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A review article by McCaughan and Courtney in NDT January 2012 reviews the situation relating to the apparaent increased incidence of PJP recipients of renal allografts. A number of recent reproted outbreaks in renal transplant recipients have raised concern about adequacy of prophylaxis strategies.  In general it is considered that PJP prophylaxis is justified and should be considered if the risk of disease is estimated to exceed 3%. The incidence of PJP infections in moderately immunosuppressed renal transplant recipients is usually <1%. Six renal centres reporting outbraks in Asia and Europe have all adopted the surveillance rather than prophylaxis approach based on the above assumptions. However, it is important toi appreciate that the risk is higher in:

1. High risk patients

2. Higher immunosuppression including use of ATG

3. Frequent rejection episodes

4. CMV infections

Currernt guidelines recommend 3-6 month prophylaxis with septrin (trimethoprim-sulfamethoxazole) from the time of transplantation. These guidelines may warrant review as most recent outbreaks took place more than 6 months after transplantation.

Therefore in higher risk and susceptibe individuals, it would be advisable to continue prophylaxis until the immunosuppression burden can be reduced.

Routine prophylaxis for all may be justifiable.

Prolonged immunosuppression may also be justifiable specially in the days of ever more agressive immunosupressive therapies.

Nephrologists need to inform their decision based on:

What is the justification of the Intervention?

Who is most susceptible to PJP and warrants prophylaxis?

Risk: benefit analysis; Septrin is not without its risks and side effects and PJP can be fatal!

Cost: benefit analysis.

McCaughan JACourtney AEPneumocystis jiroveci pneumonia in renal transplantation: time to review our practice? Nephrol Dial Transplant. 2012 Jan;27(1):13-5. Epub 2011 Aug 3.

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Anyone in the world
I attended an interesting symposium held on ESNT D4 which stimulated an intense discussion then! "Opposing Views: Stem cell and kidney tissue reconstruction; where we are? " The symposium was elegantly introduced by Prof. Meguid El Nahas. Prof. Gamal Saadi (Cairo University) presented his talk under the heading "we are already there" where he is carrying a clinical trial on a small number of CKD II to III patients treated with HSC but with no control group. He reported an improvement in terms of decline of serum creatinine and disappearance of fibrosis on post-treatment renal histopathology. Lupus patients enrolled on this study were also on their regular immunosuppressive therapy. Prof. Hussein Sheashaa (Mansoura University) delivered Prof. Mohamed Sobh view and argued against its use as a current therapeutic modality in humans in his talk "We are still far" coming across several reports of side effects and questioning the safety profile of such therapy in humans. He pointed out that stem cell therapy is still very much experimental and more animal studies are still needed to prove efficacy and safety. The talks stimulated an intense discussion and debate that was later wrapped up by Prof. El Nahas. Perhaps we can start discussing this issue more extensively here on OLA (no time limit as in the symposium!), discuss the level of evidence (if any), and share opinion regarding recent developments in stem cell research and their possible implications to attenuate fibrosis and to treat CKD.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

The answer to this question is usually that ACE inhibitors and ARBs have a protective effect by slowing the progression of CKD.

Yet, in all studeis on inhibition of RAAS and CKD progression diabetic or otherwise, there hasn't been a single study that reported the impact of the intervention on GFR. Instead, all the studies on ACE inhibition and progression since that of Lewis et al in 1993 relied on surrogate markers of progression namely: serum creatinine, creatinine clearance, 1/Cr slopes against time or more recently estimatedGFR. Not a single study published to my knowledge solid data on the hard and relevant endpoint of measured GFR and changes with time???!!!!

Authors have overlooked that changes in serum creatinine and derived formulation can be due to one of 4 factors:

1. Impact on dietary intake of amino acids or creatine

2. Creatine/Creatinine metabolism

3. GFR

4. Tubular secretion

So changes upon ACE inhibition in serum creatinine could be due to any one of these 4 confounders; yet nobody seems to take that into consideration and equate changes in serum creatinine to changes in GFR only....Why I ask myself this oversight????

This, in spite of evidence to suggest that inhibition of the RAAS system impacts on :

1. Efferent arterioles; leading to vasodialtation

2. Increased peritubular capillary circulation secondary to improved efferent arteriolar blood flow

3. Increased tubular secretion of creatinine either indirectly through 1 and 2 or directly through an increase in its organic cationic transporters (OCT1 and 2) that affect creatinine secretion by the proximal tubules (ref 1,2).

In conclusion, the oberved effect of RAA system inhibition of the rate of decline of serum creatinine may be simply the reflection of increased tubular secretion of creatinine rather than anything to do with prevention of GFR decline as the latter has never been measured!? Clearly, this is a hypothesis as much as the assumption that inhibition of RAAS slows the decline of true GFR!

Isnt it intriguing that investigators studying the progression of CKD never reported measured changes in GFR....I wonder why????

References

1. Thomas MCTikellis CBurns WCThallas VForbes JMCao ZOsicka TMRusso LMJerums GGhabrial HCooper ME,Kantharidis PReduced tubular cation transport in diabetes: prevented by ACE inhibition.Kidney Int. 2003 Jun;63(6):2152-61.

2. Thomas MCJerums GTsalamandris CMacisaac RPanagiotopoulos SCooper MEMDNSG Study GroupIncreased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes.Kidney Int. 2005 Jun;67(6):2494-9.

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Anyone in the world

Questions and answers put to Prof Glassock following his talk on the Management of Vasculitis:

Prof Salah Naga: Is there a role for CNIs in the management of ANCA associated systemic vasculitis?

Prof Glassock: CNIs do not seem to be very effective in the management of AASV. They certainly dont feature in the recognised effective therapeutic approaches.

Prof Sabry Gohar:  Is there a role for Infliximab in AASV?

Prof Glassock: No role and many reports of significant side effects including a high rate of infectious complications.

Prof Adel Afifi: IN the face of an increase in sCr, when would you rebiopsy?

Prof Glassock: Rebiopsying should be considered in the face of clinical, biochemical (CRP) or immunological (Autoantibodies) signs of disease activity.

Prof Afifi: How do you treat relapses?

Prof Glassock: I treat relapses of AASV with rituximab to avoid the toxicity of repeat courses of cyclophosphamide.

Prof Essam Nooreldin: How do you prevent hemorrhagic cystitis?

Prof Glassock: In more than 30 years of practice, I did not see a single case of hemorrhagic cystitis.

I tend to prescribe the cyclophosphamide to be taken at 9am

along with 4 glasses of water and I encourage th epatient to drink more water at bedtime (another 4 glasses).

Prof El Nahas: Do you think that Plasma exchange is beneficial outdside the indication for lung hemmorhage?

Prof Glassock: Whilst the MEPEX study showed some benfit at 12 months, follow up study over more than 3 years failed to show any advantage of plasma exchange of ESRD or death and was associated with increased toxicity/side effects (Walsh and Jayne, Personal Communication).

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Anyone in the world

Interesting data published in this months JASN again challenges the ‘one-size fits all’ approach of many guidelines in nephrology. The Correction of Anemia and PRogression of Renal Insufficiency in Transplant patients (CAPRIT) study from Amiens France, was an open label RCT that randomised patients to receive epoietin-beta to achieve either a normal haemoglobin (13-15g/dl) or a lower haemoglobin (10.5-11.5g/dl). There was no difference in baseline characteristics of the 125 patients who were randomised to the study. At 6 and 12 months the normal haemoglobin group had improvements in quality of life scores compared to the lower haemoglobin group. At 2 years progression to ESRD and return to dialysis occurred in 3 patients (4.8%) in the normal haemoglobin group and 13 patients (21%) in the low haemoglobin group (P=0.01) The death-censored graft survival at 2 years was 94.6% in normal haemoglobin group compared to 80.0% in the low haemoglobin group (P=0.01). The primary outcome was difference in eCrCl by Cockroft-Gault. At year 2, the mean eCrcl decreased by 2.4±1.1 ml/min per 1.73 m2in the normal haemoglobin group and 5.9±1.1 ml/min per 1.73 m2in the low haemoglobin group (P=0.03). There was no increase in CV events in the normal haemoglobin group. Theese results contrast the epo studies in the CKD population where normalisation of haemoglobin was harmful – TREAT, CHOIR, CREATE.

So is this a practice changing paper? I don’t think so because the study was much, much smaller than the CKD trials with a lower prevalence of cardiovascular disease – therefore the study may simply have been underpowered to detect differences in adverse cardiovascular events. Postulated mechanisms by which epo may improve transplant outcomes include a possible immunomodulatory effect or correction of tissue hypoxia and clearly warrant further investigation. Furthermore the potential impact of epo on malignancy could not be evaluated.

What the study does do is highlight the need for a larger multicentre RCT to address the issue of optimal haemoglobin in a transplant patient and the problems of 'extrapolating' guidelines from one patient group to another.

See Correction of Postkidney Transplant Anemia Reduces Progression of Allograft Nephropathy

Gabriel Choukroun, Nassim Kamar, Bertrand Dussol, Isabelle Etienne, Elisabeth Cassuto-Viguier, Olivier Toupance, François Glowacki, Bruno Moulin, Yvon Lebranchu, Guy Touchard, Maïté Jaureguy, Nicolas Pallet, Yannick Le Meur, Lionel Rostaing, Frank Martinez, and for the CAPRIT study Investigators. J Am Soc Nephrol 2012;23 360-368
http://jasn.asnjournals.org/cgi/content/abstract/23/2/360

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

I am attending the Annual meeting of the Egyptian Society of Nephrology and Transplantation (ESNT) in Marsa Alam, Egypt.

On the 13 and 14 of February and Pre Congress CME meeting is held.

On day 1 of the CME meeting, I attended a lecture by Professor Richard Glassock, USA, in which he discussed arguments related to the timing of the initiation of renal replacement therapy. He showed very elegantly in his lecture how timing of starting dialysis has evolved over the last 30 years from those who in the 70s and 80s advocated early start of RRT at GFR levels of around 15 to 20 ml/min to those morte recent observations arguing that late start of HD may be more beneficial.

A number of reviews and analysis concluded that there was little advantage in starting RRT too early; GFR>15 ml/min.

Professor Glassock referred to his work and that of Rosansky (2010) showing that those starting HD at the highest quartile of eGFR (>15) had the highest mortality. Of interest, this was more specifically evident in those with higher GFR and serum albuminlevels >35g/l. He also referred to the IDEAL study by Cooper et al (2009).

Prof Glassock explained the possible confounder of the interpretation of such observation with emphasis on the value of low serum creatinine as a marker of somatic malnutrition whilst changes in serum albumin are more reflective of visceral malnutrition. Sarcopenia and wasting may therefore explain some of the observations linking poor outcomes to early initiation of HD based on calculated GFR derived from equations such as the MDRD.

He also stressed the poor performance (imprecision and bias) of the MDRD formula in CKD stage 5. In fact, he showed data that eGFR calculated in CKD5 by such an equation considerably overestimates measured GFR. He suggested that the average of creatinine + Urea clearance may be a more accurate way of measuring GFR at this late stage of CKD.

It is also important to consider that timely referral of CKD4-5 patients to pre-dialysis care clinics and optimal preparation for RRT ar eas important in relation of the overall care of the CKD5 patient than the timing of the initiation of dialysis. Early referral to nephrologists is often not the case with patients presenting late and ill prepared for RRT. The setting up of pre-dialysis/low clearance clinics has been avocated in the UK to optimise the pre-RRT care of CKD patients. Optimal pre-ESRD care leads in many cases to prolong period of stable kidney function between eGFR of 10 and 15ml/min in asymptomatic patients. Many of the symptomas of these patients are alleviated by good anemia control as well as good control of their calcium and phosphorus metabolism as well as attention to their nutritional requirements. Pre dialysis clinics also allow for a better planning of vascular access as well as consideration/investigations for renal transplantation. Finally, good pre dialysis care involves social and psychological counselling for the patient and his family.

* See Review by Mustafa Arici in the OLA Libray on Timing of Start of RRT.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

Oscar Wilde  wrote that " a cynic is someone who knows the price of everything but the value of nothing" ....... Over 100 years later the same might be said of Medicare's attitude to kidney transplantation. In a depressing critique of Medicare's funding of kidney transplantation in the United States, Gill and Tonelli ( see NEJM online first) point out the impact of a lack of a universal funding strategy on clinical outcomes in transplantation. The 10 year graft survival in the US of 43% contrasts with a graft survival of between 55-60% in Canada, Australia and the UK.  Whilst these differences maybe due to a multitude of factors it's worth noting that in the US itself the likelihood of graft failure is much higher in the Medicare-insured group than those not insured by Medicare. The risk of graft failure rapidly increases after 3 years in the Medicare group. So what happens at 3 years? At present those insured with Medicare have their funding for immunosuppressants stopped after 3 years unless they are over 65 or deemed to have significant disability. Of course one can't prove that the cost of drugs accounts for the poorer outcomes amongst the Medicare group but the authors point to a survey of US transplant program's in which 68% of centres reported deaths or graft failures related to cost-related non-adherence.

Whilst the clinical reasons to support transplantation are overwhelming the economic reasons are just as robust. The cost of transplantation is initially estimated at $110,000 but this cost falls rapidly after the first year - making transplantation a much more cost effective therapy that dialysis which costs$75,000 per annum with the cumulative cost of dialysis much more than transplantation.  However despite the fact that Medicare won't fund immunosuppressants after 3 years ( even though effective generics for Tacrolimus and MMF now widely available) they are able to fund lifelong dialysis. The economic modelling suggests that \$200 million could be saved annually by providing universal coverage for lifetime immunosuppressive medication. An amendment to the the Social Security Act before the US Congress proposes to provide universal coverage for transplantation. A previous attempt to provide such coverage in 2009 failed. One can only hope that in the midst of a global economic crisis the policymakers can do their sums and come up with the right answer.

Penny Wise, Pound Foolish? Coverage Limits on Immunosuppression after Kidney Transplantation. John S. Gill, M.D., and Marcello Tonelli, M.D. February 1, 2012 (10.1056/NEJMp1114394) http://www.nejm.org/doi/full/10.1056/NEJMp1114394

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Anyone in the world

'Ideal Criteria' for Starting Chronic Hemodialysis: Numbers, Symptoms or an Alerting 'Traffic Light' System? (Mustafa Arici, Ankara; Nephron Clin Pract 2012;120:c17-c24) Arici writes in this issue an "Opposite View" regarding the timing of starting renal replacement therapy (RRT). He cautions readers against the misinterpretation of recent data suggesting that late onset RRT is safe and that early initiation of dialysis can be harmful. He draws attention to the use of estimated GFR equations with their limitations and inaccuracies in CKD stage 5 as well as their misrepresentation of true GFR in wasted and sarcopenic CKD5 patients. He also stresses the importance of a more holistic approach to the initiation of RRT beyond a simple eGFR value. Finally, he makes the important distinction between late onset RRT and late referral of CKD4 and 5 patients. Suffice to say that in many emerging countries the great majority of those who start RRT are seen within 3 months from the onset of dialysis. The main question in my view is not when to start RRT, but instead when to refer patients with CKD3b and 4 to Nephrology centers to prepare for RRT. All too often the timing of referral is inappropriately late, thus being the main cause of poor outcomes.

Mechanism-Based Therapeutics for Autosomal Dominant Polycystic Kidney Disease: Recent Progress and Future Prospects (Chang and Ong, Sheffield; Nephron Clin Pract 2012;120:c25-c35) The authors provide readers with an up-to-date critical appraisal of mechanisms and treatment of autosomal dominant polycystic kidney disease (ADPKD). Lessons for nephrologists from the ADPKD story so far are: (1) translation from the laboratory to the bedside can, with concerted effort, take place relatively quickly in CKD, (2) animal models of disease do not always accurately reflect the human equivalent, and (3) biomarkers and surrogate markers of disease should not be the target of interventions; instead the hard endpoints of CKD progression and end-stage renal disease should be kept in focus. Finally, most clinical trials target a single ADPKD pathway. Perhaps progression in this condition will require a multitargeted approach. The ADPKD polypill combines a range of inhibitors of cell proliferation and transduction pathways: multitargeted therapy for a multigenetic disease?

Urinary Red Blood Cells: Not Only Glomerular or Nonglomerular (Poloni, Fogazzi and colleagues, Milan; Nephron Clin Pract 2012;120:c36-c41) This review reminds nephrologists of the lost art of urine microscopy. They go well beyond glomerular and non-glomerular hematuria as distinguished by the morphology and presence of dysmorphic urinary red blood cells. They describe urinary sickle cells, anisocytes, poikilocytes, dacryocytes and elliptocytes, and illustrate these urinary red blood cells' morphological alterations by the corresponding clinical conditions. The article reflects Professor Tita Fogazzi's passion for urine microscopy. He has turned urine microscopy into a rediscovered science and art. Practicing nephrologists, however, remain divided on the value of urine microscopy. Many hold it in high diagnostic esteem and some even raise it to the level of scientific art. Others, including myself, do not use urine microscopy for diagnostic purposes. I must confess that I have not looked at a single urine sediment in the last 25 years - whether this has affected my diagnostic ability may never be known!

Towards Erythropoietin Equations That Estimate Oxygen Delivery rather than Static Hemoglobin Targets (C.J. Diskin, Opelika, Ala.; Nephron Clin Pract 2012;120:c48-c53) The author argues that current inconsistencies in diagnosis and management may be the result of overlooking some basic physiological facts and the pathophysiology of anemia and oxygen delivery in CKD. Anemia in CKD is associated with changes in the oxygen-hemoglobin dissocation curve that is affected by variables such as acidosis, hyperphosphatemia as well as circulating/cellular urea levels. The review is a reminder to readers that simplistic therapeutic algorithms such as those currently in use for the management of anemia in CKD may cause more harm than benefit when they are not fully based on a better understanding of the pathophysiology of the underlying disease. Such understanding may become even more relevant when interventions to treat anemia of CKD are based on manipulations of hypoxia-inducible factors. Whether more complicated equations based on incorporating more modulators of anemia improve practice remains to be determined.

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Anyone in the world

Semin Dial. 2012 Jan;25(1):9-14. doi: 10.1111/j.1525-139X.2011.01003.x. Epub 2011 Dec 6.

# An Obituary for GFR as the Main Marker for Kidney Function?

This editorial review in NDT challenges the use of serum creatinine and derived eGFR to estimate kidney function in terms of glomerular filtration.
We forget all too often that serum creatinine is the result of creatinine homeostasis based on:
1. Intake, amino acids and creatine
2.Cr Metabolism  from creatine to creatinine; relying on muscle mass and related enzymes
3. Glomerular filtration
4. Secretion; renal tubular and intestinal

So any intervention that seemingly lowers serum creatinine or slow its rise may be the result of any of the above or a combination of some of them. Cionsequently, interventions pertaining to slow teh progression of CKD based on a slower rise in serum creatinine compared to control may be due to:
1. Decrease intake, metabolism and secretion as with Low protein Diet
2. Secretion as with ACE inhibitors and ARBs as they improve in CKD peritubular circulation and enhance the transport and secretion of Creatinine. This raise teh question as to whether the whole literature on ACE (RAAS) inhibition and CKD is a tubular secretion paraphenomenon of these agent... Not a single study bothered measuring or reporting GFR.

It is high time nephrologists go back to basics and remember how Creatinine is handling and stop equating changes in serum creatinine to changes in glomerular filtration alone... this is wrong and misleading!

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Anyone in the world
Interesting study and exciting results! Tripathi et al. Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction. J Am Soc Nephrol 2012. doi: 10.1681/ASN.2011060566 The authors unravel the pathogenetic mechanisms at the molecular level resulting in uretero- pelvic junction (UPJ) obstruction, a common congenital anomaly and one of the most common causes of prenatal hydroneonephrosis. The TGF-b superfamily signaling is known to play an important role in normal development of the urogenital system and the pathogenesis of urinary tract defects. Moreover, a number of genes related to TGF-b super family are involved in the pathogenesis of hydronephrosis, including Bmp4, Bmp5, and Id2w. The investigators in the above study reported loss of canonical Smad-dependent TGF-b signaling in the mesenchyme that led to UPJ obstruction and severe hydronephrosis. This initial molecular lesion (deletion of Smad4 in the ureteral mesenchyme) affects the smooth muscle cell number and contractility as well as the urothelial basement membrane at stages before overt urinary tract obstruction. Such earlier deficiencies alter pelviureteric peristalsis, leading to functional obstruction that become more advanced at later stages resulting in organic obstruction, such as the severe kinking of the ureter at the UPJ and the constriction of the ureteral lumen by epithelial crowding. Thus, initial functional obstruction may progress into more damaging and more permanent physical obstruction. Would this discovery open the door in the future to intrauterine interventional targetd correction of the early and usually milder functional alterations before they lead to more irreversible damages to the kidney and the urinary tract? This remains to be answered! http://jasn.asnjournals.org/content/early/2012/01/25/ASN.2011060566.full.pdf
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