User blog: mohammad katout

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by mohammad katout - Sunday, 28 May 2017, 11:04 AM
Anyone in the world

Chronic Kidney Disease (CKD) is a major global health problem with significant morbidity and mortality and high economic burden in various geographic communities. During the 20th century, nephrology clinical practice witnessed significant achievements thanks to major technological advances that enabled provision of dialysis and transplantation to ESRD patients.

But what about nephrology in the 21st century?

The goal of “precision medicine” is to molecularly characterize diseases, in order to identify specific biomarkers and therapeutic targets that will ultimately improve clinical outcomes. The nephrology research community has developed a strong foundation for precision medicine, and recent publications demonstrate the “feasibility” of this approach to identify potential biomarkers and therapeutic targets in chronic kidney disease.

Over the past decade, rapidly growing knowledge in genomics and genomic technologies have immensely impacted nephrology clinical practice and resulted in a greater integration of genetics into nephrology healthcare:

i) providing a definitive diagnosis; ii) enabling precise genetic counselling for family planning; iii) providing guidance for monitoring of potential future complications; iv) providing guidance of transplantation strategy and evaluation of family member potential kidney donors.  

Having said that, nephrology is still lagging behind other disciplines, oncology for instance, in fully integrating genetics into nephrology clinical care. With the dramatic improvement of sequencing technologies and the enormous reduction of sequencing cost, it is high time for nephrologists to face the resulting  genetic data avalanche.

 

1. How well are we in coping with this plethora of genetic data and utilizing it properly so far?

2. Are there innovations in the pipeline for disease-specific biomarkers and/or new technologies or therapeutics targeted at enhancing the provided care, particularly in this rapidly growing genomic era?

3. Is there a strategic framework towards customization of provided healthcare in nephrology, with tailored medical decisions and targeted therapeutics?

This remains to be answered!

 

References

-       Wyatt & Schlondorff. Precision medicine comes of age in nephrology: identification of novel biomarkers and therapeutic targets for chronic kidney disease. Kidney Int. 2016 Apr;89(4):734-7

-       Poliakov  et al. Genetics in Genomic Era. Genet Res Int. 2015; 2015: 364960

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by mohammad katout - Saturday, 20 May 2017, 10:02 AM
Anyone in the world

Clinical and ultrasonographical characterization of childhood cystic kidney diseases in Egypt

Ren Fail. 2014 Jun;36(5):694-700. doi: 10.3109/0886022X.2014.883996

http://www.tandfonline.com/doi/full/10.3109/0886022X.2014.883996

From authors in brief:

Cystic kidney diseases comprise a heterogeneous group of inherited kidney disorders, where renal cysts constitute a major element of their pleiotropic clinical phenotypes.

Only few studies looked into the spectrum of pediatric cystic kidney diseases in general (not only polycystic kidney diseases). Therefore, the authors of this cross-sectional study decided to have a closer look into clinical phenotypic features of renal cystic disease patients presenting to our major referral center, over one year duration, and define the etiology based on: i) clinical characteristics; ii) renal imaging; and iii) histopathological findings to better categorize this subset of disorders. To the best of  our knowledge this is the most comprehensive analysis of renal cystic disease reported from a regional single center including 105 patients belonging to 100 families, including 59 males (56%) and 46 (44%) females (age range: 1 day to 17 years; median 2.7 years).

In brief:

-       62.9% of study patients were born to consanguineous parents with strong family history of cystic kidney disease (25.7%) as well as sibling demise to same illness (15.2%).

-       Polyuria and polydipsia were the commonest presenting manifestation (60%), followed by ESRD (46.7%), and palpable kidneys (42.9%).

-       Extra-renal manifestations were reported in (42.9%) of study patients (mainly neurological, dysmorphism and hepatic involvement). They were mainly in the context of well-defined syndromes, yet some were demonstrated in previously unreported constellations possibly representing newly described syndromes.

-       The vast ultrasonographic imaging spectrum ranged from single unilateral small cyst to innumerable multiple variable sized kidney cysts.

-       Inherited renal cystic diseases comprised the majority of childhood cystic kidney disorders (65.7%) mainly nephronophthisis and related ciliopathies (36.2%), followed by polycystic kidney diseases (29.5%). This might be peculiar to the region given the striking higher consanguinity.

-       Ultrasound scan is a useful screening and initial diagnostic tool with a possible role for additional imaging modalities in complex cases; and shrinking role for renal biopsy.

-       Moreover, in the current study, we propose a modified algorithm, based on both clinical and ultrasonographic criteria, which is particularly helpful to physicians and nephrologists to guide proper characterization of cystic kidney diseases.

-       Ongoing molecular characterization is expected to unravel further pathogenetic mechanisms and enhance our knowledge into this rapidly growing area of ciliopathy research, hopefully leading to innovative targeted therapeutics.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

AAV is a relapsing and remitting autoimmune disease characterized by vascular inflammation and organ damage.

-       Generally characterized by circulating ANCA, reactive to proteinase 3 (PR3) or myeloperoxidase (MPO).

-        Thought to be triggered by certain environmental exposures, such as silica dust, infections, or drug exposure.

-       Different clinical disease phenotypes are recognized.

-       Pharmacologically induced remission of this condition is complicated by relapses.

-       Recently, different genetic susceptibility loci have been identified according to ANCA serotype, with polymorphisms in HLAPRTN3, and SERPINA1 encoding MHC molecules, PR3, and its natural inhibitor α-1-antitrypsin, respectively, being associated with PR3-ANCA disease.

Methylation of DNA cytosine bases

-       Is an essential and well-studied epigenetic modification that may regulate and coordinate gene expression.

-       Methylated gene promoter or enhancer regions are thought to block accessibility to transcriptional activators and prevent gene transcription.

The potential link between environmental triggers, DNA methylation changes, and resultant variation in gene expression that may translate into particular phenotypes has made this topic attractive to many researchers.

 

In a recently published study in JASN by Jones et al:

http://jasn.asnjournals.org/content/28/4/1175.long

 First, they examined methylation and gene expression in patients with AAV and healthy controls:

  1. In both MPO and PRTN3 genes, DNA methylation was reduced in active disease compared with healthy controls and rebounded in disease remission.

Value: could further studies into methylation and gene expression unravel the mechanism(s) underlying ANCA formation leading to novel targeted therapeutics?

 

Second, they investigated whether DNA methylation patterns can be used to predict disease relapse:

  1. Patients with increased DNA methylation at the PRTN3 locus during remission were less likely to relapse, regardless of their autoantigen serotype. 

Value: could this be useful in the quest for biomarkers or prognostic indicators in the disease course that might later guide cessation or intensification of therapy?

 

Also future studies investigating potential key players in mediating autoimmune disease in response to environmental cues may further elucidate the role of epigenetic modifications in immune-mediated kidney diseases.

 

Jones BE, Yang J, Muthigi A, Hogan SL, Hu Y, Starmer J, Henderson CD, Poulton CJ, Brant EJ, Pendergraft WF 3rd, Jennette JC, Falk RJ, Ciavatta DJ: Gene-specific DNA methylation changes predict remission in patients with ANCA-associated vasculitis. J Am Soc Nephrol 28: 1175–1187, 2017

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

During the plenary session of the first day of the 17th International Pediatric Nephrology A ssociation Congress, September 20-24 in Iguacu, Brazil 

Professor Moin A Saleem delivered the keynote talk entitled “Molecular stratification of the nephrotic syndrome”

Being an expert in the field professor Saleem smoothly surfed in the current acumen of exponentially increasing molecular and cell biology updates into the pathogenesis of nephrotic syndrome.

The glomerular podocyte plays a key role in filtration and its loss of function results in loss of protein.  Therefore, the recent advances in molecular genetics and cell biology studies in nephrotic syndrome patients not only revealed the molecular mechanisms of podocytes dysfunction responsible for the disease, but equally importantly provide clues to focus on target molecules on the podocyte to figure out potential circulating factors.

Moreover, those molecules can be utilized as both diagnostic and prognostic biomarkers. This paves the way to personalized therapy to patients with nephrotic syndrome tailored to maximize benefit while minimizing side effects caused by drugs as well as the devastating post-transplantation disease recurrence.

It is quite interesting how whole-exome sequencing revolutionized our understanding through identifying several mutations in families with SSNS, which shed light on new mechanisms of podocyte disruption in minimal change nephrotic syndrome. For instance, epithelial membrane protein 2 (EMP2) is known to regulate the amount of caveolin-1, which contributes to endocytosis and the transcytosis of cholesterol and albumin. Lipopolysaccharide (LPS)-induced caveolin-1 phosphorylation was reported to lead to the increase of transcellular permeability [1,2].

Professor Saleem suggested that there is seemingly an evidence of overlap of SSNS and SRNS. He expects, given the preliminary results of the ongoing research as well, that nephrotic syndrome will be reclassified soon based on pathogenic mechanisms that keep evolving. These would hopefully include the mechanisms of how corticosteroid and immunosuppressives have their effect on single gene mutation nephrotic syndrome.

 

Referrences

Parton RG, del Pozo MA: Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol. 2013; 14(2): 98–112

Wang N, Zhang D, Sun G, et al.: Lipopolysaccharide-induced caveolin-1 phosphorylation-dependent increase in transcellular permeability precedes the increase in paracellular permeability. Drug Des Devel Ther. 2015; 9: 4965–77

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

Ever wondered what is renal graft outcome (patient and renal graft survival, incidence of acute rejection and long-term renal allograft function) in combined liver & kidney transplantation (CLKT) as compared to isolated kideny transplantation (KT)?


Read the below to find out what the nephrology and hepatology teams at Birmingham Children’s Hospital found when they carried out this case–control study.

Key findings:

The kidney graft survival for CLKT patients (primary diagnosis fibro-polycystic liver & kidney disease- FPLKD in 65% of them) was 87.4, 82, and 82 % at 1, 5, and 10 years .

Allograft survival rates in KT recipients were 97.2, 93, and 93 % at 1, 5, and 10 year follow-up and this was not significantly different (p > 0.05) from CLKT recipients. That being said, higher initial rate of graft loss was noted in CLKT patients given the higher morbidity and mortality associated with the operation.

CLKT recipients had fewer acute rejection episodes and better long-term renal graft survival when compared to isolated KT. Only 5 % of CLKT recipients had acute rejection compared to 12.5 % of KT recipients. If this could be attributable to a hepatic immunomodulatory effect leading to a degree of tolerance remains unclear.

Plasma creatinine at 1 and 5 years following transplantation was significantly lower in children undergoing CLKT for FPLKD compared to those with Primary hyperoxaluria- PH and a significantly higher 1-year e-GFR in patients with FPLKD than in those who had PH. This is presumably due to the risk of oxalate deposition in the transplanted kidney given oxalate mobilization from bones and tissues post-transplantation.

The decline in mean eGFR between 5 and 10 years from transplantation was greater (−19.14 ml/min/1.73 m2 in 5 years) in KT recipients compared to CLKT (−7.6 ml/min/1.73 m2 in 5 years) (p = 0.043). 

- Could the noticed trend in favor of better renal graft function in CLKT recipients in comparison to KT recipients in this study  be significantly documented in future studies? This remains remains to be answered.

READ THE ORIGINAL ARTICLE AND COMMENT!

Ranawaka R, Lloyd C, McKiernan PJ, Hulton SA, Sharif K, Milford DV. Combined liver and kidney transplantation in children: analysis of renal graft outcome. Pediatr Nephrol 2016;31(9):1539-43

http://link.springer.com/article/10.1007%2Fs00467-016-3396-3

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

Two decades ago, Hales and Barker reported the association between hypertension (HTN) in adult life and birth weight. They suggested that intrauterine environmental factors, mainly nutrition, could lead to permanent metabolic and structural changes in the fetus, influencing BP in adult life and increasing the risk of CVD in adulthood.

An inverse association exists between low birth weight (LBW) and higher blood pressures in infancy and childhood, and overt HTN in adulthood.

Impaired kidney development in an adverse intrauterine environment results in a low nephron number, which predisposes individuals to hypertension and kidney disease in adulthood. The main factors that predispose individuals to impaired kidney development are protein and calorie malnutrition, placental malfunction and maternal hyperglycemia. Complex processes with yet to be identified cellular and molecular mechanisms presumably contribute to impaired nephrogenesis. Growing evidence suggests that epigenetic modifications might explain many of the changes noted in perinatal programming.

What can we do then to ameliorate the effect of adverse fetal programming?

Prenatal care is transitioning to incorporate goals of optimizing maternal, fetal, and neonatal health to prevent or reduce adult-onset diseases including HTN and CVD morbidities.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by mohammad katout - Tuesday, 29 March 2016, 10:30 AM
Anyone in the world

 

Enormous advances continue to be made to enhance our understanding of the challenging “thrombotic microangiopathies TMA”

It is becoming clear, recently, that distinct disease mechanisms underlie the group of diseases formerly designated as TTP/HUS. Advances in molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypicalHUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor.

Interestingly close to 20,000 articles in TMA have been published since 1945, with striking increase after the completion of human genome sequencing in 2001 as more disease-causing mutations had been identified. 

The increasingly better clinical characterization and definition of the role of complement in HUS has pushed our understanding forward in an unprecedented way. Defining complement dysregulation as central to disease pathogenesis has paved the way to targeted therapeutics and improved patient clinical outcome.

Complement-mediated TMA (the preferred term) is not just a disease of children, as evidenced by the largest reported cohorts by Noris and colleagues 2010; Fremeaux-Bacchi and associates, 2013. The child-to-adult ratio is nearly comparable with respect to age-at-presentation, ranging from <1 year of age to 85 years. Interestingly the male-to-female ratio is similar in younger patients, whereas there is a female preponderance in adults (Fremeaux-Bacchi et al., 2013). Triggering events are documented in 39–70% of individuals and include most often diarrhea, respiratory illness and pregnancy.

Chantal Loirat and her colleagues recently published “An international consensus approach to the management of atypical hemolytic uremic syndrome in children” in Pediatric Nephrology Journal providing a consensus clinical practice recommendations generated by HUS International (expert group of clinicians and basic scientists with a focused interest in HUS).

They provided evidence-based answers where available (already scarce), while relying mostly on the published anecdotal literature. The consensus raises many questions as it answers: for instance when to withdraw treatment in countries where therapy is already available? On the other hand, one of the major concerns is the geographical disparity in treatment availability due to the high cost of the drug in limited resources nations worldwide. It also emphasizes the need to carefully design future studied and use data from international registries to better understand this challenging disease.

 

References

 

1. Noris, M., Caprioli, J., Bresin, E., Mossali, C., Pianetti, G., Gamba, S., Daina, E., Fenili, C., Castelletti, F., Sorosina, A., Piras, R., Donadelli, R., Maranta, R., van der Meer, I., Conway, E.M., Zipfel, P.F., Goodship, T.H., Remuzzi, G., 2010. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5, 1844–1859

2. Fremeaux-Bacchi, V., Fakhouri, F., Garnier, A., Bienaime, F., Dragon-Durey, M.A., Ngo, S., Moulin, B., Servais, A., Provot, F., Rostaing, L., Burtey, S., Niaudet, P., Deschenes, G., Lebranchu, Y., Zuber, J., Loirat, C., 2013. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin. J. Am. Soc. Nephrol. 8, 554–562

 3. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Frémeaux-Bacchi V; HUS International.An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol.2016;31(1):15-39

 

 

 

 

 

 

 

 

 

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

Vesicoureteral reflux (VUR) is the most common urologic finding in children, occurring in approximately 1 percent of newborns, and as many as 30 to 45 percent of young children with a urinary tract infection given the retrograde passage of urine from the bladder into the upper urinary tract. [1-3]

 Basically, management is mainly focused on prevention of pyelonephritis, a morbid event in itself that requires acute medical care and possible hospitalization in young infants, let alone the possible subsequent loss of renal parenchyma as a result of renal scarring resulting in a cascade of chronic kidney disease events (hypertension, proteinuria, renal insufficiency with possible ESRD). [4,5]

 Even though nephrologists had been clear on the existence of VUR and its link to renal scarring and CKD, yet they had been hazy on its management in terms of clinical impact of prophylaxis and adequate medical/surgical therapeutic interventions. The ideal management of children with VUR remains a source of debate with little evidence to support many of the current management practices for children with VUR who have had 1 or 2 febrile urinary tract infections. In fact, the long-standing notion that VUR may lead to progressive CKD and potentially ESRD has been increasingly questioned and remains controversial.

Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) is a multicenter, randomized, double-blind, placebo-controlled study to determine whether daily antimicrobial prophylaxis, in the setting of prompt evaluation and treatment of UTI, is superior to placebo in preventing recurrence UTI and/or the occurrence of, or worsening, of renal scarring in children with vesicoureteral reflux (VUR).

 In their recent publication in CJASN Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial” 607 children aged 2–71 months with grade 1–4 VUR diagnosed after a first or second febrile or symptomatic UTI were enrolled in this multicenter, randomized, placebo-controlled trial . Study participants received trimethoprim-sulfamethoxazole or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up99mtechnetium dimercaptosuccinic acid (DMSA) renal scans. 

 Authors reported that new renal scarring did not differ between the prophylaxis and placebo groups (6% versus 7%, respectively). Unsurprisingly, preexisting and new renal scars occurred significantly more in “renal units” with grade 4 VUR as compared to those with low-grade or no VUR. Children with renal scarring were significantly older (median age, 26 versus 11 months; P=0.01), had a second UTI before enrollment (odds ratio [OR], 2.85; 95% confidence interval [95% CI], 1.38 to 5.92), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). [6]

 Perhaps the most clinically relevant finding of this work that could potentially impact clinical practice is that antimicrobial prophylaxis did not decrease the risk of renal scarring whether in terms of the proportion of children (6% and 7%) or renal units (4% versus 4%) echoing the results of recent studies that evaluated the role of antimicrobial prophylaxis in reducing the risk of renal scarring (7,8).

 The question remains, should we stop antimicrobial prophylaxis to VUR infants and toddlers based on the above results?

 Caution is still warranted while interpreting the results of the above studies since they were not primarily designed to evaluate the role of antimicrobial prophylaxis in preventing scarring. Moreover, a short follow-up period of 1–2 years in the RIVUR Trial is not long enough to determine beyond any reasonable doubt the long-term risk for the development of renal scarring or the preventive effect of antimicrobial prophylaxis.

 

References

  1. Dillon MJ, Goonasekera CD. Reflux nephropathy. J Am Soc Nephrol 1998; 9:2377.
  2. Shah KJ, Robins DG, White RH. Renal scarring and vesicoureteric reflux. Arch Dis Child 1978; 53:210.
  3. Smellie JM, Normand IC, Katz G. Children with urinary infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int 1981; 20:717.
  4. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846.
  5. Willi U, Treves S. Radionuclide voiding cystography. Urol Radiol 1983; 5:161.
  6. Mattoo TK, Chesney RW, Greenfield SP, Hoberman A, Keren R, Mathews R, Gravens-Mueller L, Ivanova A, Carpenter MA, Moxey-Mims M, Majd M, Ziessman HA; RIVUR Trial Investigators. Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial. Clin J Am Soc Nephrol. 2015 Nov 10. pii: CJN.05210515. [Epub ahead of print]
  7. Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, Hodson EM, Carapetis JR, Cranswick NE, Smith G, Irwig LM, Caldwell PH, Hamilton S, Roy LP; Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) Investigators: Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 361: 1748–1759, 2009
  8. Brandstro¨m P, Neve´us T, Sixt R, Stokland E, Jodal U, Hansson S: The Swedish reflux trial in children: IV. Renal damage.JUrol 184:292–297, 2010

   

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

 

Vesicoureteral reflux (VUR) is the most common urologic finding in children, occurring in approximately 1 percent of newborns, and as many as 30 to 45 percent of young children with a urinary tract infection given the retrograde passage of urine from the bladder into the upper urinary tract. [1-3]

 

Basically, management is mainly focused on prevention of pyelonephritis, a morbid event in itself that requires acute medical care and possible hospitalization in young infants, let alone the possible subsequent loss of renal parenchyma as a result of renal scarring resulting in a cascade of chronic kidney disease events (hypertension, proteinuria, renal insufficiency with possible ESRD). [4,5]

 

Even though nephrologists had been clear on the existence of VUR and its link to renal scarring and CKD, yet they had been hazy on its management in terms of clinical impact of prophylaxis and adequate medical/surgical therapeutic interventions. The ideal management of children with VUR remains a source of debate with little evidence to support many of the current management practices for children with VUR who have had 1 or 2 febrile urinary tract infections. In fact, the long-standing notion that VUR may lead to progressive CKD and potentially ESRD has been increasingly questioned and remains controversial.

Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) is a multicenter, randomized, double-blind, placebo-controlled study to determine whether daily antimicrobial prophylaxis, in the setting of prompt evaluation and treatment of UTI, is superior to placebo in preventing recurrence UTI and/or the occurrence of, or worsening, of renal scarring in children with vesicoureteral reflux (VUR).

 

In their recent publication in CJASN Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial” 607 children aged 2–71 months with grade 1–4 VUR diagnosed after a first or second febrile or symptomatic UTI were enrolled in this multicenter, randomized, placebo-controlled trial . Study participants received trimethoprim-sulfamethoxazole or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up99mtechnetium dimercaptosuccinic acid (DMSA) renal scans. 

 

Authors reported that new renal scarring did not differ between the prophylaxis and placebo groups (6% versus 7%, respectively). Unsurprisingly, preexisting and new renal scars occurred significantly more in “renal units” with grade 4 VUR as compared to those with low-grade or no VUR. Children with renal scarring were significantly older (median age, 26 versus 11 months; P=0.01), had a second UTI before enrollment (odds ratio [OR], 2.85; 95% confidence interval [95% CI], 1.38 to 5.92), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). [6]

 

Perhaps the most clinically relevant finding of this work that could potentially impact clinical practice is that antimicrobial prophylaxis did not decrease the risk of renal scarring whether in terms of the proportion of children (6% and 7%) or renal units (4% versus 4%) echoing the results of recent studies that evaluated the role of antimicrobial prophylaxis in reducing the risk of renal scarring (7,8).

 

The question remains, should we stop antimicrobial prophylaxis to VUR infants and toddlers based on the above results?

 

Caution is still warranted while interpreting the results of the above studies since they were not primarily designed to evaluate the role of antimicrobial prophylaxis in preventing scarring. Moreover, a short follow-up period of 1–2 years in the RIVUR Trial is not long enough to determine beyond any reasonable doubt the long-term risk for the development of renal scarring or the preventive effect of antimicrobial prophylaxis.

 

 

References

  1. Dillon MJ, Goonasekera CD. Reflux nephropathy. J Am Soc Nephrol 1998; 9:2377.
  2. Shah KJ, Robins DG, White RH. Renal scarring and vesicoureteric reflux. Arch Dis Child 1978; 53:210.
  3. Smellie JM, Normand IC, Katz G. Children with urinary infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int 1981; 20:717.
  4. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846.
  5. Willi U, Treves S. Radionuclide voiding cystography. Urol Radiol 1983; 5:161.
  6. Mattoo TK, Chesney RW, Greenfield SP, Hoberman A, Keren R, Mathews R, Gravens-Mueller L, Ivanova A, Carpenter MA, Moxey-Mims M, Majd M, Ziessman HA; RIVUR Trial Investigators. Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial. Clin J Am Soc Nephrol. 2015 Nov 10. pii: CJN.05210515. [Epub ahead of print]
  7. Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, Hodson EM, Carapetis JR, Cranswick NE, Smith G, Irwig LM, Caldwell PH, Hamilton S, Roy LP; Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) Investigators: Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 361: 1748–1759, 2009
  8. Brandstro¨m P, Neve´us T, Sixt R, Stokland E, Jodal U, Hansson S: The Swedish reflux trial in children: IV. Renal damage.JUrol 184:292–297, 2010
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

 

Vesicoureteral reflux (VUR) is the most common urologic finding in children, occurring in approximately 1 percent of newborns, and as many as 30 to 45 percent of young children with a urinary tract infection given the retrograde passage of urine from the bladder into the upper urinary tract. [1-3]

 Basically, management is mainly focused on prevention of pyelonephritis, a morbid event in itself that requires acute medical care and possible hospitalization in young infants, let alone the possible subsequent loss of renal parenchyma as a result of renal scarring resulting in a cascade of chronic kidney disease events (hypertension, proteinuria, renal insufficiency with possible ESRD). [4,5]

Even though nephrologists had been clear on the existence of VUR and its link to renal scarring and CKD, yet they had been hazy on its management in terms of clinical impact of prophylaxis and adequate medical/surgical therapeutic interventions. The ideal management of children with VUR remains a source of debate with little evidence to support many of the current management practices for children with VUR who have had 1 or 2 febrile urinary tract infections. In fact, the long-standing notion that VUR may lead to progressive CKD and potentially ESRD has been increasingly questioned and remains controversial.

Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) is a multicenter, randomized, double-blind, placebo-controlled study to determine whether daily antimicrobial prophylaxis, in the setting of prompt evaluation and treatment of UTI, is superior to placebo in preventing recurrence UTI and/or the occurrence of, or worsening, of renal scarring in children with vesicoureteral reflux (VUR).

 In their recent publication in CJASN Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial” 607 children aged 2–71 months with grade 1–4 VUR diagnosed after a first or second febrile or symptomatic UTI were enrolled in this multicenter, randomized, placebo-controlled trial . Study participants received trimethoprim-sulfamethoxazole or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up99mtechnetium dimercaptosuccinic acid (DMSA) renal scans. 

Authors reported that new renal scarring did not differ between the prophylaxis and placebo groups (6% versus 7%, respectively). Unsurprisingly, preexisting and new renal scars occurred significantly more in “renal units” with grade 4 VUR as compared to those with low-grade or no VUR. Children with renal scarring were significantly older (median age, 26 versus 11 months; P=0.01), had a second UTI before enrollment (odds ratio [OR], 2.85; 95% confidence interval [95% CI], 1.38 to 5.92), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). [6]

 Perhaps the most clinically relevant finding of this work that could potentially impact clinical practice is that antimicrobial prophylaxis did not decrease the risk of renal scarring whether in terms of the proportion of children (6% and 7%) or renal units (4% versus 4%) echoing the results of recent studies that evaluated the role of antimicrobial prophylaxis in reducing the risk of renal scarring (7,8).

The question remains, should we stop antimicrobial prophylaxis to VUR infants and toddlers based on the above results?

Caution is still warranted while interpreting the results of the above studies since they were not primarily designed to evaluate the role of antimicrobial prophylaxis in preventing scarring. Moreover, a short follow-up period of 1–2 years in the RIVUR Trial is not long enough to determine beyond any reasonable doubt the long-term risk for the development of renal scarring or the preventive effect of antimicrobial prophylaxis.

 

References

  1. Dillon MJ, Goonasekera CD. Reflux nephropathy. J Am Soc Nephrol 1998; 9:2377.
  2. Shah KJ, Robins DG, White RH. Renal scarring and vesicoureteric reflux. Arch Dis Child 1978; 53:210.
  3. Smellie JM, Normand IC, Katz G. Children with urinary infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int 1981; 20:717.
  4. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846.
  5. Willi U, Treves S. Radionuclide voiding cystography. Urol Radiol 1983; 5:161.
  6. Mattoo TK, Chesney RW, Greenfield SP, Hoberman A, Keren R, Mathews R, Gravens-Mueller L, Ivanova A, Carpenter MA, Moxey-Mims M, Majd M, Ziessman HA; RIVUR Trial Investigators. Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial. Clin J Am Soc Nephrol. 2015 Nov 10. pii: CJN.05210515. [Epub ahead of print]
  7. Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, Hodson EM, Carapetis JR, Cranswick NE, Smith G, Irwig LM, Caldwell PH, Hamilton S, Roy LP; Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) Investigators: Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 361: 1748–1759, 2009
  8. Brandstro¨m P, Neve´us T, Sixt R, Stokland E, Jodal U, Hansson S: The Swedish reflux trial in children: IV. Renal damage.JUrol 184:292–297, 2010
  1. Dillon MJ, Goonasekera CD. Reflux nephropathy. J Am Soc Nephrol 1998; 9:2377.
  2. Shah KJ, Robins DG, White RH. Renal scarring and vesicoureteric reflux. Arch Dis Child 1978; 53:210.
  3. Smellie JM, Normand IC, Katz G. Children with urinary infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int 1981; 20:717.
  4. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846.

Willi U, Treves S. Radionuclide voiding cystography. Urol Radiol 1983; 5:161.

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