**11. Conclusion**

102 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

We have demonstrated significant positive correlations between LVMI and Ang-1 and VEGF in young subjects with ADPKD as shown in table 4 (Reed, et al., 2011). The relationship between LVMI and serum VEGF was apparent even in the absence of overt hypertension. This is of particular relevance as patients with ADPKD are at an increased risk for left ventricular hypertrophy (LVH) (Chapman et al., 1997). Similarly, in 33 adults a near significant relationship between LVMI and Ang-1 was observed. No relationship between VEGF and LVM was apparent in adults. However, there was a significant relationship between Log10 Ang-1/Ang-2 and LVM. As Ang-2 has been reported to be both pro-angiogenic or promote vascular regression dependent upon the presence or absence of VEGF (Holash et al., 1999; Lobov et al., 2002) assessment of the Ang-1/Ang-2 ratio may be biologically relevant. Thus, angiogenic growth factor levels may help identify children at risk for cardiovascular complications. This is important because cardiac MRI and/or

echocardiography are not routinely performed on young patients with ADPKD.

Log10 VEGF 0.0409 0.0078 <0.0001 NS Ang-1 0.0014 0.0007 0.04 0.0004 0.0002 0.06 Log10 Ang-1/Ang-2 NS 12.2718 5.4447 0.03

VEGF receptor inhibition by SU-5416 has been shown to significantly reduce liver cyst burden in pkd2(WS25/-)mice (Amura et al., 2007). Likewise, studies in the cy/+ rat model of polycystic kidney disease demonstrated that treatment with ribozymes to block VEGFR-1 and VEGFR-2 mRNA expression resulted in decreased cyst burden in the kidney (Tao et al., 2007). Metalloproteinase inhibition by batimastat in the cy/+ rat model has also been shown to significantly reduce kidney weight and cyst number in treated animals compared to

Several inhibitors that either target VEGF directly such as bevacizumab or those such as sorafenib and sunitinib that target receptor tyrosine kinases including VEGFR's and platelet derived growth factor receptors have shown some success in cancer therapy. Indicating that these drugs may have a potential role in ADPKD therapy. However, there are several side effects associated with both of these drug classes including but not limited to hemorrhage, decreased wound healing and hypertension. Side effects are a significant consideration in relation to ADPKD therapy where drug use must potentially be continued for life. While most anti-angiogenic drugs are targeted towards cancer therapy, bosutinib a receptor tyrosine kinase inhibitor targeting the Src/Abl kinases which also reduces VEGF activity is

In terms of other anti-angiogenic targets, there are several ongoing cancer clinical trials with Ang-1 or Ang-2 inhibitors. Depending on the outcome of these ongoinig trials these drugs may hold some promise for future ADPKD therapy. It is also relevant that there are many

Table 4. Relationship between VEGF, Ang1 and Ang-1/Ang-2 with Cardiac Structure.

 **Dependent Variable** 

**10. Potential benefit of anti-angiogenic therapy in ADPKD** 

currently in phase II clinical trial for ADPKD (NCT01233869).

untreated animals (Obermuller et al., 2001).

LVM

**Independent Variable** 

**Children Adults** 

**SE P SE P** 

In this chapter we have presented evidence that angiogenesis may be an important factor in the pathogenesis of ADPKD. We have highlighted the similarities between cyst growth and growth of a benign tumour. Significantly, as has been demonstrated in other disease conditions circulating angiogenic growth factor levels are abnormally elevated even early in ADPKD and may indicate the severity of underlying renal and cardiac disease. Lastly, the benefits of anti-angiogenic therapies which target restoration of angiogenic growth factor balance remain to be determined in ADPKD but may hold future therapeutic promise.
