State III to Stage V Renal Dysfunction & Significant Restoration to Normal EGFR by Novel ACE Inhibitors-A Retrospective Study

In early 2000, I had encountered a patient with declining EGFR, below normal value in addition to having uncontrolled blood pressure, (he was on Enalapril 5mg od). I had increased his Enalapril to 20mg once per day for six to eight weeks and observed a normalized EGFR with improved blood pressure control without an increase in serum potassium or creatinine. This experience inspired me to my recent trial treatment of Perindopril and Trandolopril. In addition, Olmesartan was tried and observed to be not as beneficial in renal repairment.


Introduction
In early 2000, I had encountered a patient with declining EGFR, below normal value in addition to having uncontrolled blood pressure, (he was on Enalapril 5mg od). I had increased his Enalapril to 20mg once per day for six to eight weeks and observed a normalized EGFR with improved blood pressure control without an increase in serum potassium or creatinine. This experience inspired me to my recent trial treatment of Perindopril and Trandolopril. In addition, Olmesartan was tried and observed to be not as beneficial in renal repairment.

Past Investigations
Heerspink et al. [1] described an analyses of the ADVANCE trial and outlined a high risk of cardiovascular disease in individuals with diabetes and chronic kidney disease. The authors assessed the effects of ACEI in patients with type 2 diabetes according to baseline chronic kidney disease. Blood pressure reduction prevents cardiovascular events in high risk patients [2]. In diabetic patients, ACE inhibitors and diuretics have been most commonly used for their risk reduction of renal and cardiovascular events [3].
Earlier in 2008, Sue [4] described a reduction of renal disease in diabetic patients with a treatment consisting of Perindopril/ Indapamide. The main results from the blood pressure part of the ADVANCE trial showed a reduction in major events including death with Perindopril/Indapamide compared to placebo group among diabetic patients. The researchers explained the blood pressure being a key determinant of nephropathy.
Ghiadani [5] in July 2010 provided further correction of ADVANCE trial. He stated that a blood pressure reduction and glucose lowering were effective in reducing morbidity and mortality. In the trial, further evidence was obtained of intensive glycemic control with Gliclazide MR in combination with Perindopril/Indapamide. Lewis et al. [6] outlined a study on the effect of Captopril on renal protection properties independent of it's effect on blood pressure in diabetic nephropathy.
Zhang et al. [7] in Prisma Compliant Network Meta Analysis showed a superiority of Trandolopril among ACEI in controlling the blood pressure.
Further study by Li et al. [8] in 2015 demonstrated an effective Ace inhibitor action of Trandolopril. Svenstorm et al. [9] in March 2015 also showed equal effects of different ACEI on mortality in systolic heart failure.

Method
In my practice of approximately 5 to 6 thousand patients, approximately 10% are diabetic. The factors contributing to renal dysfunction have been identified as family history, lifestyles, obesity, alcohol addiction, uncontrolled blood pressure etc. A few patients with renal dysfunction have demonstrated at the earliest stage that blood pressure control in addition to glycemic control being a challenging issue. The current study of approximately twelve months duration, of patients on ACEI trial has been based on monitoring of Hb A1C, Na, K, Urea, Creatinine and EGFR.
Patients with EGFR lower than 59 were started on either 8 mg of Perindopril/day or 2-4mg of Trandolopril in resistant cases. The increase in EGFR was observed within four to sixteen weeks. e.g. patients with EGFR of 40-42 demonstrated normalization in twelve to sixteen weeks. In cases of EGFR less than 40, Trandolopril treatment had shown beneficial effects while being resistant to Perindopril. In cases of EGFR lower than 20, the extent of increases were multi-factorial e.g. glycemic control or the degree of anemia of chronic disease. The patients were in the age group of 35 to 90 years and gender distribution of male to female was 1.5 to 0 .5.

Observations
The laboratory data of the patients from pre-treatment level to current stage are listed on the table.

a.
Improvement in renal functions on sustained basis was observed in STAGE III impairment in diabetics with a 30% decline of EGFR (from normal) to a restoration value of 59 in six to sixteen weeks with a treatment of Perindopril 8 mg/day. During this time period blood pressure control was optimal Table 1. Once restoration of EGFR to normal value, the improvements remained sustained with the continuation of ACEI Table 2.  e. Among patients with extreme stage IV dysfunction e.g. EGFR 12-20, the progression to further decline remained curtailed by Trandolopril 4mg/day treatment Table 3. f.
During the course of treatment with either Perindopril 8mg or Trandolopril 4mg serum creatinine and potassium remained in normal range.

g.
Patients with anemia of chronic disease (Hb value less than 90) showed a reduction in EGFR in spite of the optimal dose of ACE inhibitor. However an increase was observed once the value of HbA1C had improved to more than 100 Table 4. i.
The study consisted of predominantly diabetic patients however two patients with hypertension (STAGE IV ) and gout (STAGE III) showed renal dysfunction as well, however, in the latter case a normal EGFR has been restored with Perindopril. j.
Recently, a female patient, 75 yrs old with early stage diabetes and STAGE III dysfunction (EGFR 36) had improvement of EGFR to 46 with Perindopril in eight weeks. After discontinuation of ATACAND 16mg however, suffered from persistent cough from ACEI. The end result was that EGFR had declined back to 36, once the ARB was restarted.

Applications
The restoration of renal disease to a normal EGFR value has not only prevented a deterioration to ESRD, anemia, future cardiac events but also rendered the patients being able to seek treatments with newer medications which otherwise would not be accessible due to dysfunctions e.g. SGLT inhibitors. In addition the incidences of patients requiring dialysis have been drastically reduced.