"Providing guidance in the dark: rare renal diseases and the challenge to improve the quality of evidence." Bolignano and colleagues address the vexed issue of Rare and Orphan Disease and difficulties to obtain good and meaningful data either thought observational studies or through clinical intervention trials due to the small number of those affected. Small sample studies that are underpowered can lead to difficulties in statistical evaluation of the results and interpretation.
They suggest a number of approaches including:
Cross-over trials, performance of repeated measurements and analysis of covariance instead of a single comparison between treatment groups.
They also put considerable emphasis on the importance of registries and networks facilitating data collection, thus generating larger patients group more amenable to observational and cohort studies as well as randomized clinical trials.
This is a point previously elegantly made by Professor N Soliman in a similar review published a few years ago where she highlighted the importance of activism in this area of healthcare through alliance between patients groups such as the one she founded in Egypt, EGORD, and healthcare providers.
This, in turn, addressed the more urgent issue of drug provisions for Orphan and Rare Kidney Disease (ORKD) as treatment of a single patient with ORKD can cost anything between $100,000-400,000/per year!. With the ongoing economic downturn Western and high economies are finding such cost increasingly unaffordable. In emerging countries, the price of orphan therapies was never affordable. This is another reason why networks and lobbying as well as activism on behalf of patients suffering from ORKD take a more emphasis by putting pressure on the Pharmaceutical industry to address their cost issues. There is little doubt that the Pharma Industry needs a much more responsible approach to ORKD. It is up to healthcare professionals along with patients groups to keep the pressure up not only to improve research facilities but also to generate affordable therapies for these rare but often devastating diseases.
The Global Kidney Academy (ORKD initiative launched in January 2013 has one more month to run. It had little impact beyond raising awareness and education of these conditions. But perhaps as the Bolignano and Soliman reviews did, education is the first step to awareness which in turn is the first step to stimulating and facilitating research initiatives but also lobbying on behalf of ORKD sufferers.
TEXT of the MEDSCAPE VIDEO BLOG by Jeff Berns, MD
Hello. This is Jeffrey Berns, Editor-in-Chief of Medscape Nephrology. The American College of Physicians (ACP) recently released a clinical practice guideline on the screening, monitoring, and treatment of stage 1-3 chronic kidney disease (CKD). Four recommendations were provided, some generating a fair amount of disagreement with the American Society of Nephrology (ASN), the National Kidney Foundation (NKF), and the Renal Physicians Association (RPA). First, the ACP document affirms the asymptomatic nature of stage 1-3 CKD, and that having CKD has health implications, including mortality, cardiovascular disease, fractures, bone loss, cognitive dysfunction, infection, and frailty. They also comment on the common co-occurrence of hypertension, cardiovascular disease, and diabetes. Furthermore, they state that the diagnosis of CKD, regardless of stage, requires laboratory testing.
Before getting to the ACP recommendations, I find it extremely difficult to understand the rationale for lumping together stages 1, 2, 3A, and 3B CKD without specific reference to the prevailing level of albuminuria. This is a rather disparate group of patients to consider under a single guideline, and I'm not sure that I would have set out to lump all of these diverse patient groups together.
Let's look at the ACP recommendations. First there was a weak recommendation based on low-quality evidence against screening for CKD in asymptomatic adults without risk factors for CKD. The text of the article in the Annals of Internal Medicine  cites as risk factors diabetes, hypertension, older age, obesity, and family history of CKD in African American, Native American, and Hispanic patients. That seems to include a huge proportion of the US adult population. Very few people are left potentially unscreened.
Another weak recommendation based on low-quality evidence was that patients who are already on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) for hypertension do not need to be tested for proteinuria. It's not specified whether this recommendation applies to patients with known CKD. I cannot imagine that many in the nephrology community don't routinely use some measure of proteinuria or albuminuria to guide ACE inhibitor or ARB treatment of patients with CKD, and I suspect that few, if any, will change their practice on the basis of these guidelines.
Two guidelines address treatment, and both are strong recommendations. One recommendation is to use an ACE inhibitor or an ARB as treatment for hypertension in patients with stage 1-3 CKD, and the other is to use statins to treat high low-density lipoprotein (LDL) levels in these patients. This confuses me a little bit. We should use these treatments in patients with CKD stage 1-3 because they improve patient outcomes, but don't look for patients who might benefit from such therapies? I must be missing something.
An ASN press release urges screening for CKD regardless of risk factors and otherwise pretty much disagrees with the ACP guidelines. The NKF and the RPA are screening for early CKD in patients with risk factors but not in the general population without risk conditions -- again, seemingly a pretty small slice of adults living in this country.
Why look for CKD? You will find poorly controlled hypertension, poorly controlled diabetes, poorly controlled lipid disorders, people who need changes in medications, those who need to avoid certain medications, and people who should be referred for early transplant evaluation. You will find opportunities to educate patients about sodium restriction and weight loss. Our testing tools for estimating glomerular filtration rate (GFR) aren't perfect. They just estimate GFR, but using imperfect tests wisely is probably better than not using them at all.
Finally, let's be clear that screening (which is not really defined in the ACP guideline) is not the same as testing for the presence and severity of CKD in the scope of a patient encounter for general health assessment or management of diabetes, hypertension, and so forth.
Nephrologists shouldn't tell the primary care physicians that they work with to stop looking for CKD. It is still an important health measure, and finding it creates the opportunity to improve patient health.
Thanks for listening. This is Jeff Berns, Editor-in-Chief of Medscape Nephrology, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
Jeff Berns voices the confusion many physicians and nephrologists have faced since the release by the ACP of its clinical practice guidelines relating to CKD screening and management and the subsequent contradictory statements made by representatives of the ASN and NKF.
A number of issues warrant clarification:
1. Are all CKD the same?
CKD has become and all encompassing term covering a very heterogeneous group of people and patients, hence the confusion when physicians are faced with guidelines and recommendations for CKD.
A distinction has to be made between CKD in the community (cCKD) and those seen by physicians and nephrologists who are referred (rCKD) because they suffer from an intrinsic kidney disease such as glomerulonephritis, vasculitis or polycystic kidney disease.
cCKD is mostly a reflection of age-related decline in kidney function, with otherwise healthy older individuals mislabeled as suffering from a disease (CKD), when in reality they merely have a lower GFR commensurate with their age and possibly underlying age-related cardiovascular disease; hypertension and diabetes, mostly type2.
2. To Screen or Not to Screen?
Community screening of asymptomatic individuals for cCKD is not warranted and is not cost effective. Testing for abnormal kidney function in individuals with known disease predisposing to CKD such as hypertension and diabetes is good medical practice. Therefore, in cCKD there is little justification for screening asymptomatic individuals but there is full indication of testing for CKD those with known predisposing conditions such as hypertension and diabetes; both poorly detected, treated and controlled in the US. It is these two conditions that warrant screening for; thus effecting early detection and management.
Screening for rCKD is seldom an issue as these patients often present acutely with a glomerulonephritis, vasculitis, pyelonephritis or other clinical manifestation of intrinsic kidney disease; proteinuria or hematuria. Those with ADPKD often have a family history that justifies the screening.
3. To Treat or Not to Treat?
There’s another legitimate confusion; treat with RAS inhibitors and statins but don't screen? Well, the distinction between cCKD and rCKD should shed some light on such apparent contradiction. Asymptomatic cCKD, older individuals within the community, should be left alone neither screened nor treated, as there is no evidence for benefit from neither; screening or primary prevention.
By contrast, those in the community with cCKD accompanied byas hypertension and/ot diabetes, should be treated appropriately and according to established guidelines that recommend renin-angiotensin system (RAS) inhibition or other drugs to lower blood pressure and reduce the magnitude of overt proteinuria (>1+ by dipstick) inhibition and statin therapy if dys-lipidemia is present. Such treatments should impact favorably on the complications of these conditions including secondary CKD.
Finally, all would agree that rCKD often suffer from hypertension and overt proteinuria justifying treatment with RAS inhibition as recommended by most management guidelines.
I hope that this clarification and distinction between cCKD and rCKD makes some sense of the disparate recommendations and conflicting arguments made by bodies that overlook the heterogeneity of CKD and consequently fail to make coherent recommendations.
Professor Pierre Delanaye wrote in OLA French referring to the CORAL study recently published in the NEJM and not showing a therapeutic or functional advantage of renal artery stenting (PCI) over conventional medical therapy:
Résultat d'une étude très intéressante et attendue dans le NEJM de cette semaine.
La question posée est la suivante: PTCA et Stenting de l'artère rénale font ils mieux que traitement médical chez le sujet âgé?
947 sujets randomisés avec une sténose d'artère rénale (sévère mais pas complète, 80%) et soit une HTA systolique malgré 2 traitements ou plus soit une insuffisance rénale (IR). Les critères d'exclusion étaient: dysplasie fibromusculaire, IR d'autre cause, créatinine supérieure à 4 mg/dL, rein de moins de 7 cm, stenting impossible. Tous les patients devaient être traités pour leur diabète, leur dyslipémie et par antiplaquettaire. Les patients recevaient préférentiellement du candersartan avec ou sans thiazide et/ou l'association amlodipine/atorvastatine. Le contrôle tensionnelle est considéré à 140/90 et 130/80 si diabète ou IR. Le stenting était réalisé avec un systéme anti-embol chez la majorité des sujets.
Le critère de jugement principal était composite: mort CV ou de causes réanles, stroke, infarctus, hospitalisation pour décompensation cardiaque, IR progressive (GFR estimée qui diminue de plus de 30% et sur au moins 60 jours) ou la nécessité d'une dialyse. La randomisation est réussie. Les patients ont en moyenne 69 ans (50% d'hommes), 93% de caucasiens (étude américaine), 50% ont GFR inférieure à 60 ml/min/1.73 m², 33% de diabète, 90% de dyslipémique, sténose à 65-70%. 15 à 22% de sténose bilatérale ou sur rein unique. N=459 dans groupe stenting et n=472 dans groupe non stenting. 94% des patients ont eu un stent avec un résultat satisfaisant (11 dissections, pas de dialyse dans les 30 jours).
Le suivi médian fut de 43 mois. Il n'y a pas de différence en terme du jugement primaire, ni dans les critères secondaires (=les critéres dans le critère composite pris individuellement + mortalité globale). On retrouve un avantage modeste (-2.3 mm Hg) (cliniquement peu relevant) en terme de controle de la TA systolique (p=0.03). Le nombre de médicament anti-HTA augmente avec le temps dans les deux groupes mais n'est pas différent entre les groupes (3.3 +/-1.5). En terme de critère primaire on ne trouve pas de résultats meilleurs pour le stenting dans les sous groupes suivants: créatinine >ou < à 1.6 mg/dL, GFR estimée > ou < à 45 ml:min/1.73 m², diabète ou non, femme et homme, atteinte bilatérale ou pas, Noir ou blanc, TA systolique de base > ou <160 mmHG, Âge de > ou <70 ans, sténose > ou < 80%.
Donc après les études suggérant une absence de bénéfice en terme de contrôle tensionnel et en terme de fonction rénale, une étude encore plus ambitieuse démontre l'absence d'intérêt en terme d'événements cliniques.
The management of FSGS particularly post -transplantation remains difficult with no clear evidence base on how to optimally manage recurrent disease. The search for a permeability factor continues and recent work suggested that serum-soluble urokinase-type plasminogen activator receptor (SuPAR) may have an important role in FSGS by modulating integrin signalling within podocytes promoting foot process effacement and proteinuria. As yet there is significant variablility in SuPAR levels (and no standardised assay) in differing FSGS cohorts so its utility as a biomarker is far from certain.
Economic Evaluation of Frequent Home Nocturnal Hemodialysis Based on a Randomized Controlled Trial
Scott Klarenbach, Marcello Tonelli, Robert Pauly, Michael Walsh, Bruce Culleton, Helen So, Brenda Hemmelgarn, Braden Manns
Provider and patient enthusiasm for frequent home nocturnal hemodialysis (FHNHD) has been renewed; however, the cost-effectiveness of this technique is unknown. We performed a cost-utility analysis of FHNHD compared with conventional hemodialysis (CvHD; 4 hours three times per week) from a health payer perspective over a lifetime horizon using patient information from the Alberta NHD randomized controlled trial. Costs, including training costs, were obtained using microcosting and administrative data (CAN$2012). We determined the incremental cost per quality-adjusted life year (QALY) gained. Robustness was assessed using scenario, sensitivity, and probabilistic sensitivity analyses. Compared with CvHD (61% in-center, 14% satellite, and 25% home dialysis), FHNHD led to incremental cost savings (-$6700) and an additional 0.38 QALYs. In sensitivity analyses, when the annual probability of technique failure with FHNHD increased from 7.6% (reference case) to ≥19%, FHNHD became unattractive (>$75,000/QALY). The cost/QALY gained became $13,000 if average training time for FHNHD increased from 3.7 to 6 weeks. In scenarios with alternate comparator modalities, FHNHD remained dominant compared with in-center CvHD; cost/QALYs gained were $18,500, $198,000, and $423,000 compared with satellite CvHD, home CvHD, and peritoneal dialysis, respectively. In summary, FHNHD is attractive compared with in-center CvHD in this cohort. However, the attractiveness of FHNHD varies by technique failure rate, training time, and dialysis modalities from which patients are drawn, and these variables should be considered when establishing FHNHD programs.
There is a trend and fashio to promote frequent nocturnal HD based on the FHN trial implying benefit. This is of concern as the FHN trial failed to shwo survival advantage, but showed a benefit on left ventricular hypertrophy; as combined endpoints were evaluated it served to the fall impression that the combined endpoint of survival and left ventricular hypertrophy were imrpoved by Frequent HD, which wasnt the case...
Also, Frequent HD was associated with longer time, UF, as well as higher weekly KT/V in the treated group compared to standard thrice weekly HD; so to attribute the benefit to increased frequency is a misleading assertion as it could as well be due to longer weekly HD or better UF...
Form such weak, short term, data to embark on changing HD practices worldwide is a folly....the paper above also remind us of cost implications.
Nephrologist sare all too keen to embrace new practices to show that they are keeping up with the literature (often without understanding it...) and fashion (something most are attracted by....),
1. Critically examining the facts and data.
2. Examining their utility and usefulness to their own patients population.
3. Without adequate comparisons to their own practices
4. Without assessing the Risk versus Benefit; in this case the risk of jeopardising vascular access by frequent cannulation/puncture.
5. Without assessing the COST versus BENEFIT as outlines in the paper by the Alberta group. A cost benefit analysis that takes the primary intervention cost advantage over conventional HD and showing some advantages but than examining the true cost of any new intervention including the cost of complications and related medical care, the cost of technique failure and loss of vascular access, etc...ONLY THEN DOES THE TRUE COST EFFECTIVENESS OF A NEW TECHNIQUE starts to fade away as gain per QALY exceeds $50,000, the threshold for cost effectiveness in high economines.
Cost effectiveness in middle and low economies could be a gaing per QALY of as little as <$5,000, cost per QALY gained higher tha $5,000 per annum is an unacceptable cost in many low economies.
It would be great that cost benefit analysis also give some insights and figures for cost effectiveness not only in their societies and wealthy healthcare systems but also in poorer economies based on a GDP adjustement.
This would be a great excercise that would enhance the value and UTILITY of such analysis beyond a restricted healthcare system, that in which the reporting autors work within.
Prof Pierre Delanaye wrote a BLOG in OLA French:
Une étude purement observationnelle mais intéressante car spécifique aux patients insuffisants rénaux (même si la définition retenue pose un peu problème, à savoir une GFR estimée inférieure à 60 ml/min et/ou une protéinurie). Les auteurs ont comparé la prévalence du contrôle de l'HTA définie sur base d'une mesure en consultation inférieure à 140/90 ou à 130/80 ou sur base d'un monitoring de 24h avec une définition à 130/80 ou 120/75. L'hypertension blouse blanche est définie comme une HTA plus importante en consultation et une HTA masquée si c'est l'inverse (TA contrôlée en consultation mais pas sur holter de 24h). 14382 sujets espagnols ont été recrutés. 8689 n'avaient pas d'IR 72,6% étaient traités (la moitié avec plus de deux médicaments). L'utilisation et le nombre d'antihypertenseurs augmentent avec la progression de l'IR ce qui n'est pas trop étonnant. 21.7% des patients avec IRC ont une TA controlée en consultation (140/90) mais 43.5% ont un holter avec cible inf à 130/80. Le controle de la TA sur holter de 24 h ne semble pas trop différent selon le stade d'IR sur pour le controle de l'HTA nocturne qui augmente avec l'IR
14.7% des sujets sont controlés et sont concordants entre les 2 techniques
49.5% sont concordants pour une marque de contrôle de la TA
Une HTA de la blouse blanche est présente dans 28.8%
Une HTA masquée est présente dans 7% des cas
36% des sujets avec une HTA en consultation présente en fait un effet blouse blanche et 32% des patients controllés en consultation ont en fait une HTA sur le monitoring
=> intéret du monitoring en cas d'IRC?
Nephrol Dial Transplant. 2013 Oct;28(10):2553-69. doi: 10.1093/ndt/gft214. Epub 2013 Jun 4.
Cost of peritoneal dialysis and haemodialysis across the world.
International Renal Research Institute Vicenza (IRRIV), San Bortolo Hospital, Vicenza, Italy.
Peritoneal dialysis (PD) as a modality is underutilized in most parts of the world today despite several advantages including the possibility of it being offered in the remotest of locations and being significantly more affordable than haemodialysis (HD) in most cases. In this article, we will compare the cost of HD and PD in several countries to demonstrate that PD is less than, or at least as expensive as, HD. A thorough literature survey of EMBASE and PUBMED was conducted; 78 articles which compared the annual PD and annual HD costs were finally selected. Careful attention was paid to the methodology followed by each study and the year it was published in. Our final calculations included 46 countries (20 developed and 26 developing). We found that the cost of HD was between 1.25 and 2.35 times the cost of PD in 22 countries (17 developed and 5 developing), between 0.90 and 1.25 times the cost of PD in 15 countries (2 developed and 13 developing), and between 0.22 and 0.90 times the cost of PD in 9 countries (1 developed and 8 developing). From our analysis, it is evident that most developed countries can provide PD at a lesser expense to the healthcare system than HD. The evidence on developing countries is more mixed, but in most cases PD can be provided at a similar cost where economies of scale have been achieved, either by local production or by low import duties on PD equipment.
continuous ambulatory peritoneal dialysis (capd), economic analysis, economic impact, haemodialysis, peritoneal dialysis
This very interesting analysis of the cost of HD versus PD worldwide is very revealing. It shows that most Developed countries favor HD over PD as judged by the prevalence of the modalities in their RRT population; USA 93% HD versus 7% PD (1). The uptake of PD in Europe is marginally better but remains much lower than HD with for instance Germany having as few as 5% of its ESRD patients treated by PD! This, in spite of a higher cost for HD compared to PD; in the US for instance the annual patient cost for HD is around $ 87,500 compared to $66,750 for PD. It has been estimated that the US, that spends 18% of its GDP on healthcare, could save up to $1.1 billion over 5 years if the uptake of PD increased from 7% to 15% (2).
Yet there are obstacles to PD utilization in the West including: 1. Reimbursement policies (in France and Germany for instance reimbursement for HD is much higher than that for PD), 2. Physicians/Nephrologists preference, 3. Physicians familiarity with PD; a modality with which they may have little experience, 4. Patients’ preference, 5. Patients’ increasing age and dependency as well as isolation making thrice weekly HD not only a medical but also a social necessity.
The analysis under discussion paints a different cost analysis for PD in Developing countries where in the most deprived, low economies, PD is a more expensive RRT modality than HD! This has many root causes including: 1. the cost of importing PD solutions and related delivery system, 2. PD companies monopoly of pricing, 3. High export duties on such material, all combining to make PD more expensive, in some countries like Egypt 5 times more expensive [HDD/PD cost ratio = 0.22], than HD! Consequently, in Africa for instance, PD utilization is very low or non-existent outside of South Africa, where solutions can be manufactured locally bring the PD cost well below that of HD (3). Hong Kong has the highest PD utilization in the World (80%) due to the low cost of consumables and solutions (PD is half the cost of HD) as well as the PD first policy adopted in this country.
The way forward for low economy countries is to have PD as an economically viable option for RRT. For that they would have to reduce the cost of PD solutions (bags) cost considerably by:
- Imposing more acceptable prices and breaking the monopolies of major suppliers.
- Reducing import duties on bags (as has been done in Nepal and Malaysia).
- Considering the local production of Bags and PD solutions (South Africa and India).
- Negotiating import contracts with other developing countries that manufacture PD bags and solutions.
- Encouraging a PD first approach as promoted by Hong Kong and recently adopted by Thailand.
This may offer emerging countries with hardly any RRT due to unaffordability, the option of a potentially cheaper RRT modality compared to HD, thus also bypassing the cost of setting up HD units with the inherent infrastructure cost.
PD first may be, with renal transplantation as soon as possible may be a model to consider. Iran has increased considerably since 1995 its utilization of PD (manufactured locally) (4) as well as its rate of renal transplantation through a concerted centralized healthcare policy. In low and middle economies where ESRD is often a death sentence due to the lack of affordable RRT modalities, Governments have a duty to explore and provide affordable RRT options in order to comply with the moral ethics of the Istanbul Declaration banning organ trafficking. Unless, this is provided, human nature will prevail and organ trafficking will continue out of the despair of some and the greed of others…
- USRDS: http://www.usrds.org/adr.aspx
This comprehensive and well conducted meta-analysis confirms my long held bias that cardio-protection relies primarily on lowering BP regardless of the agent used. This was also the conclusion of a number of studies and meta-analysis including ALLHAT and the Meta-Analysis of Casas and colleagues in ther Lancet a number of years ago. http://www.ncbi.nlm.nih.gov/pubmed/16338452
We are often referred to the seminal study HOPE arguing that the cardioprotection conferred by RAS inhibitors is independent from their BP lowering effect and is a class specific effect that justifies their use above other anti-hypertensive agents in those at CV risk: http://www.ncbi.nlm.nih.gov/pubmed/10675071
This Mantra...like many in Nephrology has been repeated over and over again by Nephrologists keen to do their best for their patients and egged on by the Pharmaceutical Industry keen to do its best for its shraeholders....and the story went on for more than a quarter of a century inspite of dissending voices questioning the dissociation of the protective effect from the anti-hypertensive effect of RAAS inhibitors. I personally questionned that myth as far back as 2000: http://www.ncbi.nlm.nih.gov/pubmed/10754405
The confusion and issues are due to a number of reasons:
1. Pharma Industry hold of Key Opinion Leaders and Clinical Trialists over the last quarter of a century. I recollect conducting a study on progression comparing Lisinopril versus Placebo (with equal BP control) in the late 80s and study impact on progression: Result: NO difference. Outcome: Never Published...???!!!!
2. Lack of Critical Reading or Appraisal skills by most of those of us who read published material and Clinical Trials Reports; most dont bother to read the methodology section; abstracts or even title is often enough to embrace a new idea...treatment...or myth...and run with it!
3. Physicians commercialism; always keen to impress (and hence charge more...) patients with the latest treatments stemming from the latest publications even if they half understand their scientific implications as long as they fully understand their financial incolme generation implication.
4. MOST IMPORTANTLY....the alleged dissociation between the cardioprotective effect of RAAS inhibitors from their anti-hypertensive effects stems to a large extent from the fact that BP is RCTs (Clinical Trials) is seldom measured correctly; often if not invariably relying on causal office BP reading after a few minutes of rest...this is the least valuable, accurate or predictive method in terms of CVD outcomes as nocturnal, day:night and 24h Ambulatory BP measurement (ABPM) have proved much more reliable and predicitve.
In fact and of relevance, is the observation of a HOPE sub-study itself by Svensson et al (2001) who compared office BP and 24h ABPM and concluded: "Although, OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies, the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may, to a larger extent than previously ascribed, relate to effects on blood pressure patterns over the 24-hour period" .
So to conclude:
What seems to matter in the cardioprotection of CKD pateints is good BP control (KDIGO recommends <140/90mmHg) with due consideration to patients age and co-morbidities, this regardless of the class of antihypertensive agents used. Considerations should be then given to patients tolearbility, Risk versus Benefits of a given clkass of agents as well as Cost : Benefit ratio in countries where patients have to pay for their medication; a factor that greatly impacts on compliance and quality of BP control.
Finally, let us not forget that even in the US the majority of those with Hypertension are either NOT treated or POORLY CONTROLLED:
After years and even decades of total neglect, the Nephrology community is waking up to the fact that Creatinine Clearance is affected by Tubular Secretion of Creatinine (TSCr)...!!!
A recent article in the September 2013 issue of the Am J Kidney Disease by Sithoven and colleagues in Groningen, Netherlands shows that there is a good agreement in ADPKD between eGFR and measured GFR (mGFR) in individuals with normal renal function highlighting the fact that at normal eGFR range, tubular secretion (TS) Creatinine (TSCr) is relatively small and therefore doesnt confound estimation of kidney function by eGFR (MDRD or CKD EPI). They also argue that such correlation was maintained in a subgroup of patients followed-up for 3 years.
This somehow disagrees with teh observations of Rugennenti and his colleagues in Bergamo who showed poor agreement between eGFR and mGFR in estimating the rate of decline in kidney function in ADPKD and that both MDRD and CKD EPI failed to accurately detect changes in mGFR in those with ADPKD and declining renal function. This, in spite of a comparebale baseline GFR to that of the Groningen group at the onset but a significant rate of decline with time of around 8-10ml/min.
The discrepancy between the two articles highlight the fact well know to Nephrologists for the last century or so that the Tubular secretion of Creatinine is relatively small in normal GFR ranges but increases significantly as GFR declines to reach as mush as 50% of Creatinine Clearance when GFR is <20-30ml/min.
Therefore, eGFR is most likley to be useless in the evaluation of interventions aimed at impacting on the rate of GFR progression as when true GFR declines tubular secretion of creatinine increases confounding the use of serum creatinine as a parameter of progressive CKD. So whilst Spithoven et al are right in their statement that eGFR is accurate in evaluating true measured GFR in ADPKD, the difference between the studies and their resepctive and contradictory assertions may lay in the level of GFR and the rate of decline of kidney function; lower GFR and faster rate of GFR decline leads to increased tubular secretion of creatinine and consequently decreased agreement between measured and calculated GFRs.
This was also reported by Gaspari et al, 2013 in T2DM where formulated GFR underperformed and underestimated the rate of true GFR decline.
This again highlights the fact that TSCr cannot be ignored including in diabetes mellitus where changes in tubular secretion of creatinine have been reported due to the impact of diabetes on proximal tubules transporters of creatinine and changes related to impaired kidney function and metabolic control. Too many confounders for serum creatinine to be an accurate marker of glomerular filtration.
Furthermore, interventions themselves may impact on the tubular handling and secretion of creatinine and consequently making interpretation of the intervention of rate of decline of GFR impossible. Incidentally, this is the case with RAS (renin angiotensin system) inhibition that has been show both experimentally and clinically to improve tubular secretion of creatinine in diabetic nephropathy confounding ANY conclusions on the impact of RAS inhibitors on the decline in eGFR in diabetic nephropathy:
All the studies on the progression of CKD relying on measurements and changes in serum creatinine levels or the changes in formulated/estimated GFR (eGFR) are likely to be inaccurate due to the major confounding effect of Tubular Secretion of Creatinine. Not withstanding the additional confounder of the impact of any given intervention on Tubular Secretion of Creatinine. The BEAM/BEACON studies are tragic reminders of the unreliability of eGFR in interventions with agents that impact on tubular viability and function and consequently impact on serum creatinine/eGFR through mechanisms unrelated to changes in GFR.
Sadly and disappointingly, to date I am not aware of a single intervention study in CKD where GFR was measured serially to asses progression in the entire study population (with the exemption of the MDRD study in 1994 where iothalamate clearance was used throughout the study period).
Reliance on eGFR to test interventions that may slow the progression of CKD is a tragic and often wilful mistake.