Please select the eligibility criteria that correspond to the clinical trial below.
Title: Improving Outcomes in Diabetic Nephropathy
Brief Summary: Kidney disease affects about one out of three people with diabetes mellitus, a common medical problem. Treatment of kidney disease with medications that lower blood pressure can slow the kidney disease but there is no known cure. This study is designed to test the hypothesis that certain combination-based blood pressure lowering regimens (of FDA approved medications) are better than single agent-based regimens for lowering blood pressure and further slowing or preventing progression of this incurable disease


Options:
A: Inclusion Criteria:

* Proteinuria \> 500 mg/24 hours
* Hypertension or anti-hypertensive treatment

Exclusion Criteria:

* Diabetic nephropathy
* GFR\< 20 ml/min
* P-potassium between 3,5 mmol/l and 5,0 mmol/l
B: Inclusion Criteria:

* Adult male and female subjects aged 20-65 of all ethnic backgrounds.
* Type I diabetes mellitus defined as sudden onset of insulin requiring diabetes prior to age 20 and at least 5 years duration
* Type 2 diabetes mellitus defined as onset \> 20 years of age and treatment with oral hypoglycemic agent and/or insulin and increased C-peptide level.
* Seated SBP \> 130 mmHg documented at one screening visit or treated SBP \< 130 mmHg with a documented history of SBP \> 130 mmHg on more than one previous occasion
* Proteinuria defined as a 24-hour urine albumin/creatinine ratio \> 300 mg/g while on an ACE inhibitor with or without non-ARB, non-aldosterone antagonist treatment
* Ongoing treatment (\> 3 months) with an ACE inhibitor or ARB with or without additional antihypertensive therapy (e.g. CCB, a-blocker, b-blocker, clonidine).

Exclusion Criteria:

* BMI \> 45 kg/m2
* Baseline serum creatinine \> 3.0 mg/dl in females and \> 4.0 mg/dl in males or creatinine clearance \<20 ml/min estimated by Cockcroft-Gault equation (based on age, fasting serum creatinine concentration and ideal body weight in kilograms).
* Secondary cause of kidney disease other than diabetic nephropathy
* Serum potassium concentration \>5.5 mEq/L on ACE inhibitor therapy 7-10 days prior to randomization
* Poorly controlled diabetes, i.e. HgbA1C \> 11 mg/dl 7-10 days prior to randomization
* History of allergy to iothalamate or history of renal failure due to contrast nephropathy
* Stroke or myocardial infarction within the preceding 12 months prior to randomization
* Coronary revascularization procedure within past 6 months
* Clinically apparent congestive heart failure defined as clinical signs of heart failure or an ejection fraction of \< 40% (and/or depressed LV systolic function by echocardiogram).
* Terminal disease including cancer and AIDS
* Documented increase in serum creatinine \> 50% of baseline within 3 months prior to the run-in period
* Renal disease known or in the opinion of the investigator caused by a condition other than diabetes
* Known adverse reaction to study medications including ACE inhibitors, ARB and spironolactone
* History of chronic or intermittent gross hematuria
* Spontaneous 24-hour urine sodium excretion rate exceeding 350 mEq/day
* AST or ALT greater than 2.5 the upper limit of normal for the laboratory
* Pregnancy
* History of autoimmune disease, connective tissue disease or multiple drug allergies
* Anticipated need for renal replacement therapy within 12 months Inclusion criteria for normal subjects
* Adult male and female subjects aged 20-65 of all ethnic backgrounds Exclusion criteria for normal subjects
* Chronic medical conditions, including but not limited to diabetes mellitus, hypertension, chronic kidney disease, and hyperlipidemia.
* Use of medications for antihypertensive
* Inability to follow study protocol for any reason
C: Inclusion Criteria:

1. Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent ethical committee. Specifically, all participating patients will be asked to give informed consent for long-term follow-up and collection of follow-up data
2. Male or female patients ≥ 18 years and \< 75 years of age at Screening visit
3. Type 2 DM (WHO criteria)
4. Persistent normoalbuminuria (at least 2 of 3 UACR \< 30 mg/g samples from "run in"-period)
5. Estimated GFR \>45 ml/min/1.73m2 (MDRD formula) at Screening visit
6. The patient must be willing and able to comply with the protocol for the duration of the study
7. Female without child-bearing potential at the screening visit. Defined as one or more of following:

7.1) Female patients ≥ 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year 7.2) Female patients \< 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year and serum follicle stimulating hormone levels \> 40 milli International unit / mL as well as serum estrogen levels \< 30 pg/ml or a negative estrogen test.

7.3) 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy.

OR a negative urine pregnancy test at the Screening visit AND one or more of following:

7.4) Correct use of reliable contraception methods. This includes one or more of the following: hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring or oral) or an intrauterine device (IUD) OR correct use of double barrier with one of the following: barrier methods (diaphragm, cervical cap, Lea contraceptive or condom) AND in combination with a spermicide.

7.5) General sexual abstinence from the time of screening/ baseline, during the study until a minimum of 30 days after the last administration of study medication if this is already established as the patient's preferred and usual lifestyle.

7.6) Having only female sexual partners. 7.7) Sexual relationship with sterile male partners only

Exclusion Criteria:

1. Average of systolic BP\< 110 or \>160 mm Hg at baseline
2. Average of diastolic BP \> 100 mm Hg at baseline
3. Type 1 DM (WHO criteria)
4. HbA1c \<6.5% (48 mmo l/ mol) AND \> 5 years of known duration of diabetes type 2 AND never treated with an antidiabetic drug of any kind.
5. Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor)
6. Current lithium treatment
7. Known or suspected hypersensitivity to Spironolactone or to any of its excipients.
8. Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or Amiloride etc.
9. Screening (week -6) plasma (or serum) potassium level \>5.0 mmol/L
10. Low plasma sodium determine by the investigator
11. Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer)
12. Any clinically significant disorder, except for conditions associated with type 2 DM history, which in the Investigators opinion could interfere with the results of the trial
13. Cardiac disease defined as: Heart failure (NYHA class III-IV) and/or diagnosis of unstable angina pectoris and/or myocardial ischemia, stroke, cardiac re-vascularisation or coronary artery bypass within the last 3 months
14. Diagnosis of non-Diabetic CKD current or in the past
15. Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years.
16. Diagnosis of Addison's disease.
17. Being lactating.
18. Intend to become pregnant within the duration of the study or not use adequate birth control.
19. Known or suspected abuse of alcohol or narcotics
20. Not able to understand informed consent form
21. Participation in any other intervention trial than PRIORITY or a related sub-study is not allowed within 30 days before inclusion or concurrent to this study
D: INCLUSION CRITERIA:

* Heart failure as defined by at least one of symptom (paroxysmal nocturnal dyspnea; orthopnea; or dyspnea on mild or moderate exertion) at the time of screening and at least one sign (any rales post cough; jugular venous pressure(JVP) greater than or equal to 10cm of water(H2O); lower extremity edema; or chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly) within 12 months prior to study entry:
* left ventricular ejection fraction greater than or equal to 45% (per local reading); the ejection fraction must have been obtained within 6 months prior to randomization and after any MI or other event that would affect ejection fraction
* Controlled systolic blood pressure(BP), defined as a target systolic BP less than 140 mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP
* Serum potassium less than 5.0 mmol/L prior to randomization
* At least one hospital admission for which heart failure was a major component of the hospitalization some time within the 12 months prior to study entry OR brain natriuretic peptide (BNP) greater than or equal to 100pg/ml or N-terminal pro-BNP greater than or equal to 360pg/ml within the 60 days prior to study entry
* Women of child-bearing potential must have a negative serum/urine pregnancy test within 72 hours prior to randomization, must not be lactating, and must agree to use an effective method of contraception during the entire course of study participation
* Willing to comply with scheduled visits
* Informed consent form signed by the subject prior to participation in the trial

EXCLUSION CRITERIA:

* Severe systemic illness with an expected life expectancy of less than 3 years
* Chronic pulmonary disease requiring home O2, oral steroid therapy, or hospitalization for exacerbation within 12 months of study entry, or significant chronic pulmonary disease in the opinion of the investigator
* Known infiltrative or hypertrophic obstructive cardiomyopathy or known pericardial constriction
* Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant, or any valvular disease expected to lead to surgery during the trial
* Atrial fibrillation with a resting heart rate greater than 90 bpm
* MI in the past 90 days
* Coronary artery bypass graft surgery in the past 90 days
* Percutaneous coronary intervention in the past 30 days
* Heart transplant recipient
* Currently implanted left ventricular assist device
* Stroke in past 90 days
* Systolic BP (SBP) greater than 160 mm Hg
* Known orthostatic hypotension
* Gastrointestinal disorder that could interfere with study drug absorption
* Use of any aldosterone antagonist or potassium sparing medication in the last 14 days or any known condition that would require the use of an aldosterone antagonist during study participation;
* Known intolerance to aldosterone antagonists
* Current lithium use
* Current participation (including prior 30 days) in any other therapeutic trial
* Any condition that, in the opinion of the investigator, may prevent the participant from adhering to the trial protocol
* History of hyperkalemia (serum potassium greater than or equal to 5.5mmol/L) in the past 6 months or serum potassium greater than or equal to 5.0mmol/L within the past 2 weeks
* Severe renal dysfunction, defined as an estimated glomerular filtration rate(GFR) less than 30ml/min. Participants with serum creatinine greater than or equal to 2.5mg/dl are also excluded even if their GFR is greater than or equal to 30ml/min
* Known chronic hepatic disease, defined as aspartate aminotransferase(AST) and alanine aminotransferase(ALT) levels greater than 3.0 times the upper limit of normal as read at the local lab.

Answer: B