Spironolactone for Reducing Proteinuria in Diabetic Nephropathy
Condition: Diabetic Nephropathy
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Proteinuria
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): spironolactone
Intervention type(s): Drug
Intervention MeSH terms: Spironolactone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: spironolactone; aldosterone; diabetic nephropathy; proteinuria; hyperkalemia; albuminuria; renal failure