**4. Mechanism of progression**

The characteristic structural change in CKD is scarring associated with glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis. After this initial insult the kidney goes down on one of the two paths, healing and functional recovery or scarring with loss of

toxicity

The IDNT Study looked at type 2 diabetic patients treated with placebo, ibesartan or amlodipine. The ARB outperformed the placebo group and calcium channel patients in reaching doubling of the serum creatinine, ESRD, death by 20% and 23% respectively.

Patients with blood pressure 120-129/80-84 have a 1.6 fold greater risk of developing

The MRFIT study showed that hypertension was an independent risk factor for the

Blood pressure control is more important with progression of CKD in the diabetic patient, whereas hyperglycemia is important with the initiation of diabetic

LDL stimulates mesangial cell proliferation and the synthesis of proinflammatory

No large study is available to show that control of lipids is effective in slowing the progression of CKD. The SHARP study showed that CKD patients receiving

The characteristic structural change in CKD is scarring associated with glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis. After this initial insult the kidney goes down on one of the two paths, healing and functional recovery or scarring with loss of

diabetes, smoking

albumin level, late referral

Older age, family history of chronic kidney disease, reduction in kidney mass, low birthweight, U.S. racial or ethnic minority

autoimmune diseases, systemic infections, urinary tract infections, urinary stones, lower urinary tract obstruction, drug

Higher level of proteinuria, higher blood pressure, poor glycemic control in

Lower dialysis dose (Kt/V), temporary vascular access, anemia, low serum

status, low income or education

Diabetes, high blood pressure,

Risk Factor Definition Examples

Increase susceptibility to

Directly initiate kidney

Cause worsening kidney damage and faster decline in

kidney function after initiation of kidney damage

Increase morbidity and mortality in kidney failure

Blood pressure should be lowered to <120/80.

Table 2. Risk Factors for Chronic Kidney Disease and its Outcomes.

ESRD and those with pressure >210/120 have a 4.2 fold risk of ESRD.

3. Smoking cessation- smoking is a risk factor in the progession to kidney failure

simvastatin and ezetimibe had approximately 15% fewer strokes and MIs.

kidney damage

damage

Susceptibility factors

Initiation factors

Progression factors

End-stage factors

2. Hypertension

4. Glycemic control

nephropathy.

molecules.

development of ESRD.

5. Management of dyslipidemia

**4. Mechanism of progression** 

Hallan, S & Orth, S. KI 2011.157

kidney function progressing to CKD. It is less known what leads the kidney to which pathway.

Healing primarily occurs in Acute Kidney Injury (AKI) and acute interstitial nephritis, when treatment is instituted early in its course. Healing is also a hallmark of acute post infectious glomerulonephritis. Renal function typically recovers within few weeks of acute nephritic process.Chronic kidney damage on the other hand is usually induced by diabetes, hypertension, chronic glomerulonephritits, or chronic exposure to infections or nephrotoxins, progress to scarring with loss of function and CKD. (Fig. 1)

Fig. 1. Progression of initial kidney injury.

Renal cell injury results in loss of glomerular capillaries and cellular elements are replaced by extracellular matrix and fibrous tissue. Acute severe glomerulonephritis damages the capillaries and endothelium whereas sub-acute and chronic glomerulonephritis affect the mesangium or the podocytes. Progressive renal scarring is associated with progressive tubular cell loss and atrophy.

### **4.1 Role of intrinsic renal cells in kidney damage**

Endothelium: Damage to the protective anticoagulant and anti-inflamatory endothelial capillary lining in acute glomerulonephritis, transforms it into a pro-inflammatory surface leading to accumulation of inflammatory cells and platelets within golmerular capillaries as well as the stimulation of mesangial proliferation. Glomerular endothelial damage can also be due to a metabolic insult as in diabetes or a physical hemodynamic stress as in hypertension.

Mesangium: Mesangial cells respond to injury either with death, transformation, proliferation and migration,or synthesis and deposition of extracellular matrix (ECM). Scarring is usually characterized by uncontrolled mesangial proliferation and excessive deposition of mesangial matrix. This process is driven by a number of growth factors like transforming growth factor β1 (TGFβ1), platelet derived growth factor (PDGF), and fibroblast growth factor (FGF).

Severity and Stages of Chronic Kidney Disease 19

Platelets and coagulation: Platelets and their release products within the damaged glomeruli stimulate a coagulation cascade which activate the mesangial cells to induce sclerosis. Thrombin stimulates glomerular TGF-β1 leading to production of mesangial ECM and

Lymphocytes, Monocytes-Macrophages, Dendritic cells play important role in the formation

inhibition of metalloproteinases.

intracapillary leukocytes.

of glomerulosclerosis by causing inflammation.

Fig. 3. Deposition on of ECM within and around the glomerulus.

Fig. 4. Glomerular hypercellularity due to proliferation of intrinsic glomerular cells and

Podocytes: After an injury to the podocytes, the glomerular basement membrane is exposed to the parietal epithelial cells leading to the formation of capsular adhesions and segmental glomerulosclerosis. This may lead to misdirected filtration with accumulation of amorphous material in the glomerular space. Misdirected filtration causes disruption of the glomerulartubular junction resulting in atubularglomeruli. It may also contribute to tubular atrophy and interstitial fibrosis. Thus podocytes help in conserving the structural integrity of the glomerulus by forming a protective membrane over the basement membrane.

Tubular cells: As mentioned earlier, after the initial insult the tubular cells may undergo healing and recover renal function, but repeated insults stimulate epithelial mesenchymal transformation of tubular cells to myofibroblastic phenotype with excessive deposition of ECM. Thus tubular injury can lead to renal fibrogenesis.

Vascular cells: Vascular sclerosis is an intergral feature of renal scarring and is associated with progressive kidney failure in glomerulonephritis. Hyalinosis of afferent arterioles, in diabetes, and damage to the post-glomerular arteriole and peritubular capillaries cause interstitial ischemia and fibrosis.

Fig. 2. Role of Intrinsic Cells in Kidney Damage.

### **4.2 Role of extrinsic cells in kidney damage**

Infiltration of inflammatory cells into the glomeruli and the renal interstitium is the hallmark of glomerulosclerosis and tubuloiterstitial fibrosis.

Podocytes: After an injury to the podocytes, the glomerular basement membrane is exposed to the parietal epithelial cells leading to the formation of capsular adhesions and segmental glomerulosclerosis. This may lead to misdirected filtration with accumulation of amorphous material in the glomerular space. Misdirected filtration causes disruption of the glomerulartubular junction resulting in atubularglomeruli. It may also contribute to tubular atrophy and interstitial fibrosis. Thus podocytes help in conserving the structural integrity of the

Tubular cells: As mentioned earlier, after the initial insult the tubular cells may undergo healing and recover renal function, but repeated insults stimulate epithelial mesenchymal transformation of tubular cells to myofibroblastic phenotype with excessive deposition of

Vascular cells: Vascular sclerosis is an intergral feature of renal scarring and is associated with progressive kidney failure in glomerulonephritis. Hyalinosis of afferent arterioles, in diabetes, and damage to the post-glomerular arteriole and peritubular capillaries cause

Infiltration of inflammatory cells into the glomeruli and the renal interstitium is the

glomerulus by forming a protective membrane over the basement membrane.

ECM. Thus tubular injury can lead to renal fibrogenesis.

Fig. 2. Role of Intrinsic Cells in Kidney Damage.

**4.2 Role of extrinsic cells in kidney damage** 

hallmark of glomerulosclerosis and tubuloiterstitial fibrosis.

interstitial ischemia and fibrosis.

Platelets and coagulation: Platelets and their release products within the damaged glomeruli stimulate a coagulation cascade which activate the mesangial cells to induce sclerosis. Thrombin stimulates glomerular TGF-β1 leading to production of mesangial ECM and inhibition of metalloproteinases.

Lymphocytes, Monocytes-Macrophages, Dendritic cells play important role in the formation of glomerulosclerosis by causing inflammation.

Fig. 3. Deposition on of ECM within and around the glomerulus.

Fig. 4. Glomerular hypercellularity due to proliferation of intrinsic glomerular cells and intracapillary leukocytes.

Severity and Stages of Chronic Kidney Disease 21

Proteinuria is not only a marker of kidney damage, but also contributes to nephron damage. Filtered proteins are reabsorbed from the proximal tubule. Damaged tubular basement membrane causes leakage of tubular content into the interstitium, thereby causing macrophage infiltration. Macrophages produce inflammatory mediators thus mounting an

Fig. 7. Focal segmental and global Glomerulosclerosis and nephron loss is a vicious circle

Fibrosis in the kidneys initiated by a variety of insults may not be a uniform process.

Progressive disease in diabetic patients may be related to endothelial nitric oxide deficiency with resultant endothelial dysfunction.The eventual pathology of the above mentioned series of events lead to two major histologic characteristic of CKD, focal segmental glomerulosclerosis and tubulointerstitial fibrosis. An initial insult to the kidneys will cause nephron loss.The remaining nephrons work harder to compensate for the lost nephrons

immense inflammatory reaction inside the renal interstitium.

**4.4 Role of proteinuria** 

ultimately leading to proteinuria.

**5. Pathology of CKD** 

Fig. 5. Capillary tufts almost replaced by the fibous tissue forming glomerular scarring.

Fig. 6. Immunofluorescent stain shows deposition of coarsely granular deposits of complement C3.
