Kidney Disease Biomarkers
Kidney Disease Biomarkers
Kidney Disease Biomarkers

 Summary: This study will identify biomarkers (proteins and other molecules in the blood or
 urine) that may help scientists predict what kidney disease a patient has and whether a given
 patient would respond to particular therapies. The study will look for biomarkers in the
 blood and urine of patients with various kidney diseases and study of the effects of
 angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers
 (ARB) on biomarkers. Blood and urine from healthy volunteers will be studied for comparison.

 Healthy people and the following patients may be eligible for this study: adults with
 diabetic nephropathy 18 years of age and older; children with newly diagnosed clinical
 idiopathic nephrotic syndrome between 2 and 18 year of age; children and adults with
 glomerular disease (minimal change disease, focal segmental glomerulosclerosis, or collapsing
 glomerulopathy).

 Participants undergo tests and procedures as follows:

 Glomerular Disease: Adults with glomerular disease provide about four to six blood and urine
 samples over the course of 6 to 12 months. The samples are collected at the time of regularly
 scheduled visits for the NIH treatment protocol in which they are participating. Children
 provide only blood samples.

 Chronic Kidney Disease: Patients with chronic kidney disease provide a blood and urine sample
 every 6 months for 3 years or more.

 Angiotensin Antagonism: Patients with chronic kidney disease who are taking ACE inhibitors or
 ARBs stop their medicines for 4 weeks, while those who are not taking ACE inhibitors or ARBs
 begin one of the medicines. In general, patients just starting on the medications continue
 them after the study is completed, since they are beneficial for chronic kidney disease.

 -  Medication withdrawal group: Patients come to NIH for 2 successive days at the beginning
 of the study for blood and urine tests (including one 24-hour urine collection) and to
 receive iothalamate (a chemical used to measure kidney function). Iothalamate is
 delivered over 24 hours through a needle placed in the abdomen (or elsewhere) via a pump
 similar to pumps that some diabetics use to deliver insulin. Patients then stop taking
 their ACE inhibitor or ARB medication. They monitor their blood pressure every day and
 return to NIH after 1, 2 and 4 weeks for blood tests. During week 4, the iothalamate
 infusion is repeated, and blood and urine samples are collected as at the beginning of
 the study. Patients then resume taking their ACE inhibitor or ARB once a day with the
 dose being increased at 2-week intervals. They come to NIH weekly after 1 week and then
 every other week for blood tests. Four weeks after reaching the highest FDA-recommended
 dose of medication tolerated, the iothalamate infusion and blood and urine collections
 are repeated.

 -  Medication induction group: At the beginning of the study, patients have the iothalamate
 infusion and blood and urine collections described above and then begin to take either
 an ACE inhibitor or ARB. The dose is increased after 2 weeks. Patients monitor their
 blood pressure every day. After being on the highest dose for 4 weeks, patients repeat
 the iothalamate infusion and blood and urine collections. The study is then complete and
 they are provided a 2-month supply of medicine to take home.

 Information is gathered on symptoms, treatments, and results of past laboratory tests of all
 patients. Healthy volunteers provide blood and urine sample collections every month or every
 other month for up to four collections to be used for biomarker studies and the screen for
 common chronic diseases.
There is a pressing need to develop biomarkers for renal disease, which might assist in
 diagnosis and prognosis and might provide endpoints for clinical trials of drugs designed to
 slow progression of renal insufficiency. We propose to study potential biomarkers in five
 populations. First, we will study remittive therapy for glomerular disease (sample size up to
 40), enrolling children with idiopathic nephrotic syndrome (N=20) and adults with minimal
 change, focal segmental glomerulosclerosis, and collapsing glomerulopathy (N=20). We will
 collect periodic urine samples as these patients receive remittive therapy with
 glucocorticoids or other agents. We will also study up to 10 healthy adult volunteers. We
 will carry out targeted urine proteomic studies, measuring levels of glomerular cell markers
 and cytokines, and we will profile urine proteins using mass spectrometry. Our goals are to
 identify markers of particular disease entities and of steroid responsiveness and to explore
 whether biomarkers contribute to the histologic sub-classification of these diseases. Second,
 we will study up to 40 adults with progressive chronic kidney disease of various etiologies
 and glomerular filtration rate <60 ml/min/1.73m2. We will study blood and urine samples,
 using both targeted and profiling approaches. Our goal is to identify biomarkers that
 correlate with progressive loss of glomerular filtration function, which is a functional
 correlate of progressive renal fibrosis. Third, we will study up to 40 adults, primarily with
 diabetic nephropathy, who start or stop angiotensin antagonist therapy (angiotensin
 converting enzyme inhibitors or angiotensin receptor blockers) and compare urine proteomic
 profiles on therapy and off therapy (4 week interval). Our goal is to identify potential
 biomarkers that correlate with the beneficial anti-fibrotic effects of these agents. Fourth,
 we wish to define possible sex differences in urine exosome proteins, obtained from healthy
 volunteers, who are hospitalized for six days for administration of a standard diet and
 collection of research urine samples. Fifth, we wish to determine whether salt intake
 influences urine exosome proteins, obtained from healthy volunteers. These subjects will be
 hospitalized for 12 days during which time they will be placed sequentially on a high salt
 diet and a low salt diet, with collection of research urine samples and blood pressure
 monitoring. Proteomic analysis in these studies will take several approaches, including mass
 spectrometry of urinary peptides, analysis of urinary exosomes, and immunologic detection and
 quantification of candidate proteins in urine and blood.
-  INCLUSION CRITERIA:

 1. Children with newly diagnosed clinical idiopathic nephrotic syndrome between the
 ages of 2-18 years.

 2. Children with previously diagnosed clinical idiopathic nephrotic syndrome between
 the age of 2-18 years at the time of diagnosis who sustain a relapse of nephrotic
 syndrome while off steroid therapy. A relapse is defined as a urine protein level
 of 2+ (100mg/dl) or greater on a first morning urine sample for 3 consecutive
 days. While a quantitative urine protein/creatinine ratio is more precise, this
 semi-quantitative definition accords with pediatric practice. Relapses will be
 treated according to standard clinical practice.

 3. Children and adults who participate in NIH trials of remittive therapy for
 MCD/FSGS/CG (e.g. Podocyte dexamethasone or Retinoids for podocyte disease) will
 be eligible.

 4. Also, we will study up to 10 healthy adult volunteers.

 EXCLUSION CRITERIA:

 1. IN CHILDREN, ANY OF THE FOLLOWING

 1. Age less than 2 years. The rationale for excluding children under the age of 2 yr
 is that nephrotic syndrome is unusual in this age group and may have etiologies
 other than MCD and FSGS

 2. Uncontrolled hypertension (a systolic or diastolic which is greater than 95%
 population mean for child s age and sex, while receiving therapy), azotemia
 (serum creatinine greater than 1.5mg/dL), gross hematuria at the time of
 presentation (clinical markers of primary or secondary GN).

 3. Hypocomplementemia, positive ANA, anti-DS DNA, ASO, anti-DNase B, MPO, PR-3,
 Hepatitis B and C and HIV serologies.

 2. In children or adults:

 1. Clinical contra-indications to steroid therapy.

 2. The presence of medical conditions that might interfere with the interpretation
 of results, such as cancer, diabetes, or a long history of hypertension.

 3. Healthy adult volunteers:

 1. age greater than 18 yrs; no history of hypertension, diabetes, or other chronic
 illness that might complicate interpretation of the results; not taking
 prescription medication.

 CKD PROGRESSION STUDY:

 INCLUSION CRITERIA:

 1. Renal biopsy diagnosis of glomerular disease or interstitial nephritis or
 clinical diagnosis of diabetic nephropathy.

 2. Mild or moderate renal insufficiency, defined as eGFR less than 60
 ml/min/1.73m(2) but greater than 30 ml/min/1.73m(2).

 EXCLUSION CRITERIA:

 1) The presence of medical conditions that might interfere with the
 interpretation of results, such as cancer.

 ANGIOTENSIN ANTAGONISM STUDY:

 INCLUSION CRITERIA:

 1. Adults greater than 18 years old. Few children have diabetic nephropathy and
 the frequent blood draws would be problematic for children.

 2. Type 1 or Type 2 diabetes. Later studies will be expanded to other
 glomerular diseases.

 3. Urinary albumin/creatinine ratio greater than 30 mg/g. The rationale is to
 include patients with macroproteinuria and patients with microalbuminuria.

 4. Estimated GFR greater than 30 mL/min/1.73m(2). The rationale is to exclude
 patients with severe CKD.

 EXCLUSION CRITERIA:

 1. Allergy to ACE inhibitor or ARB

 2. Current or planned pregnancy; urine HCG performed at start of study and on
 the day of iothalamate infusion.

 3. Serum potassium greater than 5.0 mEq/L off angiotensin antagonist therapy

 4. The presence of medical conditions which would make interpretation of
 results difficult such as cancer.

 5. History of iodine allergy or severe asthma (history of emergency department
 visit or hospitalization).

 SEX DIFFERENCES IN URINARY EXOSOME PROTEINS:

 INCLUSION CRITERIA:

 1. Age 18-30; Young adults are less likely to have undetected chronic renal
 disease.

 2. BMI 18-27.5 kg/m(2); Obesity may alter renal function.

 3. BP consistently less than 130/80; Pre-hypertension or hypertension may
 affect the kidney.

 EXCLUSION CRITERIA:

 1. Any chronic illness that might interfere with interpretation of the study;
 certain illnesses that do not require therapy may be consistent with
 inclusion, including mild asthma or psychiatric illness.

 2. Cancer other than non-melanoma skin cancer in the past 5 years.

 3. Need for any chronic or intermittent medication other than acetaminophen.

 4. Women: amenorrhea, irregular menses, menstrual cycles less than 26 days or
 greater than 32 days, or use of contraceptive hormones (unwilling or unable
 to switch to non-hormonal means of contraception); Irregular cycle may be
 non-ovulatory and associated with abnormal sex hormone profiles, which will
 complicate data interpretation.

 5. Use of nicotine or illicit drugs.

 6. Febrile illness or urinary tract infection: postpone admission one week or
 more.

 SALT INTAKE AND BLOOD PRESSURE RESPONSES IN URINARY EXOSOMES:

 INCLUSION CRITERIA:

 1. Men Age 18-35

 2. BMI 18-25 kg/m(2)

 3. BP consistently less than 130/80

 EXCLUSION CRITERIA:

 1. Any chronic illness that might interfere with interpretation of the study;
 certain illnesses that do not require therapy may be consistent with
 inclusion, including mild asthma or psychiatric illness

 2. Cancer other than non-melanoma skin cancer in the past 5 years

 3. Need for any chronic or intermittent medication other than acetaminophen

 4. Use of nicotine or illicit drug

 5. Febrile illness or urinary tract infection: postpone admission one week or
 more