Blog entry by Arif Khwaja
Anyone in the world
A quick update from the late clinical trials session from the ERA-EDTA which was a high quality session
Jurgen Flöege presented data from the german STOP-IgA Nephropathy trial. Full details of the protocol can be found here but in essence patience patients with proteinuric IgA nephropathy were enrolled into 6 months of best medical care - ACEi,ARBs (aiming for a BP target of 125/75mmHg), statins and low salt+protein diet. After 6 months those with greater than 0.75g/24 hours of proteinuria were randomised to continuing supportive care or immunosuppressive therapy-this consisted of steroids ( 6 months therapy for those with a GFR>60) or cyclophosphamide an steroids with a switch to azathioprine after 3 months (for those with a GFR<60 with prednisolone and azathioprine continued for 3 years).
309 patients were recruited to the run in phase of the study but perhaps the most important result of the study was the finding that 34% of patients in the run-in phase weren’t eligible for the active part of the study - i.e. tight BP control alone reduced proteinuria significantly and therefore they did not meet the criteria for immunosuppression.
The 2 key primary endpoints were:
i) full remission defined as <0.2g/24hours of proteinuria and stable renal function (eGFR loss less than 5 mL/min at the end of 3 years compared to baseline
ii) GFR loss>15mls/min from baseline at the end of the 3 years.
Those who were immunosuppressed were 5 times as likely to go into remission ( as defined by criteria above) as those on supportive care but there was NO difference in those with greater than 15mls/min/1.73m2 loss of eGFR between the two groups. Furthermore there were 50% more infections in the immunosuppression and significantly worse glycemic control and new onset diabetes. Immunosuppression appeared to achieve clinical remission predominantly in those with lower proteinuria.
In summary we clearly need to wait for the full paper to look at the data more closely but this study highlights i) the paramount importance of really tight BP control in IgA nephropathy ii) suggests that immunosuppressive therapy has little effect on eGFR progression/deterioration and iii) immunosuppression has a significant cost in terms of morbidity without any clear positive impact on progression.
The second study was a fascinating and really well conducted RCT from Zarbock and colleagues in Germany which looked at the effect of remote ischaemic preconditioning (RIPC) in patients at high risk of AKI (based on Cleveland Clinic Scoring system) after cardiac surgery. Patients with a renal transplant or those with CKD4/5 were excluded. RIPC consisted of inflating BP cuff on the arm 3 times prior to surgery for 5 minutes each time. Anaesthetic protocols were standardised
The primary endpoint was AKI within the first 72 hours (defined using the AKI staging system based on creatinine) - AKI rates were 37% in the RIPC group vs 52.5% in the control group (p<0.002). This was associated with a significant reduction in those requiring RRT though it wasn’t clear if the criteria for RRT was standardised. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor–binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery. The authors speculate that the release of damage associated molecular patterns (DAMPS) from ischaemic tissue may induce cell-cycle arrest in the tubulo-epithelial cells in the kidney an thereby protect against subsequent ischameic injury.
Whilst relying on creatinine in AKI is distinctly problematic at the moment there is is no realistic way to measure GFR in the context of a real world study into AKI. RIPC is a cheap and safe intervention… this study suggests its close to being ready to move into the clinical arena as well as evaluating its role in other areas such as perhaps delayed graft function after transplantation.
The third study presented was the VITA-D study from Vienna, which was another excellent, placebo controlled RCT looking at the impact of native vitamin D3 supplementation in new renal transplant recipients with vitamin D deficiency ( vit D levels<20 ng/mL (50 nmol/L)). The primary endpoints were infection and rejection rates and allograft function at 12 months. Secondary endpoints included change in bone density as measured by DXA from baseline and 12 months. 203 patients were enrolled into the study. There was no impact of vitamin D supplementation on any of the primary or secondary endpoints. Furthermore in the per protocol analysis kidney function ( as measured by serum creatinine) had a tendency to be worse in the vitamin D arm and this effect was independent of any hypercalcaemia. Again GFR was not measured so difficult to know what to make of this. The authors sensibly concluded that their study showed that there was no evidence of any benefit of D3 supplementation and possible evidence of harm in transplant patients.
The 4th study was a phase 2 study presented by Professor de Zeuuw looking at the effect of CCX140 ( a CCR2 inhibitor - CCR2 being the receptor for monocyte chemotactic protein 1, MCP1) in patients with albuminuria and CKD (eGFR>25mls/min) and type 2 diabetes. There appeared to be a very early effect on albuminuria ( as measured by ACR) of nearly 25% by 12 weeks. The effect appeared to be less with the 10mg dose compared to the 5mg dose which is hard to explain. Furthermore the speed of the effect on proteinuria makes one wonder what the actual mechanism of proteinuria reduction is and whether there is a hamody namic element. Interestingly in the control arm albuminuria did not change through the course of the study. Furthermore there was no difference in eGFR (GFR wasn’t measured) at the end of the study between the two groups - which again makes me think that albuminuria is a nothing more than a surrogate marker in studies of progression. I am not sure the positive spin of this study by some on the stock market is actually justified.
Finally John Cunningham presented data from 2 phase 2 RCTs looking at the administration of AMG416 for secondary hyperparathyroidism. This is a synthetic peptide, has calcimimetic actions and a half life of 3-5 days in ESRD patients. Hence a dosing schedule of IV administration after each dialysis session was utilised in the study. The bottom line was that the drug worked significantly reduced PTH and FGF23 levels. Whether this translates into patient-centred improvements in outcomes is unknown. Although there were some GI side effects with the drug this seemed less than with cinacalcet. Clearly the danger with using a drug with such a long half life is inducing dynamic bone disease.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]