A Peptide, Responsible for a Wide Range of Disorders, is Produced at a Higher Rate in Patients With Nephrotic Syndrome

Patients with this serious kidney disorder could benefit from adopting a low protein diet

Bethesda, MD (July 10, 2002) -- Nephrotic syndrome (NS) is a condition marked by very high levels of protein in the urine; low levels of protein in the blood; swelling, especially around the eyes, feet, and hands; and high cholesterol. Nephrotic syndrome results from damage to the kidneys' glomeruli, the tiny blood vessels that filter waste and excess water from the blood and send them to the bladder as urine.  Nephrotic syndrome can occur with many diseases, including the kidney diseases caused by diabetes mellitus, but some causes are unknown.

Found in many patients with nephroitic syndrome and associated kidney failure are the natriuretic peptides, a class of compounds of low molecular weight, yielding two or more amino acids.  They are secreted by the heart and act as hormones causing expanded vascular tube size, increased excretion of urine, and abnormal secretions of sodium into urine.  One of the natriuretic peptides, C-type natriuretic peptide (CNP), has been found in increased levels in the blood of patients with renal failure; yet, the corresponding levels found in kidneys have been to date unclear.  Researchers have failed to establish whether CNP is present in kidneys from nephrotic patients or if a low-protein diet impacts on the peptide’s presence in the blood or urinary excretion.

A team of researchers from the United States and Italy have joined together to determine the presence and localization of CNP mRNA (a single stranded RNA molecule that specifies the amino acid sequence of one or more polypeptide chains) in the normal human kidney.  Their study objectives also included the presence of CNP in patients with nephrotic syndrome as well as the peptide’s presence in blood and urine of subjects with kidney disease and those without the disorder.  Their final objective was to assess how a low-protein diet affected CNP levels in blood and urinary excretions, primarily as an indication of how such a diet would impact on the kidney’s excretion of the peptide.

The authors of the study, “C-Type Natriuretic Peptide Production in Normal Human Kidney and Effects of Protein Intake Restriction in Nephrotic Syndrome,” are Alessandro Cataliotti MD, Michihisa Jougasaki MD, Lisa C. Costello, MD, PhD, Guido Boerrigter MD, Toshihiro Tsuruda, MD, PhD, Shang-Chiun Lee, MD, Brenda Huntley, Sharon Sandberg, and John C. Burnett, MD, all from the Mayo Clinic, Rochester, MN; Mauro Giordano, MD PhD, Emanuela De Pascale, MD, PhD, and Gelsomina Giordano, MD, from the Second University of Naples, Naples, Italy; and Pietro Castellino, MD, Paola Belluardo, MD, and Lorenzo S. Malatino, MD, from the University of Catania, Catania, Italy.  Their findings are published in the Articles in Press of the American Journal of Physiology – Renal Physiology. 

Methodology

Seven patients with nephrotic syndrome (NS) and normal blood pressure and  a control group of seven patients without the disorder were included in this study.  The NS group consisted of four men and three women with a mean age of 39 and a mean ideal body weight of 108 percent.   The control group consisted of four men and three women, a mean age of 37, and mean ideal body weight of 106 percent.  The NS patients had to be between ages 20 and 50, have a urinary protein excretion greater than 3.5 g/24 hours, serum creatinine less than 2.0 mg/dl, and no evidence of endocrine or other major organ disease.  Subjects did not take medication during the study; no NS patients had previously received steroid therapy.

Renal biopsy specimens were obtained prior to the study.  Causes for the subjects’ kidney disease were membranoproliferative glomerulonephritis  (inflammation of the capillary loops in the glomeruli of the kidney), membranous nephropathy, amyloidosis (waxy kidney), and focal segmental glomerulosclerosis.

In situ hybridization (incorporating a labeled nucleic acid with a fluorescent dye, to look for specific transcription or localization of genes to specific chromosomes) was performed on five microns sections of formalin-fixed, paraffin-embedded biopsy tissue using digoxigenin oligonucleotide probes.

The experimental protocol required that control subjects consume a weight-maintaining diet providing about 35-38 Cal/kg per day and containing about 250-300 g of carbohydrate and 1.1 g/kg of protein for at least seven days prior to their participation in the study.  Patients with NS were randomized and involved in two separate experimental protocols, specifically having a low- protein diet for four weeks and then moving to a normal protein diet for the same time period.  At the end of the two diet cycles, plasma and urine samples were extracted from the NS patients and control patients for analysis.

Results

The major findings of the study revealed that:

• In situ hybridization studies demonstrated CNP mRNA expression in tubular cells and glomeruli of normal human kidneys.

• CNP immunoreactivity was positive in close proximity, distal and medullary (marrow) collecting duct tubular cells in both control and NS patients.

• Plasma CNP and urinary CNP to creatinine (a component of urine and the final product of creatine catabolism) ratio were significantly higher in NS patients as compared to control subjects.

• Urinary CNP, but not plasma CNP, was significantly lowered in NS patients after a low protein diet.  Similarly, urinary protein to creatinine ratio and urinary albumin to creatinine ratio, but not urinary cGMP (cyclic guanosine 3c,5c-monophosphate) to creatinine ratio, decreased significantly with a low protein diet.

Conclusions

This study reports the production of CNP in the normal human kidney.  The findings also reveal increased blood CNP concentrations and urinary CNP excretions in patients with nephrotic syndrome.  Patients with the kidney disorder found that CNP concentrations did not change following a low protein diet; however, urinary CNP production, generally 12 times the rate of the control group, occurred at a lower rate with less protein consumption.

The researchers further suggest that CNP concentrations are elevated in NS patients secondary to vascular stress caused by hyperlipodemia, coagulation disorders, and renal failure.  That CNP urinary production was reduced by a low protein diet offers a theory that production of this peptide reflects activity in the kidney rather than reduced renal clearance of plasma CNP.

Essentially, CNP production is altered in NS patients.  The increased production can be partially offset by low protein intake.  Additional studies may be required regarding the role of CNP in kidney disorders, but patients with this condition can benefit now by adjusting their dietary habits.

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: To set up an interview with a member of the research team, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.