Forgive me, for I have neglected this blog.
Between my own upcoming move, getting my son out of high school, and trying to sell a house, things got a little crazy! And yes, I have been blogging at my other sites instead of this one.
I. Am. So. Sorry.
I will have a piece on kidney disease over here soon; in the meantime, try to enjoy some posts from my other projects:
The American Society of Nephrology (ASN) provides a lot of value for my membership buck.
ASN leads the fight against kidney disease by educating health professionals, sharing new knowledge, advancing research, and advocating the highest quality care for patients.
This week they sent around videos discussing the efforts at Johns Hopkins to transform the Welch Medical Library into a virtual facility. The co-evolution of print and electronic media is a hot topic in every field, not just medicine or nephrology. When I was asked if I would like to share the videos here, I jumped at the chance.
So get your popcorn and enjoy some thoughts about the curation of medical information.
Video 1: The Collection
Video 2: The Evolution of Library Services
Last week I performed a kidney biopsy on a child whose history read like the textbook description of a certain kidney disease. The parents, worried about the procedure, asked why we needed the biopsy if the history were so clear. First, with any kidney disease you often need to know how advanced it appears in the tissue to guide therapy. Some are mild enough we do not give medications, while others are so advanced that there is little point in treating. Second, any kidney disease can cause almost any clinical presentation, and we may find something completely different in the tissue.
The latter happened. We found a “primary” kidney disease called membranous nephropathy.
My brief summary here draws heavily on a recent review by Menon and Valentini in Pediatric Nephrology 25:1419-428, 2010. DOI 10.1007/s00467-009-1324-5
Primary Kidney Disease
Nephrologists refer to primary kidney diseases when no systemic disorder is producing problems in the kidney. We can see membranous nephropathy on a biopsy in patients with systemic lupus erythematosus, infections such as hepatitis and malaria, cancers, and diabetes. If the patient has no evidence of such a disease, then we call it a primary kidney disease.
Most primary kidney diseases do not start and end in the kidney. Many involve the immune system inappropriately reacting with the kidney in some way, and many disorders get better with treatments that alter the immune system.
Bottom line: we really do not understand why most “primary” kidney diseases occur. The term just means we have excluded all of the known secondary causes in that particular patient.
Why do we call this particular pattern of kidney damage “membranous?” To understand that, you have to know a bit about the filtering units of the kidney, the glomerui (see figure 1). This unit contains clusters of tiny blood vessels called capillaries that surround a supportive area called the mesangium (dark pink areas). Blood flows through the capillary loops and stuff is filtered out into the space around the glomerulus. This filtered fluid must pass through the basement membrane of the loop. The basement membrane includes cells from the blood vessel (endothelial cells), proteins made by the cells, and extensions of the visceral epithelial cells (also called podocytes).
In membranous nephropathy, on light microscopy (done with a regular microscope like you find in a high school science lab) the basement membranes of the glomeruli look thick, so the filtering unit appears “membranous.” A closer look with a special stain shows the cause of this appearance (Figure 2). Silver stain makes the proteins in the basement membrane appear black. The glomerulus in figure 2 shows a fuzzy or spikey appearance to this basement membrane material.With electron microscopy, the reason for these spikes becomes clear (Figure 3). The arrows point to a number of lumps underneath the epithelial (podocyte) cells with basement membrane between them. Those black spikes on the silver stain are the proteins of the basement membrane working their way between these deposits.
What causes these deposits? We really do not know. A variety of immune components compose them, and we suspect that the injury targets the podocyte.
Membranous nephropathy presents with protein in the urine. This proteinuria may not cause any symptoms, or it may be heavy enough to result in nephrotic syndrome. In adults, membranous nephropathy is a common cause of nephrotic syndrome. It accounts for <5% of cases in children overall; from 1-12 years of age, the incidence appears to be 1% of cases, increasing to 22% between ages 13-19. Secondary causes can be identified in 20% of adults and perhaps as many as 35% of children.
Between 40-75% of children with membranous nephropathy present with full-blown nephrotic syndrome. Another 16-38% have proteinuria in the nephrotic range, but no swelling or other symptoms. Most of the others have lower levels of asymptomatic proteinuria. Microscopic hematuria (blood in the urine) is present in most of these children, and gross hematuria, visible with the naked eye, can occur in as manyas 40% of affected children.
Because so few children have this kidney disorder, most of what we know about it comes from adult patients. Approximately 1/3 of patients show spontaneous resolution of their proteinuria, another third have persistent proteinuria but no loss of renal function, and the others progress to permanent kidney failure. In general, younger age predicts a better course, so children probably do better than adults overall. Membranous nephropathy only accounts for 0.5% of children on dialysis in the US. Some findings on biopsy may predict worse outcomes, including glomerular scarring (sclerosis) and tubulointerstitial damage (inflammation and scarring in the non-glomerular parts of the kidney).
Once again, so few children have membranous nephropathy that our treatment guidelines are extrapolated from data in adults. Children with asymptomatic low-grade proteinuria (spot urine protein:creatinine ratio <2) may be managed with observation and anti-angiotensin II medications (ACEi or ARB) to reduce proteinuria. These patients are expected to have a very high rate of spontaneous remission with little risk of progressive loss of kidney function. Children with nephrotic syndrome and a spot urine protein:creatinine ratio >2 would be first treated with prednisone. Those failing to respond to this medication alone would have cyclophosphamide added for 12 weeks. The combination of prednisone and cyclophosphamide has proved most effective in the adult studies.
If the patient continues to spill protein after 12 weeks of combination therapy, the next step would be a calcineurin inhibitor such as cyclosporine or tacrolimus. Other drugs may be effective in patients, but less data support their use.
If you watch television, you have heard about GER or gastroesophageal reflux, what most folks call heartburn. In pediatric nephrology, we chat about vesicoureteral reflux (VUR), a condition recognized for 50 years but poorly understood.
What is VUR?
Like GER, VUR involves fluid backing up in the wrong direction. When we pee, the bladder squeezes urine out. Generally the contraction of the bladder wall should close off the ureters so that the only escape route for the urine is the urethra and the outside world. With VUR, the ureters remain open and urine can back up into the ureters.
VUR has 5 grades based on findings from voinding cystourethrograms (see figure). For this study, the bladder is filled with dye via a catheter and x-rays taken to determine where the dye goes. If normal, it stays in the bladder and exits with voiding. If it backs up into the ureter but does not reach the kidney, the diagnosis is grade I VUR. With grade II, the urinary tract looks normal but dye reaches into the pelvis, the upper part of the ureter that is inside the kidney. With grade III and higher, the components of the urinary collecting system show varying amounts of enlargment.
With VUR, a couple of bad things can happen. First, urine that refluxes into the ureters immediately flows back into the bladder where it can sit and grow bacteria. Second, with grade II or higher, any bladder infection that occurs is more likely to ascend to the kidney and cause potential damage, including scars. End-stage kidney failure may be associated with VUR, but treatment does not appear to ameliorate the risk of progressive kidney damage.
Treatment of VUR
Since the 1960s, opinion-based recommendations and suboptimal studies supported the use of prophylactic antibiotics in VUR. Initial studies showed that scars in the kidney could be prevented as well by prophylaxis as by surgical repair of the reflux. Professional societies echoed this endorsement, but only recently have appropriate, randomized, prospective studies been performed. These five studies form the basis of an editorial commentary and meta-analysis in the December issue of Pediatric Nephrology:
Evidence for and against urinary prophylaxis in vesicoureteral reflux Mattoo TK. Pediatr Nephrol (2010) 25:2379-2382 DOI 10.1007/s00467-010-1632-9
Five studies made the grade for analysis, only one of which included a placebo-control arm; in the others, patients randomized to no treatment knew they were not getting antibiotics. In all of the studies, patients had a history of urinary tract infection, so we will look at the efficacy of antibiotics for preventing future UTI’s:
On their own, each of these studies showed minimal, if any, benefits for antibiotics, and the meta-analysis relative risk of 0.82 (95% confidence interval: 0.62-1.08; p=0.16) confirms this overall impression. One study from Australia found that boys with grade III reflux significantly benefited from low-dose trimethoprim-sulfa, the highest grade of reflux in the study.
So What Should We Do?
The treatment of VUR remains in flux. High-grade reflux (III or higher) associated with documented infection probably warrants prophylaxis at this time. Most pediatric nephrologists I know have not used suppressive antibiotics with grade I reflex for many years. Grade II VUR associated with infection can probably be safely managed without prophylaxis. If more infections occur, a trial of antibiotics could be in order.
Of course, none of this addresses every patient with VUR. Many children get imaged for reflux because of genetic syndromes, congenital renal anomalies, or siblings with the condition, but the kid in question has never had a urinary tract infection. Is prophylaxis of benefit in these conditions? We don’t know, and the available studies do not address these issues. Clearly, more work lies ahead if we truly want to know what we should do, not merely what we think we should do.
Congenital abnormalities of the kidney and urinary tract produce more kidney failure in children than any other disorder. A new tool in our understanding of kidney development, the zebrafish, is not a perfect model of human kidney formation, yet two recent studies show that it may help us learn a lot more about growing kidneys.
A detailed post with scientific detail (and cool pictures and videos) is up over at WhizBANG! Click on over and learn more about our friend, the zebrafish.
No post here today; I have been busy producing a Guest Post for Scientific American!
Once you know how the kidneys produce urine, it makes sense!
So click on over and enjoy.
Yesterday I posted over at WhizBANG! about Little Kitties for Big Cats, a National Geographic fundraising project. For a small donation, you can upload a picture of your feline friend and the money goes to Big Cat research and conservation. Of course, I took the opportunity to put a photo of my favorite patient online.
You can read the whole story on the other post about Denver’s life with chronic kidney disease. I won’t repeat it here.
But I will beg you to click over to The D’s image at National Geographic and “like” him on Facebook. Or send out a tweet.
I want everyone to know Denver’s story.
Nephrotic syndrome (NS) fulfills the criteria for an oxymoron. As a pediatric nephrologist, I consider it a routine, common disorder. The general public sees it as rare, given that only 4-8 children per 100,000 develop this problem.
NS can be thought of as a disorder of leaky kidneys. Normal glomerular capillaries filter out the watery portion of the blood, leaving the protein and cells behind in the capillary. If something happens to the “slits” through which this filtration occurs, protein (and sometimes cells) can enter the filtrate and end up in the urine.
The most obvious consequence of loss of protein is swelling. Protein in the blood helps keep water in the blood vessels. Blood protein levels fall when the kidney leaks this way, and water can seep out of the blood vessels. The face, especially the area around the eyes, may swell. Fluid in the belly, called ascites, may flatten the belly-button. Boys often have swollen genitals. After being upright for a few hours, the swelling (or edema in doctor talk) may drain from the face, into the legs.
Proteins lost in the urine may produce other complications. Proteins involved in immunity are lost, increasing the child’s risk of infections. The proteins that prevent blood clotting also get wasted, increasing the risk of dangerous clots. In response to these losses, cholesterol and other fats in the blood can increase.
In most children, NS is idiopathic, meaning we do not know its cause. NS can be secondary to a number of diseases, including some cancers, infections, and vasculitis disorders (such as lupus). If NS begins before the child’s first birthday, we often find a genetic disorder in one of the proteins that makes up the filtration slits in the kidneys. Some of these mutations, in less full-blown forms, may contribute to NS later in life as well.
NS requires significant proteinuria and low blood protein levels. Doctors will perform a medical history and physical examination to look for possible secondary causes of NS and to assess the amount of swelling. Some nephrologists will examine the kidneys with ultrasound. All should get some basic laboratory studies: a complete blood count; a metabolic profile including creatinine, protein, and albumin; and levels of complements (immune system proteins which may be reduced in some complex kidney problems).
If the blood creatinine level is normal and complement levels are not low, most children will receive a course of steroids. These drugs do not make children muscle-bound; these are glucocorticoids that suppress the immune system. The initial course consists of daily medication for 4 to 6 weeks. Most children respond to this treatment within the first 2 weeks. They will then receive another few weeks of steroids every other day with a gradually tapering dose. These steroid-sensitive children may suffer more episodes of NS, often triggered by colds or other infections. Most sensitive patients eventually “outgrow” the disorder, usuallly in 2 to 5 years.
Some children respond to the initial course of steroids, but relapse shortly after the drugs are discontinued. These patients may be steroid-dependent or frequent relapsers. For these children, the long-term side effects of the steroids can be problematic, so other drugs are often used to induce longer remissions. These drugs include the chemotherapy agent cyclophosphamide, anti-rejection drugs cyclosporine, tacrolimus, and mycophenolate, and the antibody rituximab.
Some children do not respond to the steroids; they are steroid-resistant. Most nephrologists will perform a kidney biopsy on children with steroid-dependent or -resistant nephrotic syndrome. Genetic testing may also be performed to look for mutations in the filtration slit proteins. Steroid-resistant children are much more likely to have focal sclerosis or other lesions of NS that tend to progress to kidney failure over time.
Most children with NS respond to steroids and do not develop kidney failure. Even though the long-term prognosis is excellent, this disorder can be a frustrating series of relapses for several years. If you want to learn more about NS and connect with other affected families, the NephCure Foundation has a great site.
A couple of recent posts at WhizBANG! would be of interest to serious medical blog readers:
Legal Eagles Fly Unequally – Women in law may have even more problems with equity than women in academic medicine!!!
Meeting the Devil You Don’t Know – My brief encounter with a disease I had not seen since residency…because of an effective vaccine.
Enjoy these posts!