User blog: Meguid El Nahas
PROFESSOR PIERRE DELANAYE REPORTING IN FRENCH:
Le docteur Warnock nous a brillamment présenté les résultats d’une analyse de la cohorte REGARDS, bien connue de tous. Son idée, simple, est la suivante. Les formules basées sur la cystatine C n’ont globalement pas une meilleure performance que les formules basées sur la créatinine pour estimer le DFG (résultats de Inker dans le NEJM de 2012). Pourtant, la cystatin C prédit mieux le risque cardiovasculaire. Cette meilleure prédiction, n’est donc pas, pour le Dr Warnock, liée à une meilleure estimation du DFG. L’hypothèse la plus communément admise est l’association entre le cystatine C et l’inflammation. L’auteur a donc simplement regardé si la cystatine C prédisait mieux le risque de mortalité qu’un autre marquer tout simple de l’inflammation, à savoir la CRP. L’auteur en a profité pour critiquer les méthodes statistiques qui sont utilisées dans ces étude de prédiction et qui ne prennent pas en compte la variations des différentes données au cours du temps. Dans la cohorte REGARD, le Dr Warnock montre clairement que la CRP prédit en fait mieux le risque de mortalité avant 3 ans que la cystatine C…Résultat très provoquant mais que je trouve assez convainquant personnellement.
J’ai aussi beaucoup aimé la remarque finale de l’auteur dans la discussion. Toutes ces études prédisent un rique épidémiologique…L’intérêt pour prédire le risque d’un patient à l’échellon individuel (le patient assis en face de vous en consultation) est sans doute beaucoup moindre (si il existe…)
David Warnock presented data from the REGARDS study showing the limited value of large population data with eGFR for predicting CV risk, SPREADSHEET NEPHROLOGY has it slimitations:
1 Predicting risk at large population scale database analysis is not always of help to the nephrologist faced with a single patient who need to have a risk assessment.
2. eGFR may be a useful predictor of CVD in isolation but not much better than conventional risk predictors.
3. Cystatin C a better predictor of CVD risk than eGFR confirming previous studeis.
4. Markers of inflammation such as CRP also better than eGFR
IT IS HIGH TIME IN MY OPINION TO STOP THE BANDWAGON OF SPREADSHEET NEPHROLOGY BASED ON LARGE SACLE EPIDEMIOLOGICAL NUMBER CRUNCHING BY COMPUTER NEPHROLOGISTS....LETS GO BACK TO BEDSIDE AND OLD FASHION CLINICAL RISK ASSESSMENTS!
PROFESSOR PIERRE DELANAYE COMMENTED ON THIS ARTICLE:
Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome.
The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.
Une étude publiée en avril 2014 dans le JASN par les collègues italiens de Bergame.
Ils ont étudié l'effet du rituximab chez 30 patients avec GN (minimal change, mesangio-proliférative ou FSGS) et une cortico dépendance ou des récidives fréquentes. Le rituximab est administré à une dose unique de 375 mg/m² (une deuxième dose chez deux patients qui n'ont pas répondu en terme de lymphocytes . Les résultats sont intéressants à 1 et à 2 ans. Le nombre de récidive est diminué de 5X. 18 patients sur 30 ne sont plus traités, y compris sans corticoides. L'effet "steroid-sparing" me parait prouvé par différente analyse. Bien sûr, il s'agit d'une étude non randomisée (le nombre de récidive à 1 an est comparé au nombre de récidive l'année précédent le ritux) mais il faut aussi avouer qu'une étude randomisée est probablement impossible vu la rareté de la maladie.
Attention cette étude concernait des patients en rémission au moment de l'administration du rituximab! Il ne s'agissait donc pas de patient coritico RESISTANT.
Très belle étude dans son genre il me semble...
Important and significant stuy in SDNS where patient salready in remission under corticotherapy were treated with a single dose (375mg/m2) of Rituximab and obtained a sustained remission compared to their frequent relapses before hand.
Of note, it is NOT a study of steroid resistant nephrotic syndrome as all th epatients were in remission by steroids at the time of Rituximab administration. So instead it is a study of Steroid Dependant (frequent relapsing) nephrotic syndrome (SDNS).
Also, this is NOT a randomised controlled study.But to conduct such a study would be difficult.
Elegant study of its kind, it seems.
It came to my attention over the years that medical education in some emerging countries is based on endless learning by rote (memorising knowledge based on repetition) without much in the way of focused or reflective learning.
Seniors educators seem to use these techniques to maintain some form of ascendency over juniors and restrict their progress. Whilst this sounds pernicious, it seems quite prevalent. Juniors learn endless list of differential diagnosis, never long enough for their seniors, who always find yet another rare or esoteric disease to trip the junior and show his supremacy. This is also the case in exams where examiners seem to take a malicious pleasure of tripping young doctors by asking them the most obtruse and obscure of medical questions...
This attitude and deference to seniority seems in the long run to hamper the intellectual development of younger doctors and keep them in a subserviant state of dependency on the unreachable heights of the "Professor" encyclopedic...but really useless....knowledge!
This also translates in overall poor medical care, as those privy to such encyclopedic knowledge acquire it through a bookish attitude to learning rathern than an experiential one based on rich and diverse clinical practice; a huge dichotomy emerges between the exhalted knowledge of these senior doctors and their appalling medical practices...
The juniors, on the other hand, remain in the land of fear of authority, unable to challenge their seniors...and unable to acquire the sound and practical knowledge they crave. Consequently, they are also in a medical no man land where they struggle to find sound clinical guidance and advice.
To please their seniors and gain their approval and promotion, they follow the lead of "impression by rarity..." raising the most unusual and improbable diagnoses to deal with common diseases; so a straightforward UTI raises the possibility of a dysmorphic dysplasia of the bladder epithelium rather than just poor hygiene and faecal contamination of the urinary tract! Or, angina in a older patient with diabetes mellitus raised the spectrum of aneurysmal destruction of the coronary arteries by polyarteritis nodosa....and son on!
What can be done to refocus the minds of new generations of younger doctors subject to this distorted way of thinking?
1. Ignore the seniors as they will not change; they have a vested interest in this pernicious system; it serves them well...
2. For the juniors to make the most of the world of the internet to find alternative methods of educating themselves.
3. Rely on peer support.
4. Rely on network learning and use the amazing range of learning media through the internet to break free from the shackles of seniors who want to keep them enslaved to their whim...
Even then...seniors have ways to keep them at their mercy..."Unless you do as I say...you will not get your higher degree...", "unless you do as I say you will not be promoted..."
Sad but true...this is the state of continuing medical education in many countries...
IT IS HIGH TIME THAT A NEW FORM OF REVOLUTION TAKES PLACE IN MEDICAL EDUCATION IN EMERGING COUNTRIES FREE OF THE RESTRAINTS OF OLDER GENERATIONS OF DICTATORIAL AND CONTROLLING EDUCATORS...
Prof Macaulay Onuigbo wrote:
Microalbuminuria in current nephrology literature revisited
There is significant evidence in the literature of temporal disassociations between measured kidney function and measured albumin creatinine ratios (ACR) in studied diabetic and non-diabetic CKD patients:
i. Tsalamandris et al. reported that of 40 patients with diabetes, followed over a period of 8-14 years, 15 developed progressive increase in albumin excretion rate (AER) with no decline in GFR, 13 had progressive increase in AER in association with decreasing GFR, and 12 (8 type 2) had decreasing GFR values without a significant increase in AER .
ii. In the DCCT/EDIC study, an extended median 13-year follow up of1441 study participants also documented regression to normoalbuminuria after more than a decade of persistent microalbuminuria, mostly without RAAS inhibitor use, and generally in the setting of excellent control of glycemia and blood pressure .
iii. In the ONTARGET trial, despite superior proteinuria reduction by combination RAAS blockade with an ACEI and an ARB, the combination group still fared worse than the monotherapy groups with regards to renal outcomes .
iv. Our experiences in the last ten years at the Mayo Clinic Health System, Eau Claire, in Northwestern Wisconsin, USA, have demonstrated similar patterns of variability of measured proteinuria by urinary albumin creatinine ratios among type II diabetic CKD patients, on and off the influence of concomitant angiotensin blockade [4-6]. Moreover, while we observed a tendency to increased proteinuria in our CKD patients following discontinuation of ACE inhibitors and/or ARBs, this was often in the face of improved kidney function [4-6].
v. El Nahas et al. from Sheffield, the United Kingdom, who reported on the results of discontinuation of ACE inhibitors and/or ARBs in 52 older CKD patients (21 females and 31 males, mean age 73 years) with advanced CKD (stages 4 and 5), showed sustained improved kidney function but no change in proteinuria following discontinuation of angiotensin blockade . Baseline urine protein:creatinine ratio (PCR) was 77 ± 20 mg/mmol, and compared to end PCR values of 121.6 ± 33.6 mg/mmol, was not statistically significant .
From the foregoing, we have therefore been repeatedly called for more caution in the interpretation of degrees of proteinuria as a definitive and proven renal surrogate, more so when it is used in combination surrogate renal endpoints for study endpoints [8-10]. Indeed, Mann et al, the investigators of the ONTARGET trial, in a post hoc analysis concluded that the ONTARGET data suggest that proteinuria reduction by itself cannot be taken as a definitive marker of improved renal function .
We agree with El Nahas on a need to re-evaluate some of the current paradigms of CKD care especially as it relates to albuminuria as a renal surrogate . Again, as El Nahas had acknowledged above, a focus on overt and progressive albuminuria is more apt and appropriate.
1. Tsalamandris C, Allen TJ, Gilbert RE, et al. Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes 1994; 43: 649-655.pmid:8168641.
2. de Boer IH, Rue TC, Cleary PA; et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 2011; 171(5): 412-420.
3. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–59.
4. Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol 2008; 40:233–9.
5. Onuigbo MA, Onuigbo NT. Late onset azotemia from RAAS blockade in CKD patients with normal renal arteries and no precipitating risk factors. Ren Fail 2008; 30:73–80.
6. Onuigbo MA, Achebe NJ. Late Onset Renal Failure From Angiotensin Blockade (LORFFAB) – The Results of a Mayo Clinic Health System Angiotensin Inhibition Withdrawal Study: A Clarion Call For More Preventative Nephrology, Also Called Renoprevention. In: Macaulay Amechi Chuka Onuigbo, Editor. ACE inhibitors: medical uses, mechanisms of action, potential adverse effects and related topics. Volume 1. New York, NY. NOVA Publishers, 2013: 75-90.
7. Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant. 2010 Dec;25(12):3977-82. doi: 10.1093/ndt/gfp511. Epub 2009 Oct 10.
8. Onuigbo MA. Relation between kidney function, proteinuria, and adverse outcomes – A critical look at the application of medical statistics in the Nephrology literature. QJM 2010 Jul; 103(7): 537-8. Epub 2010 Apr 11.
9. Onuigbo M, Onuigbo N. Aliskiren in Type 2 Diabetes and Cardiorenal End Points. N Engl J Med. 2013 Mar 14;368(11):1064-5. doi: 10.1056/NEJMc1300257#SA1. (www.nejm.org/doi/pdf/10.1056/NEJMc1300257).
10. Onuigbo MA. The Abuse of Renal Surrogates and Combination Renal Endpoints in Nephrology RCTs. In: Macaulay Amechi Chuka Onuigbo, Editor. ACE inhibitors: medical uses, mechanisms of action, potential adverse effects and related topics. Volume 1. New York, NY. NOVA Publishers, 2013: 35-40.
11. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372(9638): 547-553.
12. Onuigbo MA. Angiotensin Blockers and Renoprotection in Diabetic Chronic Kidney Disease is a Failed Paradigm? – A Revisionist View of Renoprotection in Diabetic Chronic Kidney Disease and A Novel Classification Scheme for Renoprotective Agents. In Atta ur Rahman (Editor): eBook “Frontiers in Clinical Drug Research: Diabetes and Obesity, Vol. 1”, 2014, In Print.
'Progressive diabetic nephropathy. How useful is microalbuminuria?
The concept of microalbuminuria has been central to the development of clinical practice and research in the area of diabetic kidney disease (DKD). However, in recent times, the value of a paradigm of DKD based solely on microalbuminuria has been questioned. Although both the absolute level and rate of change of microalbuminuria are linked to the development and progression of DKD, microalbuminuria on its own lacks the necessary sensitivity or specificity to accurately predict kidney outcomes for people with diabetes. The development of microalbumiuria can no longer be viewed as a committed and irreversible stage of DKD, as spontaneous remission is now reported as a common occurrence. In addition, the absence of microalbuminuria or its progression to proteinuria does not signify that an individual patient is safe from a progressive decline in glomerular filtration rate (GFR). Furthermore, although reductions in albuminuria within the microalbuminuric range can be linked to a slower GFR decline in observational studies, this relationship has not been robustly demonstrated in intervention studies. Conclusions regarding the kidney health of individuals with diabetes will continue to be flawed if an inappropriate emphasis is placed on the presence or absence of albuminuria or changes in albuminuria within the microalbuminuric range. This has important implications in terms of undermining the value of microalbuminuria as a surrogate renal end point for intervention trials. There is a need to develop broader models of progressive DKD that include novel pathways and risk markers apart from those related to the traditional 'albuminuric pathway' to renal impairment.Kidney International advance online publication, 9 April 2014; doi:10.1038/ki.2014.98.
This is an extremely timely review highlighting convincingly the limitations of using microalbuminurioa in diabetic nephropathy diagnosis, monitoring and management. It highlights that microalbuminuria lacks both sensitivity and specificity to diagnose renal involvement and their progression in people with diabetes mellitus. This is all the more significant in T2DM.
Once more, it is important to remember that microalbuminuria is a marker of a number of inflammatory and atherosclerotic conditions associated with DM.
Also within the kidneys, microalbuminuria should be thought of as the end results of abnormalities and dysfunction at many levels:
1. Glomerular filtration of albumin
2. Proximal tubular reabsorption of albumin
which can be affected by:
3. Peritubular capillary blood flow/renal perfusion
All these can be transiently and also permanently affeceted in people with DM.
It is high time Nephrologists forget about microalbuminuria and focus on overt and progressive albuminuria (dipstick positive).
It seems to me that the era of obssessive search for, and management of, microalbuminuria is coming to an end. Some of us have argued along these lines for a long time. Otherrs want to expand the search and management of microalbuminuria further beyond people with diabetes to the communtiy as a whoile.
How mislead and misleading they are...!!!
A recent paper in the Journal of the American Soceity of Nephrology has linked physical exercise with a slower rate of eGFR decline in patients with CKD3.
Physical activity may counteract metabolic disturbances that promote the progression of CKD. To address this concept, we performed a longitudinal cohort study of 256 participants in the Seattle Kidney Study, a clinic-based study of CKD. Participants with an estimated GFR (eGFR) of 15-59 ml/min per 1.73 m(2) at baseline were eligible for the study. Physical activity was quantified using the Four-Week Physical Activity History Questionnaire. We used generalized estimating equations to test associations of physical activity with change in eGFR determined by longitudinal measurements of serum cystatin C. Mean baseline eGFR was 42 ml/min per 1.73 m(2). During a median 3.7 years of follow-up, the mean change in eGFRcystatin C was -7.6% per year (interquartile range, -16.8%, 4.9% per year). Participants who reported >150 minutes of physical activity per week had the lowest rate of eGFRcystatin C loss (mean -6.2% per year compared with -9.6% per year among inactive participants). In adjusted analyses, each 60-minute increment in weekly physical activity duration associated with a 0.5% slower decline per year in eGFR (95% confidence interval, 0.02 to 0.98; P=0.04). Results were similar in sensitivity analyses restricted to participants without cardiovascular disease or diabetes, or to participants with moderate/high physical function. After adjustment for eGFR at the time of questionnaire completion, physical activity did not associate with the incidence of ESRD (n=34 events). In summary, higher physical activity levels associated with slower rates of eGFR loss in persons with established CKD.
This is an interesting observation that falls within the usual trap of eGFR calculation and measurement.
The authors used eGFR Cystatin C to estimate changes in GFR, thus equating once more changes in a surrogate marker, in this instance CystatinC, as an indicator of changes in Glomerular Filtration Rate; that wasnt measured!
As with studies relying on eGFR Creatinine (MDRD or CKD-EPI equations), the use of such surrogate markers (serum creatinine or cystatin C) needs to take into considerations the non-GFR confounders associated with such a marker:
So for serum creatinine:
Dietary protein/creatine/creatinine intake
Creatine/creatinine metabolism and muscle mass
Tubular secretion of creatinine
For serum Cystatin C:
Obesity, smoking as well as inflammation have been associated with increased circulating levels of this bioamrker.
Therefore, when considering changes in the calculated eGFR based on these biomarkers, it is essential that the intervention under study doesnt affect the variable in other ways, independently, from changes in GFR.
So for example a low protein diet would improve the eGFR (creatinine) decline rate by decreasing serum creatinine/increasing eGFR through a reduction in dietary protein, changes in creatinine meatbolism as well as the possibility muscle wasting.
Now, in the publications under discussion the biomarker used to measure and calculate eGFR is Cystatin C, thus claiming that improved eGFR Cyst takes place in those undergoing regular physical exercise.
So we have to ask ourselves is Cystatin C affected by exercise through non-GFR pathways?
And the answer is possibly. Cystatin C is know to be raised in chronic inflammation. CKD is known to be associated with chronic inflammation. And...exercise is known to reduce inflammation in CKD patients. In a recent publication in JASN (April 2014), investigators in Leicester (UK) showed that acute exercise induced a systemic anti-inflammatory environment most likely mediated by increased plasma IL-6 levels. Furthermore, they noted that 6 months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation.
So once more one has to question whether the changes observed in the under discussion publication are directly related to changes in the rate of progression of CKD OR instead in the rate of progression of inflammatory changes associated with CKD and reflected in the changes in an inflammtory marker namely serum Cystatin C; possibly wrongly assumed in this study to reflect changes in GFR.
Increasingly the literature is overloaded with publications using eGFR as a synonym for measured GFR; this is a grave error and open to considerable misinterpretation whether serum creatinine measurement is used to estimate eGFR or whether it is Cystatin C as in the publication under discussion.
It is high time Nephrologists learn that if they want to study CKD progression they need to measure CKD progression and not rely on dubious and confounded surrogate biomarkers!
An excellent editorial by Steven Rosansky and Richard Glassock review issues related to the estimation of CKD progression in renoprotection drug trials.
The authors examine the currently used parametres of CKD progression:
1. ESRD and Renal Replacement Therapy (RRT)
They note that RRT initiation as a hard point has its limitations in view of trends over the last decade in early initiation of RRT. They also note the non-GFR related alterations in serum creatinine levels including alterations in endogenous creatinine generation due to diet and sarcopenia.
the authors recommend a harder endpoint of fixed eGFR of 15ml/min/1.73m2.
Some would argue that mGFR of 10ml/min/1.73m2 is a more valid endpoint.
2. The decline in eGFR
using the decline in eGFR is fraught by the fact that many patients dont progress or progress in a non-linear fashion. Increasingly nephrologists have come to realise that CKD progression is not invariable with a significant percentage not progressing for long period of time and some progressing in a non-linear fashio whilst some even improving with time. Such non-progression or a non-linear progression RFT would make endpoints based on RFT unpredictable and difficult to interpret in a clinical trial.
They also note that some interventions such as Low protein diet (MDRD study) or ACE inhibition may lead to an initial acceleration of GFR decline before longer term stabilisation/renoprotection.
The FDA recently suggested a 30% decline and a 40% decline in GFR from baseline values as new surrogate end points in intervention studies. This on the assumption that the decline in GFR is linear.
This would be preferable to the current doubling of serum creatinine (50% decline in GFR).
3. Changes in RFT slopes:
The authors note that changes in RFT pattern in clinical trials over the duration of intervention studies usually, short term around 3 years of follow-up, may not consistently predict the progression to ESRD; Longer trials 5-10years may be required. Whether these are feasible, fundable or acceptable to Pharmaceutical sponsors in a hurry to market a new drug for CKD is questionable.
4. Patients selection:
RCTs and data analysis as well as showing intervention efficacy may benefit from a careful patients' selection favouring teh inclusion of those with faster rate of GFR decline and overt proteinuria; a faster rate of progression would require a smaller sample size and increased study power.
Also recommended is to have an observational run in phase to determine the nature and rate of the RFT and CKD progression; those with fast (-3-5ml/min/year) and linear negative (RFT) progression rate would also increase the power of the study.
The authors also touch on the most important issue in my mind, namely that fact that eGFR does NOT equate with meassured/true GFR; this was most dramatically shown in the BEAM and BEACON studies, where the impression of an improved eGFR reflected weight loss and anorexia thus changes in creatinine metabolism rather than improving renal function. Ultimately BEACON had to be stopped for toxicity of the compound (Bardoxolone) and excessive morbidity and mortality.
Also the reliability of eGFR/serum creatinine does NOT take into account the impact of renal tubular secretion of creatinine on the changes induced by an intervention on these parameters. Even ACE inhibition may affect tubular secretion of creatinine, a totally neglected variable in RAAS inhibition studies of CKD progression where GFR has seldom been measured????
Finally, when eGFR and mGFR were compared in progressive ADPKD, eGFR based on the MDRD and CKD-EPI equations was found wanting. eGFR changes poorly reflected changes in mGFR. Both formulas underestimated GFR changes by 50%.
mGFR would be preferable to eGFR, although the authors have argued that variability of a mGFR based on isotopically labelled iothalamate may be high, not withstanding the inconvenience to the patient of measuring GFR and the related cost and time requirements.
One can conclude from this excellent editorial, that to study the impact of interventions on CKD progression the ideal RCT would require:
1. Careful patients selection; preferably with fast progressors who are proteinuric. After all these are the patients who warrant intervention to stop their progression to ESRD.
2. A Run in phase to determine the nature of RFT in patients included in the trial with preference for those with fast and negative but also RFT/slopes.
3. Long follow-up as short studies relying on unpredictable (for long term outcomes/ESRD) endpoints can be misleading.
4. Validating CKD progression parameters by measured GFR as the gold standard.
Nephrologists need to think carefully and read this editorial before embarking on hastily designed and flawed clinical trials that yield inconclusive or wrongly conclusive results.
A letter to the editor in this month NEJM:
highlights the difference between the outcome of Nephropathic Cystinosis in developed and developing countries.
A survey undertaken by the authors in 17 developing and 13 developed countries showed massive differences in renal survival (ESRD) between the two groups; in fact the outcomes of developing countries nephropathic cystinosis in the 21st century is similar to that observed in developed countries 30 years ago before the advent of cysteamine treatment!
This once more highlights, many issues and problems with healthcare for Orphan and Rare Kidney Diseases (ORKD) in developing countries:
1. Poor awareness
2. Late diagnosis
3. Restricted access to medication
This in spite of the well known fact and observations that initiation of Cysteamine therapy before the age of 5 years impacts on the progression of cystinosis, renal failure, diabetes, hypothyroidism as well as patients survival.
It is high time the GAP between rich and poor countries is bridged when it comes to healthcare, but for this to be accomplished in ORKD concerted efforts have to be made between Governments, NGO as well as the Pharmaceutical Industry.
Kidney Int. 2014 Mar 5. doi: 10.1038/ki.2014.48. [Epub ahead of print]
Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing.
Brown EJ1, Pollak MR2, Barua M3.
The haploid human genome is composed of three billion base pairs, about one percent of which consist of exonic regions, the coding sequence for functional proteins, also now known as the 'exome'. The development of next-generation sequencing makes it possible from a technical and economic standpoint to sequence an individual's exome but at the cost of generating long lists of gene variants that are not straightforward to interpret. Various public consortiums such as the 1000 Genomes Project and the NHLBI Exome Sequencing Project have sequenced the exomes and a subset of entire genomes of over 2500 control individuals with ongoing efforts to further catalog genetic variation in humans.1 The use of these public databases facilitates the interpretation of these variant lists produced by exome sequencing and, as a result, novel genetic variants linked to the disease are being discovered and reported at a record rate. However, the interpretation of these results and their bearing on diagnosis, prognosis, and treatment is becoming even more complicated. Here, we discuss the application of genetic testing to individuals with focal and segmental glomerulosclerosis (FSGS), taking a historical perspective on gene identification and its clinical implications along with the growing potential of next-generation sequencing.Kidney International advance online publication, 5 March 2014; doi:10.1038/ki.2014.48.
COMMENTS BY PROF SOLIMAN:
This is a recently published, and a must read, review by Martin Pollak and colleagues. It takes the readership smoothly through the “uneasy” world of genetic testing in nephrotic syndrome (NS) and FSGS: why, when, how, who, which?
The authors go through the genetic causes of NS and FSGS including slit diaphragm, actin cytoskeleton, nuclear, glomerular basement membrane, and other genes e.g. APOL1. Nevertheless the authors did not come across the mitochondrial genes, an important entity being potentially treatable, as their main focus was nonsyndromic NS/FSGS.
Not only clinical implications of identifying a disease causing mutation in NS patient as to therapeutic intervention and transplantation strategy is discussed, but also the highly controversial area of testing the clinically unaffected members of a family with hereditary NS and the psychological ramifications that come along!
It all boils down to the wise and thoughtful use of genetic testing with considerations of its risks and benefits, and an understanding of its limitations in general as well as advantages and limitations of different procedures employed: Sanger sequencing, exome or genome sequencing, and the targeted sequencing by using panels of genes which has recently been increasingly implemented. In the latter, sequencing a panel of genes rather than the entire exome or genome allows the clinician/researcher to focus, with less complex, less time consuming and rather cheaper data interpretation.
Gained knowledge from this fascinating area of research in molecular genetics is immensely and rapidly growing, perhaps more than any other field in medicine. DNA sequencing technology is advancing at such a rapid pace, yet the challenge will always be how to translate this knowledge in terms of elucidating the pathogenesis of variable and complex renal diseases, in the best interest of affected patients and their families.
Blog By Dr Sherif AlHammady (Edited by Prof El Nahas)
My advice to you if you are optimistic about the era of guidelines is to read the BMJ article:
WHY WE CAN NOT TRUST CLINICAL GUIDELINES?
The BMJ in a series of article on Guidelines, and their value as well as issues with transparency and conflict of interest, highlights the ways the pharmaceutical industry influence the thrust of many guidelines. It often starts with the selection of panellists on guidelines committees; the overwhelming majority of committee chairs and co-chairs have ties to industry, and selection of panellists with industry-friendly viewpoints can make a desire outcome a foregone conclusion. Committee stacking may be one of the most powerful and important tools to achieve a desired outcome. Although guidelines are usually issued by large panels of key opinion leaders (KOL), the BMJ articles highlight to their careful selection by the industry as well as the choice of single issue fanatics (SIF) who are uncritically wedded to a dogma to which they steer the guidelines panels towards. A recent survey found that 71% of chairs of clinical policy committees and 90.5% of co-chairs had financial conflicts (2).
Take the LIPIDFS GUIDELINES as an example:
(a) In 2004, cholesterol guidelines greatly expanded the number of people for whom treatment is recommended. A firestorm broke out when it was learnt that all but one of the guideline authors had ties to the manufacturers of cholesterol lowering drugs (4).
(b) In 2013, the situation doesn't seem much better, as the new lipids guidelines released by the American College of Cardiology–American Heart Association (ACC-AHA) Task Force on Practice Guidelines seem to lower the threshold for prescribing statins based on an unvalidated cardiovascular scoring system.
(c) In 2013, KDIGO also seem equally indiscriminate as to who should receive statins amongst CKD patients…it seems as if statins for all is the flavour of our times…although evidence is seriously lacking…this is often acknowledged by the guidelines themselves awarding 1C or even 2C (NO EVIDENCE) to some of their recommendations; but all too often unaware physicians take the guidelines at face values and don't seem too concerned about their level of validity or utility…
IF WE SEE HOW GUIDELINES PANELISTS AND CHAIRS ARE CHOSEN…
IF WE SEE HOW KOL ARE GROOMED…
IF WE SEE HOW THE GUIDELINES PROCESS IS MANAGED…
IF WE SEE HOW NEGATIVE TRIALS ARE RE-ANALYSED AND POSTHOC AS WELL AS SUBGROUP DARTED PROMOTED BY KOL AND INDUSTRY AS FACTS... http://www.ncbi.nlm.nih.gov/pubmed/24038560
IF WE SEE HOW NEW THRESHOLDS ARE RE-DEFINED FOR TREATING MORE PATIENTS...
IF WE SEE HOW NORMALITY IS SLOWLY CONSIDERED A DISEASE...WITH LOWER THRESHOLDS...FOR PRE-DIABETES, PRE-HYPERTENSION, PRE-CKD, ETC...ALL AIMED TO MEDICALISE NORMALITY AND AGE RELATED INCREASED FASTING BLOOD SUGAR, BLOOD PRESSURE AND FALLING GFR...AND TREATING MORE PATIENTS...
AFTER ALL THAT HOW COULD I TRUST GUIDELINES?!
1-Jeanne Lenzer, medical investigative journalist Why we can’t trust clinical guidelines
BMJ 2013; 346 doi: dx.doi.org/10.1136/bmj.f3830 (Published 14 June 2013) Cite this as: BMJ 2013;346:f3830
2- Kung J. Failure of clinical practice guidelines to meet institute of medicine standards: two more decades of little, if any, progress. Arch Intern Med2012;172:1628-33.
3-Lenzer J, Epstein K. The Yaz men. Washington Monthly2012 Jan 9. www.washingtonmonthly.com/ten-miles-squa...of_fda_pan034651.php
4-Abramson JE, Barnard RJ, Barry HC, Bezruchka S, Brody H, Brown DL, et al. E.petition
to the National Institutes of Health seeking and independent review panel to re-evaluate
the national cholesterol education project guidelines. 2004. cspinet.org/new/pdf/
finalnihltr.pdf. Cite this as: BMJ 2013;346:f3830© BMJ Publishing Group Ltd 2013