Table 7 RIISC protocol; areas of controversy

No gold standard measure of kidney function used for either screening or renal progression

While inulin and iohexol clearance are the gold standard measures of kidney function, radioisotope methods are accepted as they are easier and less expensive [159]. However these are still invasive and costly and would increase the burden on potential and actual participants. The MDRD equation with IDMS traceable creatinine results was chosen because it is part of routine clinical practice (thus making our cohort representative of the CKD population). The application of other creatinine-based equations (e.g. CKD EPI) will also be explored.

No dietary restrictions placed upon patients prior to clinic attendance

Serum creatinine is affected by diet and meat consumption prior to testing can influence the result obtained [53]. In some studies participants are asked to refrain from eating meat in the 24 hours preceding testing [37], however we decided that this placed an additional burden on patients and would make results obtained is not generalisable to routine clinical practice.

No cardiac imaging (CT or echocardiography)

While coronary calcification has been described in CKD and detailed cardiac imaging has been conducted as baseline in some cohort studies; this is invasive and adds complexity to the protocol. The non-invasive measures of arterial stiffness have been shown to correlate well with more invasive methods [32, 93, 160].

No use of Dexa scanning to measure bone health

Patients with CKD are known to be at risk of bone loss and fractures, renal bone disease is also a risk factor progression and cardiovascular events [161]. Dexa scanning is the gold standard measurement of bone density but novel biomarkers of bone turnover, such as FGF 23, have been shown to be associated with progressive CKD and cardiovascular risk, without radiation exposure and at lower cost and inconvenience to the participant [162].

The use of a short quality of life questionnaire that is non-renal specific

There are a number of renal specific quality of life measures available, they vary in detail but tend to focus on symptom burden specific to the renal population. The SF 36 is a generic questionnaire that has been validated in CKD, though there is no evidence that using it in combination with the KDQOL questionnaire is additive [77, 163, 164]. There is evidence that the EQ5D in combination with the KDQOL provide complementary information on patient perception of disease; however even the abbreviated the KDQOL contains 36 questions (some being very detailed) and would be difficult to complete for patients who do not speak English as a 1^st language (as many of the RIISC cohort may not) [77, 163].

The recruitment of patients from secondary care only

The majority of CKD is managed in the community (primary care) [165] and that the data obtained from this, higher risk, cohort may not be applicable to primary care patients. However the focus on RIISC is specifically on those patients at highest risk of progression to ESKD and under secondary care follow-up; that is those patients who have the highest disease burden.