Metabolic Syndrome Predicts Progressive Kidney Disease In African-Americans

For African-Americans with high blood pressure, the combination of risk factors known as metabolic syndrome brings an increased risk of worsening kidney disease, reports a paper being presented at the American Society of Nephrology’s 39th Annual Meeting and Scientific Exposition in San Diego.

“Our study shows a 38 percent increased risk of progressive chronic kidney disease in hypertensive African-Americans classified as having the metabolic syndrome,” comments Dr. J. P. Lea of Emory University, lead author of the new study. “This has important public health implications, as treatments are available to reduce the severity of the metabolic syndrome and may have an impact on reducing the rate of progressive kidney disease.”

Dr. Lea and her fellow researchers analyzed data from a large study of treatment for hypertension (high blood pressure) in African-Americans. Twenty-five percent of the patients had metabolic syndrome, meeting at least three of the five diagnostic criteria: high blood sugar, low high-density lipoprotein (“good”) cholesterol, high triglycerides, and obesity, and high blood pressure. (All patients automatically had one of the criteria, because all were hypertensive.)

Sometimes called insulin resistance syndrome or “syndrome X,” metabolic syndrome is a known risk factor for diabetes, cardiovascular disease, and chronic kidney disease (CKD). Patients with CKD have gradual, irreversible loss of kidney function. Over time, CKD can lead to end-stage renal disease (ESRD)-permanent loss of kidney function requiring dialysis or kidney transplantation.

After four years’ follow-up, the patients with metabolic syndrome had significantly higher rates of progressive CKD, defined as continued declines in kidney function, ESRD, or death. The risk of progressive CKD was about 40 percent higher for patients with metabolic syndrome, even after adjustment for other factors known to affect kidney disease outcomes-such as age, sex, obesity, and initial level of kidney function.

On their own, none of the individual metabolic syndrome risk factors was related to progressive CKD. The increased risk associated with metabolic syndrome was also unaffected by which blood pressure treatment the patients received.

Although previous studies have linked metabolic syndrome to an increased risk of CKD, it has been unclear whether metabolic syndrome contributes to progression of established CKD. Once CKD is present, African-Americans have higher rates of progression to ESRD.

“Diabetes and hypertension are the leading causes of kidney failure, which disproportionately affects African-Americans,” says Dr. Lea. “Despite good treatments for diabetes and hypertension, there is still a continued rise in the rates of kidney disease. More studies are needed to determine why some patients with CKD progress more rapidly to ESRD-that is, to dialysis-than others.”

This study of African-Americans with high blood pressure finds that metabolic syndrome is a significant risk factor for progressive CKD. “Metabolic syndrome can contribute to worsening kidney disease,” adds Dr. Lea. “That’s important, because if we can reduce the severity of metabolic syndrome through diet and medication, it may help to reduce the rate of progressive kidney disease-and thus delay ESRD and the need for dialysis therapy, which is very costly and debilitating.”

Pre-eclampsia Kidney Disease Link

Pre-eclampsia is a complication in pregnancy occurring in approximately eight percent of all pregnancies. It is characterised by elevated blood pressure and protein in the urine. It generally develops after 20 weeks of pregnancy.

Medical doctor and researcher Bjoern Egil Vikse from the Department of Medicine at University of Bergeb is the first author of an upcoming article in the March issue of the Journal of the American Society of Nephrology.

Vikse explains that there were two reasons for becoming involved in this work. The first was that a collegaue had previously found a strong correlation between pre-eclampsia and a later incidence of cardiovascular disease. The second is that UiB researchers have a unique research tool. They have access to two large databases: one is a birth registry; the other is a kidney biopsy registry. This enables them to use large, well-documented data pools in their work.

The Birth Registry provided Vikse with data from 1967 and the Kidney Biopsy Registry dates from 1988.

Unexpectedly strong correlation

Vikse and his colleagues first compared data from the two registries to see if there was a correlation between the children of mothers who had experienced pre-eclampsia and incidence of kidney disease in these children. They found no correlation.

They then compared the two databases for a possible correlation between the incidence of pre-eclampsia and later incidence of kidney disease in the mothers and found an unexpectedly strong result.

“We were amazed that the correlation was so strong,” says Vikse. The data showed that pre-eclampsia alone was responsible for the mothers having a 3.3% increased risk of developing kidney disease later. If, in addition, the child had a low birth weight, the risk increased to a 4.8% increased risk with low birth-weight and a dramatic17% increased risk with very low birth-weight.

Another unexpected finding was that the increased risk was not associated with any particular kidney disease: all kidney diseases had a similar increased risk.

“You would expect the risk increase to be linked to a particular disease,” explains Vikse. “It was most unusual to find that this was not the case.”

Future directions

Vikse explains that the researchers will now try to characterise the correlation further as well as checking for correlations with other medical conditions such as kidney failure. Studies into the development of both pre-eclampsia and kidney disease are also needed to see if there are any similarities between the mechanisms by which both medical conditions develop.

According to Vikse, there are also more far-reaching consequences as well. This result suggests that information about having experienced a pregnancy with pre-eclampsia should be included in a woman’s medical history record. Such women need to be followed up for the rest of their lives because of their increased risk of cardiovascular and kidney disease.

Racial Disparities in Children with End-stage Kidney Disease

Anemia, an important marker of ill health, is persistently worse in African-American children with end-stage kidney disease than in their white counterparts, according to results of a study by scientists at the Johns Hopkins Children’s Center.

In an analysis of 677 patient records from a national registry, the Hopkins team found 71 percent of the white males, but only 59 percent of black males, had healthy levels of hemoglobin, the iron-rich oxygen transporters in red blood cells. Seventy-four percent of white girls had healthy levels, compared to 51 percent of black girls.

“Racial disparities are well-established among adult patients with kidney disease, but our findings show the same worrisome picture for children,” says Meredith Atkinson, M.D., a third-year nephrology fellow at the Children’s Center. “The next step is to figure out what combination of factors, such as differences in biology or access to health care, are responsible for the disparities.”

Patients with uncontrolled anemia, a well-known complication of kidney disease, generally have worse outcomes and worse quality of life than patients whose anemia is under control.

Mutant Gene Causes Severe Kidney Disease In Infants

Scientists at the University of Michigan Medical School have discovered a previously unknown cause for a severe, early-onset form of kidney disease and renal failure in children: recessive mutations in a gene called phospholipase C epsilon or PLCE1.

Identifying the mutant gene is important to scientists because PLCE1 affects the development of podocytes – specialized cells that play a vital role in the kidney’s ability to remove waste products from blood, while retaining important blood proteins.

To parents of infants with inherited PLCE1 mutations, the study is especially significant because it provides the first evidence that some types of a kidney disease called nephrotic syndrome, if diagnosed early in infancy, may be treated successfully in children.

“This is the first report of infants with two mutations in a recessive gene for steroid-resistant nephrotic syndrome who nevertheless responded to steroid treatment,” says Friedhelm Hildebrandt, M.D., the U-M’s Frederick G L Huetwell Professor for the Cure and Prevention of Birth Defects. “The early onset form of the disease is severe and infants often go into end-stage renal disease within the first year of life. So, until now, most physicians believed there was no point in trying treatment.”

The study will be published Nov. 5 in Nature Genetics as an Advance Online Publication, and will be printed in the journal’s December 2006 issue.

There are many types and many causes of nephrotic syndrome, but basically it is a disease of the glomerulus, the kidney’s main blood filtration unit. There are about one million of these filtration units in each human kidney. As blood flows through a network of tiny capillaries in the glomerulus, excess water, salts and toxic molecules are removed and flushed out in urine, while important blood proteins like albumin are retained in the bloodstream. If the kidney’s filtering units don’t work properly, nephrotic syndrome develops. Proteins leaking out from the glomerulus are excreted in urine, and body tissues retain too much water, which causes swelling around the eyes and throughout the body.

Some types of nephrotic syndrome can be treated with steroids or other drugs, but steroid-resistant forms of the disease as a rule do not respond to treatment. Untreated nephrotic syndrome often causes severe scarring and a condition called focal segmental glomerulosclerosis (FSGS), which progresses about 50 percent of the time to end-stage kidney disease and renal failure.

PLCE1 is the seventh gene scientists have found to be involved in different types of steroid-resistant nephrotic syndrome, and the second gene that is expressed in podocytes – specialized cells with octopus-like tentacles surrounding the glomerulus.

Podocytes are currently under intensive study, because scientists believe they play a vital role in the blood filtration process. Identifying genes and proteins that are active in podocytes will help scientists understand how they work.

“We found that PLCE1 is expressed in developing and mature podocytes,” says Hildebrandt. “Most of the PLCE1 mutations we identified apparently prevented podocytes from developing normally in the embryo, so defects were present at birth. A milder mutation seemed to interfere with repair mechanisms in the glomerulus, so defects didn’t show up until later in life.”

U-M scientists used DNA microarrays to analyze blood samples from 26 families around the world who had children diagnosed with steroid-resistant nephrotic syndrome. After eliminating known mutations, the study team was left with DNA from 12 children with the disease. All 12 had inherited recessive mutations in PLCE1 from both parents. None of the seven different PLCE1 mutations were present in the 138 control subjects in the study.

All 12 children developed symptoms of nephrotic syndrome before age four. Five children progressed to end-stage renal disease before age 5. But surprisingly, two children who received early treatment with steroids or cyclosporin A were still alive and healthy, with no symptoms of the disease.

Hildebrandt and his research team couldn’t believe children with the most severe form of nephrotic syndrome had been cured of the disease. So they tracked down their physicians – one in Israel and one in Turkey – to confirm that the information was correct.

“These children were very fortunate,” Hildebrandt says. “Their physicians told us they decided there was nothing to lose by trying a course of treatment. Based on this information, we now think that there may be a critical time window during which treatment can overcome the development defects caused by PLCE1’s loss of function.”

The discovery has important implications for pediatric nephrologists and pediatricians who treat infants with nephrotic syndrome, according to Hildebrandt.

“In very early-onset nephrotic syndrome, it’s important to find out if the child has mutations in PLCE1,” says Hildebrandt. “Some infants with PLCE1 mutations might be treated successfully with steroids. It’s not a golden bullet, but there’s a slim chance, if the treatment is given early.

“Unfortunately, mutations in other podocyte genes, like NPHS2 – also referred to as podocin – are more common,” he adds. “Based on all our knowledge so far, there is no effective therapy when nephrotic syndrome develops as a result of podocin mutations.”

In future research, Hildebrandt and colleagues will continue searching for the causes of nephrotic syndrome. Using zebrafish that lack working copies of plce1, they hope to identify drugs that could reverse the damage to podocytes and the glomerulus caused by the disease.

“Because PLCE1 is an enzyme, we have a much better chance of finding ways to modify its activity,” Hildebrandt explains. “Using the zebrafish model, we can do high-throughput screening of many possible drug candidates for this form of nephrotic syndrome.”

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Citation: Nature Genetics: DOI 10.1038/Ng1918