- Email: [email protected]
Progress Toward Novel Treatments for Chronic Kidney Disease
Progress Toward Novel Treatments for Chronic Kidney Disease Sudhir V. Shah, MD, FACP Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin–angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
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HRONIC KIDNEY DISEASE (CKD) is a global public health problem that affects approximately 10% to 15% of the adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. The expected marked increase in diabetes, the most common cause of CKD, increasing incidence of end-stage kidney disease despite the use of angiotensin receptor blockers, and the multiplier effect of CKD on cardiovascular disease, all point to a major challenge facing healthcare systems worldwide. In this review, we summarize information related to potential new treatments for halting the progression of kidney disease. We also emphasize the importance of basing treatment on well-controlled, randomized trials, as illustrated by 2 examples in which initial, promising results were not borne out by adequately controlled trials.
Aliskiren Aliskiren, an oral renin inhibitor,1 has been approved recently by the U.S. Food and Drug Administration and the European Medicines Agency.
Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Renal Section, Medicine Service, John L. McClellan Memorial Veterans Hospital, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. S.S. has a financial interest in Shiva Biomedical, LLC, and CorMedix, Inc., companies which are exploring the use of iron chelators for treatment of kidney disease. Address reprint requests to Sudhir V. Shah, 4300 West 7th Street, 111D, Little Rock, AR 72205. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.06.013
S122
The renoprotective effect of adding aliskiren to a regimen of losartan for patients with diabetic nephropathy has been reported recently.2 In a study published in New England Journal of Medicine, 599 patients were enrolled in a randomized, doubleblind study during which patients received 100 mg of losartan daily. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20%, with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P , .001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P 5 .07] and diastolic, 1 mm Hg lower [P 5 .08] in the aliskiren group). It was concluded that aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. Despite promising results, it should be emphasized that the reduction in proteinuria does not necessarily translate into long-term protection against progressive kidney disease. A recent example of this is the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study, where a combined administration of angiotensin receptor blockers and angiotensinconverting enzyme (ACE) inhibitors resulted in decreased proteinuria but had an adverse effect on the decrease in the glomerular filtration rate.3 Thus, there is a large, randomized, placebocontrolled, ongoing trial in diabetic nephropathy, ALTITUDE (Aliskiren Trial in Type 2 Diabetes using Cardiovascular and Renal Disease
Journal of Renal Nutrition, Vol 20, No 5S (September), 2010: pp S122–S126
PROGRESS TOWARD NOVEL TREATMENTS FOR CKD
Endpoints).4 This trial will compare aliskiren at a dose of 300 mg daily with placebo in patients with type 2 diabetes undergoing conventional therapy who are at high risk for cardiovascular and renal mortality and morbidity. The primary endpoints of this study will be doubling of serum creatinine, onset of end-stage renal disease (ESRD), cardiovascular-related death, myocardial infarction, and stroke.
Sulodexide Sulodexide is a glycosaminoglycan composed of 80% heparin sulfate and 20% dermatan sulfate, but does not have anticoagulation properties when administered orally.5 The mechanism is unknown but may include restoration of the ionic charge barrier of the glomerular basement membrane, suppression of mesangial cell proliferation, and reduction of matrix formation. The efficacy of sulodexide in diabetes has been evaluated in several studies including the diabetic nephropathy and albuminuria sulodexide (DiNAS) study. In addition, in a study of 149 patients with type 2 diabetes and microalbuminuria, the primary endpoint of 50% reduction in albumin-to-creatinine ratio or return to normoalbuminuria was achieved in a significant number of patients.6 However, a randomized, double-blind, placebo-controlled trial involving 1,000 patients with diabetes and persistent microalbuminuria (SUN-Micro Trial) failed to reach the primary endpoint of reduction in urine albumin. As a result, another phase 4 trial that had already been planned, the SUN-Macro Trial, was cancelled. Thus, a promising therapy on change in a marker of nephropathy progression (i.e., microalbuminuria) tested early in its development failed to perform in an adequately powered study.
Ruboxistaurin: A Protein Kinase C Inhibitor A key metabolic pathway involved in the pathogenesis of diabetic complications is overexpression of protein kinase C (PKC). Several activators of this family of intracellular kinases have been identified, and PKC activation may result in tissue damage through a variety of mechanisms, including activation of an extracellular signal-regulated kinase pathway and generation of oxidants through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In animal models, the PKC-b inhibitor ruboxistaurin reduced oxida-
S123
tive stress by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activation and provided functional and histological protection. Human studies using ruboxistaurin in patients with diabetic nephropathy have provided mixed results. In preliminary human studies, ruboxistaurin therapy resulted in a 24% reduction in proteinuria at 1 year and stabilization of the glomerular filtration rate as compared with placebo. However, all enthusiasm for this initial finding was tempered when the investigators of the PKC Diabetic Retinopathy Study 2 reported that the occurrence of diabetic nephropathy was more frequent in ruboxistaurin-treated patients as compared with placebo (n 5 7 [2%] versus n 5 0; P 5 0.015). A recent, more extensive and collective evaluation of all diabetic retinopathy trials has shown that there was no difference in diabetic nephropathy in ruboxistaurin-treated patients compared with placebo.7 Larger clinical trials are clearly needed to further evaluate the usefulness of this drug in treating diabetic nephropathy. The Food and Drug Administration did not give approval for treatment of retinopathy and required further testing. As a result, the company has halted further development of the product.
Pirfenidone Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is a low-molecular-weight synthetic molecule with antifibrotic properties. The mechanism of action is not well understood, but pirfenidone has been shown to reduce transforming growth factor beta 1 (TGF-b1) production, antagonize tumor necrosis factor a signaling, and scavenge reactive oxygen species. In the 5/6 nephrectomy rat model of postadaptive focal segmental sclerosis, pirfenidone treatment attenuated the accumulation of glomerular matrix protein, the expression of glomerular transforming growth factor beta (TGF-b), and the loss of glomerular filtration. Clinical trials have evaluated the safety and efficacy of pirfenidone in various fibrotic diseases including liver cirrhosis and pulmonary fibrosis.8 In a model of diabetic nephropathy, pirfenidone was shown to reduce generation of reactive oxidant species and to significantly reduce mesangial matrix expansion without affecting albuminuria. The authors concluded that pirfenidone may be renoprotective in diabetic kidney disease and may exert its antifibrotic effect in part by inhibiting
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RNA processing.9 In an open-label trial, pirfenidone was shown to slow the loss of kidney function in patients with focal segmental sclerosis. It is noteworthy that this effect was observed without any reduction in proteinuria.10
Pentoxifylline Pentoxifylline, a nonselective phosphodiesterase inhibitor, exerts potent inhibitory effects against cell proliferation, inflammation, and extracellular matrix accumulation.11 Pentoxifylline appears to have anti-inflammatory properties, with the ability to decrease serum and tumor necrosis factor in patients with diabetic nephropathy. A meta-analysis evaluating its utility as a potential therapeutic agent for diabetic nephropathy included 10 studies investigating 476 patients with a median duration of 6 months of treatment. Pentoxifylline significantly decreased proteinuria, the decrease being similar to that obtained by an angiotensin-converting enzyme (ACE) inhibitor.12 In a randomized, controlled study, the addition of pentoxifylline to patients with persistent proteinuria, after treatment with losartan, resulted in further reduction in proteinuria.11
Bicarbonate Experimental evidence that metabolic acidosis may be important in progression of renal failure has been conflicting. In a recent study, the hypothesis that oral bicarbonate supplementation in patients with acidosis would be associated with attenuation of the rate of decline in renal function was examined. Adult patients (n 5 134) with CKD (creatinine clearance, 15 to 30 mL/min; serum bicarbonate, 16 to 20 mmol/L) were randomly assigned to supplementation with oral bicarbonate or standard care for 2 years. In comparison with the control group, the decline in creatinine clearance was slower with bicarbonate supplementation (5.93 versus 1.88 mL/min/1.73 m2; P ,.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression and develop ESRD. Nutritional parameters improved significantly with bicarbonate supplementation, which was well tolerated. This study demonstrates that bicarbonate supplementation slows the rate of progression of renal failure to ESRD and improves nutritional status among patients with CKD.13
Allopurinol There is evidence to suggest that hyperuricemia may have a pathogenetic role in progression of kidney disease. In a prospective, randomized control trial of 54 hyperuricemic patients with CKD, patients were assigned to treatment with allopurinol or to continue usual therapy for 12 months.14 There was a trend toward lowered serum creatinine levels in the treatment group compared with controls, although, given the small numbers, it was not statistically significant. The availability of new compounds that can decrease serum uric acid may result in larger clinical trials to evaluate halting progression by reducing serum uric acid levels.
Labile Iron The pathological effects of iron accumulation in tissue in iron-overload states, such as described in thalassemia patients, are well known. What is new in the field is the recognition that iron plays an important role in the pathophysiology of tissue injury in the absence of systemic iron overload. Iron is the most abundant transitional metal in the body. The ability to cycle reversibly between its ferrous and ferric oxidation states is critical to the importance of iron in biological processes. This precise property, which is essential for its functions, also makes it very dangerous, because free iron can catalyze the formation of free radicals which can damage the cell.15 The role of labile iron in a disease model has been delineated by demonstration of both an increase in labile iron and the protective effect of an iron chelator. The role of labile iron has been examined in several models of leukocyte-dependent and leukocyte-independent models of glomerular disease (reviewed by Shah et al.)16 The antiglomerular basement membrane antibody is a well-characterized model of complement- and neutrophil-dependent glomerular injury. In a rabbit model,16 reported that an iron chelator significantly attenuated proteinuria. In addition to proliferative glomerulonephritis, the ability of glomerular cells to generate oxidants suggests that they may act as important mediators of injury in glomerular diseases that lack infiltrating leukocytes. An animal model of minimal change disease is induced by a single intravenous injection of puromycin aminonucleoside. Labile iron (measured as bleomycin-detectable iron) was markedly increased in glomeruli from nephrotic rats, and an
PROGRESS TOWARD NOVEL TREATMENTS FOR CKD
iron chelator prevented an increase in catalytic iron in glomeruli and provided complete protection against proteinuria, suggesting an important pathogenic role for labile iron in this model. Baliga and colleagues have demonstrated that cytochrome P45017 and, more specifically, cytochrome P450 2B1, an isozyme present in the glomerulus, are sources of catalytic iron that participate in glomerular injury in this model. Passive Heymann nephritis, induced by a single intravenous injection of anti-Fx1A, is a complement-dependent model of glomerular disease that resembles membranous nephropathy in human beings. The administration of an iron chelator markedly reduces proteinuria, suggesting the role of labile iron in passive Heymann nephritis. The severity of tubulointerstitial injury is a major determinant of the degree and rate of progression of renal failure. The data supporting the role of iron in models of progressive renal disease consist of demonstration of increased iron in the kidney; enhanced oxidant generation, which provides a mechanism by which iron can be mobilized; and the beneficial effect of iron-deficient diets and iron chelators. Several studies have demonstrated an important role of iron in progressive kidney disease. It was reported that an iron-deficient diet or iron chelators prevent the development of tubulointerstitial disease and renal functional deterioration in nephrotoxic serum nephritis. Remuzzi et al. have shown that rats fed on an iron-deficient diet had a significant reduction in proteinuria and developed less glomerulosclerosis, as reviewed by Shah et al. in Journal of the American Society of Nephrology.16 Most importantly, in preliminary studies we have shown that treatment with deferiprone (L1) leads to a marked reduction in proteinuria over a 9-month period in patients with diabetic nephropathy.18 In addition, in a preliminary, open-label, proofof-concept study, patients with biopsy-proven glomerulonephritis were treated with deferiprone, and the urinary protein and serum creatinine were obtained 2 to 6 months after the administration of the iron chelator. Treatment with the iron chelator significantly decreased the amount of total urinary protein in patients with glomerulonephritis.19
Conclusion Chronic kidney failure remains a major health problem worldwide. Although current treatment
S125
is focused on the renin–angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.
References 1. Gradman AH, Schmieder RE, Lins RL, et al: Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 111:1012-1018, 2005 2. Parving HH, Persson F, Lewis JE, et al: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358:2433-2446, 2008 3. Mann JFE, Schmieder RE, McQueen M, et al: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 372:547-553, 2008 4. Parving HH, Brenner BM, McMurray JV, et al: Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 24:1663-1671, 2009 5. Burney BO, Kalaitzidis RG, Bakris GL: Novel therapies of diabetic nephropathy. Curr Opin Nephrol Hypertens 18: 107-111, 2009 6. Heerspink HL, Greene T, Lewis JB, et al: Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria. Nephrol Dial Transplant 23:1946-1954, 2007 7. Tuttle KR, McGill JB, Haney DJ, et al: Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin J Am Soc Nephrol 2:631-636, 2007 8. Azuma A, Nukiwa T, Tsuboi E, et al: Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 171:1040-1047, 2005 9. RamachandraRao SP, Zhu Y, Ravasi T, et al: Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol 20: 1765-1775, 2009 10. Cho ME, Smith DC, Branton MH, et al: Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2:906-913, 2007 11. Lin SL, Chen YM, Chiang WC, et al: Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12-month randomized trial. Am J Kid Dis 52:464474, 2008 12. McCormick BB, Sydor A, Akrari A, et al: The effect of pentoxifylline on proteinuria in diabetic kidney disease: a metaanalysis. Am J Kidney Dis 52:454-463, 2008 13. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 20:2075-2084, 2009
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14. Siu YP, Leung KT, Tong MKH, et al: Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kid Dis 47:51-59, 2006 15. Halliwell B, Gutteridge JMC: Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 186:1-85, 1990 16. Shah SV, Baliga R, Fonseca VA, et al: Oxidants in chronic kidney disease. J Am Soc Nephrol 18:16-28, 2007
17. Liu H, Shah SV, Baliga R: Cytochrome P-450 as a source of catalytic iron in minimal change nephrotic syndrome in rats. Am J Physiol Renal Physiol 280:F88-F94, 2002 18. Rajapurkar MM, Alam MG, Bhattacharya A: Novel treatment for diabetic nephropathy [abstract]. J Am Soc Nephrol 18:329A, 2007. 19. Rajapurkar MM, Baliga R, Shah SV: Treatment of patients with glomerulonephritis with an oral iron chelator [abstract]. J Am Soc Nephrol 18(Abstracts issue):57A-58A, 2007
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HRONIC KIDNEY DISEASE (CKD) is a global public health problem that affects approximately 10% to 15% of the adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. The expected marked increase in diabetes, the most common cause of CKD, increasing incidence of end-stage kidney disease despite the use of angiotensin receptor blockers, and the multiplier effect of CKD on cardiovascular disease, all point to a major challenge facing healthcare systems worldwide. In this review, we summarize information related to potential new treatments for halting the progression of kidney disease. We also emphasize the importance of basing treatment on well-controlled, randomized trials, as illustrated by 2 examples in which initial, promising results were not borne out by adequately controlled trials.
Aliskiren Aliskiren, an oral renin inhibitor,1 has been approved recently by the U.S. Food and Drug Administration and the European Medicines Agency.
Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Renal Section, Medicine Service, John L. McClellan Memorial Veterans Hospital, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. S.S. has a financial interest in Shiva Biomedical, LLC, and CorMedix, Inc., companies which are exploring the use of iron chelators for treatment of kidney disease. Address reprint requests to Sudhir V. Shah, 4300 West 7th Street, 111D, Little Rock, AR 72205. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.06.013
S122
The renoprotective effect of adding aliskiren to a regimen of losartan for patients with diabetic nephropathy has been reported recently.2 In a study published in New England Journal of Medicine, 599 patients were enrolled in a randomized, doubleblind study during which patients received 100 mg of losartan daily. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20%, with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P , .001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P 5 .07] and diastolic, 1 mm Hg lower [P 5 .08] in the aliskiren group). It was concluded that aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. Despite promising results, it should be emphasized that the reduction in proteinuria does not necessarily translate into long-term protection against progressive kidney disease. A recent example of this is the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study, where a combined administration of angiotensin receptor blockers and angiotensinconverting enzyme (ACE) inhibitors resulted in decreased proteinuria but had an adverse effect on the decrease in the glomerular filtration rate.3 Thus, there is a large, randomized, placebocontrolled, ongoing trial in diabetic nephropathy, ALTITUDE (Aliskiren Trial in Type 2 Diabetes using Cardiovascular and Renal Disease
Journal of Renal Nutrition, Vol 20, No 5S (September), 2010: pp S122–S126
PROGRESS TOWARD NOVEL TREATMENTS FOR CKD
Endpoints).4 This trial will compare aliskiren at a dose of 300 mg daily with placebo in patients with type 2 diabetes undergoing conventional therapy who are at high risk for cardiovascular and renal mortality and morbidity. The primary endpoints of this study will be doubling of serum creatinine, onset of end-stage renal disease (ESRD), cardiovascular-related death, myocardial infarction, and stroke.
Sulodexide Sulodexide is a glycosaminoglycan composed of 80% heparin sulfate and 20% dermatan sulfate, but does not have anticoagulation properties when administered orally.5 The mechanism is unknown but may include restoration of the ionic charge barrier of the glomerular basement membrane, suppression of mesangial cell proliferation, and reduction of matrix formation. The efficacy of sulodexide in diabetes has been evaluated in several studies including the diabetic nephropathy and albuminuria sulodexide (DiNAS) study. In addition, in a study of 149 patients with type 2 diabetes and microalbuminuria, the primary endpoint of 50% reduction in albumin-to-creatinine ratio or return to normoalbuminuria was achieved in a significant number of patients.6 However, a randomized, double-blind, placebo-controlled trial involving 1,000 patients with diabetes and persistent microalbuminuria (SUN-Micro Trial) failed to reach the primary endpoint of reduction in urine albumin. As a result, another phase 4 trial that had already been planned, the SUN-Macro Trial, was cancelled. Thus, a promising therapy on change in a marker of nephropathy progression (i.e., microalbuminuria) tested early in its development failed to perform in an adequately powered study.
Ruboxistaurin: A Protein Kinase C Inhibitor A key metabolic pathway involved in the pathogenesis of diabetic complications is overexpression of protein kinase C (PKC). Several activators of this family of intracellular kinases have been identified, and PKC activation may result in tissue damage through a variety of mechanisms, including activation of an extracellular signal-regulated kinase pathway and generation of oxidants through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In animal models, the PKC-b inhibitor ruboxistaurin reduced oxida-
S123
tive stress by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activation and provided functional and histological protection. Human studies using ruboxistaurin in patients with diabetic nephropathy have provided mixed results. In preliminary human studies, ruboxistaurin therapy resulted in a 24% reduction in proteinuria at 1 year and stabilization of the glomerular filtration rate as compared with placebo. However, all enthusiasm for this initial finding was tempered when the investigators of the PKC Diabetic Retinopathy Study 2 reported that the occurrence of diabetic nephropathy was more frequent in ruboxistaurin-treated patients as compared with placebo (n 5 7 [2%] versus n 5 0; P 5 0.015). A recent, more extensive and collective evaluation of all diabetic retinopathy trials has shown that there was no difference in diabetic nephropathy in ruboxistaurin-treated patients compared with placebo.7 Larger clinical trials are clearly needed to further evaluate the usefulness of this drug in treating diabetic nephropathy. The Food and Drug Administration did not give approval for treatment of retinopathy and required further testing. As a result, the company has halted further development of the product.
Pirfenidone Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is a low-molecular-weight synthetic molecule with antifibrotic properties. The mechanism of action is not well understood, but pirfenidone has been shown to reduce transforming growth factor beta 1 (TGF-b1) production, antagonize tumor necrosis factor a signaling, and scavenge reactive oxygen species. In the 5/6 nephrectomy rat model of postadaptive focal segmental sclerosis, pirfenidone treatment attenuated the accumulation of glomerular matrix protein, the expression of glomerular transforming growth factor beta (TGF-b), and the loss of glomerular filtration. Clinical trials have evaluated the safety and efficacy of pirfenidone in various fibrotic diseases including liver cirrhosis and pulmonary fibrosis.8 In a model of diabetic nephropathy, pirfenidone was shown to reduce generation of reactive oxidant species and to significantly reduce mesangial matrix expansion without affecting albuminuria. The authors concluded that pirfenidone may be renoprotective in diabetic kidney disease and may exert its antifibrotic effect in part by inhibiting
S124
SUDHIR V. SHAH
RNA processing.9 In an open-label trial, pirfenidone was shown to slow the loss of kidney function in patients with focal segmental sclerosis. It is noteworthy that this effect was observed without any reduction in proteinuria.10
Pentoxifylline Pentoxifylline, a nonselective phosphodiesterase inhibitor, exerts potent inhibitory effects against cell proliferation, inflammation, and extracellular matrix accumulation.11 Pentoxifylline appears to have anti-inflammatory properties, with the ability to decrease serum and tumor necrosis factor in patients with diabetic nephropathy. A meta-analysis evaluating its utility as a potential therapeutic agent for diabetic nephropathy included 10 studies investigating 476 patients with a median duration of 6 months of treatment. Pentoxifylline significantly decreased proteinuria, the decrease being similar to that obtained by an angiotensin-converting enzyme (ACE) inhibitor.12 In a randomized, controlled study, the addition of pentoxifylline to patients with persistent proteinuria, after treatment with losartan, resulted in further reduction in proteinuria.11
Bicarbonate Experimental evidence that metabolic acidosis may be important in progression of renal failure has been conflicting. In a recent study, the hypothesis that oral bicarbonate supplementation in patients with acidosis would be associated with attenuation of the rate of decline in renal function was examined. Adult patients (n 5 134) with CKD (creatinine clearance, 15 to 30 mL/min; serum bicarbonate, 16 to 20 mmol/L) were randomly assigned to supplementation with oral bicarbonate or standard care for 2 years. In comparison with the control group, the decline in creatinine clearance was slower with bicarbonate supplementation (5.93 versus 1.88 mL/min/1.73 m2; P ,.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression and develop ESRD. Nutritional parameters improved significantly with bicarbonate supplementation, which was well tolerated. This study demonstrates that bicarbonate supplementation slows the rate of progression of renal failure to ESRD and improves nutritional status among patients with CKD.13
Allopurinol There is evidence to suggest that hyperuricemia may have a pathogenetic role in progression of kidney disease. In a prospective, randomized control trial of 54 hyperuricemic patients with CKD, patients were assigned to treatment with allopurinol or to continue usual therapy for 12 months.14 There was a trend toward lowered serum creatinine levels in the treatment group compared with controls, although, given the small numbers, it was not statistically significant. The availability of new compounds that can decrease serum uric acid may result in larger clinical trials to evaluate halting progression by reducing serum uric acid levels.
Labile Iron The pathological effects of iron accumulation in tissue in iron-overload states, such as described in thalassemia patients, are well known. What is new in the field is the recognition that iron plays an important role in the pathophysiology of tissue injury in the absence of systemic iron overload. Iron is the most abundant transitional metal in the body. The ability to cycle reversibly between its ferrous and ferric oxidation states is critical to the importance of iron in biological processes. This precise property, which is essential for its functions, also makes it very dangerous, because free iron can catalyze the formation of free radicals which can damage the cell.15 The role of labile iron in a disease model has been delineated by demonstration of both an increase in labile iron and the protective effect of an iron chelator. The role of labile iron has been examined in several models of leukocyte-dependent and leukocyte-independent models of glomerular disease (reviewed by Shah et al.)16 The antiglomerular basement membrane antibody is a well-characterized model of complement- and neutrophil-dependent glomerular injury. In a rabbit model,16 reported that an iron chelator significantly attenuated proteinuria. In addition to proliferative glomerulonephritis, the ability of glomerular cells to generate oxidants suggests that they may act as important mediators of injury in glomerular diseases that lack infiltrating leukocytes. An animal model of minimal change disease is induced by a single intravenous injection of puromycin aminonucleoside. Labile iron (measured as bleomycin-detectable iron) was markedly increased in glomeruli from nephrotic rats, and an
PROGRESS TOWARD NOVEL TREATMENTS FOR CKD
iron chelator prevented an increase in catalytic iron in glomeruli and provided complete protection against proteinuria, suggesting an important pathogenic role for labile iron in this model. Baliga and colleagues have demonstrated that cytochrome P45017 and, more specifically, cytochrome P450 2B1, an isozyme present in the glomerulus, are sources of catalytic iron that participate in glomerular injury in this model. Passive Heymann nephritis, induced by a single intravenous injection of anti-Fx1A, is a complement-dependent model of glomerular disease that resembles membranous nephropathy in human beings. The administration of an iron chelator markedly reduces proteinuria, suggesting the role of labile iron in passive Heymann nephritis. The severity of tubulointerstitial injury is a major determinant of the degree and rate of progression of renal failure. The data supporting the role of iron in models of progressive renal disease consist of demonstration of increased iron in the kidney; enhanced oxidant generation, which provides a mechanism by which iron can be mobilized; and the beneficial effect of iron-deficient diets and iron chelators. Several studies have demonstrated an important role of iron in progressive kidney disease. It was reported that an iron-deficient diet or iron chelators prevent the development of tubulointerstitial disease and renal functional deterioration in nephrotoxic serum nephritis. Remuzzi et al. have shown that rats fed on an iron-deficient diet had a significant reduction in proteinuria and developed less glomerulosclerosis, as reviewed by Shah et al. in Journal of the American Society of Nephrology.16 Most importantly, in preliminary studies we have shown that treatment with deferiprone (L1) leads to a marked reduction in proteinuria over a 9-month period in patients with diabetic nephropathy.18 In addition, in a preliminary, open-label, proofof-concept study, patients with biopsy-proven glomerulonephritis were treated with deferiprone, and the urinary protein and serum creatinine were obtained 2 to 6 months after the administration of the iron chelator. Treatment with the iron chelator significantly decreased the amount of total urinary protein in patients with glomerulonephritis.19
Conclusion Chronic kidney failure remains a major health problem worldwide. Although current treatment
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is focused on the renin–angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.
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