Spironolactone for Reducing Proteinuria in Diabetic Nephropathy
Spironolactone for Reducing Proteinuria in Diabetic Nephropathy
Introduction: Aldosterone seems to have deleterious effects on the kidneys. Many animal
 studies and few clinical trials now have shown that suppression of aldosterone by aldosterone
 receptor blockers ameliorated these effects.

 Method: In a double-blind, cross over study, 24 patients with diabetic nephropathy who were
 already receiving either ACE inhibitor(lisinopril 20-40 mg/day ) or ARB( losartan 25-100
 mg/day )were given spironolactone( 25 mg during the first month and 50 mg during the second
 and third month if serum K remained ok) or matching placebo with 1 month of washout in
 between. All patients were from a single center and exclusively male veterans. Blood
 pressure, serum creatinine, serum K and spot urine protein/creatinine were measured at the
 beginning and end of each study period. The study was started in May of 2003 and completed in
 May 2006.
Spironolactone for reducing proteinuria and progression of renal failure in diabetic
 nephropathy

 Introduction:

 Diabetic nephropathy is the leading cause of ESRD in USA now and accounts for 40% of all new
 patients that begins renal replacement therapy each year. The number of new patients starting
 chronic dialysis therapy is 70,000 each year and is increasing. This number does not include
 patients who decline dialysis therapy or die soon after starting dialysis. The economic and
 human cost of diabetic nephropathy is therefore enormous.

 Aggressive control of blood pressure especially with ACE-inhibitor had been shown to reduce
 proteinuria and progression of renal dysfunction in both type 1 and type 2 diabetics. Use of
 ACE-inhibitor reduced proteinuria even in normotensive diabetics with microalbuminuria.
 However even with optimal use of ACE-Inhibitor the progression of renal dysfunction is not
 completely stopped. Other additional treatment strategies therefore need to be explored.

 Studies in animals and small pilot studies in humans have shown that nondihydropyridine
 calcium channel blockers (e.g. diltiazem or verapamil) may have additional protective effect
 in reducing proteinuria when used in conjunction with ACE-inhibitor. Use of angiotensin
 receptor blockers along with ACE-inhibitors also had been tried but results are not
 dependable because of the short sample size.

 While angiotensin plays the major role in glomerular hemodynamics there is increasing
 evidence that aldosterone plays a significant role in renal hemodynamics independent of
 angiotensin. In a remnant kidney model in the rat Greene et al showed that there was greater
 than 10-fold rise in aldosterone in the remnant kidney rats (REM) compared to SHAM operated
 ones. As expected, the proteinuria, hypertension and glomerulosclerosis in the REM rats were
 attenuated with treatment with ACE-inhibitor and angiotensin receptor blockers (REM AIIA).
 However when these rats (REM AIIA) were treated with aldosterone infusion the proteinuria,
 hypertension and glomerulosclerosis seen were similar to REM alone rats, suggesting
 deleterious renal hemodynamic effects of aldosterone independent of angiotensin II. Use of
 spironolactone in these rats transiently reduced proteinuria and lowered arterial pressure.

 Previous experiment in remnant kidney model also showed that adrenalectomy with adequate
 glucocorticoid replacement reduced the proteinuria and other evidence of renal injury usually
 seen in REM rats. Similarly heparin administration provides remarkably complete protection
 from injury in remnant kidney model. Although this effect could be due to any of several
 actions of heparin (anticoagulant and hemodynamic), it could be due to known suppressive
 action of heparin on aldosterone synthesis.

 In stroke-prone spontaneously hypertensive rats (SHRSP), renal vascular injury causing
 proteinuria and malignant nephrosclerotic lesions were markedly reduced by treatment with
 spironolactone, an aldosterone receptor blocker. The effect of spironolactone alone was
 comparable to effect of treatment with captopril, an ACE-inhibitor. In further studies Rocha
 et al had shown that the ameliorating effect of ACE-inhibition in the SHRSP rats could be
 fully reversed by infusion of aldosterone, suggesting a major role for aldosterone in the
 vascular injury in these rats as well. Importantly the deleterious effect of aldosterone and
 the protective effect of spironolactone against end organ damage in SHRSP rats appeared to be
 independent of the blood pressure effects.

 In another experiment, the Wistar-Furth rat, an inbred strain resistant to actions of
 mineralocorticoids, was used to study the concept that mineralocorticoids contribute to
 progressive renal injury. Renal damage, as evidenced by albuminuria and glomerulosclerosis,
 in response to 5/6 nephrectomy was markedly less in Wistar-Furth rats compared to Wistar
 rats. Treatment of hypertension seen in the nephrectomized Wistar rats did not protect them
 from renal injury suggesting again that mineralocorticoid mediated deleterious effect was
 independent of the blood pressure effect.

 Hyperaldosteronism has been noted as a component of clinical chronic renal insufficiency of
 various etiologies. In a cross sectional study of patients with mild to moderate renal
 insufficiency Hene et al observed that level of serum aldosterone increased as creatinine
 clearance fell below 70 cc/min and went up as high as 3-4 fold the baseline. Similarly in a
 study of 9 patients with average inulin clearance of 27cc/min, Bauer and Reams noted plasma
 aldosterone level to be four fold greater than normal. The significance of this
 Hyperaldosteronism as to the progression of the renal insufficiency had not been studied
 systematically, but in one longitudinal study Walker noted a significant correlation between
 aldosterone level and rate of progression of renal failure. In this longitudinal study of 131
 diabetic cohort, Walker noted that hypertension, plasma angiotensin II and aldosterone were
 independent predictors of accelerated loss of renal function.

 Although the distal tubule is considered the target for aldosterone action, aldosterone
 receptors had been found in myocardium, vascular smooth muscle cells and glomeruli .In vitro
 studies of cultured mesangial cells revealed increased production of type IV collagen after
 incubation with aldosterone. In a double blind controlled study MacFadyen and colleagues
 observed that spironolactone treatment reduced circulating levels of procollagen type III
 N-terminal amino peptide, a marker of vascular collagen turnover. Weber and other
 investigators have observed that aldosterone caused myocardial fibrosis and this effect could
 be ameliorated by treatment with spironolactone. In addition to the classical genomic action
 through the type 1 mineralocorticoid receptor, aldosterone is now known to have significant
 non-genomic mediated action in many different tissues including kidney tubules and vascular
 smooth muscle cells. Aldosterone also up regulates Angiotensin II membrane receptors thereby
 multiplying the vascular effect of Ang II. This upregulation was inhibited by treatment with
 spironolactone. These findings are consistent with a synergistic action between Ang II and
 aldosterone in the production of vascular injury as first proposed by Masson et al almost 4
 decades ago.

 The use of ACE inhibitors may strongly inhibit the RAAS, but their suppressive effect on
 aldosterone production may not be satisfactory. Indeed, in hypertension as well as in CHF,
 continuous treatment with ACE inhibitor did not produce a sufficient decrease in plasma
 aldosterone level, which remained high or increases eventually during long term use. In one
 study, patients treated with hefty doses of captopril (300 mg/day) had a doubling of the
 plasma aldosterone level at the end of 12 months of therapy despite marked decrease in ANG II
 level. The reasons for the unsatisfactory suppressive effect of ACE inhibitors on plasma
 aldosterone could be partly due to tachyphylaxis and also very likely due to predominance of
 the non-RAAS component of the control system for aldosterone production. Urinary clearance of
 aldosterone may also be reduced in CHF and CRF. On the basis of these understandings,
 spironolactone (25-50 mg a day) was used in a large multi-centered randomized controlled
 trial for treatment of congestive heart failure who already were receiving standard therapy
 with Ace inhibitors, diuretics and digoxin. The study was terminated in midway because
 interim analysis showed 30% reduction in mortality in the spironolactone treated group as
 opposed to the control. Of note, the incidence of hyperkalemia in the treatment group was
 only 1.7% as opposed to 1% in the placebo group. The incidence of gynecomastia was also
 modest (10% Vs 1%) in spite of use of other drugs like digoxin that are known also to cause
 gynecomastia.

 Planned Study:

 For this study we will recruit patients from the renal clinic at the VA medical center and
 also some patients from the primary care clinics at the same hospital. The study will be a
 double blind control study using each patient as his own control after a period of wash out
 phase.

 Inclusion criteria

 Patients with diabetic nephropathy (with proteinuria exceeding 100 mg per day while on ace
 inhibitor ) who are already being treated with ACE-Inhibitor at maximum tolerated dose. For
 lisinopril this dose usually will be 20-40 mg per day. Patients who are on angiotensin
 receptor blocker ( ARB ) due to inability to tolerate ace inhibitor ( e.g. due to cough )
 will be also considered for the study provided they stay on the same ARB at same dose
 throughout the study period.

 Exclusion criteria:

 Serum creatinine greater than 2.0 mg/dl Serum K greater than 5.0 meq/L Patients who need to
 use spironolactone for some other reasons Life expectancy less than 1 year For this pilot
 phase of the study we will investigate 30 patients (see attached sample size calculation)
 equally divided into control and treatment groups. Patients will be randomly allocated to the
 different groups by using computer generated randomization sequence. After 3 months on study
 medication (or placebo) the study group of patients will be switched to the placebo group and
 vice versa. Thus each patient will be his own control. There will be a month of wash out
 period in between this change over.

 Study drug:

 Study drug will be spironolactone. The starting dose will be 25 mg orally every day, which
 will be increased to 50 mg every day, if tolerated after 4 weeks. A matching placebo will be
 used for the placebo group. The VA pharmacy will prepare and provide the study drug as well
 as the placebo. The pharmacy will create and maintain the randomization numbers in a safe
 place so that the investigators and the study nurses remain blind to the whole randomization
 process all throughout the study period.

 Protocol of lab studies and follow up:

 All patients will be seen by one of the investigator and have a brief history and physical
 examination prior to randomization. All patients will have their blood pressured measured by
 a study nurse in a sitting position (average of two BP readings taken at 5 minutes interval
 will be recorded). Patients will be weighed at each visit also.

 The study related visits would be prior to randomization, day of randomization, at 1 month
 and at 3 month in study.

 The cycle will be repeated again for each patient after one month washout period after which
 their study drug will be reversed (placebo to study and study to placebo)

 All patients will have the following lab studies at the beginning (prior to randomization),
 at 1 month and at 3 month clinic visits:

 Renal panel 24 hours urine for protein and creatinine Renal panel can be done in between the
 prescribed study visits for clinical reasons.

 All patients will be continued on their other usual medication during the study period and
 changes will be made as deemed necessary by the clinicians taking care of patients. As far as
 possible the dose of ace inhibitor (or angiotensin receptor blocker) will be kept the same as
 at the beginning of randomization. Doses of calcium channel blocker (if they are on it) will
 also not be changed as much as possible during the study.
Inclusion Criteria:

 The study is completed. Inclusion criteria was diabetic nephropathy

 Exclusion Criteria:

 Scr >2 mg/dl and serum K > 5meq/L