmol/mol (7%) | Individualise. May relax in frail/elderly or hypoglycaemia-prone. |
| SGLT-2 Inhibitors | Dapagliflozin, Empagliflozin – Renoprotective INDEPENDENT of glucose control. |
| GLP-1 Agonists | Semaglutide, Liraglutide – CV and Renal benefits. |
| Metformin | Safe down to eGFR 30. Stop if <30. |
| Insulin | Often required as eGFR declines. |
Blood Pressure Control
| Drug Class | Target | Notes |
|---|---|---|
| ACEi or ARB | BP <130/80 mmHg. | First-line. Renoprotective. Reduce intraglomerular pressure. |
| Do NOT Combine ACEi + ARB | No benefit. Increases harm. |
SGLT-2 Inhibitors (Game-Changer)
| Drug | Indication | Benefit |
|---|---|---|
| Dapagliflozin | T2DM with DKD. Also CKD without diabetes. | 39% reduction in kidney progression (DAPA-CKD trial). |
| Empagliflozin | T2DM with DKD. | Significant renal and CV benefit. |
| Canagliflozin | T2DM with DKD. | CREDENCE trial. |
SGLT-2 inhibitors can be used down to eGFR 20-25 for renoprotection.
Finerenone (MRA)
- Non-steroidal MRA.
- Approved for DKD. Further reduces progression.
- FIDELIO-DKD, FIGARO-DKD trials.
Cardiovascular Risk Reduction
| Intervention | Notes |
|---|---|
| Statin | High intensity (Atorvastatin 20-80mg). |
| Aspirin | If established CVD. Primary prevention debated. |
| Smoking Cessation | |
| Weight Management |
Avoid Nephrotoxins
| Avoid | Notes |
|---|---|
| NSAIDs | Reduce renal blood flow. AKI. |
| Contrast (If Possible) | Contrast-Induced Nephropathy. Pre-hydration if needed. |
| Aminoglycosides | If must use, monitor levels. |
Monitoring
| Test | Frequency |
|---|---|
| ACR + eGFR | At least annually. More frequent if declining. |
| U&E | After starting/changing ACEi/ARB. Monitor K+. |
| HbA1c | Quarterly if not at target. |
Renal Replacement Therapy (ESRD)
- Haemodialysis, Peritoneal Dialysis.
- Renal Transplant (Often combined Pancreas-Kidney in T1DM).
- Pre-emptive transplant preferred.
7. Complications
| Complication | Notes |
|---|---|
| ESRD | Dialysis or Transplant. |
| Cardiovascular Disease | Major cause of death in DKD patients. |
| Hyperkalaemia | ACEi/ARB. CKD. |
| Metabolic Bone Disease | CKD-MBD. Secondary hyperparathyroidism. |
| Anaemia | Reduced EPO production. |
| Fluid Overload | Hypertension. Oedema. |
8. Prognosis & Outcomes
| Stage | Prognosis |
|---|---|
| Microalbuminuria (Early) | Reversible with good control. |
| Macroalbuminuria | Progressive. Slower with ACEi/ARB + SGLT-2i. |
| ESRD | Reduced life expectancy. Dialysis/Transplant improves survival. |
Key Trials
| Trial | Drug | Outcome |
|---|---|---|
| DAPA-CKD | Dapagliflozin | 39% reduction in kidney progression. |
| CREDENCE | Canagliflozin | ~30% reduction in kidney progression. |
| FIDELIO-DKD | Finerenone | 18% reduction in kidney progression. |
9. Evidence & Guidelines
Key Guidelines
| Guideline | Organisation | Notes |
|---|---|---|
| NICE NG28 | NICE | Type 2 Diabetes Management. |
| KDIGO 2022 | Kidney Disease: Improving Global Outcomes | CKD in Diabetes. ACEi/ARB + SGLT-2i for all. |
| ADA Standards of Care | American Diabetes Association | Annual screening. Renoprotection. |
10. Exam Scenarios
Scenario 1:
- Stem: A 55-year-old T2DM patient has ACR 15 mg/mmol and eGFR 55. What is the diagnosis and management?
- Answer: Diabetic Kidney Disease (Stage 3 CKD, A2 Albuminuria). Start ACEi/ARB and SGLT-2 inhibitor (Dapagliflozin). Optimise glycaemic control. BP target <130/80.
Scenario 2:
- Stem: What is the pathognomonic histological finding in Diabetic Nephropathy?
- Answer: Kimmelstiel-Wilson Nodules (Nodular glomerulosclerosis).
Scenario 3:
- Stem: A diabetic has significant proteinuria but no diabetic retinopathy. What should you consider?
- Answer: Consider an alternative cause of renal disease (Non-diabetic nephropathy). May need renal biopsy.
11. Triage: When to Refer
| Scenario | Urgency | Action |
|---|---|---|
| ACR >0 (Macroalbuminuria) | Routine | Nephrology referral. Optimise therapy. |
| eGFR <30 or Rapidly Declining | Urgent | Nephrology. Pre-dialysis planning. |
| Atypical Features (No retinopathy, Haematuria) | Routine | Nephrology. Consider biopsy. |
| Hyperkalaemia on ACEi/ARB | Routine | Review medications. Dietitian. |
12. Patient/Layperson Explanation
What is Diabetic Kidney Disease?
Diabetic Kidney Disease happens when high blood sugar damages the tiny blood vessels in your kidneys. Over time, this can lead to kidney failure.
How do we detect it?
A simple urine test (ACR) looks for protein leaking into your urine. A blood test (eGFR) tells us how well your kidneys are working.
How is it treated?
- Blood pressure tablets (ACE inhibitors or ARBs) – Protect the kidneys.
- SGLT-2 Inhibitors (e.g., Dapagliflozin) – A newer medicine that significantly slows kidney damage.
- Blood sugar control – Keeping HbA1c at target.
- Lifestyle – Healthy diet, Weight loss, Quit smoking.
Key Counselling Points
- Take Your Medications: "ACE inhibitors and SGLT-2 inhibitors protect your kidneys."
- Annual Screening: "Get your urine and blood tested every year."
- Control Blood Sugar and Blood Pressure: "These are the most important things you can do."
14. Quality Markers: Audit Standards
| Standard | Target |
|---|---|
| Annual ACR + eGFR in all diabetics | >0% |
| ACEi/ARB prescribed for ACR > | >0% |
| SGLT-2 inhibitor offered for DKD | >0% |
| BP <130/80 achieved | >0% |
15. Historical Context
- Kimmelstiel & Wilson (1936): Described nodular glomerulosclerosis in diabetics.
- ACEi for DKD (1993): Landmark trials (Captopril Collaborative Study) proved renal protection.
- SGLT-2 Inhibitors (2019-2020): CREDENCE, DAPA-CKD trials transformed DKD management.
16. References
- NICE NG28. Type 2 diabetes in adults: management. nice.org.uk
- KDIGO 2022. Management of Diabetes in CKD. kdigo.org
- Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD). N Engl J Med. 2020. PMID: 32970396
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. If you have diabetes, please ensure regular kidney screening.