Diabetic nephropathy is a clinical syndrome characterized by the following : Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at least 2 occasions 3-6 months apart. Progressive decline in the glomerular filtration rate (GFR). Elevated arterial blood pressure. Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy: First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycation of matrix proteins. Second, thickening of the glomerular basement membrane (GBM) occurs. Third, glomerular sclerosis caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). These different histologic patterns appear to have similar prognostic significance. Several issues are key in the medical care of patients with diabetic nephropathy. These include glycemic control, management of hypertension, and reducing dietary salt intake and phosphorus and potassium restriction in advanced cases. A meta-analysis from the Cochrane Database shows a large fall in blood pressure with salt restriction, similar to that of single-drug therapy

1. Diabetic Nephropathy
Presented by:
Khagendra joshi

2. Introduction:
Diabetic nephropathy is a clinical syndrome characterized by the
following :
a) Persistent albuminuria (>300 mg/d or >200 μg/min) that is
confirmed on at least 2 occasions 3-6 months apart.
b) Progressive decline in the glomerular filtration rate (GFR).
c) Elevated arterial blood pressure.

3. Epidemiology:
• Since the 1950s, kidney disease has been clearly recognized as a
common complication of diabetes mellitus (DM), with as many
as 50% of patients with DM of more than 20 years’ duration
having this complication.
• Diabetic nephropathy rarely develops before 10 years’ duration
of type 1 DM. The peak incidence (3%/y) is usually found in
persons who have had diabetes for 10-20 year.
• Although in general, the incidence of diabetic kidney disease is
higher among elderly persons who have had type 2 diabetes for
a longer generation.

4. Cont..
• According to the International Diabetes Federation, about 463
million people worldwide had diabetes in 2023, and this
number is expected to rise to 700 million by 2045.
• About 20-50% of people with diabetes will develop diabetic
nephropathy, depending on the type and duration of diabetes,
the level of glycemic control, and other risk factors.

5. Signs and symptoms:
Diabetes-related nephropathy symptoms usually don’t appear until it
has affected at least 80% to 90% of your kidneys. These symptoms
include:
• Edema
• Fatigue
• Dyspnea
• Loss of appetite
• Foamy or bubbly pee
• Difficulty focusing or confusion
• Dry, itchy skin
• Muscle cramps.

7. Three major histologic changes occur in the glomeruli of persons
with diabetic nephropathy:
• First, mesangial expansion is directly induced by
hyperglycemia, perhaps via increased matrix production or
glycation of matrix proteins.
• Second, thickening of the glomerular basement membrane
(GBM) occurs.
• Third, glomerular sclerosis caused by intraglomerular
hypertension (induced by dilatation of the afferent renal artery
or from ischemic injury induced by hyaline narrowing of the
vessels supplying the glomeruli).
These different histologic patterns appear to have similar
prognostic significance.

9. Stages:
There are certain diabetes-related nephropathy stages according to your estimated
glomerular filtration rate (eGFR) – ml/min/1.73m2 of BSA.
eGFR is a calculation of how efficiently the kidneys filter substances.
A normal eGFR is about 100. The lowest eGFR is 0, which means there is no
remaining kidney function.
The stages of any kidney disease, including diabetes-related nephropathy, include:
• Stage I: GFR is 90 or higher, At this stage, kidneys have mild damage but still
function normally.
• Stage II: GFR may be as low as 60 or as high as 89, have more damage to kidneys
than in stage I, but they still function well.
• Stage III: GFR may be as low as 30 or as high as 59, may have mild or severe loss
of kidney function.
• Stage IV: GFR may be as low as 15 or as high as 29, severe loss of kidney function.
• Stage V: GFR is below 15, kidneys are nearing or at complete failure

11. Treatment and Management:
Several issues are key in the medical care of patients with diabetic nephropathy.
These include glycemic control, management of hypertension, and reducing dietary salt intake and
phosphorus and potassium restriction in advanced cases.
A meta-analysis from the Cochrane Database shows a large fall in blood pressure with salt
restriction, similar to that of single-drug therapy. [Suckling RJ, He FJ, MacGregor GA. Altered
dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database of
Systematic Reviews. 2010(12).]
Glycemic Control:
a) Dipeptidyl peptidase inhibitors: The DPP–4 inhibitors (ie, gliptins) include sitagliptin,
saxagliptin, linagliptin, and alogliptin, and they decrease the breakdown of the incretin hormones
such as glucagonlike peptide 1 (GLP-1).
Sitagliptin was the first available DPP-4 inhibitor. Approximately 80% of sitagliptin is cleared by the
kidney; therefore, the standard dose of 100 mg daily should be reduced in patients with reduced GFRs.
With an eGFRof 30 or greater to less than 50 mL/min/1.73 m2, the recommended dose is 50 mg once
daily, and with an eGFR less than 30 mL/min/1.73 m2, a dose of 25 mg once daily is advised.
[Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, Gottesdiener K, Wagner J, Herman GA.
Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor.
Diabetes care. 2007 Jul 1;30(7):1862-4.]

12. Treatment and Management:
b) Alpha-glucosidase inhibitors:
Alpha-glucosidase inhibitors (acarbose, miglitol) decrease the breakdown of oligosaccharides and
disaccharides in the small intestine, slowing the absorption of glucose after a meal. The major adverse
effects are bloating, flatulence, and abdominal cramping.
c) Sodium-glucose cotransporter 2 (SGLT2) inhibitors: Canagliflozin , dapagliflozin
d) Glucagonlike peptide-1 (GLP-1) receptor agonists / incretin mimetics: semaglutide, liraglutide
Management of Hypertension
a) ACE inhibitors: Captopril, Enalapril
b) ARB: Losartan, Ibresartan
The choice between an ARB and an ACE inhibitor is made more difficult by the results of the
Microalbuminuria-Heart Outcomes Prevention Evaluation (MICRO-HOPE) Trial, in which ramipril reduced
the risk for myocardial infarction, stroke, or cardiovascular death by 26% after 2 years. Perhaps the more
interesting question is whether the combination of an ACE inhibitor and an ARB is more effective than
either drug alone. One meta-analysis showed that ACEI + ARB reduced 24-hour proteinuria to a greater
extent than ACEI alone. However, this benefit was associated with small effects on GFR, serum creatinine,
potassium, and blood pressure. [Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J. Combination
therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy-a meta-
analysis. Clinical Diabetology. 2007;8(6):219-28.]

13. Treatment and Management:
c) Direct renin inhibitors:
In a small double-blind, randomized, crossover trial, Persson et al observed the combination of
aliskiren and irbesartan to be more antiproteinuric in type 2 diabetes mellitus than was monotherapy
with either drug. This study assessed the effect of aliskiren, a direct renin inhibitor, on proteinuria in
patients with type 2 DM (n = 26) and compared the effect with that of placebo, irbesartan (an ARB),
and the combination of aliskiren and irbesartan. [Persson F, Rossing P, Reinhard H, Juhl T,
Stehouwer CD, Schalkwijk C, Danser AJ, Boomsma F, Frandsen E, Parving HH. Renal effects of
aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes,
hypertension, and albuminuria. Diabetes care. 2009 Oct 1;32(10):1873-9.]
Mineralocorticoid Receptor Antagonist Therapy:
o In July 2021, the FDA approved Finerenone ,to lower the chances of sustained eGFR decline, end-
stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for
heart failure in adults with CKD associated with type 2 DM. [Bakris GL, Agarwal R, Anker SD, Pitt B,
Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G. Effect of
finerenone on chronic kidney disease outcomes in type 2 diabetes. New England Journal of
Medicine. 2020 Dec 3;383(23):2219-29.]
Endothelin Antagonist Therapy
o Endothelin antagonists (Avosentan) have demonstrated antifibrotic, anti-inflammatory, and
antiproteinuric effects in experimental studies.[https://doi.org/10.1681/ASN.2008050482]

14. Treatment and Management:
Renal Replacement Therapy:
In principle, diabetic patients who require renal replacement therapy have the following 4 options:
- Refusal of further treatment for uremia, leading to a progressive decline in general health and
ultimately leading to death
- Peritoneal dialysis
- Hemodialysis
- Renal transplantation
Measures for Prevention of Diabetic Nephropathy :
Efforts should be made to modify or treat associated risk factors such as hyperlipidemia, smoking, and
hypertension.
Specific goals for prevention include the following:
Optimal blood glucose control (hemoglobin A1c [HbA1c] < 7%)
Control of hypertension (BP < 120/70 Hg)
Avoidance of potentially nephrotoxic substances such as NSAIDs and aminoglycosides
Early detection and optimal management of diabetes, especially in family history of diabetes

15. American Diabetes Association’s “Standards of Medical Care in Diabetes-
2018” include the following recommendations regarding diabetic kidney
disease :
• Optimize glucose control to reduce the risk or slow the progression of
diabetic kidney disease
• Optimize blood pressure control to reduce the risk or slow the progression
of diabetic kidney disease
• For people with nondialysis-dependent diabetic kidney disease, dietary
protein intake should be approx. 0.8 g/kg body weight per day ; for
patients on dialysis, higher levels of dietary protein intake should be
considered
• In nonpregnant patients with diabetes and hypertension, either an ACE
inhibitor or an ARB is recommended for those with a modestly elevated
urinary albumin-to-creatinine ratio (30-299 mg/g creatinine) and is
strongly recommended for those with a urinary albumin-to-creatinine ratio
of 300 mg/g creatinine or above and/or an eGFR below 60 mL/min/1.73
m 2
• Monitor serum creatinine and potassium levels periodically for the
development of increased creatinine or changes in potassium when ACE
inhibitors, ARBs, or diuretics are used.

16. • Continued monitoring of the urinary albumin-to-creatinine ratio in
patients with albuminuria treated with an ACE inhibitor or an ARB is
reasonable to assess the response to treatment and progression of diabetic
kidney disease
• An ACE inhibitor or an ARB is not recommended for the primary
prevention of diabetic kidney disease in patients with diabetes who have
normal blood pressure, a normal urinary albumin-to-creatinine ratio (< 30
mg/g creatinine), and a normal eGFR
• When the eGFR is below 60 mL/min/1.73 m 2, evaluate and manage
potential complications of chronic kidney disease
• Patients should be referred for evaluation for renal replacement treatment
if they have an eGFR below 30 mL/min/1.73 m 2
• Promptly refer to a physician experienced in the care of kidney disease for
uncertainty about the etiology of kidney disease, difficult management
issues, and rapidly progressing kidney disease

17. Bibliography:
1) Tang SC, Chan GC, Lai KN. Recent advances in managing and
understanding diabetic nephropathy. F1000Research. 2016;5.
2) Reutens AT, Prentice L, Atkins RC. The epidemiology of
diabetic kidney disease. The epidemiology of diabetes
mellitus. 2008 Sep 19:499-517.
3) Diabetic kidney disease: Pathogenesis and epidemiology –
UpToDate
4) https://my.clevelandclinic.org/health/diseases/24183-
diabetic-nephropathy#symptoms-and-causes (2024-01-22
10:54 am)

18. Bibliography :
5) Care D. Standards of medical care in diabetes 2019. Diabetes
Care. 2019 Jan 1;42(Suppl 1):S124-38.
6) https://emedicine.medscape.com/article/238946-
treatment?form=fpf#showall