Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.
The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure toPPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2blockers;n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.
PPI have been over prescribed and over used in the last 2 decades...
Whilst we all came across many cases of AIN due to PPIs, new concern about incident and progressive CKD linked to PPIs is being raised (see above).
This is difficult to ascertain in terms of causality as these associations are often biased and confounded by indication...like analgesics and CKD...those with underlying medical problems, comorbidities, consume them...then of course those same individuals are at increased risk of CKD...and ESRD! Also, those with ischemic heart disease and atherosclerotic renal ischemia are often given anti-platelet agents and...PPIs prophylactically...
Of interest, a similar association has been put forward between PPIs and CVD, adverse cardiac events,
...the same logic of "confounded by indication" may underly such association; those with CVD are often are on anti-platelt agents and...PPIs prophylactically?!
However, the use of PPIs in renal transplant recipients, in association with steroids, has been linked to osteoporosis and fractures... in fact, there are 34 studies in almost 2 million participants that have reported an association between PPIs and risk of fracture...http://www.ncbi.nlm.nih.gov/pubmed/25209137
...here again, this association doesnt prove causality as older patients are prescribed PPIs more than younger individuals...and the former also tend to be more prone to falls and fractures...
PPIs are more expensive than H2-blockers and tend to be for life...with rebound acidity making rapid withdrawal quite difficult...
So, should we still prescribe them...with doubts over their association with CVD, MBD, CKD progression and ESRD... or is it time to ditch them?!
Share your views on OLA.
MAREMAR STUDY: CKD CLASSIFICATION, TIME TO RE-THINK?
The MAREMAR study of CKD diagnosis and detection in Morocco is now published. This long awaited publication is an example of good quality epidemiology aimed at defining the prevalence of true CKD in Morocco.
A stratified, randomized, representative sample of 10,524 participants was studied. Weight, height, blood pressure, proteinuria (dipstick), plasma creatinine, estimated glomerular filtration rate, and fasting glycemia were measured.
Also, testing was repeated within 2 weeks and eGFR reassessed at 3, 6 and 12 months.
More interestingly, the authors compared “CKD” as defined by the cut off definition of KDOQI/KDIGO of 60ml/min to a more age-sensitive and more sensible classification based on the deviation from the percentile range for age; less than 3rd percentile.
This study highlights major points:
- Upon re-testing (Dipstix testing and/or eGFR) at 3 months, as recommended by KDOQI CKD definition and classification, 25-30% were found to be false positive and no longer classified as suffering from CKD; a sobering lesson for all those “epidemiological” reports of CKD prevalence that test the population ONCE and claim to define prevalence rates of CKD…RE TESTING IS A MUST TO DEFINE CKD.
- More interestingly, when CKD was defined as eGFR levels below the 3rd percentile for the individual's age-sex matched population, the study highlighted the serious shortcomings of the current cut off of 60ml/min/1.73m2 that is currently applied to all ages and genders: The MAREMAR showed that for younger individuals the current classification based on the 60ml/min arbitrary cut-off point, significantly UNDERDIAGNOSED CKD, whilst in older individuals over the age of 60 years, the current cut off significantly OVERDIAGNOSED CKD, mainly in those previously classified as CKD3A.
- When a study such as MAREMAR, that is well conducted with expertly validated methodologies, is undertaken, the prevalence of CKD (eGFR <60) falls to as low as 1.6% of the general population, a value well below the misleading prevalences reported in other poorly conducted studies claiming ~5-10%. Also, proteinuria is detected consistently in as few as 1.3%, again a prevalence well below the values previously branded upon single testing for ~7-10%.
MAREMAR is a landmark publication and a must read for all those aspiring to do epidemiological surveys on CKD in their populations. It shows that well conducted epidemiological studies can be undertaken. It also shows how they should be conducted with careful validation of methodologies and interpretation of results.
MAREMAR shows that CKD classification based on a SINGLE 60ML/MIN CUT OFF POINT FOR ALL AGES IS NOT FIT FOR PURPOSE; age and gender sensitive classification based on deviations from age and gender specific population norms (percentiles between 3-97th) is the way forward. This can be easily automated and reported. It will free millions worldwide from the misleading label of “CKD” based on an artificial and arbitrary cut off point.
IT IS HIGH TIME WE, AS NEPHROLOGISTS, RE-THINK THE CKD DEFINITION.
The latest analysis by the Non-Communicable Disease worldwide collaboration gives an intriguing picture of the prevalence of Diabetes Mellitus (DM) worldwide.
Age-standardised prevalence, shows:
NO increase in prevalence of DM from 1980 to 2014 in Europe!
NO overall increase in Africa
NO increase in Central and Latin America
NO increase in Japan
Significant increase in the Middle East and North Africa
Significant increase in Central Asia
So how can we explain the absence of increase in the prevalence of DM in Europe, Central and Latin America or Japan where the prevalence of OBESITY has considerably increased, along with other regions of the world?!
Does this mean that the “epidemic” of DM is only due in Europe, Latin America, Japan and parts of Asia to the ageing of the populations and not Obesity….?!
On the other hand, genetic factors may explain the rise in the prevalence of DM in the Middle East, North Africa as well as in Polynesia? In these regions, DM (mainly T2DM) may be a two hit phenomenon where genetic predisposition combined with environmental factors, such as diet and obesity, may be required for the phenotypic expression of the disease.
Is the dogma linking DM and Obesity a geographical phenomenon that doesn't apply to Europe?
Is the increase prevalence of DM in Europe merely the reflection of the ageing of the population?
Is it time to rethink the “association” linking obesity to Diabetes mellitus?
This excellent paper proposes an age-sensitive CKD classification:
<40 years: CKD threshold = 75 ml/min
40-65years: CKD threshold = 60 ml/min
>65 years: CKD threshold =45 ml/min
this in the absence of other corroborating signs of kidney damage.
It is high time we move away from one classification and one CKD threshold (60 ml/min) for all...
It is also high time to appreciate that CKD is not a single disease...with a single definition...and a single classification...
A GFR of 60 ml/min in a 25 year old patient with glomerulonephritis is a very different proposition than a GFR of 60 in a 75 year old with longstanding hypertension...
GFR thresholds are therefore meaningless in isolation as they serve no medical or clinical purpose...in fact, they have not changed clinical practice of referred patients with kidney damage...they only generated interest and research by "epidemiologists" that created a "Disease" to generate interest in a small subspecialty that looked for a way to enhance its significance by claiming that 1 in 4 of the general population, 1 in 3, 1 in 2 in a lifetime, is or will...suffer from CKD...
In my opinion, it is high time to drop CKD thresholds all together and define referred kidney damage patients by their medical condition, as to the general population define those affected by their underlying condition (hypertension, diabetes) and detail the degree and nature of their kidney damage.
This is an interesting blog by Dr Ben Goldacre who basically is arguing that academic journals are effectively not a 'fit for purpose' arena to publish results of clinical trials.
This is an interesting, (though long) blog by Dr Ben Goldacre who basically is arguing that academic journals are effectively not a 'fit for purpose' arena to publish results of clinical trials.
Whilst the benefits of transplantation are well established, finding suitable donors for ‘sensitised’ patients with anti-HLA antibodies remains a significant barrier to transplantation. The options for such patients are to stay on the deceased donor waiting list, participate in the paired+pooled donation scheme (and hope they get a donor) or undergo densistisation and transplant from a live HLA incompatible (HLAi) donor. However the outcomes HLAi live donor transplantation are significantly worse than those receiving compatible kidneys. In reality given the chances of receiving an HLA compatible transplant are so slim, the choice these patients face is to either be desensitised and receive an HLAi live kidney or remain on dialysis.
Enormous advances continue to be made to enhance our understanding of the challenging “thrombotic microangiopathies TMA”
It is becoming clear, recently, that distinct disease mechanisms underlie the group of diseases formerly designated as TTP/HUS. Advances in molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypicalHUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor.
Interestingly close to 20,000 articles in TMA have been published since 1945, with striking increase after the completion of human genome sequencing in 2001 as more disease-causing mutations had been identified.
The increasingly better clinical characterization and definition of the role of complement in HUS has pushed our understanding forward in an unprecedented way. Defining complement dysregulation as central to disease pathogenesis has paved the way to targeted therapeutics and improved patient clinical outcome.
Complement-mediated TMA (the preferred term) is not just a disease of children, as evidenced by the largest reported cohorts by Noris and colleagues 2010; Fremeaux-Bacchi and associates, 2013. The child-to-adult ratio is nearly comparable with respect to age-at-presentation, ranging from <1 year of age to 85 years. Interestingly the male-to-female ratio is similar in younger patients, whereas there is a female preponderance in adults (Fremeaux-Bacchi et al., 2013). Triggering events are documented in 39–70% of individuals and include most often diarrhea, respiratory illness and pregnancy.
Chantal Loirat and her colleagues recently published “An international consensus approach to the management of atypical hemolytic uremic syndrome in children” in Pediatric Nephrology Journal providing a consensus clinical practice recommendations generated by HUS International (expert group of clinicians and basic scientists with a focused interest in HUS).
They provided evidence-based answers where available (already scarce), while relying mostly on the published anecdotal literature. The consensus raises many questions as it answers: for instance when to withdraw treatment in countries where therapy is already available? On the other hand, one of the major concerns is the geographical disparity in treatment availability due to the high cost of the drug in limited resources nations worldwide. It also emphasizes the need to carefully design future studied and use data from international registries to better understand this challenging disease.
1. Noris, M., Caprioli, J., Bresin, E., Mossali, C., Pianetti, G., Gamba, S., Daina, E., Fenili, C., Castelletti, F., Sorosina, A., Piras, R., Donadelli, R., Maranta, R., van der Meer, I., Conway, E.M., Zipfel, P.F., Goodship, T.H., Remuzzi, G., 2010. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5, 1844–1859
2. Fremeaux-Bacchi, V., Fakhouri, F., Garnier, A., Bienaime, F., Dragon-Durey, M.A., Ngo, S., Moulin, B., Servais, A., Provot, F., Rostaing, L., Burtey, S., Niaudet, P., Deschenes, G., Lebranchu, Y., Zuber, J., Loirat, C., 2013. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin. J. Am. Soc. Nephrol. 8, 554–562
3. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Frémeaux-Bacchi V; HUS International.An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol.2016;31(1):15-39
I received this letter from a US Nephrologist working in non fee for service environment...
Hello Professor Meguid El Nahas,
I saw your article in Jama from August 2015, regarding CKD staging,
I am a practicing nephrologist in Baltimore, MD, and I practice with Kaiser, in a non fee for service environment. I feel like the diangosis of elderly CKD pts has gotten out of control. CKD staging was developed as an epidemiologic tool that has turned into clinical practice, and very badly. Telling an 85 yo female, who have about 1% chance of reaching ESRD in the their lifetime that they have stage 3 CKD , is awful and unnecessary. In fact, telling pts they have stage 3 anything, is legitimately criminal when they have little increased risk of actually needing intervention in their lifetime.
To this end I wanted to propose a new CKD staging system that would be more pt centric:
CKI Stage 0 - GFR > 60, with some structural abn or proteinuria
CKI stage I - GFR 45-60 mild kidney impairment
CKI stage II - GFR 30-45 mod kidney impairment
CKI stage III - GFR 15- 30 severe kidney impairment
CKI stage IV - GFR 0 -15 kidney failure
a - < 1 gm proteinuria
b - 1-3 gm proteinuria
c - > 3 gm proteinuria
For pts with no change to GFR by MDRD
1. It is unlikely will be getting rid of MDRD in the near future, and now it is commonly reported with all labs. Pt get anxious when they see an abnormality in their labs.
2. Pts with known significant proteinuria, or structural defects, i.e. PKD, pts don't need another diagnosis of CKD. GIving them a secondary diagnosis like IgA nephropathy and stage 1 CKD does not change their diagnosis or their prognosis, and is only useful from an epidemologic standpoint. for which CKI Stage 0 can be used.
This model was conceived based on patient centric care, instead of epidemiology.
The changes have many pt centric benefits,
1. We stop calling patients with low GFR diseased, which is hard to justify that 30% of the adult population over 70 should be described.
2. When a lab is reported as abn. low GFR, this will be able to tell pts they have a mild impairment, which is much more relieving to hear than stage 3 kidney disease. And enough for pts to remember and dose meds accordingly.
3. Informing pts on stage 3 CKD , the first questions, are: what happened to stage I and 2, why wasn't I informed then? Other than explaining the complex epidemiology that led to this staging system, and that's just the way it is, there is no good reason for this.
4. It closely matches a 4 stage system, which patients are more familiar with, in regards to cancer staging. Stage 3 actually means something.
I am not sure what to do with this now, as many colleagues work in a fee for service model, and seem to need the referral base, but I feel like it is ethically wrong that we have created an epidemic of kidney disease where none existed. We have given a diagnosis to age, and the repercussions are unclear. I would like to propose this model to someone in academics, and since I saw your article, felt you might be able to guide me in the right direction.
Thank you for your time,
Atif K. Jensen
Dept of Nephrology, Towson
This message implies that the notion of "Epidemic of CKD" is linked to financial incentives for fee for service Nephrologists in the USA who aim to increase their referral basis on the back of medicalising the aging of the older population with age-related reduced kidney function and GFR...
Medicine and Money are not compatible bed fellows....
National trends in acute kidney injury requiring dialysis in England between 1998 and 2013.
Acute kidney injury (AKI) severe enough to require dialysis is increasing and associated with high mortality, yet robust information about temporal epidemiology of AKI requiring dialysis in England is lacking. In this retrospective observational study of the Hospital Episode Statistics (HES) data set covering the entire English National Health Service, we identified all patients with a diagnosis of AKI requiring dialysis between 1998 and 2013. This incidence increased from 774 cases (15.9 per million people) in 1998-1999 to 11,164 cases (208.7 per million people) in 2012-2013. The unadjusted in-hospital case-fatality was 30.3% in 1998-2003 and 30.2% in 2003-2008, but significantly increased to 41.1% in 2008-2013. Compared with 2003-2008, the multivariable adjusted odds ratio for death was higher in 1998-2003 at 1.20 (95% CI: 1.10-1.30) and in 2008-2013 at 1.13 (1.07-1.18). Charlson comorbidity scores of more than five (odds ratio 2.35; 95% CI: 2.20-2.51) and emergency admissions (2.46 (2.32-2.61) had higher odds for death. The odds for death decreased in patients over 85 years from 4.83 (3.04-7.67) in 1998-2003 to 2.19 (1.99-2.41) in 2008-2013. AKI in secondary diagnosis and in other diagnoses codes had higher odds for death compared with AKI in primary diagnosis code in all three periods. Thus, the incidence of AKI requiring dialysis has increased progressively over 15 years in England. Improvement in case-fatality in 2003-2008 has not been sustained in the last 5 years.
An increased trend of AKI has been observed in the UK over the last 15 years. The ageing of the population and increasing co-morbidities have to be contributing factors.
Of note the sharp in increase in AKI between 2004-2008. So we have to ask ourselves what happened in the UK during that time that may explain the sudden, and it is a sudden surge in 2006-2008 in the number of cases of AKI.
2003: KDOQI: CKD Classification
2004-5: eGFR reporting in the UK NHS and associated increase in RAAS prescribing. THis was observed in other countries worldwide. http://www.ncbi.nlm.nih.gov/pubmed/22437415
2004: Introduction of Quality and Outcomes Framework (QOF) to General Practitioners in the UK, encouraging to detect "CKD" and prescribe ACE inhibitors and other Renin Angiotensin Aldosterone System (RAAS) blockers. In fact, they get renumerated and increase their income if they prescribe ACE inhibitors...
2006: Onward surge in numbers of cases of AKI in the UK...
Is that a coincidence?!
Or is the rise in AKI in the UK the direct consequence of the inappropriate and increased prescribing of these potentially nephrotoxic agents?
In one study, up to 15% of the increase in AKI admissions in England over a 4-year time period (2007-2010) could be traced and attribued to increased prescribing of ACE-I and ARBs. http://www.ncbi.nlm.nih.gov/pubmed/24223154
The authors of the above report on AKI national trends in the UK are questioning what needs to be done to prevent further rise in AKI,
The answer is simple:
1. Educate GP to stop the indiscriminate prescribing of RAAS blockers to older people with co-morbidities including those with T2DM
2. Stop rewarding GPs in the UK for prescribing potentially nephrotoxic agents such as ACE inhibitors to the older population with comorbidities and vascular pathologies including CKD due to ischemic nephropathy
3. Educate Non-Nephrologists to the potential nephrotoxicity of RAAS blockers more specifically amongst the older population
4. Improve the understanding of CKD in the elderly; a mere reduction in eGFR that is age-related in most and inconsequential...that doesnt warrant RAAS blockade! In fact recent evidence suggest that aggressive BP control in this age group increases the incidence of both AKI and CKD: http://www.ncbi.nlm.nih.gov/pubmed/26551272
5. In fact, stopping RAAS blockers in this age group may be protective!:
6. Declassify many older patients from the label of "CKD" by a more age-sensitive CKD classification: http://www.ncbi.nlm.nih.gov/pubmed/26023760
7. Stop treating microalbuminuria in the older population with RAAS blockers; it is merely a reflection of age-related vascular disease.
8. Debunk the myth that early treatment of CKD prevents late complications...in fact, the number needed to treat (NNT) with a RAAS blocker in those with early CKD (3a), in the absence of proteinuria, is 2,500 to prevent 1 case of ESRD...and NNT in those with CKD3a and microalbuminuria (or proteinuria = 1+) exceeds 1,000 patients treated with RAAS blockers to prevent 1 ESRD...
ALL IN ALL,
IT IS HIGH TIME TO RETHINK THE USE OF RAAS BLOCKERS IN THE OLDER GENERAL POPULATION AND IN CKD.
IT IS HIGH TIME THAT PRESCRIBING OF RAAS BLOCKERS IS CURBED AND CONTROLLED IN THE UK TO PREVENT MORE AKI AND CKD...!!!