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mitochondria

Treating nephrotic-range proteinuria with tacrolimus in MTP

mitochondria

Mitochondria are the cell’s powerplants and inside them the MTP enzymatic complex catalyzes three steps in beta-oxidation of long-chain fatty acids.

In one family, genetic lightning struck twice. Two sisters were diagnosed with mitochondrial trifunctional protein (MTP) deficiency. This is a rare condition that stops the body from converting fats to energy, which can lead to lactic acidosis, recurrent breakdown of muscle tissue and release into the bloodstream (rhabdomyolysis), enlarged heart (cardiomyopathy) and liver failure.

Mitochondria are the cell’s powerplants and inside them the MTP enzymatic complex catalyzes three steps in beta-oxidation of long-chain fatty acids. MTP deficiency is so rare that fewer than 100 cases have been reported in the literature says Hostensia Beng, M.D., who presented an MTP case study during the American Society of Nephrology’s Kidney Week.

The 7-month-old girl with known MTP deficiency arrived at Children’s National lethargic with poor appetite. Her laboratory results showed a low corrected serum calcium level, elevated CK level and protein in the urine (proteinuria) at a nephrotic range. The infant was treated for primary hypoparathyroidism and rhabdomyolysis.

Even though the rhabdomyolysis got better, the excess protein in the girl’s urine remained at worrisome levels. A renal biopsy showed minimal change disease and foot process fusion. And electron microscopy revealed shrunken, dense mitochondria in visceral epithelial cells and endothelium.

“We gave her tacrolimus, a calcineurin inhibitor that we are well familiar with because we use it after transplants to ensure patient’s bodies don’t reject the donated organ. By eight months after treatment, the girl’s urine protein-to-creatinine (uPCR) ratio was back to normal. At 35 months, that key uPCR measure rose again when tacrolimus was discontinued. When treatment began again, uPCR was restored to normal levels one month later,” Dr. Beng says.

The girl’s older sister also shares the heterozygous deletion in the HADHB gene, which provides instructions for making MTP. That missing section of the genetic how-to guide was predicted to cause truncation and loss of long-chain-3-hydroxyacl CoA dehydrogenase function leading to MTP deficiency.

The older sister was diagnosed with nephrotic syndrome and having scar tissue in the kidney’s filtering unit (focal segmental glomerulosclerosis) when she was 18 months old. By contrast, she developed renal failure and progressed to end stage renal disease at 20 months of age.

“Renal involvement has been reported in only one patient with MTP deficiency to date, the older sister of our patient,” Dr. Beng adds.

Podocytes are specialized cells in the kidneys that provide a barrier, preventing plasma proteins from leaking into the urine. Podocytes, however, need energy to function and are rich in mitochondria.

“The proteinuria in these two sisters may be related to their mitochondrial dysfunction. Calcineurin inhibitors like tacrolimus have been reported to reduce proteinuria by stabilizing the podocyte actin cytoskeleton. Tacrolimus was an effective treatment for our patient, who has maintained normal renal function, unlike her sister,” Dr. Beng says.

American Society of Nephrology’s Kidney Week presentation

  • “Treatment of nephrotic-range proteinuria with tacrolimus in mitochondrial trifunctional protein deficiency

Hostensia Beng, M.D., lead author; Asha Moudgil, M.D., medical director, transplant, and co-author; Sun-Young Ahn, M.D., MS, medical director, nephrology inpatient services, and senior author, all of Children’s National Health System.

Asha Moudgil examines a young patient

Preventing cardiovascular disease after pediatric kidney transplant

Asha Moudgil examines a young patient

Pediatric nephrologist Asha Moudgil, M.D. examines a kidney transplant patient.

As obesity has continued to rise among children in the U.S., so has a condition called metabolic syndrome – a constellation of factors, including high abdominal fat, insulin resistance, high blood pressure, high triglycerides and low amounts of high-density lipoprotein (“good” cholesterol), that increase future risk of cardiovascular disease.

Although metabolic syndrome is dangerous in otherwise healthy children, it’s particularly so for those who’ve received kidney transplants due to chronic kidney disease, says pediatric nephrologist Asha Moudgil, M.D., medical director of transplant at Children’s National Health System. Dr. Moudgil and Children’s National co-authors, Registered Dietitian Kristen Sgambat, Ph.D., RD, and Cardiologist Sarah Clauss, M.D., published a literature review in the February 2018 Clinical Kidney Journal outlining recent research about the cardiovascular effects of metabolic syndrome after kidney transplantation.

“Simply having this transplant multiplies the risk of cardiovascular disease in this vulnerable population,” Dr. Moudgil says. “Combined with lifestyle factors that are driving up metabolic syndrome in general, it’s a ‘one-two punch’ for these patients.”

Dr. Moudgil explains that chronic kidney disease itself leads to poor growth, resulting in shorter stature that’s a risk factor for developing increased waist-to-height ratio upon becoming overweight. When children with this condition undergo long-awaited transplants, it reverses some factors that were suppressing appetite and keeping weight in check: The chronically high levels of urea in their blood decrease after transplant, improving their appetites; and there’s no need to maintain the restrictive diets they had been required to follow for kidney health prior to transplant.

The pharmaceutical regimen that patients follow post-transplant often includes steroids that independently contribute to weight gain and insulin resistance. Combined with the typical American high-fat, high-sugar, and high-sodium diet and low levels of physical activity, the majority of patients with chronic kidney disease gain significant weight after they receive transplants. The prevalence of obesity doubles the first year after transplantation, from about 15 percent to 30 percent, not only driving up cardiovascular disease risk but endangering the longevity of their transplant.

At the same time, says Sgambat, risk factors before and after transplantation drive up prevalence of other parts of metabolic syndrome. These include hypertension, which affects the majority of patients with chronic kidney disease before transplant and typically worsens due to sodium and water retention from immunosuppressive drugs. Dyslipidemia, or abnormal lipid concentrations in the blood, is also common among pediatric kidney transplant patients. One study included in the review showed that 71 percent of patients had high triglycerides three months post-transplant.

Ethnicity also can drive up risk for metabolic syndrome and cardiovascular disease. For example, the literature review says, individuals of African descent have a higher risk of these two conditions potentially due to genetic factors, such as high risk apolipoprotein L1 gene variants.

Together, these factors spur production of inflammatory molecules that trigger the development of early cardiovascular disease. Many kidney transplant recipients die from cardiovascular complications in early adulthood, Sgambat says, driving the need for early detection.

To that end, Dr. Moudgil says pediatric patients don’t typically show overt abnormalities in standard measures of cardiac functioning, such as echocardiography. As an alternative, she and colleagues cover three tools in the literature review that could offer advanced insight into whether patients have initial signs of cardiovascular disease. One of these is carotid intima-media thickness, a measure of the thickness of the carotid artery that can be obtained noninvasively by ultrasound. Another is myocardial strain imaging by speckle tracking echocardiography, a global measure of how the heart changes shape while beating. Cardiac magnetic resonance imaging (MRI), a relatively new technique, is already showing promise in detecting signs of early cardiovascular dysfunction.

A far simpler way to gauge cardiovascular risk, Sgambat adds, is calculating patients’ waist-to-height ratio. This measure doesn’t require sophisticated tools and can be tracked in any clinic over time, alerting patients to health-altering changes before it’s too late.

“It’s even more important to treat cardiovascular risk factors aggressively in this population,” Sgambat says. “Getting a concrete measure that something is trending in the wrong direction may motivate patients to change their diet or lifestyle in ways that a simple recommendation may not.”

Connecting allied health professionals in pediatric nephrology

With the meeting in Washington this year, Children’s National Health System will be the local host, a distinct honor for an academic medical center that treats hundreds of nephrology patients each year, says pediatric Nephrologist Asha Moudgil, M.D., who directs Children’s kidney transplant service.

Pediatric nephrology is a relatively small specialty worldwide, encompassing just a few hundred doctors in the U.S. For each allied health field that provides collaborative care with these physicians – including nutrition, child-life, psychology and social work – the numbers of providers are even smaller. There are no national meetings for these individual subspecialty fields and no venues to meet new like-minded colleagues or learn about new research or protocols.

Six years ago, the American Society of Pediatric Nephrology (ASPN) aimed to help resolve this dilemma by launching a new multidisciplinary symposium that brings together allied health professionals of all kinds within pediatric nephrology.

Each year, the “ASPN Multidisciplinary Symposium” changes locations, allowing the meeting to target different regional groups of allied health professionals based on geography. With the meeting in Washington this year, Children’s National Health System will be the local host, a distinct honor for an academic medical center that treats hundreds of nephrology patients each year, says pediatric Nephrologist Asha Moudgil, M.D., who directs Children’s kidney transplant service.

There are multiple advantages to having the symposium in Washington, Dr. Moudgil explains. One is access to Children’s experts in this field, who have a wealth of experience in managing issues that affect patients who live in the greater Washington area. For example, the keynote address scheduled for the meeting’s opening night will be delivered by Jennifer Verbesey, M.D., Children’s surgical director of pediatric kidney transplantation, focusing on living donation in minority populations. Living kidney donors and recipients who are minorities have unique issues that can affect organ longevity, explains Dr. Moudgil, which may not be well known by all clinicians.

Children’s speakers also focus prominently in the main session on the second day, including:

  • Angela Boadu, RD, LDN/LD, a registered dietitian, and Kaushalendra Amatya, Ph.D., a psychologist, are giving a talk about nutrition and the psychosocial aspects of obesity
  • Surgeon Evan Nadler, M.D., director of Children’s Bariatric Surgery Program, is speaking about bariatric surgery before and after transplantation
  • Nurse Practitioner Christy Petyak, CPNP-PC, and Social Worker Heidi Colbert, LICSW, CCTSW, NSW-C, are leading breakout sessions about the practical aspects of immunosuppressive therapy and resources for uninsured patients
  • Amatya, the Children’s psychologist, also is leading a breakout session on internalizing psychological disorders in pediatric renal patients and
  • Registered Dietitian Kristen Sgambat, Ph.D., RD, and Dr. Moudgil are co-leading a breakout session on nutritional challenges and enteral supplementation in chronic kidney disease.

Another advantage to holding the meeting in the nation’s capital is its close proximity to government research and federal regulatory agencies, such as the Food and Drug Administration (FDA) and the National Institutes of Health (NIH). Speakers from both agencies will be present, talking about how the FDA approves medicines for pediatric patients and offering details about the NIH’s rare disease program.

Besides the abundance of more formal knowledge-sharing, Dr. Moudgil adds, there will be plenty of opportunities for attendees to network, making connections within and outside their own respective fields.

“This is a platform for making long-term professional relationships,” Dr. Moudgil says. “Even if you’re the sole clinician representing your specialty at your own institution, you’ll be able to connect with other specialists at institutions across the country. You’re not only acquiring new information, you’re acquiring a group of colleagues you can connect with this year and those professional relationships can extend far into the future.”

antibodies-illustration

Detecting and treating dnDSA early preserves allograft function

antibodies-illustration

Monitoring and treating de novo donor-specific antibodies (dnDSA) before they could cause graft damage helped to decrease dnDSA in a majority of pediatric kidney transplant recipients at Children National Health System and prevented graft failure in the first few years.

Development of de novo donor-specific antibodies (dnDSA) is known to cause graft failure. Therefore, a protocol aimed at prospective monitoring and treating dnDSA – before they can cause graft damage – was developed for kidney transplant recipients at Children National Health System. This helped to decrease dnDSA in 76 percent of pediatric patients and prevented graft failure in the first few years, indicates a longitudinal cohort study published online Jan. 22, 2018, in Pediatric Transplantation. However, the benefit of preserving function of transplanted kidneys came at a price: Heightened hospitalization rates for infection.

An estimated 20 percent to 30 percent of children develop dnDSA and many of these patients go on to develop allograft failure after three to six years, write the study authors.

Clinical signs of graft failure due to antibodies appear too late to safeguard long-term graft survival. According to the study authors, developing earlier methods to detect dnDSA offers the opportunity to intervene before irreversible graft injury occurs.

“Children’s National Health System instituted a routine protocol that standardizes monitoring and treatment of dnDSA,” says Asha Moudgil, M.D., FASN, associate chief of the Division of Nephrology at Children’s National and the study’s senior author. “We followed this protocol as we monitored and treated all children younger than 19 who received a kidney transplant at Children’s National from Jan. 1, 2008, to Dec. 31, 2013.”

After transplant, these children were monitored for development of dnDSA at six months and then yearly. Upon detection of DSA, these children underwent kidney biopsy to assess for acute rejection. Additionally, monitoring was intensified to every two months.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” says Asha Moudgil, M.D., FASN.

Sixty-seven of the 72 children who received kidney transplants during that six-year period were included in this retrospective analysis. Their mean age was 14.1 years. Acute cellular rejection was treated according to a prespecified protocol.

  • The team treated de novo DSA with high-dose intravenous immunoglobulin (IVIG) if antibody titers were low and added two doses of rituximab to that treatment regimen if antibody titers were high.
  • If either C1q binding of immunodominant DSA was present or C4d+ were seen on biopsy, six sessions of plasma exchange were added to the above protocol.
  • Kids who were resistant to such treatment approaches received an additional four doses of IVIG monthly.

Nearly 39 percent of the children developed dnDSA within a median of 1.36 years. Ten of these 26 children had increased creatinine, 12 had new onset proteinuria and six had newly diagnosed hypertension at the time the dnDSA was detected. The multivariate analysis found that the coefficient of variance of tacrolimus, which measures adherence to immunosuppressive drugs, was the only statistically significant predictor for developing dnDSA.

DSA-positive patients had a higher rate of admissions (1.23 hospital admissions for infectious- or immunosuppressive-related side effects per patient, compared with 0.59 hospital admissions for the DSA-negative patients), which the study team attributes to aggressive treatment of dnDSA.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” Dr. Moudgil adds. “There was a higher risk of treatment-related complications, however, and this risk must be balanced against the short-term benefit of prolonging allograft function.”

Study co-authors include Olga Charnaya, M.D., a Children’s fellow when the study was designed and the article was drafted, now at Johns Hopkins; and Children’s Nephrologist, Shamir Tuchman, M.D.