There has been much interest in the last couple of years in the potential of renal denervation to manage resistant hypertension particularly after the SYMPLICITY-HTN-2 study was published in the Lancet several years ago.
There have been a number of studies sponsored by medical device companies including SYMPLICITY and EnligHTN that have been active recently. At last we have the data with the publication of SYMPLICITY HTN-3 in the New England Journal of Medicine.
In this study patients with severe resistant hypertension (all patients were on the maximum doses of at least 3 drugs including a diuretic) were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. The primary end point was change in office blood pressure (probably a poor surrogate for actual blood pressure) and a secondary endpoint including a safety composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis. A particular strength of the study was that 24 hour ambulatory BP was measured as well as office BP as a secondary endpoint and an impressive 535 patients were included in the study
The bottom line was that there was NO significant difference in the primary endpoint in both groups. Furthermore whilst blood pressure fell significantly in the denervation group it also fell in the sham group ( the mean (±SD) change in systolic blood pressure at 6 months was −14.13±23.93 mm Hg in the denervation group as compared with −11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline) with no significant differences in office BP between the groups. 24 hour ambulatory BP failed to show a positive impact of denervation either: 6.75±15.11 mm Hg fall in BP in the denervation group and −4.79±17.25 mm Hg. Again this difference was not significant.
There were no safety concerns with denervation. Subgroup analysis did not show any positive impact in any subgroup including 10% of patients with 'renal impairment'
The findings are at odds with previous studies such as the unblinded SYMPLICITY HTN-2 trial which showed significant reductions in blood pressure with denervation.
So how come the difference - well what the study highlights is the importance of blinding in a clinical trial. The positive results from earlier trials were from unblinded studies whilst in this study blood pressure fell significantly in the sham-procedure group as well... the reasons of this aren’t clear but we know that there can be a powerful 'placebo' effect in any clinical study. In medical device studies 'sham' interventions are the equivalent of the placebo or control arm - yet such sham interventions are often not performed for 'ethical' reasons of not wanting to subject patients to a sham-intervention that maybe associated with risk to the patient. Yet SYMPLICITY HTN-3 clearly demonstrates the absolute necessity for having such a sham-intervention group when evaluating the impact of medical devices. The reasons underlying the BP fall in the sham group aren’t clear but we know that being enrolled in any clinical trial often brings improvements even in the control/placebo arm. This may simply be as a result of increased contact with medical professionals resulting in improved patient adherence in medications and general good care.
Enthusiasts for denervation may say that one of the problems is that the radiologist has no 'read out' to tell them whether denervation has been successful and this may account in part for these disappointing results. However ablation catheter used in the SYMPLICITY HTN-3 study was no different from that used in the SYMPLICITY HTN-1 and HTN-2 studies.
My colleague Will McKane who has considerable expertise in denervation tells me that he has anecdotal experience of denervation being a huge success in some patients with resistant hypertension with some patients achieving good control on minimal medication after years of intractable, severe hypertension. Indeed the standard deviations indicate that there can be a very broad response to denervation and so it is possible that a positive impact of denervation in selected patients was ‘hidden’ in the mass of data from the trial. However we don’t have good evidence to support this nor is there anyway of identifying those who may respond.
As was pointed out in an accompanying editorial in NEJM there has been enormous hype around denervation with many claiming it to be a potential ‘cure’ for hypertension. That bubble has now burst and at the moment its difficult to see any significant future for denervation in the management of resistant hypertension
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
Dr Shanmuga KUMAR (Sheffield Kidney Institute) wrote:
A recent paper assessing exercise capacity of patients with chronic kidney disease (CKD) has rekindled some interest in the application of cardiopulmonary exercise testing (CPX) in CKD. The last such work was published a decade ago which showed that exercise capacity, as measured by peak oxygen consumption (peak VO2), is a good predictor of survival in dialysis patients. The recent paper has shown similar results albeit utilising a different CPX parameter, anaerobic threshold (AT) presented as a percentage of peak VO2. However the question remains: What do we measure when we measure exercise capacity in CKD patients? The claim that measures of exercise capacity could serve as a surrogate of cardiac reserve function in CKD needs verification. The claim is based on the premise that VO2 is a product of cardiac output (CO) and arterio-venous difference in oxygen concentration [VO2= CO x C(a-v)O2] and hence VO2 could serve as a surrogate of cardiac output. There are several physiological considerations, commonly described in text books of exercise physiology, which would render this simplified model less applicable in CKD.
Anaemia: Oxygen is primarily transported as oxyhaemoglobin (and a small fraction dissolved in plasma) and it has been estimated that the O2 carrying capacity of the blood falls from 22.5ml/dL to 14.1ml/dL as the haemoglobin concentration drops from 16gm/dL to 10gm/dL.3 Hence, for a given cardiac output, the impaired O2 delivery to exercising skeletal muscles results in reduced peak VO2 and anaerobic threshold (AT).
Chronic metabolic acidosis: Exercising skeletal muscles generate acidic end products and the ventilation must keep in pace with the acid load to maintain normal pH. The presence of metabolic acidosis in CKD would add to the acid load and limit exercise capacity because of higher ventilatory requirements.
Peripheral vascular disease: PVD is a common co-morbidity of CKD. The diseased vasculature with reduced internal diameter impairs blood flow to the exercising skeletal muscles. The relative ischaemia leads to early onset of lactic acid production and reduced AT irrespective of normal cardiac performance.3
Skeletal myopathy: Muscle wasting is not an uncommon finding in ESRD. Reduced skeletal muscle mass limits the utilisation of delivered O2. This coupled with the less studied phenomenon of skeletal myopathy secondary to uraemia would limit exercise capacity in spite of a normal cardiac output.
It has indeed been shown that haemoglobin, serum albumin, co-morbid diabetes mellitus and cardiovascular disease are significant determinants of exercise capacity in dialysis patients. Therefore one wonders whether exercise capacity in CKD is just a composite marker of co-morbidities rather than a true representation of cardiac performance. Better interpretation of conventional CPX parameters in CKD can be achieved by employing techniques that simultaneously measure direct indicators of cardiac performance as well as exercise capacity.
 Ting S.M. et al. Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation. J Am Soc Nephrol 25, 187-95 (2014).
 Sietsema K.E. et al. Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease. Kidney Int 65, 719-24 (2004).
 Wasserman K. et al. Principles of exercise testing and Interpretation. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
 Sietsema K.E. et al. Clinical and demographic predictors of exercise capacity in end-stage renal disease. Am J Kidney Dis 39, 76-85 (2002).
Cooke G.A. et al. Physiological cardiac reserve: development of a non-invasive method and first estimates in man. Heart 79, 289-94 (1998).
Evidence-based cardiology in hemodialysis patients.
This is an interesting review article in JASN December 2014 reviewing major CVD RCTs in CKD patients treated by HD.
Renoprotective Effect of Renin-Angiotensin-Aldosterone System Blockade in Patients With Predialysis Advanced Chronic Kidney Disease, Hypertension, and Anemia.
IMPORTANCE The benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients with advanced chronic kidney disease (CKD) remains undetermined. OBJECTIVE To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia. DESIGN Prospective cohort study. SETTING Taiwan. PARTICIPANTS From January 1, 2000, through June 30, 2009, we selected 28 497 hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis-stimulating agents. INTERVENTIONS Users (n = 14 117) and nonusers (n = 14 380) of ACEIs/ARBs. MAIN OUTCOMES AND MEASURES We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers. RESULTS In a median follow-up of 7 months, 20 152 patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, 0.91-0.97]) and the composite outcome of long-term dialysis or death (0.94 [0.92-0.97]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, 0.92-1.16]; P = .30). CONCLUSIONS AND RELEVANCE Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality.
Having read this article more than once, I find it somewhat incoherent and also potentially misleading.
Before, I go any further, let me declare my serious conflict of interest with this publication...I personally think it is abhorrent to start ACE inhibitors and even to continue them in CKD stage5...and I also published 2 papers to the effect that stopping ACE inhibtiorts in CKD4-5 is BENEFICIAL with renal functional recovery in a majority:
Now, that is out of the way...lets look at this publication from China that pretends that RAS inhibiton delays ESRD in CKD5 and improves survival.
1. It isnt clear at all when RAS inhibitors where started or even STOPPED in this publication, other than the fact that patients HAD been on an ACEi and/or ARB: inclusion criteria most unusual and most confusing:
"...patients who had taken any ACEI/ARB within 90 days after the first ESA prescription were defined as ACEI/ ARB users; the remaining patients were defined as ACEI/ARB nonusers...."
whether they took it for a day...or a year...whether they were still on them or not....seems lost in translation...
2. Follow-up period of 7 months, is far to short to ascertain any impact on mortality; regardless of how high the mortality of CKD5 in Taiwan is...
3. Looking at the figures, I strained my eyes to see a difference between the ESRD and composite ESRD + survival lines...although the p value is statistically significant, I very much doubt th eclinical relevance of the number needed to treat (NNT) to prevent a Single death.
4. Is the use of composite endpoint a misleading way/ploy to hide the lack of impact on survival...or to imply a protection by linking it to ESRD delay...??? Statistics...statistics...statistics...and their manipulations to serve researchers and their sponsors objectives...?!
5. The whole paper striking as lacking information about one thing: BLOOD PRESSURE and its control. This is hardly mentioned knowing how poorly BP is controlled in Chinese community. A topic we previously commented upon:
6. The authors even advocate DUAL BLOCKADE as protective, when the rest of the world deems it contraindicated in view of its increased morbidity and mortality; see ONTARGET and Subsequent publications.
It is disturbing that such poor quality publications find their way to top medical journals.
It is disturbing that reviewers in such journals are incapable of critically appraise a manuscript.
It is disturbing to see that misleading and potentially dangerous message unchallenged by an editorial to moderate its impact.
JAMA has a lot to answer!
THE PASSING OF PROFESSOR ZAKARIAH EL BAZ.
VERY SAD NEWS OF THE LOSS OF PROFESSOR ZAKARIAH EL BAZ.
PROFESSOR EL BAZ WAS A PIONEER OF NEPHROLOGY IN EGYPT AND THE ARAB WORLD.
PROFESSOR EL BAZ WAS ONE OF THE FATHERS OF EGYPTIAN NEPHROLOGY AND A LEADER IN THE FIELD.
HE MADE MAJOR CLINICAL CONTRIBUTIONS TO THE DEVELOPMENT OF DIALYSIS AND TRANSPLANTATION IN EGYPT IN THE 60s and 70S.
HE WAS ALSO VERY INTERESTED IN NUTRITION AND CKD.
PROFESSOR EL BAZ WAS ALWAYS THE CKD PATIENTS ADVOCATE AND FOUNDER OF THE EGYPTIAN KIDNEY PATIENTS ASSOCIATION.
PROFESSOR EL BAZ WAS A GREAT TEACHER AND ALWAYS ATTENDED NEPHROLOGY CONFERNECES WERE HE SAT IN THE FRONT ROW TO LEARN MORE AND SHARE HIS EXPERIENCE. I ALWAYS ASKED HIM A QUESTION AND LEARNED FROM HIS CONTRIBUTIONS.
MORE THAN ANYTHING, PROFESSOR EL BAZ WAS A GREAT MAN AND HUMANIST.
HE WILL BE GREATLY MISSED BY ALL OF US WHO KNEW HIM AND LOVED HIM.
A window for novel collagen IV nephropathy therapeutics?
Myrtani Pieri, Charalambos Stefanou and Constantinos Deltas
Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus
Alport Syndrome (AS) is inherited as an X-linked (COL4A5) or autosomal recessive disorder (COL4A3/A4) while thin basement membrane nephropathy (TBMN) follows autosomal dominant inheritance (COL4A3/A4). They are collectively known as collagen IV nephropathies and are characterized by phenotypic heterogeneity. AS is a rare disorder with an incidence of about 1/5000 live births, although it varies among ethnic populations. Most patients reach ESRF before the age of 30 years. TBMN is a much more frequent cause for developing ESRF compared to AS, although at later ages, owing to its much higher frequency in the general population (reported as high as 1%) [1, 2].
Hundreds of different mutations have been identified in the implicated genes that partly explain inheritance patterns and phenotypic heterogeneity [3-5]. Nonetheless, we still have a long way to go before determining the molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus.
It has been shown that most mutation carriers have limited or no expression of the collagen IV chains in the glomerular basement membrane (GBM) and Bowman’s capsule. Interestingly, a recent publication revealed that X-linked AS patients that actually do express the a5(IV) chain in the GBM, exhibit milder clinical manifestations compared to those lacking GBM expression . Therefore, presence of collagen IV chains in the GBM appears to exert a protective effect on disease course. But does more chains out, also means less chains in the cell? And could increased amount of misfolded protein inside the podocyte be toxic and add to disease progression? As our recent publication in JASN revealed, it does .
The focus of our study was the mutational effect on the cell responsible for collagen IV chain expression in the adult glomerulus, the podocyte . For the first time we provided evidence linking collagen chain mislocalization with triggering of the Unfolded Protein Response (UPR), an important cellular pathway . This link, we believe, is a window for testing novel treatments for AS and TBMN.
The glycine missense mutation, COL4A3-G1334E, endemic in the Cypriot population, was expressed in human cell lines and its defective trafficking caused a strong intracellular effect on the podocyte. Interestingly, both overexpression and downregulation of the COL4A3 chain was associated with activation of UPR. This result demonstrates that collagen IV misfolding does not only result in reduction of all chains in the GBM, but also triggers a cellular pathway that has the potential to drive the cell towards apoptosis should the stress be long lasting . This link was also verified in an in vivo model, the first knock-in mouse model carrying a missense glycine mutation which produced a phenotype consistent with AS. It was also further verified in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation . The variable contribution of this intracellular vs. the extracellular pathological effect for these particular syndromes is something that is yet to be determined.
Interestingly, this link between a collagen IV mutation and the UPR pathway is a very important one, as this particular pathway can be manipulated pharmacologically. Next up, would be to try to treat cells and mutant mice with pharmacological chaperones which can facilitate protein folding and trafficking to examine whether this will increase secretion of the mutant COL4A3 and hopefully decrease hematuria and proteinuria in mutant mice. A similar approach was recently shown for a mutation in the laminin β2 gene (LAMB2) that causes Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects .
UPR activation has been observed in many diseases, including cancer, autoimmune conditions, diabetes, liver disorders, obesity and neurodegenerative disorders . UPR in renal pathophysiology is a relatively new area of research [11-14]. Therefore, recognizing its contributory role to the deleterious consequences of collagen IV-trafficking defects would greatly improve AS/TBMN patient prognosis and would pave ways for development of novel, true therapeutics to improve or ameliorate disease.
1. Savige, J., et al., Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol, 2013. 24(3): p. 364-75.
2. Deltas, C., A. Pierides, and K. Voskarides, Molecular genetics of familial hematuric diseases. Nephrol Dial Transplant, 2013.
3. Jais, J.P., et al., X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. J Am Soc Nephrol, 2003. 14(10): p. 2603-10.
4. Jais, J.P., et al., X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol, 2000. 11(4): p. 649-57.
5. Gross, O., et al., Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant, 2002. 17(7): p. 1218-27.
6. Hashimura, Y., et al., Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV alpha5 chain. Kidney Int, 2013.
7. Pieri, M., et al., Evidence for Activation of the Unfolded Protein Response in Collagen IV Nephropathies. J Am Soc Nephrol, 2013.
8. Boot-Handford, R.P. and M.D. Briggs, The unfolded protein response and its relevance to connective tissue diseases. Cell Tissue Res, 2010. 339(1): p. 197-211.
9. Rajpar, M.H., et al., Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet, 2009. 5(10): p. e1000691.
10. Chen, Y.M., et al., Laminin beta2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am Soc Nephrol, 2013. 24(8): p. 1223-33.
11. Kitamura, M., Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008. 12(5): p. 317-25.
12. Inagi, R., Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol, 2010. 10(2): p. 156-65.
13. Inagi, R., Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol, 2009. 112(1): p. e1-9.
14. Dickhout, J.G. and J.C. Krepinsky, Endoplasmic reticulum stress and renal disease. Antioxid Redox Signal, 2009. 11(9): p. 2341-52.
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end stage kidney disease in adults. Advances in molecular biology and genetics unravelled the underlying genetic mutations in either of two genes: PKD1 (encoding polycystin-1) or PKD2 (encoding polycystin-2) [1,2].
This opened the door for increasingly greater understanding of the, previously obsecure, cellular pathophysiologic mechanisms responsible for the development and progression of PKD. To date major factors contributing to cyst formation include mechanisms [3,4]:
- controlling tubular diameter. excessive cell proliferation and fluid secretion.- influencing pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages.
The comprehensive review article by Torres and Harris smoothly introduce the readership to the so far identified pathogenic mechanisms of ADPKD and the whole series of performed clinical trials employing various targeted interventional therapeutics .
The above unravelled pathogenic mechanisms laid the foundation for the development of numerous potential new therapies targeting diverse pathophysiologic mechanisms. Most therapies at the present time are aimed at delaying the growth of the cysts and associated interstitial inflammation and fibrosis by targeting tubular epithelial cell proliferation and fluid secretion by the cystic epithelium. It have proven efficacious in animal models of PKD, yet with very limited safety profile precluding its expected lifelong use in humans [6-8].
- Therapies targeting Gs (tolvaptan) or Gi (somatostatin analogs) protein–coupled hormonal receptors with relative tissue and cell specificity have been used in clinical trials with relative safety.
- The concern about safety profile prompted change in strategy to repurpose drugs with safe profile that are currently used for other indications (e.g., metformin and peroxisome proliferator–activated receptor γ agonists).
- Exploring synergisms between different classes of drugs that may increase their efficiency and safety.
Patient selection and determination of the optimal timing for intervention deserve consideration, not all patients with PKD will require treatment.
Thanks to the revolution in molecular genetics and biology, more pathogenic mechanisms in ADPKD keep unfolding ADPKD so as trials to circumvent them aiming at targeted therapy.
Reading this interesting article makes you wonder if ADPKD would soon become a treatable disease?
1. Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, Ingber DE, Loghman-Adham M, Zhou J: Loss of poly- cystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol 17: 1015–1025, 2006
2. WangS,ZhangJ,NauliSM,LiX,Starremans PG, Luo Y, Roberts KA, Zhou J: Fibrocystin/ polyductin, found in the same protein complex with polycystin-2, regulates cal- cium responses in kidney epithelia. Mol Cell Biol 27: 3241–3252, 2007
3. Takiar V, Nishio S, Seo-Mayer P, King JD Jr., Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ: Activating AMP-acti- vated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A 108: 2462–2467, 2011
4. Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, Somlo S, Cantley LG: Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol 22: 1809–1814, 2011
5. Torres VE, Harris PC: Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease. JASN ASN.2013040398; published ahead of print December 12, 2013, doi:10.1681/ASN.2013040398
6. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang JJ, Czerwiec FS: Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study. Am J Kidney Dis 57: 692–699, 2011
7. Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X, Kim B, King BF, Glockner J, Holmes DR 3rd, Rossetti S, Harris PC, LaRusso NF, Torres VE: Randomized clinical trial of long-acting somatostatin for auto- somal dominant polycystic kidney and liver disease. J Am Soc Nephrol 21: 1052–1061, 2010
8. Hogan MC, Masyuk TV, Page L, Holmes DR 3rd, Li X, Bergstralh EJ, Irazabal MV, Kim B, King BF, Glockner JF, Larusso NF, Torres VE: Somatostatin analog therapy for severe polycystic liver disease: Results after 2 years. Nephrol Dial Transplant 27: 3532– 3539, 2012
Subclinical cardiovascular disease is associated with a high glomerular filtration rate in the nondiabetic general population.
1] Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway  Section of Nephrology, University Hospital of North Norway, Tromsø, Norway  Department of Clinical Research, University Hospital of North Norway, Tromsø, Norway.
A reduced glomerular filtration rate (GFR) in chronic kidney disease is a risk factor for cardiovascular disease. However, evidence indicates that a high GFR may also be a cardiovascular risk factor. This issue remains unresolved due to a lack of longitudinal studies of manifest cardiovascular disease with precise GFR measurements. Here, we performed a cross-sectional study of the relationship between high GFR measured as iohexol clearance and subclinical cardiovascular disease in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6), a representative sample of the middle-aged general population. A total of 1521 persons without cardiovascular disease, chronic kidney disease, diabetes, or micro- or macroalbuminuria were examined with carotid ultrasonography and electrocardiography. The GFR in the highest quartile was associated with an increased odds ratio of having total carotid plaque area greater than the median of non-zero values (odds ratio 1.56, 95% confidence interval 1.02-2.39) or electrocardiographic signs of left ventricular hypertrophy (odds ratio 1.62, 95% confidence interval 1.10-2.38) compared to the lowest quartile. The analyses were adjusted for cardiovascular risk factors, urinary albumin excretion, and fasting serum glucose. Thus, high GFR is associated with carotid atherosclerosis and left ventricular hypertrophy and should be investigated as a possible risk factor for manifest cardiovascular disease in longitudinal studies.Kidney International advance online publication, 4 December 2013; doi:10.1038/ki.2013.470.
Interesting study showing an association between high measured GFR (iohexol clearance) and subclinical CVD. It is remarkable as it did MEASURE GFR, but also measured 24h Ambulatory Blood pressure measurements (ABPM) as well as undertook measurements of atherosclerosis (Carotid intima media thickness) and LVH by ECG (would have been better by echocardiography).
Adjustment were also made for obesity and BMI.
But pre-diabetes, metabolic syndrome or insulin resistance cannot be excluded as an underlying cause for both raised GFR and increased atherosclerosis. Multivariate analysis adjusted for fasting blood glucose but not for HbA1c.
Insulin resistance and suboptimal hyperglycemia may impact on both GFR, LVH as well as ATS by altering autoregulation thus increasing glomerular blood flow and GFR. Insulin resistance is also known to be associated with atherosclerosis and LVH. Additionally, the study being cross-sectional and measured once, ABPM may underestimate the overall rise in BP over a longer period of time in those affected.
The authors also put forward the possibility of sympathetic overactivity.
Having said all that, this is a very interesting observation that ties up nicely with the so-called hyperfiltration of early diabetes mellitus. It associates such early hyperfiltration with sub-clinical CVD. This may in itself also explain the strong link between subclinical CVD and CKD in the community;
Perhaps starting with hyperfiltration and progressing to hypofiltration and CKD.
As with many previous publications, this paper highlights the close association between underlying CVD and renal abnormalities, be it hyperfiltration, incident CKD or even progressive CKD.
CKD in the community (cCKD) is a manifestation of underlying subclinical or over CVD and atherosclerosis.