It hit the news today that Facebook now lets you share your organ donor status with your friends. This grew out of the use of Facebook in various natural disasters, as well as his friendship with Steve Jobs and others:
Zuckerberg also cites his girlfriend, Priscilla Chan, who is studying to become a pediatrician. “Our dinner conversations are often about Facebook and kids, and the kids that’s she’s meeting,” he says. “She’ll see them getting sicker, then, all of a sudden, an organ becomes available, and she comes home and her face is all lit up because someone’s life is going to be better because of this.”
Quote from USA Today
If you want to note your status as an organ donor, first go to your page. In the update box, click “Life Event” on the far right, then hit “Health & Wellness.” A sub-menu with organ donor status will be at the top of the next menu (see screenshot below). Click and fill it out; the information goes into your timeline.
If you have not yet signed up to be a donor, the dialog box gives you a link so you can do it right now from Facebook.
In some ways, my patients are lucky. They can go on dialysis to stay alive while they await a precious kidney. Others die waiting for an organ every day. I hope Facebook can get more donors to sign up. You may save a life, or your life may be saved.
Membranoproliferative glomerulonephritis (MPGN) is inflammation of the filtering units of the kidney (glomerulonephritis or GN) that occurs with activation of the complement system of immunity.
The Complement System
The complement system of proteins provides immunity through 2 pathways. In the classical pathway (blue half of cartoon), an antigen-antibody forms an immune complex that activates C1. C4 gets activated and consumed. After a couple of steps it activates C3. Ultimately C5 and other complements come together, resulting in a membrane attack complex (MAC) that can, well, attack the membrane of the foreign invader. The alternative pathway (pink half of cartoon) activates C3 directly with the same end result, often via contact with a surface that consumes the C3 protein. Clinical laboratories usually measure C3 and C4. If C4 is low, then the classical pathway has been stimulated; C3 may be suppressed as well. If C4 remains normal with a low C3, the alternative pathway is the culprit.
MPGN must be diagnosed by kidney biopsy. The “membrano” part of the name refers to characteristic changes in the glomerular basement membrane (GBM) of the filtering capillaries. Abnormal material “splits” the GBM and fills this space, giving a duplicated appearance on light microscopy. Mesangial cells “proliferate,” completing the name. Other studies demonstrate components of the complement system depositing within the glomeruli.
In addition to the kidney biopsy, patients need lab studies for hepatitis, cryoglobulinemia (a circulating immune complex disorder), and complements: C3, C4, and C3 nephritic factor. The latter, an antibody to the activated form of C3 that can activate C5, is positive in 60-70% of patients with type 2 disease, but only 20% of other types.
The pattern of immune complexes in the kidney defines 3 forms of MPGN:
- Type 1: Subendothelial deposits (between the cells lining the capillaries and the GBM)
- Type 2: Large, ribbon-like intramembranous (within the GBM) deposits (dense deposit disease); patients with this form do worse
- Type 3: Subendothelial and subepithelial deposits (on both sides of the GBM)
Natural History and Treatment
MPGN is a rare disease, affecting 1 to 2 per million population per year. Unlike many kidney diseases, MPGN is “equal-opportunity.” All ethnic groups, both genders, and all ages suffer the same. The disorder progresses slowly. Approximately half of affected patients require treatment of permanent kidney failure in 5-10 years.
At this time, treatment for MPGN includes normalizing blood pressure and reducing proteinuria as with all chronic kidney disorders. In children, immunosuppression with oral steroid every other day for several years may retard progression of disease; in adults, steroids are not recommended. If a secondary cause of MPGN is demonstrated, treatment of that disorder may also benefit the kidney involvement. Drugs that specifically target complement activation (eculizumab) offer novel options for research. Kidney transplant can be performed in these patients, but MPGN may recur. Once again, type 2 disease fares worse with 80-90% risk of recurrence, compared to ~30% in those with the other forms.
If you or your child has high blood pressure and chronic kidney disease, you should read my post today at Scientific American on a study in adult patients. Moving at least one blood pressure medication to bedtime slashed the risk of death and heart disease in these patients with no bad effect on blood pressure control.
Taking a medication at bedtime is easy and low-risk and something to discuss with your physician.
The current issue of Journal of the American Society of Nephrology includes a “Brief Review” of Current Therapy for IgA Nephropathy. Floege and Eitner (of RWTH University of Aachen, Germany) point out that IgA nephropathy (henceforth IgAN) is a common cause of permanent kidney failure in many countries. Therapy of IgAN is based more on opinion than evidence at this point in time.
When experts get together to examine evidence and rate it, they produce a document based on the quality of the evidence supporting various treatment options. Recommendations are based on strong evidence, while suggestions are less supported.
They divide their “best opinion” approach by patient presentation:
- The silent majority – 5 to 20% of kidneys from people “without kidney disease” show IgA deposits, suggesting that most patients never develop symptoms of the disorder. Over ten years, many patients with biopsy-proven IgAN show spontaneous remission of hematuria (blood in the urine); repeat kidney biopsy confirmed that IgA deposits were gone in many of these patients. Approximately one-third of these patients showed evidence of progressive disease, including the development of proteinuria (spot urine protein:creatinine ratio >1 mg/mg).
- The typical patient – These patients have proteinuria and/or reduced estimated glomerular filtration rate (eGFR, a measure of how well the kidneys clear waste) and/or high blood pressure.
- The atypical patient – presentation with either rapid loss of kidney function or with nephrotic syndrome (very heavy protein loss in the urine) may warrant early treatment with immunosuppressive agents because other kidney disorders may be present.
- The transplant patient – IgAN may recur after transplantation; unfortunately, none of our current immunosuppressive agents prevent or treat this condition.
They present a nice algorithm for best suggested treatments (see figure). The silent majority warrant annual follow-up for at least 10 years to detect progression (proteinuria, falling eGFR, and/or high blood pressure) or spontaneous remission.
Other patients first warrant optimal supportive therapy:
- Control blood pressure with anti-angiotensin II drugs (converting enzyme inhibitors or receptor blockers) as first-line agents (the only treatment that will rise to the level of “recommended” in the pending KDIGO Clinical Practice Guideline for Glomerulonephritis). Encourage smoking cessation and weight loss, if overweight.
- Reduce dietary salt intake and/or add diuretics for edema control.
- Control each component of the metabolic syndrome, if present (obesity, high blood cholesterol, high blood glucose)
- Consider other supportive therapies, including aldosterone blockers, beta blockers, allopurinol, and/or sodium bicarbonate
- Other nonspecific measures to retard disease progression including avoiding nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) and controlling other abnormalities of blood chemistry, especially potassium and phosphorus.
Patients with eGFR of at least 30 mL/minute who show no reduction in proteinuria and/or a falling eGFR after 6 months of supportive treatment warrant a course of steroids. Two approaches have shown promise in this patient population, including a 6-month course that starts with oral prednisone 1 mg/kg body weight/day for 2 months followed by a reduction of 0.2 mg/kg/day monthly.
A variety of other therapies have been reported in small groups of patients; however, these treatments do not make the cut to even be suggested based on the evidence. These include fish oil, antiplatelet drugs, and tonsillectomy.
The authors also point out that several high-quality trials of treatments for IgAN will be completed in the coming years. Perhaps we will have strong enough evidence to make recommendations in the near future, rather than suggestions for mostly nonspecific treatments.
The bottom line: Most patients with IgAN have asymptomatic hematuria that resolves on its own after several years. Signs of progressive (or potentially progressive) disease include proteinuria, falling eGFR, and high blood pressure. If these develop, more follow-up and treatment will be necessary.
Back in August a publication in JAMA (Journal of the American Medical Association) made the news. Vivante et al examined the risk of end-stage kidney failure in Israeli military recruits with and without isolated asymptomatic microscopic hematuria twenty years after screening.
What is this diagnosis?
Isolated: Hematuria was the only abnormality identified; no proteinuria, high blood pressure, or abnormal kidney function
Asymptomatic: The subject had no complaints
Microscopic: The urine never looked bloody; blood cells could only be detected by dipstick or microscopic examination
Hematuria: At least 5 red blood cells in every high power field of urine examined.
In addition, patients have undergone studies to rule-out malformations or disorders that may produce blood in the urine
What is the study?
The screening scheme for the study is shown in the figure. Well over one million Israeli military recruits had screening physicals with urinalysis prior to military conscription. Of these, 96.9% had no evidence of kidney problems or disorders that might lead to kidney failure (controls). Another 2.8% had chronic diseases that could produce kidney failure or damage. Only 3,690 individuals met the criteria for isolated asymptomatic microscopic hematuria (0.3% of overall population). Twice as many hematuria patients were male as female.
After 20 years, the risk of kidney failure requiring dialysis or transplant was 2.05 per 100,000 person-years in the control group. The hematuria patients risk was increased to 34.0. Diabetes was the most common cause of kidney failure in controls; a variety of glomerular disorders presented in the hematuria group.
What does this mean?
Only 0.7% of asymptomatic microscopic hematuria subjects required kidney failure treatment after 20 years of follow-up, even though this is substantially higher than individuals with no evidence of kidney problems at screening (0.04%). Children with this degree of hematuria should know their long-term prognosis is generally good.
The results of this study may not be applicable to children who are not Israeli Jews. Other ethnic groups may show different risk with this condition. Also, screening and work-up tests have changed over time. Today we screen affected children for a number of disorders that would not have been tested in the 1970s. Since longitudinal data on development of other signs and symptoms are not available, it is not clear how these tests might alter the results.
The study is strong because of the large numbers initially enrolled and the linkage with the end-stage kidney failure database of the country.
The bottom line: people with isolated asymptomatic microscopic hematuria should have periodic monitoring of urinalysis and other measures of kidney function because they do have an increased risk of kidney failure when compared with the general population.
The New England Journal of Medicine features a veritable pediatric UTI festival in its July 21, 2011, issue. First Montini et al provide a Medical Progress review, highlighting the history of our understanding and treatment strategies for this common condition. Since the middle of the last century, we have recognized a link between recurrent febrile UTIs, vesicoureteral reflux, and kidney scarring. Since the 1970s such children have been subjected to repeated imaging studies, long-term antibiotic prophylaxis, and surgical procedures.
We forgot that association is not the same as causation.
Even with our aggressive intervention, the rate of permanent kidney failure attributed to reflux has not changed in any country over the past 40 years. Wide-spread use of prenatal ultrasound demonstrated abnormalities prior to infection in many of these children. We now know, from the use of animal models and in vitro studies, that abnormal ureteral budding can produce hypoplasia and dysplasia. While the role of recurrent pyelonephritis in the evolution of kidney scars cannot be denied, it is clear that scarring may occur in the absence of UTIs as well.
Earlier studies of surgical and medical intervention to prevent kidney scarring were not well-done. More recent randomized prospective studies thus far do not support the aggressive treatment approach of the past, particularly for lower grade (I, II, or III) VUR. Other studies underway may help narrow our knowledge gap further, providing important evidence that we can use to rationally treat this condition.
To illustrate the issue, the Journal then presents a case scenario of a 6-year-old girl with one documented febrile UTI and grade III reflux; three specialists then make the case for three different treatments: observation without prophylaxis, long-term antibiotic therapy, and surgical repair of the reflux. The site includes a poll to see which therapy the readership favors (my choice was in the majority at the time of this post).
Parents often find reflux confusing as they read about it online. The problem really comes down to the history. We saw an association of reflux, UTIs, and scars, and we assumed that reflux + UTIs = scars. Based on this equation, which certainly has an intuitive, intellectual appeal, generations of children got aggressive treatment. Today, we have reexamined our assumptions; many of us now recommend a less aggressive approach to the management of these related conditions.
Studies underway may change our approach even more. In the meantime, all options must be discussed with families, and treatment individualized as necessary.
Click here to view my post over at WhizBANG! where I discuss a couple of tricks I have learned so far. There we can talk about this brave new electronic world and what it may mean for online interactions.
Back in January, I addressed the topic of childhood nephrotic syndrome, a common rare disorder. One of the forms that we often see in children with steroid-resistance is focal segmental glomerulosclerosis (FSGS).
What is FSGS?
FSGS can be diagnosed only after a kidney biopsy. The term describes what we see in the kidney:
- Focal, meaning only some of the filtering units (glomeruli) have lesions
- Segmental, meaning affected glomeruli have only a portion of each tuft involved
- Glomerulosclerosis, meaning glomerular scarring
The cartoon shows that a portion of the blood vessels in the glomerular tuft become choked by scar material. How this leads to proteinuria remains unclear.
What causes FSGS?
A number of diseases may cause secondary FSGS. The disorder has been associated with obesity, and excess body fat may be a secondary cause. Primary FSGS means that no known secondary cause can be identified.
A variety of mechanisms for primary FSGS have received scientific attention. Gene mutations in kidney proteins may predispose some patients to this disorder. Others may develop circulating factors in the blood that promote proteinuria and scarring. Blood tests may be used to check these possibilities.
What treats FSGS?
If a secondary cause is identified for FSGS, its should be treated. If proteinuria continues after treatment, then other therapies should be considered, especially those that ameliorate the proteinuria.
Patients with primary FSGS have often failed a course of steroids by the time a biopsy is performed. Next line therapies include calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate (Cellcept), intravenous steroids, or chemotherapy drugs. The latter category includes rituximab (which I blogged about at WhizBANG!), a humanized antibody that can produce long-lasting remissions in patients with FSGS, even in those whose disease recurs after transplantation. Some centers use plasma exchange, especially if heavy proteinuria develops immediately after transplantation.
Other treatments may treat symptoms or reduce the progression of FSGS. Normalizing blood pressure remains important in any kidney disease, especially with therapies that suppress angiotensin II (angiotensin converting enzyme inhibitors or angiotensin receptor blockers). Diuretics can help control the swelling that accompanies nephrotic syndrome, as will a low-salt diet. Children with nephrotic syndrome may have elevated blood cholesterol and lipids that require changes in the diet or additional medications. Finally, loss of protein in the urine increases risk of blood clots and infections. The latter can be a big problem when these children also receive drugs that suppress the immune system.