**2. Initiation Factor**

An initiation factor is one that directly initiates kidney damage in an individual who is susceptible to kidney damage. An ideal study design for identification of initiation factors is a prospective cohort study. This would involve identification and follow up of a group of individuals free of kidney disease at baseline, with known susceptibility factors and with or without exposure to initiation factors, for the development of kidney disease.

#### **3.2 Risk factors effecting adverse outcome of CKD**

#### **1. Progression Factors**

Progression factors worsen the kidney damage caused by initiation factors and lead to further decline in kidney function. Indicators of progression may include progression of microalbuminuria to overt proteinuria or reduced GFR, rate of decrease of GFR, or development of kidney failure necessitating dialysis or transplantation.

#### **2. End-Stage Factors**

End –stage factors are those that exacerbate the morbidity and mortality associated with kidney failure. Examples of indicators of mobidity include hospitalizations, poor quality of life measures, and cardiovascular disease complications.

#### **3.3 Risk factors for progression of chronic kidney disease**

1. Proteinuria

Proteinuria is associated with faster rates of CKD progression. It contributes to nephron loss; filtered proteins are reabsorbed by the proximal tubular cells. Tubular cell contents may leak into the interstitium. This can cause macrophage infiltration and inflammatory mediators produced by them. The MDRD study showed proteinuria to be the strongest predictor of kidney disease progression in non diabetic patients. The REIN study done in non diabetic patients with proteinuria, showed the protein excretion rate to be the best single predictor of GFR decline to ESRD. This finding was independent of the initial insult.

The US Collaborative Study in type 1 diabetic patients with >500mg proteinuria/day and serum creatinine values of 2.5mg% or less showed a 50% reduction in the risk of combined endpoints (death, dialysis, transplantation) in patients treated with an ACE inhibitor.

Severity and Stages of Chronic Kidney Disease 17

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

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

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

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

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

nephrotoxins, progress to scarring with loss of function and CKD. (Fig. 1)

Fig. 1. Progression of initial kidney injury.

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

tubular cell loss and atrophy.

fibroblast growth factor (FGF).

hypertension.

pathway.


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

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.

2. Hypertension

Blood pressure should be lowered to <120/80.

Patients with blood pressure 120-129/80-84 have a 1.6 fold greater risk of developing ESRD and those with pressure >210/120 have a 4.2 fold risk of ESRD.

The MRFIT study showed that hypertension was an independent risk factor for the development of ESRD.


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

5. Management of dyslipidemia

LDL stimulates mesangial cell proliferation and the synthesis of proinflammatory molecules.

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