I am currently on an academic visit in Tehran having conducted a Master Class on behalf of the Global Kidney Academy.
I took this opportunity to further familiarise mysef with the Iranian Transplantation model.
I was most impressed with the efforts made by the National Transplantation team at the Tissue Bank of the National Renal Centre under the leadership of Professor Mitra Mahdavi-Mazdeh to promote Brain Death Donations (BDD). It is remarkable that in excess of 20% of all renal transplants now undertaken in Iran are from cadaveric donors. This growing program warrants recognition and support.
The Iranian unrelated living donor transplantation program, inspite of its limitations, has allowed thousands of ESRD patients to be transplanted in this country. Opinions are divided on its merits but we should all have open minds when it comes to saving ESRD lives and providing them with improved outcomes after renal transplantation.
More debate is warranted on the optimisation of organ donation in emerging countries.
The Raimipril Efficacy in Nephropathy (REIN) study has perhaps been one of the most influential studies in clinical nephrology over the last 20 years. It is cited as a seminal study in justifying the use of ACEi in proteinuric CKD though careful reading of the study shows that ACEi had little benefit on progression when the baseline proteinuria was less that 1.5 g/24hours and it's also with noting that the baseline GFR was better in the Ramipril group.
2 post-hoc analyses of the REIN study have been published this year - one implying that obese patients are more likely to benefit from ACEi and the second showing an association between the baseline serum phosphate and the response to ACEi.
I always find the value of post-hoc analysis difficult to interpret. I never quite know what the authors are trying to say. At best they can be hypothesis-generating but all too often they appear to be statistical quirks - Phosphate is a marker of kidney function and patients with worse kidney function are more likely to progress to ESRD .... Thus it's perhaps not surprising that those with worse serum phosphate are more likely to progress. i.e. The combination of serum phosphate and GFR may more accurately kidney function than GFR alone. Of course the other possibility as the authors suggest is that phosphate per se interferes with the response to ACEi and maybe a target for CKD progression. The only way this could be addressed is by a clinical trial assessing the impact of phosphate lowering on CKD progression.
1.Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect= of ACE Inhibition. Carmine Zoccali, Piero Ruggenenti, Annalisa Perna, Daniela Leonardis, Rocco Tripepi, Giovanni Tripepi, Francesca Mallamaci and Giuseppe Remuzzi for the REIN Study Group.J Am Soc Nephrol 2011, 1923-1930
2.ACE inhibition is renoprotective among obese patients with proteinuria. Mallamaci F, Ruggenenti P, Perna A, Leonardis D, Tripepi R, Tripepi G, Remuzzi G, Zoccali C; REIN Study Group. J Am Soc Nephrol. 2011 Jun;22(6):1122-8
The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.
The original publication by the Frequent Hemodialysis Network (FHN) implied positive impact of Frequent Daily Dialysis on the coprimary outcomes:
Left ventricular mass index (LVMI) + Death and LVMI + Quality of Life
This, in spite of the fact that the study was underpowered with an inadequate sample size to estimate impact on death over such a short observation time (12 months)! The results of the Daily trial were comparable to those in the literature describing improvements by salt restriction and volume control.
Now the same group publishes that if you do frequent HD at night, there is no benefit on any of the Primary endpoint: LVMI, Death or Quality of Life!
In fact, The FHN Daily and the Nocturnal trial differ in some respect: Time of dialysis, location and length of treatment but laso in the degree of residual renal function.
So, is Frequent HF, 6 times/week, only beneficial if it is done in Daytime not Nightime...???
Are all these trials and sub-trials un-interpretable because they are badly designed and underpowered?!
So don't rush to switch all your patients at a huge cost and inconvenience to frequent HD. Make sure they are not fluidoverloaded with careful ultrafiltration/volume control and dietary salt restriction.
Wait until Nephrologists know how to conduct and interpret clinical trials....
Although the term "Ciliopathies" surfaced only recently, yet it is an increasingly exciting study field with numerous recent publications [58 articles in Pubmed only in 2011 and it is not over yet!]
Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in abnormal formation or function of cilia. As cilia are a component of almost all cells, ciliary dysfunction can manifest as a constellation of features that include primarily retinal degeneration, renal disease and cerebral anomalies.
A role for the primary cilium in cystic disease was suggested following the observation that almost all proteins implicated in cystogenesis are localised to the primary cilium. Evidence that cilia are important in cystic kidney disease stems from the initial observation of renal cysts in the Oak Ridge Polycystic Kidney (orpk) mouse that mimic ARPKD.
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that represents the most frequent genetic cause of end-stage renal disease (ESRD) in the first 3 decades of life. So far, 13 genes (NPHP1–NPHP11, AHI1, and CC2D2A) have been identified that cause NPHP when mutated. Interestingly, NPHP can occur with isolated kidney involvement or in combination with diverse extrarenal manifestations specifically: (i) retinal degeneration in Senior–Løken syndrome (SLSN); (ii) cerebellar vermis aplasia (CVA)/hypoplasia (CVH), retinal degeneration, and mental retardation in Joubert syndrome (JBTS) and Joubert syndrome related disorders (JSRD); and (iii) dysplastic phenotypes of multiple organs leading to lethal Meckel–Gruber syndrome (MKS).
Since genotype–phenotype correlation in NPHP-related ciliopathies (NPHP-RC) seems to be governed by three genetic mechanisms: gene locus heterogeneity, allelism, and modifier genes; Chaki and et al kidney Int, 2011 evaluated the genotype–phenotype correlation in a cohort of 440 patients from 365 families with NPHP-RC in whom both mutations were identified.
In 248 individuals from 235 families, the cause of the disease was two recessive NPHP1 mutations, with 93%(219 families) being the homozygous deletion of NPHP1. The patients exhibited a ‘typical’ juvenile NPHP (ESRD more than 4 years) and most of them (180/235 families, 76.5%) had isolated kidney involvement. In 55 families, extrarenal manifestations were noted: specifically, central nervous system and eye involvement.
Authors observed that a genotype of two null alleles causes phenotypes in the following increasing order of severity: NPHP1, NPHP4, NPHP5, NPHP2, NPHP10, NPHP6 toAHI1. They also suggested a cpmprehensive genetic analysis pathway based on the presence of frequent and less frequent phenotypes. Athors concluded that the ‘gene locus heterogeneity’ is the prime factor in determining the disease phenotype, whereas ‘allelism’ might be somewhat important only for certain genes such as NPHP6, NPHP8, and NPHP11.
Nevertheless, since mutation screening was not done for all NPHP genes, the influence of the modifier genes on a phenotype can not be excluded.
Finally, this work emphasizes that while identification of new genes and new ciliary proteins are of fundamental biological interest, it is perhaps even more important to understand the mechanisms underlying the functional consequences of ciliary dysfunction in an organ-specifc context for proper genotype-phenotype correlation, if any!
Chaki M, Hoefele J, Allen SJ, Ramaswami G, Janssen S, Bergmann C, Heckenlively JR, Otto EA, Hildebrandt F. Genotype–phenotype correlation in 440 patients with NPHP-related ciliopathies. Kidney Int. 2011 Aug 24. doi: 10.1038/ki.2011.284.
As with many practices in nephrology, dialysis scheduling has evolved through historical accident rather than clinical design. Most patients around the world will dialyse 3 times a week for 3-4 hours either on a Monday, Wednesday and Friday or a Tuesday, Thursday, Saturday. This utilitarian approach has evolved through a combination of economic and capacity associated factors rather than any solid evidence base. Two randomised controlled trials ( the Frequent Hemodialysis Network study and the Canadian Frequent Nocturnal Hemodialysis Study) have shown improvements in surrogate markers such as left ventricular mass index and mineral metabolism in patients dialysed six times a week. Neither study was powered to evaluate the impact on mortality alone. Furthermore its long been recognised that sudden cardiac death is a common cause of cardiac death amongst dialysis patients. A study published by Rob Foley from the USRDS in this weeks NEJM highlights some interesting data. In an analysis of over 32000 haemodialysis patients the authors evaluated all-cause mortality and hospital admissions on the day after the long dialysis interval ( i.e. Monday or Tuesday) as compared to the rest of the week. All-cause mortality, mortality from cardiac causes, infection-related mortality, mortality from cardiac arrest, mortality from myocardial infarction and admissions for myocardial infarction, congestive heart failure, stroke, dysrhythmia and any cardiovascular event were all higher on the day after the long dialysis interval than on other days. While clearly one cant ascribe causality from observational data, it is interesting that mortality rises incrementally during the long interval and supports the observations of some that the long dialysis interval is a time of heightened cardiovascular risk due to metabolic disturbance. The data provides a compelling reason to do an adequately powered randomised controlled trial examing the impact of dialysis frequency and duration on clinical outcomes - though the logistical and funding issues around such a trial would be challenging to say the least.
Reference: Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis. Foley, Robert N. M.B.; Gilbertson, David T. Ph.D.; Murray, Thomas M.S.; Collins, Allan J. M.D. The New England Journal of MedicineIssue: Volume 365(12), 22 September 2011, p 1099–1107
Finally, the assumption that one size fits all with targets systolic levels of <130 or 120mmHg is preposterous. Age, race and comorbidities may dictate different target levels. This is becoming apparent in patients on hemodialysis were older and diabetic individuals had higher mortality rates at lower (<140/70mmHg) blood pressure levels. More remarkably was the observation in this cohort analysis that survival did not seem to be harmed by higher systolic and diastolic values: 140-160 and 70-100mmHg (1).
1. Myers OB, Adams C, Rohrscheib MR, Servilla KS, Miskulin D, Bedrick EJ, Zager PG.Age, race, diabetes, blood pressure, and mortality among hemodialysis patients. J Am Soc Nephrol. 2010 Nov;21(11):1970-8.
An article in the August issue of cJASN by Schinstock and colleagues from the Mayo clinic describe the experience with AVF. They report a large primary and secondary failure rate and identify diabetes mellitus and the size of the arteries as major determinants of reduced primary patency. Larger arteries are associated with better AVF outcomes thus advocating doppler testing and sizing of arteries and veins prior to AVF fashioning. They also raise the important issue of morbidity, complications and subsequent hospitalisations associated with AVF failure.
This leads them to questions whether in elderly patients with comorbidities and reduce life expectancy on HD, the Fistual First approach still holds as failure rate with the associated hospitalisations should be taken into consideration.
In my experience, older age and the associated atherosclerotic arteries specially in those with DM has been a major cause of raised primary and secondary AVF failure. This is indeed associated with frequent hospitalisations, imaging and re-interventions. The question should be raised if AVF in those with low life expectancy and small arteries on doppler should follow the Fistula First Stategy or whether a judicious and careful treatment plan with a permanent internal jugular dialysis catheter is a viable alternative. Some (Allon et al. 2010) have advocated a RCT to address some of these issues.
In the meanwhile, we should not forget the high morbidity and mortality associated with dialysis catheters and should make every asttempt at timely insertion of native AVF.
There has been recent discussion of how to develop a vibrant transplant program in low income/developing economies. An inspiring article is published in this months AJT by Rizvi and colleagues in the Sindh Institute of Urology and Transplantation, Karachi, Pakistan charting the development of a renal replacement therapy program over the last 30 years.
Pakistan has a population of 184 million and 60% of the population live on less than $2USD a day. Yet the cost of dialysis in the private sector is upto $25USD per session whilst transplantation can cost upto $10000USD. Whilst treatment in the government sector is free the facilities are scarce with government dialysis centres only accounting for 38.5% of dialysis centres in the country. Only 1.3 % of GDP is spent on healthcare by the government. The result of this bleak economic backdrop is that the authors estimate that over 90% of the ESRD population being disenfranchised from RRT. Central to the success of this centre in developing a vibrant transplant and dialysis program has been it's ability to secure sustainable funding which has involved partnership with government, the community and business to sponsor individual patients, equipment and staffing resources. This unique partnership has enabled investment in human and physical infrastructure developing a sustainable RRT program.
Interestingly the institute has campaigned hard for the instigation of a transplant law that outlaws commercialism in transplantation - this actually resulted in an increase in transplant activity at the centre with a rising rate of live related donation amongst the relatives of wealthy patients who were no longer able to 'buy' kidneys. Despite the failure of a deceased donor program to take off, the centre transplanted 544 patients in 2009 and dialysed over 1300 patients. The success of the transplant program has enabled more people to be offered dialysis and the authors strongly argue that free transplantation has allowed the development of an altruistic donor program.
For those of us working in wealthy societies it is difficult for us to comprehend the decisions made by clinicians and patients in such countries. Rizvi and colleagues have achieved extraordinary things in an extraordinary environment - see here