Blog entry by Meguid El Nahas

Picture of Meguid El Nahas
by Meguid El Nahas - Tuesday, 14 June 2016, 11:06 AM
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FGF23: A novel role in systemic immunosuppression:

FGF23 an osteoblast produced key stimulator of renal phosphate excretion has previously been known to be associated with CKD-MBD, hypertension, CVD

http://www.ncbi.nlm.nih.gov/pubmed/24677555

and now with an immunosuppressive effect through an inhibition of neutrophil recruitment and anti-bacterial activities.

http://www.ncbi.nlm.nih.gov/pubmed/26878171

New therapies aimed at neutralising FGF23 may prove to be effective at many levels.

Comments:

However, like with all Cytokines, the story is never that simple as experimental data based on neutralisation of FGF23 and/or its receptor Klotho have not proved universally successful. 

http://www.ncbi.nlm.nih.gov/pubmed/22396168

Nephropathic cystinosis: Conclusions from a KDIGO Controversies Conference

This conference held in 2015 involving Prof Neveen Soliman reviewed diagnostic and management approaches to nephropathic cystinosis. Amongst other issues it highlight the discrepancy between access to care in developed and devloping countries. Research questions were discussed including WBC and gene testing for the disease, access to treatment but also issues related to children and adolescent non-compliance. The conference also put a lot of emphasis on the recognition of the systemic nature of cystinosis thus stressing the importance of early diagnosis and initiation of therapy  with cysteamine. Beside the kidneys, bones, eyes, the neurological system, the endocrine system (diabetes, hypothyroidism, GH deficiency) and fertility can all be affected.

Comments:

A major challenge resides in how the medical community can address the issue of limited access to healthcare for cystinosis sufferers in non-western world countries and disadvantaged population. Cost of treatment is often unaffordable in these communities. It is high time the Pharmaceutical Industry show more social and global responsibility towards those millions denied care!

Mining the human urine proteome for monitoring renal transplant injury. Sidgel et al.

This study shows the result on searching for urine proteins that could enhance teh diagnosis, prognosis and management of renal allograft recipients.

Out of over 900 proteins identified in the urine of those tested, 11 showed interest in relation to acute rejection, 12 for chronic allograft nephropathy and 12 for BK virus nephropathy.

Comments:

This obssession with urinary proteomic in renal transplantation goes back over 20 years and so far has yielded no clinical useful results. One is entitled to ask, whether any of the putative proteins identified in this study are superior in predictive value to; raised serum creatinine (for acute rejection), proteinuria and declining function as well as renal biopsy (for CAN) and to urinary and serum PCR for BKV nephropathy specially when associated with a rising serum creatinine. Also cost-effectiveness of these techniques and the time lag between sampling and obtaining results are likely to be of little value in acute rejection when a prompt diagnosis and treatment is required, as to the other conditions...well there is usually plenty of time to confirm their diagnosis by conventional means without requiring the sophistication and unreliability of urine proteomic analysis. I guess it keeps some scientists interested and giving lectures...many such tests have been validated more than 10-15 years ago and never made it to the bedside...?!

http://www.ncbi.nlm.nih.gov/pubmed/11750404

http://www.ncbi.nlm.nih.gov/pubmed/12777869

http://www.ncbi.nlm.nih.gov/pubmed/20526237

Endostatin and Transglutaminase 2 are involved in fibrosis ageing. Lin et al.

Endostatin (EST) a pletropic anti-angiogenic factor and transglutaminase 2 (TG2) its molecular partner may be implicated in renal fibrosis; through the dual mechanism of vascular rarefication and the association interstitlal fibrosis that underly renal fibrosis and scarring. In this study, the injection of EST and/or TG2 to young mice led to an accelerated renal ageing process.

Comments:

We, Tim Johnson and myself, were the first to draw attention in the 90s to the putative role of TG2 in experimental renal fibrosis through the observation of an increased levels in scarred SNx rat kidney sassociated with renal fibrosis

and subsequently through the design of specific TG2 inhibitors that attenuated experimental renal fibrosis.

http://www.ncbi.nlm.nih.gov/pubmed/10505691

http://www.ncbi.nlm.nih.gov/pubmed/12874459

http://www.ncbi.nlm.nih.gov/pubmed/18003782

The authors of this paper chose to overlook the bulk of our pioneer experiments as it is often the case with medical publications. They should be informed that clinical experimentation is already under discussion aimed at manipulating TG2 in human nephropathies. 

It is a sad fact of medical research publications for authors to wish to appear to have discovered facts and mechanisms that are already well established and validated by others, years before, that they chose to ignore. It does them little credit...

Association of short sleep duration and rapid decline in renal function. McMullan et al.

This paper follows a prospective cohort of 4238 middle aged women participants of the Nurse's Health Study and shows that over an observation period of 11 years those who sleep on average <5h per night are at significantly higher risk of a faster decline in renal function, eGFR.

Sleep disturbances can be associated with hypertension, metabolic syndrome/diabetes and CVD; the authors however adjusted for incident hypertension, DM and CVD and found that it did not impact on the relative increased risk associated with short sleep duration.

Comments

Whilst this observation is of interest, and worthy to be pursued, such analysis is always difficult to validate and interpret as:

1. It could be counfounded by underlying co-morbidity; those who dont sleep well may have illnesses that distrub their sleep and also predispose them to declining kidney function.

2. Sleep apnea cannot be discared as a cause of distrubed sleep; sleep apnea has been associated with impaired kidney function.

http://www.ncbi.nlm.nih.gov/pubmed/27152260

2. Hypertension in cohort studies is difficult to validate  as causal and occasional measurement of BP is seldom good enough to exclude underlying or incident hypertension. Also sleep disturbance may be associated with nocturnal hypertension, known to impact of CKD and its progression.

3. Serum creatinine/eGFR occasional (twice in 11 years) measurements may also mislead and give false positive results of decline, in the absence of a truly negative slope of eGFR decline ;non-linear decline may confound the interpretation of the renal functional data in this study.

http://www.ncbi.nlm.nih.gov/pubmed/22284441

4. Sleep disturbance may also be associated with medication, to alleviate the underlying cause or the associated symptoms including headaches, analgesics and others, that could in turn be instrumental in impacting negatively on renal function.

In conclusion, the association of sleep disturbances with CKD progressionmay be difficult to untangle by just counting sleep hours through a self reported questionaire.

CKD, Hypertension and diabets in the adult population of Morocco. Gharbi et al.

This is the publicationof the MAREMAR study that showed the prevalence of NCD and CKD in samples of the Moroccan adult population. CKD prevalence was around 5%. The study showed the importance of re-testing for proteinuria and eGFR in population screening studeis as the prevalence falls significantly upon validation of the initial positive testing...It also showed the important finding of underdiagnosis of CKD in the younger population and overdiagnosis in the older population when relying on one size fit all eGFR cut off of 60 ml/min comapred to teh more age-senstive cut-off of below the third age adjusted percentile.

Comments:

This is an example of how epidemiological studies on CKD detection and prevalence should be conducted.

It also shows the serious limitations of eGF <60 ml/min to define CKD in all age groups.

Underestimation, in younger patients whereby a 25 year old with a GFR of 70 ml/min would be considered as no suffering from CKD in the absence of proteinuira/hematuria, in spite of a significant reduction in kidney function...

Overestimation, by using an inappropriate and age-insensitiev cut off of 60 ml/min for a 75 year odl when 45 ml/min would be much more appropriate.

http://www.ncbi.nlm.nih.gov/pubmed/27057075

http://www.ncbi.nlm.nih.gov/pubmed/26932693

It is time for a rethink of the KDOQI/KDIGO CKD classification with a single defining cut off of 60 ml/min for all ages!

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]