Diabetic nephropathy

Amrina Rosyada & Haifa Albiyola R

- Definition

Adalah syndrome yang dikarakteristikan dengan ekresi urine albumin, diabetic glomerular lesion,
and loss of GFR in diabetics.

- Epid :

Diabetic nephropathy dapat terjadi pada pasien type 1 dan type 2 diabetes. Diabetic
nephropathy merupakan penyebab yang umum dari Chronic renal failure di united states.
Diabetic nephropathy menyebabkan end-stage renal disease di United States. Sekitar 30-40%
pasien diabetes terjadi nephropathy,dengan Type 2 DM (90%) type 1 (10%). Renal lesion banyak
terjadi pada Afirican-American, Native America, Polynesian, dan Maori population. 45% pasien
menerima renal replacement therapy dan telah menjadi permasalahan dunia.

- Risk factor :

Hyperglycemia (menyebabkan hyperfiltration dan renal injury), hypertension, dyslipidemia,

smoking, family history of diabetic nephropathy, gene polymorphism affecting the activity of
renin-angiotensin-aldosterone axis, advanced glycation product, dan aktivasi sitokin

Gene :

Genes involved in the genetic predisposition to diabetic nephropathy, are likely to be those
involved in reninangiotensin system, nitric oxide pathway, aldose reductase pathway, GLUT-1,
and lipoproteins metabolism.

Polymorphism in the 5′ end of aldose reductase gene and the development of diabetic
nephropathy in type 1 diabetes

Family history :

Familial predisposition to raised arterial pressure increases the susceptibility to renal disease in
patients with diabetes. Studies have demonstrated that mean blood pressure levels are
significantly higher in those who progress to microalbuminuria, than in those who do not,
indicating that hypertension is an important risk factor for diabetic nephropathy

Hyperglycemia :

 alteration of extracellular matrix formation

 mesangial cells cause hypertrophy, increase gene expression and protein secretions like
collagen, laminin and fibronectin

 reduces the activity of metalloproteases, enzymes responsible for extracellular matrix

degradation

 increased formation of Advanced Glycation End products (AGE). Apa efeknya?

  directly alter the structural and functional properties of extra-cellular matrix
proteins, increase their rigidity, and favour the trapping of LDL and
immunoglobulin-G

 interaction of AGEs with its receptors in the kidney induces the synthesis and
release of many cytokines like TGF-b1, and IGF and results in enhanced
production of collagen, laminin and fibronectin

 over expression of receptors of AGE (RAGE) in glomerulus and tubular epithelial

cells and the AGE-RAGE complexes can produce tubulointerstitial fibrosis

 AGE-RAGE interaction promotes polymorphonuclear leukocyte generated

cascade of highly reactive oxygen species, which ultimately lead to production
of lipid peroxidases. Lipid peroxidation products like ALEs and lipid
hydroxyperoxidase produce endothelial and glomerular basement membrane
injury by altering proteins like nephrin and connectin and thereby resulting in
proteinuria

- Sign and symptom:

 Swelling of ankle, feet, lower legs or hands yang disebabkan oleh retensi air

 Darker urine, karena adanya darah di urine

 Short of breath, when climbing stairs for instance

 Kelelahan karena berkurangnya oksigen di darah

 Mual dan muntah

- Lesion :
1. Glomerular lesion

2. Renal vascular lesion

3. Pyelonephritis, including necrotizing papillitis

Yang terpenting dari lesi glomerular adalah adanya penebalan pada glomerular capillary
basement membrane (GBM) terjadi di hampir semua kasus diabetic nephropathy.
Penebalan terjadi dimulai pada sekitar 2 tahun setelah onset type 1 diabetes dan dalam 5
tahun terjadi kenaikan 30%. Penebalan terjadi secara progresif dan biasanya terdapat
pelebaran mesangial dan penebalan tubular basement membranes.

Diffuse mesangeal sclerosis, adanya peningkatan diffuse di mesangial matrix. mild

proliferation pada awal proses penyakit. Matrix deposisinya adalah PAS-positive. Seiring
progresi penyakit, ekspansi mesangeal areadapat meluas ke nodulr configuration. Ekspansi
mesangium ini berhubungan dengan memburuknya fungsi ginjal seperti : peningkatan
proteinuria.
 Nodular glomerulosclerosis, disebut juga sebagai intercapillary glomerulosclerosis /
kimmelstiel- Wilson disease. Lesi glomerular membentuk bentukan ovoid / spjherical, often
laminated, nodulesnya berada di periphery glomerulus. Nodulesnya PAS positive. Terletak
diantara mesangial core glomerular lobules dan dikelilingi oleh patent peripheral capillary
loops. 15-30 %pasien DM terjadi nodular glomerulosclerosis, dan berhubungan dngan renal
failure.

Renal atherosclerosis, dan arteriolosclerosis, termasuk macrovascular disease pada

diabetic. Hyaline arteriolosclerosis tidak terjadi hanya pada afferent tetapi juga efferent
arteriole. Jarang pada efferent arteriole, biasanya pada individu yang tidak diabetes.

Pyelonephritis, inflamasi akut atau kronis pada ginjal biasanya dimulai di jaringan
interstitial dan menyebar ke afferent tubules.special pattern pada acute pyelonephritis yaitu
necrotizing papillitis (papillary necrosis), banyak terjadi di pasien diabetes dibanding yang
tidak DM.

- Natural history :

Bergantung kepada type DM, pada type 1 untreated DM, sekitar 80% pasien with
sustained microalbuminuria meningkatkan albumin ekresi 10-20% per tahun hingga
nephropathy berkembang. Dengan berkembangnya nephropathy, GFR menurun 2-
20ml/menit/tahun dan ESRD berkembang sekitar 50 % within 10 years dan sekitar 75%
within 20 years. Albuminuria dan penurunan GFR, dengan penebalan glomerular basement
membrane dan ekspansi mesangial dapat dideteksi as early as 2-8 years after onset DM.

In type 2 DM, kebanyakan diabetic nephropathy, pada saat di diagnosis DM type 2 dapat
tidak disadari dalam beberapa tahun. 20-40% type 2 DM dengan microalbuminuria terjadi
nephropathy dan sekitar 20% berkembang ESRD setelah perkembangan nephropathy.

The natural history of DN is divided into five stages :

1. Stage 1: Renal pathology develops at the onset of diabetes. The growth of the
kidney increases by several centimetres. By the time of diagnosis, the GFR and
 urinary albumin excretion (UAE) have been increased. It can be controlled at
this level by onset of insulin

2. Stage 2: The second phase typically lasts for 5-15 years after diagnosis of
diabetes. The characteristics of the second phase include: 1. GFR remains
elevated due to hyperfiltration. 2. Kidneys remain hypertrophied and UAE rate
stays normal.

3. Stage 3: The characteristics of stage three are: 1. Microalbuminuria is present. It

occurs in 30-50% of patients after diabetes onset, 80% of whom go on to
develop overt nephropathy over 10-15 years. 2. GFR remains elevated or
returns to normal range 3. Blood pressure starts to rise in 60% of patients
Histological changes-progression is as seen in stage two

4. Stage 4: This stage is also known as clinical nephropathy or overt nephropathy.

The characteristic histological features of stage four are formation of the
Kimmelstiel-Wilson nodule (focal glomerular sclerosis) and macroproteinuria. It
can progress to nephrotic in 30% of patients or may decline in 80% depending
on deterioration of GFR.

5. Stage 5: As the GFR continues to decline, ESRD may develop. DN is considered

the most common cause of ESRD because of associated autoimmune
neuropathy and cardiac disease

- Metabolic Abnormality

Dyslipidemia :

Most patients with DN have dyslipidaemia, characterised by low levels of HDL cholesterol, high
triglycerides (TG levels), and a shift from larger towards smaller LDL cholesterol. Dyslipidaemias
in diabetic patients may contribute to the development of glomerulosclerosis and progressive
renal disease.

- Pat-Pat
 - Diagnosis

‘
- Classification
- Treatment :

Adequate control of metabolic and hemodynamic abnormalities. Adequate blood

glucose lowering and control hypertension. Antihypertensives dapat menurunkan
proteinuria,/ preservation GFR.
 - Prevention

Specific goals in the prevention of DN

1. Optimal blood glucose control

2. Control of blood pressure at 120/70 mmHg

3. Avoidance of potential use of nephrotoxic drugs such as nonsteroidal Antiinflammatory Drugs

(NSAIDs), aminoglycosides, etc.

4. Early detection and management of diabetes, especially in setting of family history.

 - Mortality risk and DN

In both types of diabetes, persistent proteinuria is a common finding. Long-term studies show that the
life expectancy of type 1 diabetic patients is approximately 10 years after the onset of proteinuria, with
two-thirds of deaths related to end stage renal failure (ESRF) and one third to cardiovascular disease.
In type 2 diabetes, due to the presence of comorbid conditions and cardiovascular disease in those with
overt nephropathy, the risk of mortality is so extraordinary that many die before they reach end-stage
renal failure (ESRF)

According to NICE guidelines, the following patients should be referred early to the specialist :

1) Stage 4 and 5 CKD (with or without diabetes)

2) Proteinuria together with hematuria

3) Rapidly declining GFR

4) Hypertension that remains poorly controlled despite use of at least four antihypertensive drugs at
therapeutic doses

5) People with, or suspected of having, rare or genetic causes of CKD.

The mortality of DN patients is extremely high. For example, patients with type 1 diabetes have a
mortality 20 times greater than that of the general population, and this relative risk may be magnified by
a further 25 times for those with proteinuria (e.g. 2 years mortality for 30% of patients with ESRD). The
mortality of DN patients is largely the result of comorbid cardiovascular disease. Most patients with
stage 4 DN die before they reach ESRF.

Sumber :

Robbin, harrison

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484995/

https://link.springer.com/article/10.1007/s13410-011-0055-x

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