**3.5 Thrombotic thrombocytopenic purpura (TTP)/ haemolytic-uremic syndrome (HUS)**

Thrombotic thrombocytopenic purpura/haemolytic uremic syndrome are often considered variants of a disease characterized by microangiopathic haemolytic anaemia [53]. Platelets are consumed by spontaneously developing microscopic thrombosis. ADAMTS-13, the enzyme which normally processes the very large von Willebrand factor (vWF) is missing [54] or disabled [55, 56] in this disease. Therefore, the very large vWF "capture" circulating platelets and initiates microthrombi formation. The red blood cells passing through the damaged arteries experience excessive shear stress which leads to haemodialysis. Besides purpura and anaemia there are often fever and neurologic symptoms present and the disease can lead to both acute kidney failure and CKD [57, 58]. Interestingly, a recent study which investigated plasma level of vWF in patients with chronic kidney disease of different origin found decreased level of vWF-cleaving protease [59]. Level of vWF was higher in stage IV patients compared to stages II and III, but whether the increased vWF contributed to the worsening of CKD is currently not known.

### **4. ADAMs in kidney cancer**

Several ADAM enzymes were upregulated at the message level in human renal cell carcinomas. Compared to normal tissue mRNA levels of ADAM8, -17, -19, -28 as well as ADAMTS-2 were upregulated. Interestingly, mRNA level of ADAMTS-1 did not change [60]. In other studies, ADAM10 [61] and ADAM9 expression was increased in renal cancer cells and associated with tumor progression [62] suggesting that expression of these enzyme may be used as tumor markers. ADAM15 and -17 contributed to the migratory potential of kidney cancer cells through activation of the EGFR [63] and ADAM17 silencing disabled the capability of renal carcinoma cells to form in vivo tumors [64]. Therefore these enzymes seem to have direct role in renal cancer pathophysiology.

#### **5. Conclusion**

ADAM and ADAMTS families include growing number of metalloenzymes which have important role in kidney development and are indispensable to normal kidney function.

ADAM Proteases as Novel Therapeutic Targets in Chronic Kidney Disease 9

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Lack or overactivation of certain ADAM enzymes (especially ADAM17 and ADAMTS-13) can have major pathophysiological role in development of various type of CKD. Therefore, targeting these enzymes can be an exciting novel therapeutic approach in the future and a new hope for CKD patients.

#### **6. Acknowledgment**

This work was partly supported by the Paul Teschan Research Fund of the Dialysis Clinic Incorporated.

### **7. References**


Lack or overactivation of certain ADAM enzymes (especially ADAM17 and ADAMTS-13) can have major pathophysiological role in development of various type of CKD. Therefore, targeting these enzymes can be an exciting novel therapeutic approach in the future and a

This work was partly supported by the Paul Teschan Research Fund of the Dialysis Clinic

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**2**

*USA* 

Syed Ahmed and Gerard Lowder

*Internal Medicine, Harbor Hospital, Baltimore,* 

**Severity and Stages of Chronic Kidney Disease** 

Nearly ten years ago Nephrologists began using asystem of classification for chronic kidney disease (CKD). This was established in 2002 by the Kidney Disease Outcome Quality Initiative (KDOQI) to estimate kidney function in a given patient regardless of the etiology of the primary insult to the kidneys. Physicians were able place their patients in stages from mild disease to end stage renal disease (ESRD).CKD is defined as glomerular filtration rate

Each stage served as a "mile marker" on life's road for the patient with CKD. The natural history of CKD usually is a steady decline in kidney function, as found in the relationship between the reciprocal of serum creatinine values and time. A percentage of patients do not follow this linear pattern, suggesting either worsening or improvement in their kidney function. Factors which may cause worsening of CKD in such individuals are often infections, dehydration, poor control of systemic blood pressure and exposure to nephrotoxins, in particular nonsteroidal anti-inflamatorydrugs and radiocontrast agents. Other individuals who do not follow the steady decline may actually show improvement in their GFR. The potential to improve the natural history of CKD is through tight blood

The early stages of kidney dysfunction are often clinically silent, especially when the condition is only slowly progressive and symptoms are nonspecific. Stages 1 & 2 show decreased kidney function without signs or symptoms of disease although the estimated GFR is less than 120 ml/min per 1.73 m2 but greater than 60 ml/min per 1.73 m2. The rate of progression is influenced by a wide range of factors which may or may not have the potential of modification and varies among different individuals and with the underlying cause of nephropathy.When the patient enters Stage 3 he or she has lost approximately half their kidney function. It is less likely for the kidney disease to progress unless more than 50% of the nephron function is lost. For example, individuals with a solitary kidney after unilateral nephrectomy for living kidney donation usually do not progress to CKD.Increased risk of natural progression with less than 50% of nephron loss can occur in persons of African ancestry with hypertensive nephrosclerosis. In 2008, the U.K National Institute of Health and Clinical Excellence (NICE) sub divided the stage 3 into 3A and 3B with estimated GFRs of 45 to 59 ml/min per 1.73 m2 and 44 to 30 ml/min per 1.73 m2

(GFR) below 60 ml/min per 1.73 m2 for 3 months or more.

**2. Stages of chronic kidney disease** 

pressure control and inhibition of rennin-angiotensin-aldosterone system.

**1. Introduction** 

