Let it Pee: Pentoxifylline for Proteinuria

Jacquelyn Brondo, PharmD. PGY2 Ambulatory Care Pharmacy Resident, South Texas Veterans Health Care System

Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center

UT Health San Antonio August 21, 2020

Learning Objectives

1. Describe key clinical characteristics of chronic kidney disease and proteinuria 2. Understand the physiology of proteinuria and progression of chronic kidney disease 3. Explain treatment goals and the available treatment options for proteinuria 4. Analyze available data on use of pentoxifylline for reduction of proteinuria and slowed

progression of chronic kidney disease

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Background

1. CKD Definition a. Chronic kidney disease (CKD)1,2

i. Kidney damage usually detected as urinary albumin ≥30mg/day or decreased kidney function estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2

for three or more months ii. Any of the following presents for >3 months

1. Albuminuria ≥30mg/day 2. Urine sediment abnormalities 3. Electrolyte and other abnormalities due to tubular disorders 4. Abnormalities detected by histology 5. Structural abnormalities detected by imaging 6. History of kidney transplantation 7. Decreased eGFR <60mL/min/1.73m2

b. Stages

Figure 1: CKD staging

c. Proteinuria1 i. Increased amounts of protein in the urine due to increased glomerular

permeability to large molecular weight proteins, incomplete tubular reabsorption of normally filtered low-molecular-weight proteins, or increased plasma concentration of low-molecular-weight proteins

d. Albuminuria1,3 i. Abnormal loss of albumin in the urine

ii. Generally, appears prior to reduction in eGFR in diabetic kidney disease iii. Often associated with underlying hypertension, obesity, and vascular disease

Table 1: Albuminuria definitions1

Term Measurement Normoalbuminuria <30mg/day Microalbuminuria (Moderately increased) 30-300mg/day

Macroalbuminuria (Severely increased) >300mg/day

Image from http://www.medcomic.com

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2. CKD Epidemiology4 a. As of 2019 15% of adults in the United states are estimated to have CKD b. More common in adults 65 years or older, women, African Americans, and Hispanics c. 1 in 2 people with very low kidney function (not on dialysis) are unaware that they have

CKD

Figure 2: CKD statistics

3. CKD Etiology a. Risk Factors4

i. Diabetes, hypertension, heart disease, obesity, family history, previous kidney damage, age >60

Figure 3: CKD risk factors

Image from: https://www.siemens-healthineers.com/laboratory-diagnostics/assays-by-diseases-conditions/kidney-disease/about-kidney-disease#Chronic_Kidney_Disease

4. CKD Pathophysiology5 a. Kidney damage

i. Can result from a multitude of causes ii. See Etiology above

iii. See Appendix A

Image from https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html

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b. Key features i. Loss of nephron mass

1. Due to exposure to any risk factors mentioned above 2. Remaining functional nephrons compensate through autoregulation in

response to decreased nephron function ii. Glomerular capillary hypertension

1. Because of the nephron loss and reduction in perfusion pressure and filtration rate, renin is released which increases conversion of angiotensinogen to angiotensin I, which is then converted to angiotensin II

2. Angiotensin II vasoconstricts both efferent > afferent arterioles which leads to increased pressure within the capillaries

iii. Proteinuria 1. Increased pressure impairs size-selective function of glomerular

permeability resulting in increased excretion of proteins5 2. Can promote loss of nephrons as a result of cellular damage5 3. Presence of proteins in renal tubule leads to increased production of

inflammatory and vasoactive cytokines5 4. Proteinuria is associated with the risk of CKD progression in both non-

diabetic and diabetic patients6

Figure 4: Proteinuria in the progression of CKD

iv. Other 1. Aldosterone and angiotensin II can also mediate progression by

increasing growth factors, causing cellular proliferation, hypertrophy of glomerular endothelial/epithelial cells and fibroblasts

2. Causes further inflammation and fibrosis

Image from Cravedi P. Pathophysiology of proteinuria and its value as an outcome measure. 2013.

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5. CKD Presentation/Diagnosis5

a. Often asymptomatic until progressed to further stages

b. Labs

i. Decreased eGFR, bicarbonate, hemoglobin/hematocrit, transferrin saturation, ferritin (might increase secondary to inflammatory conditions), vitamin D levels, albumin, glucose, and calcium

ii. Increased SCr, BUN, potassium, phosphorus, PTH, albumin creatine ration, blood pressure, glucose, LDL, triglycerides, and calcium

iii. Can see hemoccult-positive from GI bleed secondary to uremia c. Diagnosis tests

i. Urine sediment abnormalities ii. Pathologic abnormalities

1. Glomerular, vascular, tubulointerstitial disease, cystic and congenital diseases

iii. Structural abnormalities 1. Polycystic kidneys, renal artery stenosis, renal masses, cortical scarring

due to pyelonephritis, small kidneys iv. Imaging studies

1. Ultrasound, CT, MRI, angiography 6. CKD Management

a. Treatment goals2 i. Treatment of reversible causes and management of complications

ii. Prevention or slowing of renal disease progression iii. Adjust drug therapy as necessary

b. Non-Pharmacotherapy1 i. Lowering protein intake to 0.8g/kg/day in patients with CKD stage 4-5

ii. Avoid high protein intake >1.3g/kg/day in patients with CKD at risk of progression

iii. Lower salt intake to <2g/day of sodium iv. Encourage physical activity aiming for at least 30 minutes 5 times per week v. Maintain a healthy weight (body mass index 20-25)

vi. Smoking Cessation c. Pharmacotherapy1

i. Use guideline directed therapy to manage hypertension, diabetes, hyperlipidemia, and cardiovascular disease1,7

1. Individualize blood pressure targets and agents according to age, coexistent cardiovascular disease/other comorbidities, retinopathy, tolerance of treatment, and risk of progression of CKD

Table 2: Symptoms/Signs5

Symptoms Weakness, fatigue, nausea, vomiting, bleeding, shortness of breath, loss of appetite, cold intolerance, peripheral neuropathies

Signs Weight gain, edema, changes in urine output, abdominal distension, “foaming of urine” (proteinuria)

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Table 3: Blood pressure goals1

Albuminuria BP Goal <30 mg/24 hrs ≤ 140/90 mmHg

30-300 mg/24 hrs ≤ 130/80 mmHg >300 mg/24 hrs ≤ 130/80 mmHg

2. Individualize HbA1c targets ranging from <6.5% to <8.0% in patients

with diabetes and non-dialysis dependent CKD7

Figure 5: Considerations in HbA1c goals

3. Statin or statin/ezetimibe combination therapy recommended for adults

≥50 years old with eGFR ≤ 60 ml/min/1.73m2 not on dialysis or history of kidney transplant1

4. Statin therapy recommended for adults ≥50 years old with eGFR ≥ 60 ml/min/1.73m2 1

5. Statin therapy recommended in adults 18-49 years old with CKD not on dialysis or history of kidney transplant if one or more of the following are present1

a. Known coronary disease b. Diabetes c. Prior ischemic stroke d. Estimated 10-yr ASCVD score ≥ 10%

6. Dialysis-dependent CKD1 a. Do NOT start statin or statin/ezetimibe combo BUT can

continue therapy if initiated prior to patient becoming dialysis dependent

7. Adults with CKD at risk for atherosclerotic events should be offered treatment with antiplatelet agents unless bleed risk is increased and risk > benefit of treatment1

8. Adults with CKD and heart failure with escalation in therapy and/or clinical deterioration should have eGFR and serum potassium levels evaluated1

ii. Use guideline directed therapy to manage complications of CKD to include anemia, electrolyte imbalances, and bone and mineral disorders

1. See Appendix C

Image from KDIGO clinical practice guideline on diabetes management in chronic kidney disease.2019.

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d. Pharmacotherapy for prevention/slowing of rapid CKD progression to ESRD i. Non-diabetic CKD

1. ACEI/ARB1,2,8 a. Utilize angiotensin converting enzyme inhibitor (ACEI) or

angiotensin receptor blocker (ARB) in diabetic adults with CKD and urine albumin excretion 30-300mg/day1

b. Utilize ACEI or ARB in both diabetic and non-diabetic adults with CKD and urine albumin excretion >300mg/day1

c. ACEI block the conversion of angiotensin I to angiotensin II d. ARBs competitively antagonize the interaction between

angiotensin II and angiotensin receptors e. Lowers glomerular capillary blood pressure and systemic blood

pressure2 f. Vasodilatation of the efferent > afferent glomerular arterioles,

resulting in decreased intra-glomerular pressure and reduction in both eGFR and urine albumin excretion

i. Generating long-term renoprotection in patients with albuminuria1

g. ACEI/ARB have the potential to reduce microalbuminuria by ~29%3

ii. Diabetic kidney disease (DKD) 1. Metformin7,8

a. Activation of AMP-activated kinase (AMPK) suppresses endoplasmic reticulum stress caused by angiotensin II, aldosterone, and high glucose levels8

b. In metformin treated rat models without diabetes, significantly less cellular infiltration, fibrosis, and inflammation were noted as well as protection against development of severe renal failure8

c. Noted cardiovascular benefit in patients with CKD7 d. Reduction of albuminuria, slowing of eGFR reduction, and

decreased progression to ESRD have yet to be proven in human studies8

2. Sodium-glucose transport protein 2 (SGLT2) inhibitors3,8 a. Associated with reduced glomerular hyperfiltration (mediated

through increased natriuresis)8 b. Noted afferent vasoconstriction and reduction of diabetes-

induced renal hyperfiltration8 c. May improve renal oxygenation and cellular energy metabolism

and reduce intrarenal inflammation leading to slowed progression of kidney function decline8

d. Associated with slower progression of kidney disease and lower rates of clinically relevant renal events3

e. Possible benefit with progression of albuminuria, reduction of eGFR, need of renal replacement therapy, and death from renal causes3

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f. Reduction of urine albumin creatine ratio (UACR) from 7%, 25%, and 32% in normoalbuminuria, microalbuminuria, and macroalbuminuria patients respectively8

3. Glucagon-like peptide (GLP1) agonist3,8 a. GLP1 has been noted to increase eGFR, renal blood flow, and

fractional excretion of sodium and potassium8 b. Renal GLP1 receptors exist in afferent arteriolar vascular

smooth muscles, glomerular endothelial cells, macrophages, juxtaglomerular cells, and proximal tubule8

c. Reduction in angiotensin II concentration and decreased proximal tubular sodium-reabsorption may contribute to renal protective effects8

d. Statistically significant decrease in proteinuria and slowed rate of eGFR decline have been noted3

e. Lower rates of new or deteriorating nephropathy3 f. Reduction of ~27% urine albumin excretion rate3

4. Dipeptidyl peptidase 4 (DPP4) inhibitors3,8 a. Renal protection demonstrated in various animal models8 b. Reduction of inflammatory activation, reduction of oxidative

stress, mitochondrial dysfunction and apoptosis, and attenuation of rises in blood pressure8

c. Reduction in albuminuria/improved albuminuria was noted in few human studies3

d. Retrospective review showed a 28% reduction in urine albumin creatine ratio8

5. Other agents3 a. See Appendix B for additional novel agents for treatment of

diabetic kidney disease

Reduction of Proteinuria

1. Why is reduction of proteinuria important in slowing rapid progression of CKD to end-stage renal disease (ESRD)?

a. Albuminuria >30mg/day has been associated with an increased risk for complications of CKD

i. Increased risk of all-cause mortality, cardiovascular mortality, kidney failure, acute kidney injury, and chronic kidney disease progression in both general populations and populations at increased risk of cardiovascular disease14,15,16

2. For non-diabetic CKD as above, evidence only supports use of ACEI/ARB for the reduction of proteinuria and slowing of rapid progression to ESRD

a. For patients who are already receiving maximum tolerated ACEI/ARB dosing what else can be done?

i. A need for research surrounding add-on therapy for the slowing of rapid progression to ESRD is needed

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Pentoxifylline (PTF)

1. Mechanism of action10,11 a. Methylxanthine derivative and nonspecific phosphodiesterase inhibitor b. Increases blood flow to microcirculation, blood viscosity is lowered, erythrocyte

flexibility is increased, leukocyte deformability is increased, and neutrophil adhesion/activation are decreased

c. Tissue oxygenation is significantly increased 2. Proposed mechanism related to proteinuria and progression of CKD11,12

a. Anti-inflammatory, antiproliferative, and antifibrotic actions associated with beneficial effects

Figure 6: Proposed mechanism of PTF12

3. Dosing

a. Normal dosing for FDA indicated intermittent claudication10 i. 400mg three times daily

ii. Renal adjustment 1. For CrCl <30 then 400mg daily

b. Proposed dosing11,13 i. 800mg-1200mg total daily dose two to three times daily

4. Contraindications10 a. Previous intolerance to PTF, xanthines, or any component of the formulation b. Recent cerebral and/or retinal hemorrhage

Image from: Chen YM. Therapeutic efficacy of pentoxifylline on proteinuria and renal progression update. 2017.

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5. Adverse effects10 a. Nausea, vomiting, GI side effects b. Palpitations, anxiety, chest pain, flushing, dizziness, headache

6. Monitoring10 a. Renal function and hemoglobin/hematocrit

Clinical Question and Literature Review

1. Literature Review

Table 4: Perkins et al.13

Perkins RM, Aboudara MC, Uy AL, et al. Effect of Pentoxifylline on GFR Decline in CKD: A Pilot, Double-Blind, Randomized, Placebo-Controlled Trial. American Journal of Kidney Diseases. 2009;53(4):606-616.

Purpose • To assess the impact of PTF on glomerular filtration rate during a one-year period in patients at high risk of progressive CKD and ESRD currently treated with ACEI/ARB

Design • Pilot, double-blind, randomized, placebo-controlled trial

Patient Population

• Inclusion: o ≥ 18 yo, HTN, urinary proteinuria of 1g/24h or greater, and estimated eGFR 20-40ml/min/1.73m2 or 3g/24h of

urinary protein excretion and eGFR 20ml/min/1.73m2 or greater o Required to have ACEI/ARB at least 2 weeks before enrollment

• Exclusion: o Acute kidney failure (>25% decrease in eGFR 30 days prior to enrollment), pregnancy or currently breast-feeding,

current use of PTF, theophylline, or allergy to such, history of retinal or cerebral hemorrhage, < two SCr values 6 months before enrollment

Intervention • Patients were randomized to either PTF 400mg BID or once daily for eGFR <30 mL/min/1.73m2 or matching placebo with follow-up at 6 and 12 months

Outcomes • Primary outcome: difference in rate of change in eGFR from randomization to final follow-up

• Secondary outcome: difference in 24hr urinary protein values, rate of change in eGFRs within the PTF group during study period vs. during the year prior, rate of change in eGFRs during each of the 6-month assessment periods

Statistics • It was estimated that 73 patients in each arm would be needed to detect with 80% power a difference in the rate of change in eGFR

• Per protocol analysis was used in that only participants who completed the study were included in primary outcome analysis

• Intention to treat protocol was also evaluated after per protocol analysis

• P <0.05 was considered statistically significant

• Independent sample t-tests were used for analysis

Clinical Question: Should pentoxifylline be used to slow progression of CKD to ESRD?

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Results • N=33 total patients with N=17 in the PTF arm and N= 16 in the placebo arm

• Median follow up was 11.2 months

• Rate of eGFR decrease was statistically significantly less during the one-year study period in the PTF group than the placebo group and similar findings were noted in the intention to treat analysis

• PTF group experienced a slower rate of decrease in kidney function than placebo group at 6 and 12 months

• No statistically significant differences between groups in regard to proteinuria at either 6 or 12 months

• At study entry most patients had been treated with ACEI/ARB for at least 3 months Figure 7: Change in eGFR prior to and throughout study period

Strengths • Baseline characteristics were well matched between groups to include blood pressure and other prescription medications

• Both per protocol and intention to treat analysis were evaluated in this study giving more robust data • Demographic, clinical, and laboratory relevant data was included in the report of this study

Limitations • Non-significant difference between groups and African American study participants with DM; PTF group having more African American patients with DM than control though,

• Proteinuria levels were larger in placebo group at baseline and 12 months but lower at 6 months which may have impacted outcomes

• Incomplete follow-up at 12 months occurred in both groups

• Low percentage of Caucasian patients enrolled making it difficult to extrapolate

• Small participant population

• Did not document patients using antidiabetic agents with noted renal protection Conclusions • Author: PTF has the potential to adjunctively enhance the beneficial impact of ACEI/ARB inhibition in this population

with proteinuria, hypertension, and decreased kidney function

• Pilot study established the feasibility and safety of conducting larger trials with this patient population

• Reviewer: PTF may have a role in decreasing CKD rate of decline when added to ACEI/ARBs

• Caution should be used when applying these results due to the above-mentioned limitations

• Additional trials are needed that are blinded, accurately powered, include a larger and more variable patient population

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Table 5: Chen et al.17 Chen PM, Lai TS, Chen PY, et al. Renoprotective effect of combining pentoxifylline with angiotensin-converting enzyme inhibitor or

angiotensin II receptor blocker in advanced chronic kidney disease. J Formos Med Assoc. 2014;113(4):219-226. doi:10.1016/j.jfma.2014.01.002

Purpose • To assess whether there is an increased benefit of including PTF with ACEI or ARB in the treatment of CKD

Design • Single-center retrospective chart review

Patient Population

• Inclusion: o Patients between 18-80 years old with eGFR <45ml/min/1.73 m2 and in the pre-ESRD program at the reviewing

institution for at least 3 months between 2007-2011 • Exclusion:

o Patients not meeting inclusion criteria and those not prescribed ACEI or ARB treatment

Intervention • Data was collected retrospectively via chart review and patients were designated as having PTF use versus non-use

• PTF dose ranged from 400-800mg daily

Outcomes • Primary outcome: initiation of renal replacement therapy (RRT) defined as hemodialysis, peritoneal dialysis, and renal transplantation

• Secondary outcome: death of any cause

Statistics • Kaplan-Meier method was used to evaluate risk of initiation of RRT between groups

• P <0.05 was considered statistically significant

• Statistical tests were utilized to include t-test, chi-square test, Mann-Whitney U test, and Wilcoxon signed-rank test

• Multivariable models were adjusted for age, sex, blood pressure (BP), eGFR, history of diabetes, and urine protein to creatinine ratio (UPCR)

• Subgroup analysis was performed by dividing patients into lower UPCR (<1g/g) and higher UPCR (>1g/g) subgroups

Results • N = 661 total patients with a median follow-up of 2.25 years

• N= 242 had no PTF use and N=419 had PTF use documented

• Baseline characteristics were well matched except for diabetes with more diabetic patients in the PTF group (statistically significant)

• 19.3% of PTF users required RRT and 25.2% of non PTF users required RRT

• No change in UPCR was noted in either group after 1 year of follow-up

• No between-group difference in mortality or cardiovascular events was noted with mortality rate of 5.3% and 4.1% for PTF and no PTF respectively

• Statistically significant protective effect of add-on PTF was seen in the higher UPCR group

• No difference in renal outcomes noted in lower UPCR group

• Following multivariate analysis PTF users were noted to have 29.5% lower risk of developing ESRD necessitating RRT

Figure 8: Sub-group analysis of proportion free from RRT between groups

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Strengths • Median follow-up period was 2.25 years

• Demographic, clinical, and laboratory relevant data was included in the report of this study

• Results were adjusted for differences in age, sex, BP, eGFR, history of diabetes, and UPCR

Limitations • Retrospective design might cause biases due to the prescribing physician’s preference

• Stage 5 CKD patients and rapidly progressing DKD patients were excluded due to their tendency to NOT be prescribed ACEI/ARB

• Duration of PTF use was not the same for all patients and there were different follow-up periods noted as well

• Did not evaluate the effect of different dosages of PTF; unable to report the dose-effect of PTF

• More patients were included in the PTF arm than control and more diabetic patients were included in the PTF group as well making comparison of groups difficult

• Did not document patients using antidiabetic agents with noted renal protection

Conclusions • Author: This study provided evidence of the effectiveness of PTF combined with ACEI or ARB • Large-scale randomized control trials are still needed to provide more concrete evidence

• Reviewer: PTF showed statistically significant improvement in renal outcomes

• PTF did not demonstrate mortality benefit or reduction of cardiovascular events

• Caution should be used when applying these results due to the above-mentioned limitations

• As mentioned by the authors, additional studies are needed to further demonstrate positive effects of PTF

Table 6: PERDIAN trial11

Navarro-Gonzalez JF, Mora-Fernadez C, Muros de Fuentes M, et al. Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease: The PREDIAN Trial. J Am Soc Nephrol. 2015;26:220-229. Doi:10.1681/ASDN.2014010012

Purpose • To determine whether PTF in addition to renin-angiotensin system (RAS) blockade can slow progression of renal disease

Design • Open-label, prospective, randomized trial

Patient Population

• Inclusion: o Age >40, clinical diagnosis of T2DM, diabetic nephropathy, CKD stages 3-4, and therapy with ACEI or ARB at the

maximal recommended dosage for >6 months

• Exclusion: o T1DM, nondiabetic kidney disease, history of chronic inflammatory, immunologic, or tumoral disease, acute

inflammatory or infectious intercurrent episode in previous 3 mo, institutionalization, immunosuppressive treatment, previous therapy w/ PTF, treatment w/ combination ACEI/ARB or aldosterone antagonists or direct renin inhibitors, A1c >10.5, BP >180/110, or pregnancy

Intervention • Patients were randomized to receive either PTF (1200mg/day) or control for 2 years

• Patients received similar doses of ACEI/ARB inhibitors

Outcomes • Primary outcome: progression of DKD, assessed by change from baseline eGFR after 2 years of follow-up

• Secondary outcome: percentage of patients with a reduction of eGFR ≥25%, percentage of patients with eGFR decline greater than the median rate of decline in eGFR per month, and changes from baseline in the urinary albumin excretion (UAE)

Statistics • Baseline comparisons were completed by independent t-test, chi-squared test, or Fisher exact test • Intention to treat protocol was utilized

• P <0.05 was considered statistically significant

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Results • N=462 participants were initially screened with N=169 randomly assigned to either control or treatment groups

• All patients were Caucasian with a mean age~69 and ~47% being female

• Mean baseline eGFR~37 ml/min/1.73m2; N=116 patients with CKD stage 3 and N=53 with CKD stage 4 • All patients were hypertensive, most had hyperlipidemia, and >40% had history of heart disease

• Mean duration of follow-up was 23.6 months with no differences between groups

• A significant overall between-group difference in primary endpoint (P<0.001) from baseline to end of the study was seen

• A significant mean difference in eGFR decrease was noted at 4.3 ml/min/1.73m2 with the PTF group experiencing a slower rate of eGFR decline

• Proportion of patient with reduction of eGFR>25% from baseline was statistically lower in the PTF group

• Statistically significant mean difference of 20.6% in UAE favoring PTF was seen at study end

• UAE differences between groups were statistically significant from 6 months Table 7: Changes from baseline in eGFR and albuminuria

Variable Control PTF P Value

eGFR (ml/min/1.73 m2) Least-square mean change ± SEM (95% CI) per follow-up period

6 mo −1.7±0.1 (−2.1 to −1.4) −1.4±0.1 (−1.7 to −1.0) 0.1

12 mo −3.4±0.3 (−4.1 to −2.8) −1.2±0.3 (−1.9 to -0.6) <0.001

18 mo −5.3±0.3 (−6.1 to −4.5) −1.7±0.4 (−2.5 to -0.9) <0.0001

24 mo −6.5±0.4 (−7.3 to −5.6) −2.1±0.4 (−3.0 to -1.2) <0.0001

UAE Least-square mean percentage change per follow-up period ± SEM (95% CI)

6 mo 1.4±1.1 (−0.8 to 3.8) −10.6±1.2 (−13.0 to -8.2) <0.001

12 mo 4.9±2.8 (−0.7 to 10.6) −13.0±2.9 (−18.8 to −7.2) <0.0001

18 mo 4.9±2.6 (−0.3 to 10.1) −14.8±2.7 (−20.1 to −9.4) <0.0001

24 mo 5.7±2.7 (−0.3 to 11.1) −14.9±2.7 (−20.4 to −9.4) <0.0001

Strengths • Baseline characteristics were well matched between groups to include other medications being used such as insulin, statins, beta blockers, and diuretics

• Medical history, concomitant medication use, and lab values were all included to gain a better understanding of patient population

• Adverse effects were reported in detail to include GI side effects being most problematic for PTF group

Limitations • All participants were Caucasian, making it difficult to extrapolate data to other populations

• This was an open label trial and participants were not blinded

• Did not disclose number of patients using antidiabetic agents with noted renal protection

Conclusions • Author: Patients with T2DM and CKD stage 3-4 under standard care with ACEI/ARBs who received treatment w/ PTF had smaller decrease in eGFR and higher reduction of residual UAE

• PTF could be an effective therapeutic option for treatment of DKD in T2DM

• Reviewer: PTF has the potential to slow the progression of CKD to ESRD in patients with T2DM, CKD stage 3-4, who are taking ACEI/ARBs

• It is important to take caution in the value of this conclusion as this trial has many limitations

• Additional trials are needed that are blinded, accurately powered, include a larger and more variable patient population

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Summary Table 5: Summary Table

Albuminuria >30mg/day has been associated with an increased risk of developing complications of CKD

ACEI/ARBs and antidiabetics are utilized for their renal protective effects

PTF is noted to exert anti-inflammatory, antiproliferative, and antifibrotic actions associated with beneficial effects in patients with CKD Questions surrounding utility of PTF for the reduction of proteinuria and slowed progression of CKD still exist

Current evidence is focused on PTF as add-on therapy to ACEI/ARBs rather than as a single agent

Evidence surrounding PTF use for DKD patients being treated with ACEI/ARBs AND antidiabetic medications is still lacking

PTF may have a potential role in slowing the progression of CKD but additional trials evaluating use with antidiabetic medications, measuring progression to ESRD, and in larger populations are still needed

Recommendations

1. ACEI/ARBs have established evidence in slowing the progression to ESRD and should remain first-line therapy for those without contraindications

2. For DKD patients, stronger evidence exists for standard of care antidiabetic medications including metformin, SGLT2 inhibitors, and GLP1 agonists

a. These agents should be preferred over the addition of PTF in patients who can tolerate therapies

3. Additional evidence is still needed before recommending PTF for all patients with CKD, but relatively fair evidence exists for use in certain patients

a. For patients with non-diabetic CKD who are on maximally tolerated ACEI/ARB therapy and continue to see rapid progression of CKD, PTF may be considered as add-on therapy to slow the progression of ESRD

b. For patients with DKD who cannot tolerate the addition of antidiabetic medications to slow progression of CKD, PTF may be considered as add-on therapy to ACEI/ARBs to slow the progression to ESRD in patients with CKD stage 3-4

c. For patients utilizing PTF goal length of therapy should be ≥ 12 months 4. For patients with DKD utilizing antidiabetic medications and ACEI/ARBs to slow progression of

CKD, add-on PTF therapy may be considered on a case-by-case basis a. Data to support additional benefit of PTF in patients taking SGLT2 inhibitors/GLP1

agonists AND ACEI/ARBs is lacking 5. For patients who cannot tolerate ACEI/ARBs, evidence is lacking to support use of PTF as single

agent therapy for the slowed progression of CKD

Studies in the Pipeline

1. The Veterans Affairs Cooperative study: Pentoxifylline in Diabetic Kidney Disease16 a. ClinicalTrials.gov Identifier: NCT03625648

2. Centro de Investigación Biomédica de Michoacán: Pentoxifylline Effect in Patients With Diabetic Nephropathy. (PENFOSIDINE STUDY) (PENFOSIDINE)

a. ClinicalTrials.gov Identifier: NCT03664414

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3. Lin YC, Chang YH, Yang SY, et al. Update of pathophysiology and management of diabetic kidney disease. Journal of the Formosan Medical Association. 2018; 117:662-675. https://doi.org/10.1016/j.jfma.2018.02.007

4. Chronic Kidney Disease in the United States, 2019. (2019, March 11). Retrieved July 31, 2020, from https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html

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6. Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure. British Journal of Clinical Pharmacology. 2013;76(4):516-523. doi:10.1111/bcp.12104

7. KDIGO 2019. Clinical Practice Guideline on Diabetes Management in Chronic Kidney Disease. 2018. 8. Scheen AJ. Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in

patients with type 2 diabetes. Diabetes Metab. 2019;45(2):110-121. doi:10.1016/j.diabet.2018.10.003 9. Slow Progression &amp; Reduce Complications. (n.d.). Retrieved July 31, 2020, from

https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/identify-manage-patients/manage-ckd/slow-progression-reduce-complications

10. Pentoxifylline [package insert]. Parsippany, NJ: Validus Pharmaceuticals LLC; 2016. 11. Navarro-Gonzalez JF, Mora-Fernadez C, Muros de Fuentes M, et al. Effect of Pentoxifylline on Renal

Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease: The PREDIAN Trial. J Am Soc Nephrol. 2015;26:220-229. Doi:10.1681/ASDN.2014010012

12. Chen YM, Chiang WC, Lin SL, et al. Therapeutic efficacy of pentoxifylline on proteinuria and renal progression: an update. Journal of Biomedical Science. 2017;24(84). doi 10.1186/s12929-017-0390-4

13. Perkins RM, Aboudara MC, Uy AL, et al. Effect of Pentoxifylline on GFR Decline in CKD: A Pilot, Double-Blind, Randomized, Placebo-Controlled Trial. American Journal of Kidney Diseases. 2009;53(4):606-616.

14. Gansevoort RT, Matsushita K, van der Velde M et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011; 80: 93–104.

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Abbreviations ACEI: angiotensin converting enzyme inhibitor ARB: angiotensin receptor blocker BP: Blood pressure BUN: blood urea nitrogen CKD: chronic kidney disease CT: computed tomography DKD: diabetic kidney disease eGFR: estimated glomerular filtration rate ESRD: end-stage renal disease GI: gastrointestinal HbA1c (A1c): hemoglobin A1c LDL: low density lipoprotein mo: month(s) MRI: magnetic resonance imaging PTF: pentoxifylline PTH: parathyroid hormone SCr: serum creatine SEM: standard error of the mean T1DM: type 1 diabetes mellitus T2DM: type 2 diabetes mellitus UAE: urinary albumin excretion w/ or w/o: with or without yo: year old

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Appendix A: Proposed mechanisms for CKD progression

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Appendix B: Novel medical treatment for DKD3

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Appendix C: Complications of CKD

Image from: https://www.grepmed.com/images/3122/pathophysiology-complications-nephrology-ckd