The purpose of the study is to provide pertinent information to enable decisions regarding the developability of LHW090 for use in patients with chronic renal insufficiency, including a comparison of the potential risk-benefit ratio of several doses of the study drug to enable optimal doses to be tested in later studies.

Inclusion Criteria: For Stage 1, 2 and 3 subjects only:

Subjects eligible for inclusion in these stages of the study have to fulfill all of the following criteria at screening:

• Healthy male and female subjects age 18 to 45 years of age included, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
• At screening, and first baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes, and again (when required) after three minutes in the standing position. Sitting vital signs should be within the following ranges:

oral body temperature between 35.0-37.5 °C systolic blood pressure, 90-140 mm Hg diastolic blood pressure, 50-90 mm Hg pulse rate, 40 - 90 bpm

For Stage 4 subjects only:

• Male and female subjects, age 18 to 75 years of age included, with previously identified chronic renal insufficiency (estimated or measured GFR ≤ 45ml/min/1.73m2, or diabetic with estimated or measured GFR ≤ 60ml/min/1.73m2.) Diabetes can be established by the prescription and current use of anti-glycemic drugs, a random fasting glucose level of ≥ 144mg/dl or a hemoglobin A1c of ≥ 6.5%
• At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes, and again (when required) after three minutes in the standing position. Sitting vital signs should be within the following ranges:

oral body temperature between 35.0-37.5 °C systolic blood pressure, 90-179 mm Hg diastolic blood pressure, 50-100 mm Hg pulse rate, 40 - 95 bpm

Exclusion Criteria:

For Stages 1, 2 and 3, subjects fulfilling any of the following additional criteria are not eligible for inclusion in this study:

• An active history of clinically significant ECG abnormalities as determined by the Investigator, or any of the following ECG abnormalities at Screening or Baseline:
• Long QT syndrome
• QTcF > 450 msec (males; at screening)
• QTcF > 460 msec (females; at screening)
• Known history of current clinically significant arrhythmias.
• Use of phosphodiesterase-5 inhibitors, UNLESS subjects agree to discontinue use of the drug for the duration of the study.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant
• Smokers (use of tobacco products in the previous 3 months). Urine cotinine levels will be measured during screening and at each baseline for all subjects. Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine ≥ 500 ng/ml.
• Hemoglobin levels below 11.0 g/dl at screening.
• Subjects in Stage 3 only of the study will be excluded if they have any of the following:
• A history of allergy to topical anesthetic drops
• A history of corneal disease
• A history of eye surgery within three months prior to screening
• A history of corneal surgery (including refractive surgery and corneal transplantation)

For Stage 4, subjects fulfilling any of the following additional criteria are not eligible for inclusion in this study:

• An active history of clinically significant ECG abnormalities as determined by the Investigator, or any of the following ECG abnormalities at Screening or Baseline:
• Long QT syndrome
• QTcF > 480 msec at screening
• Use of phosphodiesterase-5 inhibitors, UNLESS subjects agree to discontinue use of the drug for the duration of the study.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant
• Significant smokers. Significant smokers who are unable to tolerate using no more than 4 cigarettes a day should be excluded
• History of right ventricular dysfunction within the last 12 months
• Hemoglobin levels below 9.0 g/dl at screening.
• Use of angiotensin converting enzyme inhibitors (ACEi), UNLESS subjects agree to either a withholding of their ACEi, or a switch to an angiotension receptor blocker, starting 5 days (or 5 half-lives which ever is longer) prior to initiation of study and extending to the end-of-study visit. Patient who withhold their ACEi for the specified duration must first consult with their primary physician to determine their suitability and safety for this temporary withholding of ACEi.
• Diuretic-dependence, i.e. unable to produce urine without diuretics, or at high risk of flash pulmonary edema without diuretics. Use of diuretics will exclude subjects UNLESS subjects agree to withhold diuretics starting the day prior to check-in and extending to discharge. Consultation of the subject with their primary physician must be used to determine their suitability and safety for temporary withholding of their diuretics.