Archive for the 'Journal Club' category

Urine Science as Promised: Microalbuminuria in Toddlers

Jan 08 2016 Published by under Journal Club, Kidney Function

So-called microalbuminuria first gained attention as a predictor or marker of diabetic kidney disease. We now know that it is not as good as we thought for that condition, but it is associated with renal and cardiovascular disease risk in adults. Is shedding extra albumin in the urine a risk marker or, perhaps, does it contribute to the development of these conditions? After all, these are major causes of morbidity and mortality.

Could it be that microalbuminuria precedes any of the other stuff? Are we born this way?

The first question to answer is the prevalence of microalbuminuria in children. A group in The Netherlands organized a cohort study over the first two years of life in its general population, the Groningen Expert Center for Kids with Obesity (GECKO). All children born in Drenthe, a northern Dutch province, were eligible for enrollment From April 2006 through April 2007. The primary goal of this study was to identify factors associated with overweight. Data included pregnancy complications, birth weight, placenta weight, and longitudinal anthropomorphic measurements through 5 years of age. Lifestyle and environment factors were assessed by questionnaires beginning in the last trimester of pregnancy. Over the 2-year enrollment period 4778 eligible births were recorded. For this study, a urinary albumin measurement had to be performed; 1352 children did this and were included in their analysis. Children with urine studies did not differ from the overall population for any variable studied.

Their method of urine collection sparks some controversy. Two-year-olds usually do not pee in a cup on command. Sticking a plastic baggy on the perineum requires some skill so that it hangs on long enough for the collection but does not get contaminated by stool. The investigators gave the parents a cotton wool pad to place in the diaper and mail back into the center within 24 hrs. They compared this method to voided urines and found acceptable performance for their method with bias -14 mg/dL albumin, precision 31.3 mg/L, and accuracy 48.1%. Contact with cotton is known to decrease albumin levels within 15 minutes by an average of 40% with high variability.  A nice review of issues with pediatric urine collection can be found at another link.

The standard clinical measurement of microalbuminuria is the albumin:creatinine ratio to correct for the amount of hydration. The median ratio in this study was 14.0 mg/g creatinine. The 75th percentile was 25.6 and the 95th percentile 89.3 mg/g, respectively. Based on the current criteria for microalbuminuria (ratio > 30 mg/g), 23.4% of their kids had microalbuminuria. However, this normal range comes from adult data. Toddlers often have lower creatinine levels because of their lower muscle mass. More study will be needed to determine a level of risk in this population.

F3.medium

Fig 3. doi: 10.1093/ndt/gfv407

The authors had data from another regional adult study (PREVEND) for comparisons, although it used concentration of albumin rather than the ratio. Using albumin concentrations, 6.9% of toddlers met criteria for microalbuminuria, similar to levels seen in healthy adults overall (Fig 3, right). This is especially true for young adults (Fig 4, below).

Fig 4. doi:  10.1093/ndt/gfv407

Fig 4. doi: 10.1093/ndt/gfv407

Effects of prenatal and early life factors to promote disease later in life have been proposed for years, most famously by Barker in the relationship between low birth weight and later cardiovascular risk.  No association could be demonstrated with birthweight, gestation age, impaired placental growth, gestational hypertension, or smoking during pregnancy, providing no support for the Barker hypothesis.

Other issues include the use of a single specimen for determination of albuminuria. A variety of factors can cause transient urinary abnormalities. Repeated elevations over weeks to months are required for clinical use at this time.

While not definitive, this study provides valuable information on microalbuminuria in toddlers. Might we be born with differences in endothelial function, or in other kidney structures, that make our kidneys leaky and predispose us to later cardiovascular disease? Only time, and further study, will tell.

One response so far

Is the Answer at the RIVUR? #NephJC

Jul 16 2014 Published by under Evidence Based Medicine, Journal Club

This study will be discussed as part of the online, twitter-based Nephrology Journal Club on July 22,2014. More information about the workings of #NephJC can be found here.

The Problem of Reflux

Vesicoureteroreflux (VUR) occurs in approximately 10% of children overall, but about one-third of those with a febrile or otherwise symptomatic urinary tract infection (UTI). VUR is associated with an increased risk of renal "scars." Since it was first described in the 1960's, treatment of this backflow of urine from the bladder to the ureter has been recommended for all affected children. Surgery can create a competent valve at the vesicoureteral junction during voiding, but an early randomized trial showed that prophylactic antibiotics to prevent infection were just as effective as surgery in the scarring outcome.

Despite the recommendations for treatment for 50 years, permanent kidney failure attributed to VUR has not declined in the end-stage database of any country. Improved prenatal diagnosis of infant renal anomalies have allowed us to diagnose VUR in the first weeks of life, prior to any UTIs. Some children without UTIs still get renal scarring, leading some to suspect that "scars" may actually be areas of hypoplasia or other abnormal development due to an abnormal ureteric bud.

The original study showed equivalent results from surgery and antibiotic prophylaxis, but it included no untreated control group to assess the strategy of intermittent treatment of  UTIs when they occurred. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial set out to determine if long-term prophylaxis prevented recurrence of UTIs, occurrence of "scars," or contributed to antimicrobial resistance.

The Study

The study was a randomized, double-blind, placebo-controlled trial of prophylaxis with trimethoprim-sulfamethoxazole (TMPS). Children were screened and enrolled after 1 or 2 febrile or otherwise symptomatic UTIs, including positive culture. Bagged urine samples were not allowed. Children in the study ranged in age from 2 months to 6 years and had grades I to IV VUR (severe grade V patients were excluded). Exclusion criteria included other urinary abnormalties, chronic kidney disease, inability to take TMPS, and other selected medical issues.

Studies included dimercaptosuccinic acid (DMSA) scans at baseline and 1 and 2 years later. These scans (the gold standard for kidney scars) were read and scored centrally by two pediatric nuclear medicine radiologists.

Treatment failure was defined as:

  • 2 febrile UTIs
  • 1 febrile and 3 symptomatic UTIs
  • 4 symptomatic UTIs
  • New or worsening "scars" at 1 year

The Results

Baseline characteristics of the children enrolled can be seen here. No significant differences on any parameter existed between the treatment and control groups. Time to first febrile or symptomatic UTI after trial enrollment is shown below:

Figure2

As shown in the paper’s figure 2 above, the two groups separated significantly within the first 6 months of treatment, with TMPS prophylaxis clearly preventing UTIs. By the end of 2 years, approximately one quarter of the placebo group had experienced an infection, while only half that many in the prophylaxis group had fallen ill.

A number of potential modifying factors were assessed for impact on the results, shown in the figure below:

Figure 3

As shown prophylaxis was more valuable for children who presented with febrile, as opposed to symptomatic but afebrile, UTI. Bowel and bladder dysfunction, determined via a standardized survey, also favored the use of TMPS.

Renal “scars” showed no difference throughout the study. Rectal swabs showed no significant difference in the rate of resistance of E. coli to TMPS between the prophylaxis and control groups.

Remaining Questions

Clearly antibiotic prophylaxis reduces the risk of recurrence of UTIs in children with VUR. However, about 75% of children receiving placebo had not suffered a recurrence after 2 years of study. UTIs cause discomfort, school absence, and lost work for parents; even after this trial we have no evidence of long-term damage prevention through the use of TMPS. Antibiotic resistance does not seem to be a big problem in this patient population.

So the question remains: what should we do about VUR?

In my mind, the question is still open. Many families today have qualms about long-term exposure to these medications. Other families dread missing a UTI and would far prefer to take the antibiotic. The tolerance of the family for illness vs the small risks of prophylaxis often prove to be a big factor driving therapy.

That leaves us each a lot of flexibility in our approach to VUR. My personal preference is to watch most cases without prophylaxis initially. Those who have further UTIs in the first few months after diagnosis are encouraged to start prophylaxis and consider surgical treatment. Those without significant recurrences receive follow-up on a regular basis. All of this requires ongoing discussion with the parents and input regarding their tolerance for urinary symptoms.

The pediatric nephrology community hoped that RIVUR would answer our managment questions about VUR. It would appear that we still have more we need to know.

No responses yet

Shameless Bragging: A Student's Paper

Aug 19 2013 Published by under Journal Club

Last week my former grad student started her post-doc in another time zone. In her honor, I am blogging her first first-author paper which recently came out in PLoS ONE. It's my first open access paper as well!

Irsik DL, Carmines PK, Lane PH (2013) Classical Estrogen Receptors and ERα Splice Variants in the Mouse. 

doi: 10.1371/journal.pone.0070926

When I started exploring the role of puberty and hormones in the kidney disease of diabetes mellitus (DM), two schools of thought drove the relationship between traditional sex steroids and the kidney:

  1. Estrogen good
  2. Testosterone bad

From epidemiological studies, we know that men fare less well than women with many kidney disorders, at least until after menopause. Over time, we have discovered that the world is far more complicated than what we thought. The hormone balance specific for each sex may determine the risk or rate of progression of DM kidney disease. But I am getting ahead of myself.

My hypothesis fell into the "bad testosterone camp." I came upon an opportunity to acquire estrogen receptor alpha knock-out mice, and I conceived an experiment. I  would make them diabetic for 2 weeks. Over that time, if estrogen were protective, the knockout mice should get really bad glomerular enlargement, an early marker of DM glomerulopathy. If they did not, then we could feel comfortable rejecting the "estrogen good" hypothesis.

Click to enlarge

This study appeared in 2004 (freely available here) with the surprising finding that the mice lacking estrogen receptors (ER) seemed to be protected from glomerular enlargement. Lack of the full-length ER alpha had no discernible effect in the boys, but the girls had no change in glomerular size with DM, even though their wild-type sisters did (See figure).

WTF?

This observation led to a lot of reading about estrogen. Two major families of ERs had been identified at that time, designated alpha and beta. Our mouse lacking ER alpha was known to lack hypothalamic feedback, leading to high levels of gonadotropins and circulating estrogen. The existence of ER beta in the kidney was unconfirmed, with many doubting its expression in post-natal life. Undaunted by this supposition, we hypothesized that elevated circulating estrogen, through interactions with ER beta, could lead to the protective effects we demonstrated.

Funding agencies generally agreed that our findings and thoughts were interesting. Not interesting enough to send money, but interesting.

I had almost given up ever finding the answer when Debra Irsik came into my lab, eager to study sex differences in the kidney. We settled on this project, and then I went to a conference given by Zhao-Yi Wang of Creighton University Medical Center. He studied the role of ER alpha splice variants in cell signaling in breast cancer. Splice variants? That do stuff? Did our knock-out have those?

Turns out, they sure could. The initial ER alpha null mouse, created by Lubahn and Korach, did not eliminate these splice variants, further complicating out potential explanations for the initial observation.

We decided our first step would be to find out what ER variants were expressed in normal wild-type mice. After all, Wang's experiments were in breast cancer cell lines; we might not find these in normal cells. Our first paper represents a survey of normal male and female mice for these receptors, with special attention to the kidney.

The full length ER alpha 66  was mainly present in female reproductive tissues but was also found in non-reproductive tissues at lower levels. ER alpha 46 was most highly expressed in the heart of both sexes. ER alpha 36 was highly expressed in the kidneys and liver of female mice but not in the kidneys of males. ER beta was most abundant in non-reproductive tissues and in the ovaries.

Because ER alpha 36 has a unique C-terminus, Wang was able to create an antibody specific for this variant. No antibody for the ER alpha 46 variant can be made. We were able to use an N-terminus antibody to localize ER alpha 66 by immunofluorescent confocal microscopy.

ER alpha 36 localization; Click to enlarge

In female mice, ER alpha 66 showed up in blood vessels, glomeruli, proximal tubular brush border, and the cortical collecting duct. ER alpha 36 localized to the mesangial cells, tubular epithelia, and podocytes (see the pretty immunofluorescent pictures in the figure). ER beta also localized in mesangial cells and podocytes. The boys showed little staining for ER alpha 66; the guys did stain for ER alpha 36 in measangial cells and tubular epithelia. Male mesangial cells also demonstrated ER beta staining.

So what is the bottom line here? First, estrogen receptors are much more complicated that initially thought, with at least two known functional splice variants for the alpha receptor. Makes you wonder how many more of those "junk bands" on western blots may be doing something in vivo! Also, estrogen is far more than a "sex hormone." Sure, its receptors are expressed at far higher levels in female reproductive tissues, but they are still hanging out in other organs, just waiting for that hormone to come around. And those are only the receptors we have identified so far!

Now we have a much more complicated story to tease out; can we possibly isolate the role of splice variants in an in vivo model? Stay tuned for Deb's next paper!

No responses yet

Journal Club Today: eGFR

Jul 10 2012 Published by under Journal Club

Glomerular filtration rate (GFR) measures the ability of the kidneys to clear wastes. Glomeruli are tiny clusters of blood vessels in the kidney. As the blood flows through them, the water and chemicals in it get squeezed out into the tubules of the kidney, leaving behind cells, proteins, and a tiny amount of water. As this filtered liquid goes through the tubules, most of it (95-98%) gets taken up by tubular cells and returned to the body. Under normal conditions, an adult produces 144 liters of filtrate each day, but puts out less than 2 liters of urine.

To measure GFR we need a substance that is freely filtered in the glomeruli and not altered by the tubules of the kidney. Inulin and other manufactured substances can measure GFR most accurately, but these methods require continuous intravenous drips. They are inconvenient and expensive. Doctors and scientists looked for a chemical within the body that met these criteria. They identified creatinine, a muscle protein now included on most routine biochemical panels.

Measuring clearance of creatinine requires a measurement of the blood level, a timed urine collection, and measurement of the creatinine in the urine. Collecting urine over a given period of time can be annoying. Thus began the search for a way to estimate GFR from just a blood test.

Click to enlarge: From J Am Soc Nephrol 23:995, 2012

Since muscles make creatinine, people with more muscle have higher levels regardless of kidney function. In pediatrics, where patients normally change size over time, these issues cause even more problems. The first pediatric formula, developed by Schwartz et al in the 1970s, used height as a proxy measure of muscle mass. Over time, this equation has been refined as our methodology to measure creatinine has improved. Several large studies of chronic kidney disease in adults led to other equations (see table).

The question remained when to switch from the pediatric formula to one of the adult equations. Selistre et al recently looked at correlation and agreement among these calculated values and measured inulin clearance (that gold standard) in adolescents and young adults from 10 to 25 years of age. Subjects had kidney function ranging from stage 1 (normal) to stage 4-5 (<20% of normal) in all age groups.

They found that the Schwartz 2009 equation provided the most accurate estimation of true GFR, across all age groups and all ranges of kidney function.  This formula tended to underestimate GFR in those with normal function, but provided good agreement in other categories. The adult equations tended to overestimate GFR by up to 30%.

As the population of patients with chronic kidney disease grows, we need convenient ways to track kidney function over time. This study fills a gap, telling us the best way to do this in adolescents and young adults.

At least for now.

4 responses so far

Shhh! I Hear a Paradigm Shifting!

The February issue of the Journal of the American Society of Nephrology includes a science in renal medicine article that caught my eye:

It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis. Luke and Galla. J Am Soc Nephrol 23:204-207, 2012. doi:   10.1681/ASN.2011070720

If I ever teach metabolic alkalosis again, I have to revise my lecture!

Ever since loop diuretics became available in the 1960s, they have been a recognized cause of metabolic alkalosis. These drugs cause the kidney to excrete excess volume (Na + Cl + water), which is very useful if you have swelling from heart failure or liver disease or kidney problems. If the volume loss goes too far, the patient could develop alkalosis (too little acid/too much base in the blood). The major base in the blood is bicarbonate (HCO3-). Our "old-school" explanation of the pathophysiology follows. Volume depletion turns on aldosterone which controls a number of transporters in the distal nephron. The net effect of these transporters is retention of Na+ with concurrent excretion of K+ or H+. The latter would help perpetuate the alkalosis, because excreted H+ (acid) does not consume any of the blood's buffering bicarbonate. Restoring the patient's volume turns off aldosterone and allows the alkalosis to resolve.

How simple! How elegant! How wrong!!!!!

A number of human and animal studies are reviewed in the article. The alkalosis formerly known as contraction can be induced with diuretics plus dietary maneuvers. If volume is expanded without chloride, using albumin or other solutes, the alkalosis remains. If chloride is replenished without volume repletion, the alkalosis resolves (even though the subject remains volume depleted).  Thus, this form of alkalosis is better described as chloride dependent (CDA).

Click for original source

The figure from the paper summarizes the new explanation. First note that unlike most tubular cartoons, the peritubular capillary is central in this one. Either side of the cells is a urinary space. The cortical collecting duct contains 3 cell types. Principal cells (middle of cellular column) reabsorb Na+ and excrete K+ to maintain electroneutrality in the luminal fluid. A-type intercalated cells (Acid secreting; top of cellular column) can transport H+ into the lumen. This activity during alkalosis with volume contraction may be driven against the H+ concentration gradient because of Na+ absorption by the principal cell, as in the old-school explanation above. Of more importance to the alkalosis, B-type intercalated cells (bicarbonate secreting; bottom of cellular column) express pendrin (Pn) on their luminal membranes. This protein transports bicarbonate into the luminal fluid while reabsorbing Cl-.

In states of chloride depletion (left side of cartoon), Cl- is not available to exchange with bicarbonate, so the latter cannot be excreted. After Cl- repletion (right side) this exchange can occur. Bicarbonate can be excreted to correct the alkalosis, without any alteration in the functions of the aldosterone-dependent transporters in the other cells.

Medical students have always been frustrated that we classify volume status by urine Na during "pure" volume depletion, but with urine Cl during metabolic alkalosis. Various explanations have been offered along the way, the most reasonable being that in periods of excess bicarbonate filtration (like alkalosis) a cation has to accompany it in the urine. Thus, urine Na may be falsely elevated in this setting. Turns out, the urine chloride concentration really is the critical component.

Will any clinical changes result from this new nomenclature? For the most part, no - when patients lose chloride and become alkalotic, they generally suffer volume depletion. We treat this with Na + Cl + water, repleting volume and chloride together.  The paper summarizes a number of relatively recent studies and provides a great illustration of the shifting nature of established physiology.

There is always something new to discover.

4 responses so far

New Data; Now What?

Sep 12 2011 Published by under Journal Club

One of the most common reasons children get sent to see me is persistent microscopic hematuria. In non-doctor-talk, they have red blood cells in their urine that can only be detected by dipstick or microscope. The prevalence of children affected is not clear, but less than 1% in most studies where at least 3 urine specimens are checked.

My approach has been fairly laid-back. Most children with significant kidney disease warranting intervention have some other indicator, such as gross hematuria (visible with the naked eye), protein in the urine, high blood pressure, and/or an abnormal glomerular filtration rate (GFR, the measurement of how the kidneys clear waste products). In the absence of these findings, or other abnormalities on blood tests, the probability of finding a treatable, progressive disorder on biopsy remains very low. These children warrant follow-up every year or two so that biopsy and treatment can be reconsidered if other signs or symptoms develop.

When the following article hit the news, I knew it would impact my life:

Persistent Asymptomatic Isolated Microscopic Hematuria in Israeli Adolescents and Young Adults and Risk for End-Stage Renal Disease.

Click to embiggen

Vivante A, et al. JAMA 2011; 306:729-36

All Jewish Israeli adolescents and young adults must undergo medical board examination 1 year before conscription into military service. All screened participants from 1975 - 1997 were included in the study. The recruitment schema is shown at left. The investigators then linked these records to the Israeli end-stage renal disease registry to look at outcomes in these subjects.

One of the powers of this study is its numbers. Well over one million individuals underwent initial screening, and 1,199,936 ultimately did not have persistent microscopic hematuria or other risk factors for kidney disease (Control Group). Some screened individuals had diabetes or other conditions putting them at risk of kidney failure (34,243), while 3,690 (0.3%) met the criteria for isolated microscopic hematuria after multiple urinalyses with microscopic examination, kidney and bladder imaging studies, and measurement of serum creatinine level. All of these subjects visited a nephrologist who confirmed the diagnosis.

People with hematuria were twice as likely to be male as female. No differences in country of origin, blood pressure, or body size were identified at military screening.

Click to embiggen

After a median follow-up of 20 years, end-stage kidney failure developed in 539 people without hematuria (0.045%) and in 26 patients with hematuria (0.7%), an approximately 20-fold elevation in risk.  The cause of kidney failure in hematuria patients was mostly glomerular disorders including IgA nephropathy (see table at right). Hematuria patients had lower body mass index, younger age at start of kidney failure therapy, and shorter time to kidney failure than those who developed kidney failure without preceding hematuria. Multivariate analysis revealed no mediating factors that changed these relationships.

The risk of end-stage kidney failure was 2.05 per 100,000 person-years in the Control Group and 34.0 in the hematuria group. While this represents a substantial increase in relative risk, the absolute risk remains low when compared with other chronic diseases. These hematuria patients produced 4.3% of treated end-stage kidney failure during the study period.

There are some problems with this study. First, the study population is limited, and results may not generalize to other patient groups. Second, historical evaluation techniques may not produce the same diagnoses as those of today. Intravenous pyelography was the standard for imaging in the first part of the study; ultrasound replaced it over time. Proteinuria screening has also changed; today, the more sensitive measurement of microalbuminuria might skew some patients out of the isolated hematuria group. Also, the only assessment of kidney function available was a nephrologist's statement that the serum creatinine was "normal." Calculated GFR might also have altered some of these results.

The real question is how should these data alter current medical practice? For now, I do not believe they should. The patients I see have documented persistent microscopic hematuria. We screen for a variety of systemic and glomerular disorders up front. We use state-of-the-art imaging for anatomic abnormalities, and we measure microalbuminuria to look for very low levels of proteinuria. These children then get followed-up annually, either with a primary care physician or in our office. If any other signs or symptoms of kidney disease develop, we perform a biopsy. Still, we fail to make a diagnosis or find a treatable illness in many cases.

The other question raised is the use of screening urinalysis. Data from Japan's childhood screening program suggest that an aggressive approach may reduce the risk of kidney failure due to glomerular diseases in that country. At this point, it remains unclear if more screening or biopsies would prevent enough end-stage kidney failure to justify the expense and risk of  the procedure, especially when the risk is low (even though the relative risk is high).

 

No responses yet

Is Volume Toxic? Part 2

Jul 06 2011 Published by under Journal Club

Over at the blogspot place in May 2010 I reviewed an article for journal club showing that children requiring continuous renal replacement therapy did worse with greater volume overload at the start of therapy. Query: Is saline toxic?

The current New England Journal of Medicine reports a trial of children in Africa who presented with a febrile illness and impaired perfusion who were randomized to first receive a bolus of saline or albumin or to proceed directly to maintenance fluid therapy. Bolus therapy is given to rapidly restore circulating volume. Children with hypotension (low blood pressure) were assigned to either bolus group, but not the maintenance fluid group. Children with gastroenteritis were excluded from the study; 57% of participants had malaria. The primary endpoint was 48 hour mortality, with secondary endpoints including pulmonary edema; increased intracranial pressure; 4 week mortality; or 4 week neurologic sequelae.

The trial stopped ~500 patients before the initial estimated enrollment on the advice of the Data and Safety Monitoring Board (DSMB). In stratum A (patients with impaired perfusion but without frank hypotension) bolus therapy of either type increased 48 hour mortality (Relative risk 1.45; 95% confidence interval, 1.13 to 1.86; p=0.003) and mortality at 4 weeks (12% vs. 8.7%; p=0.004). No other secondary endpoints showed any differences. Stratum B (patients with frank hypotension) included only 29 patients, and no difference between albumin (69% mortality) and saline (56% mortality; p=0.45) was demonstrated.

Impaired perfusion can be diagnosed by physical exam. Prolonged capillary refill time (after skin compression, blanching should resolve in 2-3 seconds; see figure) provides the most common assessment of this state, although cyanotic extremities may also be a sign. In the presence of normal blood pressure, bolus therapy appears to be contraindicated in children with these signs, although generalizing the findings from this study of children primarily affected by malaria may not be valid to children in countries such as the US where the underlying conditions may be different.

Other questions arise. First, do boluses help children with frank hypotension? Perhaps they might do better with pressors rather than volume expansion? What about children with gastrointestinal volume losses, a common cause of shock? A recent Clinical Pathological Conference from NEJM demonstrated the apparent benefits of intravenous fluid boluses in a child with cholera. Are these benefits real for children with all gastrointestinal illnesses?

Volume expansion, with saline or colloid, has been a mainstay of therapy for as long as I can remember. Restoration of circulating volume has a place; however, in other cases, additional volume could be toxic. Further studies are needed to define the risk:benefit ratio and conditions of fluid resuscitation.

Performing these studies in the US may be extremely difficult. First, getting informed consent for critically ill children can be fraught with difficulty, especially when one might get randomized to nonstandard care. Do I want to take that chance with my child's life on the line? For a condition like infant diarrhea that is far less likely to lead to death in this country than in Africa?

I am afraid that the initial exploration of these questions will have to happen in other countries with fewer resources and laxer protection of research subjects. Perhaps once we have more information we can perform a meaningful study in a "first-world" country.

2 responses so far

My Grandma's Cure-All

Feb 02 2011 Published by under Journal Club

The Magic of Windex (Click for Source)

Back in 2002 when My Big Fat Greek Wedding hit the theaters, audiences learned about Chicago's Greek community and the healing powers of Windex. My parents laughed, because their parents also had a magical remedy for everything: Vicks Vaporub.

Having a cough or cold meant a thick layer of the mystical ointment on your chest and neck, with a towel tucked around to hold in the heat, although I cannot completely rule-out an anti-sheet-staining effect. Family lore includes the night my maternal grandmother stubbed her toe, eventually found to be broken. Her husband, the pharmacist, told her to put some Vicks on it. Such healing powers!

As time went on, we grew up and moved onto other remedies for our colds (like Nyquil, another product from the Vicks' people). Proper clinical studies showed more risk than benefit from many of hese drugs in young children. What should tired, cranky parents with sick, cranky children do?

Vapor Rub, Petrolatum, and No Treatment for Children With Nocturnal Cough and Cold Symptoms.
Paul et al. Pediatrics 2010: 126

The authors did a trial comparing VapoRub, its petrolatum base, and no treatment in children seeking treatment for cough and cold symptoms. Children could not have used topical or systemic cold remedies (including honey!) the night before. A validated symptom survey was administered after obtaining informed consent; the parents completed it again the night after the test treatment.

The most creative part of the study involved participant blinding. Investigators gave parents an opaque bag containing a glass specimen cup filled with the assigned treatment, so the treating physician remained masked to study group. At bedtime, parents opened the bag and found either an empty cup or a grease-filled cup. Parents in the no treatment group obviously knew their assignment. Those who found ointment also has a small packet of VapoRub to apply under their nose before massaging the treatment onto their child. The investigators hoped this would mask the treatment from parents. Even with all of these efforts, more than 80% of parents in each of the ointment groups correctly identified the treatment assigned to their child.

So what happened? All measures of symptoms significantly improved with the VapoRub. Of course, symptom relief came with side effects including mild skin irritation. No neurologic issues arose, a particular concern with camphor-containing agents. The authors conclude that topical VapoRub may be helpful for improving cough and cold symptoms in children at least 2 years of age.

Vicks VapoRub is more than my grandparents' placebo; it is evidence-based medicine!

Click for Source

What will be next - Windex for acne?

6 responses so far

Journal Club: Rituximab Off-Label

Jan 12 2011 Published by under Journal Club

My last act before I pack for Science Online will be journal club.

Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report

Gulati et al. Clin J Am Soc Nephrol. 2010 Dec;5(12):2207-12

PMID: 20798255   PMCID: PMC299408

I chose this article because it is one of the few in which patients with nephrin (NPHS1) and podocin (NPHS2) mutations have been treated with rituximab for steroid-resistant nephrotic syndrome (NS); unfortunately, the authors don't answer the question I had in mind.

Anyway, here it goes:

NS is relatively common in the world of pediatric nephrology. Approximately 85% of affected children have minimal change disease (kidney looks normal by light microscopy) and respond to glucocorticoid treatment. Most will have a relapsing course, with respiratory infections triggering proteinuria, but the condition then resolves after a few years. (Lay summary of NS here.)

Some children with NS relapse so quickly that we consider them steroid-dependent, and the side effects of glucocorticoids become problematic. Other children do not respond at all to the medication, and they are steroid-resistant. This latter group often has focal segmental sclerosis or other nasty kidney lesions that often lead to kidney failure. Since some children respond to immunosuppressive therapy, we began trying other immunosuppressive agents. Cyclophosphamide, calcineurin inhibitors, and mycophenolate may each be effective in some children, particularly those who are steroid-dependent. Some resistant patients also respond to these agents. Some children respond to none of the above.

Rituximab: Usual course is 2 injections (Image courtesy PhotoXpress)

A few years back, in a desperate attempt to treat these children, someone tried the newest immunosuppressant-on-the-block, rituximab. This drug is a chimeric monoclonal antibody that targets the CD20 receptor on B lymphocytes. Its FDA approval is for treatment of non-Hodgkin lymphoma, but it has been used successfully in rheumatoid arthritis and vasculitis syndromes including systemic lupus erythematosus. Most reports focused on immediate response to rituximab in NS; this report looks at patients followed for at least 12 months after treatment.

Of the patients classified as steroid-resistant, approximately half had no response to rituximab. About half of the remaining patients had a reduction in proteinuria, but continued to have active NS (partial remission), while the others had a complete remission. Most of these patients maintained their complete response over 12 months after therapy. Two of these patients had heterozygous mutations (1 copy bad, 1 copy normal) in NPHS2, the gene that codes podocin; however, the authors never comment on whether these particular patients had any response to the medication!

Overall, the steroid-dependent patients did better. One year after treatment, more than 80% remained in remission, often without other medications.

None of the 57 patients in this series suffered any infectious complications of treatment. Only 3 had mild infusion-related reactions, including chills and muscle pain.

Numerous reports now support rituximab's ability to induce remission of NS, particularly in steroid-dependent children. The results lag a bit in steroid-resistant patients, but given the lack of other treatments, a course of rituximab is ultimately indicated for most of those children as well. Having recently found a heterozygous mutation of NPHS1 in one of my steroid-resistant patients, I would like to know if anyone has experience treating patients with these mutations with this agent. Unfortunately, this is the only paper I have located where patients with mutations were treated with rituximab, and the results in those two patients were not specified.

Filtration Slit (From Medscape.com)

So why would rituximab not work in a patient with a mutation?

NPHS1 (nephrin) and NPHS2 (podocin) initially came to light through studies of children with severe congenital NS that results from homozygous mutations (both copies bad) in these genes.  The proteins coded by these genes form the slit diaphragm, the barrier to protein leakage in the filtration unit of the kidney (see diagram above). Having one copy of nephrin or podocin mutated may result in milder, later-onset NS. Not all people who have one bad gene copy get NS, though, making a "2-hit model" a likely scenario. Thus, even though a structural protein may be out-of-whack, some dysregulation of the immune system may trigger the onset of NS, making immunosuppressant therapy effective.

We also do a lot of "let's see if this works" treatment in nephrology:

  • Most patients with NS respond to steroids
  • This patient did not respond
  • Try another immunosuppressant drug
  • Repeat until one works or you run out of drugs.

I hope someday we get a study that reports about rituximab in heterozygous NPHS1 and NPHS2 mutations. If it does not work in the face of these mutations in structural proteins, then relatively simple genotyping can spare our patients the side effects and expense of rituximab. If it does work, it provides further evidence to the "2-hit model" of NS, and may open up other novel research avenues and therapeutic targets.


No responses yet

Journal Club: Isolated Renal Pelvis Dilatation

Oct 09 2010 Published by under [Medicine&Pharma], Journal Club

Background

Normal Urinary Tract (Click to embiggen)

Normal urinary tract anatomy is shown in the figure. As nephrons come together in the kidney, the tubules join into a central collecting system, the pelvis. This space is continuous with the ureter, the tube that leads from the kidney to the bladder. One of the most common abnormalities on prenatal ultrasound is dilatation of these urine collecting structures. The area where the pelvis becomes the ureter (the ureteropelvic junction or UPJ) is a common site of narrowing and obstruction in children.

The natural history and treatment of urinary tract dilatation remains unclear, even as our ability to detect subtle abnormalities increases. Prospective urinary tract screening in Messina, Italy, may help answer these questions.

Outcome and management of isolated severe renal pelvis dilatation detected at postnatal screening

Mami et al. Pediatr Nephrol 25:2093, 2010

Study Design

The authors performed a prospective screening study of healthy 2-month-old infants from January 1, 2001, through December 31, 2005. Over the 5 years, 11,801 infants were screened with ultrasound (US) for hip dysplasia and renal abnormalities. 46 infants had severe renal pelvis dilatation (RPD; pelvis diameter 15-20 mm) without other abnormalities of the urinary tract and became the study group. In addition, 240 healthy infants with normal US were enrolled as a control group.

All infants in both groups had prospective follow-up US every 3-4 months for 1 year. No prophylactic antibiotics were given to prevent urinary tract infections (UTIs). If a UTI was diagnosed and/or RPD persisted after 1 year of age, voiding cystourethrogram and nuclear scans were performed to assess vesicoureteroreflux and functional obstruction, respectively.

Results

RPD on one or both sides occurred in 0.4% of screened infants with approximately twice as many males as females affected. When only one side showed RPD, the left kidney was twice as likely as the right to be affected. Over 12 months of follow-up, one-third of infants demonstrated resolution of RPD. Of the children with persistent abnormalities, 2/3 had UPJ obstruction (see figure) and the others had vesicoureteral reflux.

Renal Pelvic Dilatation (RPD) from UPJ Obstruction

Only 5 of 46 infants (14%) developed UTIs during the study, with 3 of the 5 having reflux. In contrast, the normal control group showed 2.5% of participants having UTIs in the same time period.

So What?

Our current practice following abnormal prenatal US of the urinary tract is to obtain an US 7-14 days after birth. If the tract still appears dilated, we see the baby at 1-2 months of age with voiding cystourethrogram and nuclear scan.

Obviously, we are doing a lot more imaging on a lot more infants.

This study suggests that it is safe to wait for "invasive" imaging studies until RPD has persisted for a year or the child suffers a UTI. Since at least a third of these infants will resolve their RPD, they would not have to undergo catheterization with radiation exposure for the cystogram or nuclear scan.

The authors also discuss the relevant literature; the incidence of RPD and UTI was similar to previously published work. They also touch briefly on some of the controversies surrounding UTI prophylaxis. Current practice favors such treatment in infants with reflux, and many babies with RPD would receive such treatment until imaging studies were completed. The present study suggests a less aggressive approach is safe.

The study is a well-done prospective single-center endeavor. Based on these results, plus others discussed in the paper, we can safely reduce the studies and antibiotics we use in children with RPD.

One response so far