1. Andy Bomback Maya Rao Eric Siddall Pietro Canetta
CKD, DM and HTN
Andy Bomback
Maya Rao
Eric Siddall
Pietro Canetta

2. Case
A 42 year old man with CKD III-IV due to DM nephropathy is seen in clinic.
He is asymptomatic
His current medications include:
HCTZ 25 mg qAM
Losartan 100 mg qAM
Metoprolol-ER 100 mg qAM
Amlodipine 10 mg qAM
Lantus (nightly) and short-acting insulin (tid)
Vit D units weekly

3. Case (cont’d)
Office blood pressure today is 156/92. Reviewing notes from prior visits, his office BPs consistently fall in the systolic range, diastolic range
On exam, other than BP elevation, the only positive finding is trace to 1+ pitting edema in bilateral feet
His most recent labs include
Creatinine 2.3 (eGFR 31 ml/min/1.73m2)
Potassium 4.0 mEq/L
Albumin 3.9 g/dl
Urine protein:creatinine ratio 2100 mg/g

4. Case 1 Issues: What are some options to manage this patient?
Resistant HTN – 3 anti-HTN, one of which is a diuretic
Edema
Proteinuria in a diabetic on a maximum dose of losartan
What are some options to manage this patient?

5. Overview – CKD Diagnosis
Renal Handling:
Mostly filtered
10-40% Prox tubular secretion – gets saturated by the time creatinine is 2
Underdiagnosis
creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary meat intake. Release into the circulation at a relatively constant rate. Freely filtered bt also secreted.
a small rise in serum creatinine usually reflects a marked fall in GFR, whereas a marked rise in serum creatinine in patients with advanced disease reflects a small absolute reduction in GFR.
However, this curve depicts a hypothetical relationship between GFR and serum creatinine (figure 1). In reality, a reduction in GFR results in increased tubular creatinine secretion that blunts the rise in serum creatinine. Thus, a 50 percent reduction in GFR does not produce a doubling of serum creatinine, but rather a smaller rise than would have occurred if the decrease in GFR had occurred without an increase in secretion. Talk about hyperfiltering also

6. Secondary Process: Hyperfiltration
First phase – absolute supraphysiologic increase in whole kidney GFR (sum of filtration of all the nephrons)  glomerlar hyperfiltration, due to diabetic induced changes in structural and dynamic factors that determine GFR
Hyperfiltration precedes the onset of albuminuria and or decline in renal function and predisposes to progressive nephron damage by increasing glomerular pressure and convective flux of ultrafiltrate
In longer standing diabetics, increase in single nephron GFR of remnant nephrons to compensate for reduced nephron number
Tonneijck T, JASN, 2017

7. CKD and Proteinuria Hemmelgarn, JAMA, 2010
community based cohort study in alberta canada, 902K people with creatinine and ACR measurement. full adjusted rate of all cause mortality higher in participants with lower egfrs or heavy proteinuria. Adjusted mortality was 2 fold higher among those w heavy proteinuria and egfr > 60 as compared with egfr and normal proteinuria. Rosk of mortality, MI, progression associated with a given level of egfr are independently increased in pts with higher levels of proteinuria
Hemmelgarn, JAMA, 2010

8. What is his goal blood pressure?

9. CKD, DM and HTN Targets No DM, no albuminuria
No DM, + albuminuria (> 30mg/g)
DM, no albuminuria
DM, + albuminuria (> 30mg/g)
ADA (2016) NA
<140/90
KDOQI (2012)
≤ 140/90
≤ 130/80
JNC VIII (2014)
Two RCTS – MDRD and the AASK looked at progression of kidney disease and found no differences comparing mean change in iothalamate GFR from baseline to end between standard 140/90 to more intensive 125/75
Nearly had enough power to look at CV outcomes
SPRINT: Mild CKD, no proteinuria, lower SBP of 120 did not result in improved renal outcomes (though total numbers were small) but did result in reduced CV outcomes

10. ACCORD TRIAL: Mean Systolic BP Levels at Each Study Visit in Diabetics
RCT 4733 subjects with DM2 and HTN to intensive tx SBP < 120 versus standard tx SBP < 140.
SCr > 1.5 mg/dL excluded.
4733 participants with type 2 DM and HTN randomly assigned to intensive therapy (SBP<120) or standard therapy (SBP<140). The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
Excluded patients with serum creatinine > 1.5
The ACCORD Study Group. N Engl J Med 2010;362:

11. ACCORD TRIAL: Kaplan–Meier Analyses of Selected Outcomes
Serious side effects 3xs as frequent in those in the intensive arm
What about ? Not answered here
Does not include patients with advanced CKD
Primary outcome: composite of time to first nonfatal MI, CVA or CV death
Thus, the message from ACCORD to guidelines and clinical practice is that in diabetic patients it is not necessary to adopt an aggressive BP-lowering strategy because an SBP reduction to the 130- to 140-mm Hg range (for which the beneficial effects are documented) appears to suffice. Indeed, a more aggressive BP-lowering strategy may be detrimental because the ACCORD patients in whom in-treatment SBP was <120 mm Hg had an incidence of serious side effects that was almost 3 times as frequent as that of patients remaining >130 mm Hg.
hird, the difference in achieved BP between the 2 groups was large (≈14 mm Hg), which leaves the possibility that the group in which SBP was reduced to 119 mm Hg fell in the ascending portion of a J curve for cardiovascular events. That is, SBP values <130 but >120 mm Hg may be associated with a maximal benefit that vanishes when BP is further reduced.
The ACCORD Study Group. N Engl J Med 2010;362:

12. AASK: Blood-Pressure Levels in Patients with Chronic Kidney Disease
RCT of 1094 black patients with HTN and CKD to an intensive goal MAP <=92 or standard goal MAP After the trial, cohort phase where target
< 130/80
Randomly assigned 1094 black patients with hypertensive CKD to receive either intensive (goal MAP <=92) or standard (goal MAP ) blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. Follow-up ranged from 8.8 to 12.2 years, GFR 20-65
Appel LJ et al. N Engl J Med 2010;363:

13. AASK: Event rates for primary and secondary outcomes
Outcomes were renal outcomes
Not powered to look at CV outcomes
Note: not powered for CV outcomes
Appel LJ et al. N Engl J Med 2010;363:

14. AASK: Incidence of the composite primary outcome (doubling of Scr, ESRD, or death) according to baseline proteinuria
Appel LJ et al. N Engl J Med 2010;363:

15. HTN and CKD: The SPRINT Trial
Study Population:
50 years and older
HTN SBP
Increased CV risk: age ≥75 years; clinically evident or subclinical cardiovascular disease; eGFR mL/min; or a 10-year Framingham Risk Score ≥15 percent.
No Diabetes, Stroke, Symptomatic CHF, or proteinuria > 1000mg
28% were 75 years or older (all community dwelling)
28% had CKD (mean GFR 48ml/min in those with GFR < 60ml/min)
Mean Albuminuria 44mg/g (more than 1 gram/day excluded)
RCT 9361 with HTN and increased CV risk (CKD, clinical or subclinical CVD - but no stroke,
Subclinical CVD (ie, an elevated coronary artery calcification score by computerized tomography scan, left ventricular hypertrophy, or an ankle-brachial index <0.9)
NO DM, 10 yr risk of 15% Framingham risk score, age 75 and older)
< 140 versus < 120
28% had CKD
NEJM, 373, Nov 2015

16. HTN: The SPRINT Trial 1st
occurrence of MI, acute coronary syndrome, stroke, CHF, or death
from CV causes.
primary outcome: first occurrence of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death
from cardiovascular causes.
composite renal outcome for participants with CKD at baseline: the first occurrence of a reduction in the estimated GFR of 50% or
more, longterm dialysis, or kidney transplantation.
Incident albuminuria was defined by a doubling of the ratio of urinary albumin (in milligrams) to creatinine (in grams) from less than 10 at
baseline to greater than 10 during followup. The denominators for number of patients represent those without albuminuria at baseline.
Among participants who had chronic kidney disease at baseline, no significant between-group
difference in the composite outcome of a decrease in the eGFR of 50% or more or the development of ESRD was noted, though the number
of events was small (Table2).
Among participants who did not have chronic kidney disease at baseline, the incidence of the outcome defined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute was higher in the intensive-treatment group than in the standard-treatment group (1.21% per year vs. 0.35% per year; hazard ratio, 3.49; 95% CI, 2.44 to 5.10; P<0.001)
Among participants who did not have CKD, more decrease in GFR of 30% or more to a value less than 60 and more AKI in the intensive group
In those with CKD, no difference between rates of ESRD (no one) or decline in GFR (number of events small, trials was stopped early)
Standard vs intensive treatmetn Subgroups: previous CKD, age less than or greater than 75, gender, race, previoud CVD, SBP cut offs no difference except SBP < 132
NEJM, 373, Nov 2015

17. Kaplan-Meier curves for pre-specified outcomes in SPRINT participants with CKD
Primary CV outcome
Mean age pts with CKD 72, 44% 75 and older
Mean SBP was 123 intensive and 136 standard
Mean number of study drugs in intensive 2.9 and standard 2.0
All cause mortality
Increase risks of hypo and hyperkalemia and AKI in the intensive group
Kidney outcome
Kaplan-Meier curves for pre-specified outcomes in SPRINT participants with CKD. Panel A shows the primary cardiovascular outcome, defined as the composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, and death from cardiovascular causes. Panel B shows the all-cause death outcome. Panel C shows the main kidney outcome, defined as the composite of a decrease in eGFR of ≥50% from baseline (confirmed by repeat testing ≥90 days later) or the development of ESRD. The broken lines depict the intensive group; the solid lines depict the standard group.
Alfred K. Cheung et al. JASN doi: /ASN
©2017 by American Society of Nephrology

18. Copyright 2017 American Medical Association. All Rights Reserved.
From: Association Between More Intensive vs Less Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease Stages 3 to 5A Systematic Review and Meta-analysis
JAMA Intern Med. 2017;177(10): doi: /jamainternmed
Study Selection  All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016.
Results  This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, ; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups.
Conclusions and Relevance  Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.
More intensive (132) vs less intensive (140) BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, ; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups.
Date of download: 10/16/2017
Copyright 2017 American Medical Association. All Rights Reserved.

19. How should we treat this patient?

20. The RAAS and site of action of RAAS-blocking drugs.
Faruk Turgut et al. CJASN 2010;5:
©2010 by American Society of Nephrology

21. Collaborative Study - RAAS inhibition
Irbesartan 300mg vs amlodopine 10mg vs placebo
1715 pts DM2, HTN, proteinuria 900mg, SCr
RCT irbesartan 300mg vs amlodopine 10mg vs placebo in 1715 pts DM2, HTN, proteinuria 900mg, SCr
Lewis E, et al, NEJM 2001

22. IDNT – Early Diabetic CKD
590 pts microalbuminuria, SCr < 1.5 for men and 1.1 for women, DM2, HTN
Diabetic nephopathy 30% increase in proteinuria above 200mg
RCT 590 pts microalbuminuria, SCr < 1.5 for men and 1.1 for women, DM2, HTN
ADA does not recommend ACEI/ARB if no microalbuminuria and normal GFR
Parving H, et al, NEJM 2001

23. RAASi: When to stop Hou, NEJM, 2006
Angiotensin-converting–enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency.
Full Text of Background...
Methods
We enrolled 422 patients in a randomized, double-blind study. After an eight-week run-in period, 104 patients with serum creatinine levels of 1.5 to 3.0 mg per deciliter (group 1) received 20 mg of benazepril per day, whereas 224 patients with serum creatinine levels of 3.1 to 5.0 mg per deciliter (group 2) were randomly assigned to receive 20 mg of benazepril per day (112 patients) or placebo (112 patients) and then followed for a mean of 3.4 years. All patients received conventional antihypertensive therapy. The primary outcome was the composite of a doubling of the serum creatinine level, end-stage renal disease, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease.
Full Text of Methods...
Results
Of 102 patients in group 1, 22 (22 percent) reached the primary end point, as compared with 44 of 108 patients given benazepril in group 2 (41 percent) and 65 of 107 patients given placebo in group 2 (60 percent). As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005). This benefit did not appear to be attributable to blood-pressure control. Benazepril therapy was associated with a 52 percent reduction in the level of proteinuria and a reduction of 23 percent in the rate of decline in renal function. The overall incidence of major adverse events in the benazepril and placebo subgroups of group 2 was similar.
Hou, NEJM, 2006

24. RAASi: When to stop
hypertensive adult patients with creatinine levels greater than 6 mg/dL
Objective  To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia.
Design  Prospective cohort study.
Setting  Taiwan.
Participants  From January 1, 2000, through June 30, 2009, we selected hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis-stimulating agents.
Interventions  Users (n = 14 117) and nonusers (n = 14 380) of ACEIs/ARBs.
Main Outcomes and Measures  We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers.
Results  In a median follow-up of 7 months, patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, ]) and the composite outcome of long-term dialysis or death (0.94 [ ]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, ]; P = .30).
Conclusions and Relevance  Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality.
Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, ]) and the composite outcome of long-term dialysis or death (0.94 [ ]).
Hsu, JAMA IM, 2014

25. Combination Therapy: ACEI + ARB
ONTARGET
-established atherosclerotic vascular disease OR DM with end organ damage
-25,000 patients RCT telmisartan 80mg, ramipril 10mg, or combination
Not very proteinuric, COOPERATE trial not real
Looking at renal outcomes as primary endpoint
Mann J, et all, ONTARGET, The Lancet, 2008

26. Combination Therapy Fried, NEJM, Nov 2013 Median UACR 800mg
DM2 + UACR > 300mg and egfr
losartan 100mg/day for everyone, then placebo or lisinopril 10 or lisinopril 40
Primary endpoint: dcline of egfr > 50% if egfr > 60 or decline >30ml if egfr > 60, ESRD or death
Secondary endpoint: above without death, ESRD, Death, MI, CHF
No change any outcomes
Fried, NEJM, Nov 2013

27. Combination Therapy: ACEI + ARB
Safety Outcomes.
Table 3 Safety Outcomes.
Fried LF et al. N Engl J Med 2013;369:

28. Plasma aldosterone rises as GFR falls
a study was done in 28 selected patients with varying degrees of renal insufficiency whose serum potassium and PRA concentrations were within the normal range. The results indicate that at compa
group 2: CrCl 21-70
group 3: CrCl 11-20
group 4: 3-10
22 healthy volunteer controls
rable serum potassium and PRA concentrations, plasma aldosterone is in most instances elevated when creatinine clearance is lower than 50% of normal.
Kidney Int Jan;21(1):
Plasma aldosterone concentrations in chronic renal disease.
Hené RJ, Boer P, Koomans HA, Mees EJ.

29. Aldosterone breakthrough
aldosterone breakthrough: increase in circulating aldosterone after the initation of RAAS bloackade and compared w baseline values, despite blockade of AGII effects. Occirs in 10-50% of patients with 6-12 months of initiation of a RAAS inhibitor
Proposed mechanism: activation of non ACEI enzymes that cleave AGI in AGII and stimulate aldo release, but also happen when ARBs are used (thought to be due to K levels as a stimulant)
In a short period after treatment with a renin–angiotensin (RA) system inhibitor, the plasma aldosterone concentration (PAC) significantly decreased because the PAC is primarily controlled by angiotensin II. Short-term suppression of the PAC is similarly observed in all RA system inhibitors, and the PAC can be suppressed by blockading one point in the RA system (left panel). However, with relative long-term treatment (>6 months) using an RA system inhibitor, continuous suppression of the PAC becomes difficult, and aldosterone-stimulating factors from non-RA systems may greatly increase. Therefore, even if the inhibitor blocks the RA system, the PAC is not controlled completely. For the long-term suppression of harmful aldosterone actions, it is more effective to use one RA system inhibitor in combination with a mineralocorticoid receptor (MR) antagonist (right panel)
Increase in circulating aldosterone after the initiation of RAAS blockade and compared w baseline values, despite blockade of AGII effects. Occurs in 10-50% of patients with 6-12 months of initiation of a RAAS inhibitor
Soto, HTN Research, 2013

30. Combination Therapy: ACEI + aldosterone blocker
RCT 81 patients with DM, HTN, and albuminuria all received lisinopril (80 mg once daily). Then randomly assigned to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk.
We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial.
Mehdi, JASN, 2009

31. Resistant HTN and Aldo Blocker
RCT cross-over trial
HTN on 3 drugs (ACEI/ARB + calcium channel + diuretic)
Randomized to 12 weeks each of spironolactone, bisoprolol, doxazosin and placebo
GFR < 45 excluded
 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 [–5·13 to −3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 [–5·04 to −3·02]; p<0·0001) and versus bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion.
The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 [–5·13 to −3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 [–5·04 to −3·02]; p<0·0001) and versus bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001).
William, PATHWAY-2 Trial, Lancet 2015

32. Risk of hyperkalemia with MRBs
Khosla N, Kalaitzidis R, Bakris GL: Predictors of Hyperkalemia Risk following Hypertension Control with Aldosterone Blockade. Am J Nephrol 2009;30:

33. Volume/Salt/Diuretics

34. Volume mediated BP in CKD
“Pressure-natriuresis” theory  renal handling of sodium is the ultimate determinant of blood pressure
Normal renal function  effectively excrete Na loads
Impaired renal function  must raise BP to efficiently excrete Na and stay in steady state
Diuretics are usually necessary to control BP in CKD

35. Low Sodium Diet, CKD and HTN
Cross over trial of 20 patients with Stage III-IV CKD and HTN
There is a paucity of quality evidence regarding the effects of sodium restriction in patients with CKD,
particularly in patients with pre-end stage CKD, where controlling modifiable risk factors may be
especially important for delaying CKD progression and cardiovascular events. We conducted a doubleblind
placebo-controlled randomized crossover trial assessing the effects of high versus low sodium
intake on ambulatory BP, 24-hour protein and albumin excretion, fluid status (body compositionmonitor),
renin and aldosterone levels, and arterial stiffness (pulse wave velocity and augmentation index) in 20
adult patients with hypertensive stage 3–4 CKD as phase 1 of the LowSALT CKD study. Overall, salt
restriction resulted in statistically significant and clinically important reductions in BP (mean reduction of
systolic/diastolic BP, 10/4 mm Hg; 95% confidence interval, 5 to 15 /1 to 6 mm Hg), extracellular fluid
volume, albuminuria, and proteinuria in patientswithmoderate-to-severe CKD. The magnitude of change
was more pronounced than the magnitude reported in patients without CKD, suggesting that patients
withCKDare particularly salt sensitive. Although studieswith longer intervention times and larger sample
sizes are needed to confirm these benefits, this study indicates that sodium restriction should be emphasized
in the management of patients with CKD as a means to reduce cardiovascular risk and risk for CKD
Progression.
McMahon, JASN, 2013

36. HCTZ vs Chlorthalidone
We conducted a randomized, single-blinded, 8-week active treatment, crossover study comparing chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients
Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day (24-hour mean = −12.4±1.8 mm Hg versus −7.4±1.7 mm Hg; P=0.054; nighttime mean = −13.5±1.9 mm Hg versus −6.4±1.8 mm Hg; P=0.009). Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day (−15.7±2.2 mm Hg versus −4.5±2.1 mm Hg; P=0.001); however, by week 8, reductions were statistically similar (−17.1±3.7 versus −10.8±3.5; P=0.84). Within recommended doses, chlorthalidone is more effective in lowering systolic BPs than hydrochlorothiazide, as evidenced by 24-hour ambulatory BPs. These differences were not apparent with office BP measurements.
Mean 24-hour, daytime, and nighttime ambulatory SBP with change from baseline
Ernst, M. E. et al. Hypertension 2006;47:

37. Loop Diuretics in CKD Often needed when GFR < 30 or a lot of edema
Higher doses needed in CKD
Decreased RBF  reduces the fraction of an administered dose of a diuretic that is presented to the kidney
Metabolic acidosis and increased organic anions in CKD  Decrease PT diuretic secretion due to competition
Decreased GFR --> decreased delivery of Na
Find an effective dose then increase frequency
Decreased RBF  reduces the fraction of an administered dose of a diuretic that is presented to the kidney

38. Calcium Channel Blockers

39. Calcium channel blockers and CKD
Animal data in CKD and DM models support
Dihydropyridine CBs reduce BP but do not affect proteinuria or glomerular scarring
Non-Dihydropyridine CBs blunt the rise in proteinuria, mesangial matrix expansion, glomerular scarring
Differential effects on glomerular hemodynamics
Tarif and Bakris, NDT 1997

40. Calcium channel blockers and CKD
No difference in BP control
Secondary analysis looking at Ca2+ blocker +ACEI/ARB, proteinuria change of 2% for DCAs and -39% for NDCAs (41% Difference, 95% CI 19 to63%, p = .002)
Not enough data to look at CKD progression
Twenty-three studies had both baseline and end-of-study proteinuria levels documented. As a result, 510 patients contributed data for this analysis. The baseline characteristics were not significantly different between the 510 patients included in the analysis and the 1081 patients excluded because of missing values. The baseline, end-of-study, and change in proteinuria values are shown in Table 4. A 32% difference in proteinuria values was observed between the two subclasses. There was +2% change in proteinuria for DCAs and -30% change for NDCAs (95% CI, 10% to 54%, P < 0.01) Figure 1. There were consistently greater reductions in proteinuria associated with the use of NDCAs than with the use of DCAs, despite no statistically significant differences in blood pressure between the groups.
A systematic review was conducted to assess the differential effects of DCAs and NDCAs on proteinuria in hypertensive adults with proteinuria, with or without diabetes, and to determine whether these differential effects translate into altered progression of nephropathy. Studies included in the review had to be randomized clinical trials with at least 6 months of treatment, include a DCA or NDCA treatment arm, have one or more renal end points, and have been initiated after Summary data were extracted from 28 studies entered into two identical but separate databases, which were compared and evaluated by independent reviewers. The effects of each drug class on blood pressure (N = 1338) and proteinuria (N = 510) were assessed.
Results
After adjusting for sample size, study length, and baseline value, there were no statistically significant differences in the ability of either class of calcium antagonist to decrease blood pressure. The mean change in proteinuria was +2% for DCAs and -30% for NDCAs (95% CI, 10% to 54%, P = 0.01). Consistently greater reductions in proteinuria were associated with the use of NDCAs compared with DCAs, despite no significant differences in blood pressure reduction or presence of diabetes.
Conclusion
This analysis supports (1) similar efficacy between subclasses of calcium antagonists to lower blood pressure, and (2) greater reductions in proteinuria by NDCAs compared to DCAs in the presence or absence of diabetes. Based on these findings, NDCAs, alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), are suggested as preferred agents to lower blood pressure in hypertensive patients with nephropathy associated with proteinuria.
Bakris, KI, 2004

41. Chronotherapy

42. Diuretics restore Dipping Pattern
Methods and Results—We studied 21 patients with essential hypertension during both a baseline period and a period of treatment with hydrochlorothiazide (25 mg daily). The periods lasted 4 weeks each. Twenty-four hour ambulatory blood pressures were measured on the same day of the week at the end of the each period. In nondippers (n=11), but not in dippers (n=10), a significant interaction existed between diuretic therapy and nocturnal fall in systolic and diastolic blood pressure, which indicated that the degree of nocturnal blood pressure fall was affected by diuretic therapy. Nocturnal fall, which was diminished in nondippers, was restored by diuretic therapy with hydrochlorothiazide, indicating that the circadian rhythm of blood pressure shifted from nondipper to dipper patterns.
Effects on MAP of diuretic therapy with hydrochlorothiazide, nocturnal fall, and their interaction in dippers (left) and nondippers (right). Two-way ANOVA and ANCOVA with repeated measures clearly demonstrated the presence of an interaction (alternating action, P<0.001) only in nondippers, indicating that diminished nocturnal BP decline was restored by hydrochlorothiazide therapy, and circadian rhythm of BP shifted from nondipper to dipper. ○ and □, MAP values during baseline and diuretic treatment periods, respectively. Error bars indicate either upper or lower half of 95% confidence interval.
Effects on MAP of diuretic therapy with hydrochlorothiazide, nocturnal fall, and their interaction in dippers (left) and nondippers (right).
Takashi Uzu, and Genjiro Kimura Circulation. 1999;100:
Copyright © American Heart Association, Inc. All rights reserved.

43. Chronotherapy in CKD
Chronotherapy in CKD (mean eGFR 46 ml/min/1.73m2) restores nocturnal dipper status
Minutolo R, Gabbai FB, Borrelli S, et al. Am J Kidney Dis 2007;50(6):

44. Chronotherapy in CKD Total CV events
Major CVD events = cardiovascular deaths, MI, ischemic CVA, and hemorrhagic CVA
Kaplan-Meier survival curves as a function of time-of-day of hypertension treatment, i.e., for patients with CKD ingesting either all their BP-lowering medications upon awakening or ≥1 medication at bedtime, for total CVD events (top) and major CVD events (cardiovascular deaths, myocardial infarction, ischemic stroke, and hemorrhagic stroke; bottom).
Hermida R C et al. JASN 2011;22:

45. Algorithim – Proteinuric CKD + HTN
First Line: ACEI or ARB + Diuretic
Maximize ACEI or ARB, check BMP after dose changes
GFR < 30 or a lot of edema or proteinuria consider loop
Caution in the elderly
Calcium Channel Blocker
If proteinuria consider verapamil or diltiazem
If GFR ≥ 45 (>30) and K ≤ 4.5 and proteinuria or resistant HTN
All others
Aldosterone blockade
Sprinolactone 12.5 – 25mg or Eplerenone 25-50mg, follow BMP
Can reduce ACEI/ARB to allow
Move RAASi to PM dosing
Alpha/Beta blockade

46. CKD Consequences

47. Anemia Initial work up CBC, retic, ferritin, Tsat, B12, folate Follow
CBC q 3 months
Iron
Maintain Tsat > 20% and ferritin > 100 and consider stopping if ferritin > 500 (KDOQI)

48. Anemia and CKD Pfeffer, TREAT, NEJM, 2009
Goal of treatment – lowest dose needed to reduce the need for transfusion
4000 patients with DM and CKD RCT of placebo vs darbe to achieve hgb 13, gave rescue if the hgb dropped below 9
There were fewer transfusions increase in transfusions in placebo (496 vs 297)
Pfeffer, TREAT, NEJM, 2009

49. Mineral Bone Disease

50. Consequences of CKD – Mineral Bone Disease
loss of renal mass – decreased eGFR
Replace vitamin D 25 > 30
Phosphate Retention
Decreased Vitamin D
Hypocalcemia
Dietary restriction
Phosphate Binders
Secondary Hyperparathyroidism
Activated Vitamin D
Renal Osteodystrophy

51. Acidosis in CKD
As kidney function declines, the kidneys lose the capacity to generate ammonia and excrete hydrogen
Western diets are high in acid
High net endogenous acid production is associated with a faster decline of GFR in CKD

52. Oral Bicarbonate Therapy in CKD
Control: decline 5.93 ml/min
Bicarb: decline 1.88 ml/min
serum HCO3 at teh end of the trial was 21 in the placebo group and 25 in the treated group, no difference in the BP
RCT of CKD GFR and serum bicarb to supplementation or placebo for two years
ABSTRACT
The primaryend points were rate of CrCl decline, the proportion of patients with rapid decline of CrCl (3 ml/min
per 1.73 m2/yr), and ESRD (CrCl 10 ml/min).
Compared
with the control group, decline in CrCl was slower with bicarbonate supplementation (5.93 versus 1.88
ml/min 1.73 m2; P ). Patients supplemented with bicarbonate were significantly less likely to
experience rapid progression (9 versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P
0.0001). Similarly, fewer patients supplemented with bicarbonate developed ESRD (6.5 versus 33%;
relative risk 0.13; 95% confidence interval 0.04 to 0.40; P ).
J Am Soc Nephrol 20: 2075–2084, doi: /ASN
Brito-Ashurst, JASN, 2009

53. RRT Planning Planning begins at egfr < 20 Transplant
Peritoneal Dialysis
Hemodialysis
PD cath 2 weeks before initiation. Need training
AVF egfr < 20
LRD vs DDRT
Dialysis initiation at egfr < 10 – 15 and uremic signs or sx, fluid overload, or hyperkalemia

54. Nephrology Referral Guidelines recommend Egfr < 30
If an action plan cannot be put in place
Consider if egfr is declining rapidly, if proteinuria is persistently above 1 gram on ACEI or ARB

55. Case
BP goal: < 130/80
Edema  volume overload vs calcium channel blocker effect
Options
Change hctz to Lasix, consider lowering amlodipine to see if there is improvement in edema
Move the losartan to PM dosing
add spironolactone 12.5mg daily
If amlodipine not thought to be the cause of edema consider change to diltiazem
Reinforce low salt diet

57. RAASi: Risk of AKI Bakris, Arch Int Med, 2000
The most common cause of an acute rise in serum creatinine level, following inhibition of the renin angiotensin system (RAS), results from a decreased effective arterial blood volume. This is due to hypoperfusion secondary to volume depletion from overaggressive diuresis, low cardiac output seen in heart failure, or both.21 In these clinical settings, the reduced pressure head from the afferent arteriole further lessens the already reduced intraglomerular pressure imposed by ACEIs. Thus, the compensatory elevation of single-nephron glomerular filtration rate (GFR) seen in renal insufficiency and diabetes is reduced in an almost additive fashion when hypoperfusion and ACE inhibition coexist.21,22
Factors to consider when an acute rise in serum creatinine level is observed are
decreased effective circulating volume (most common);
advanced age (>65 years) with and without preexisting lipid abnormalities; and
baseline serum creatinine level of 124 µmol/L or greater (≥1.4 mg/dL), either alone or in association with (1) diabetes, (2) heart failure, or (3) achievement of low blood pressure goal, ie, less than 125/75 mm Hg when previously elevated to levels greater than 180/110 mm Hg for long periods of time.
The clinical studies reviewed indicate that a limited elevation in serum creatinine, ie, 30% or less above baseline, following initiation of therapy with an ACEI or ARB was seen in patients with renal insufficiency who achieved their blood pressure goal.1,8- 19,25,26 Moreover, an increase in serum creatinine level, if it occurs, will happen within the first 2 weeks of therapy initiation (Figure 1). Assuming normal volume and sodium intake, a rise in serum creatinine that follows ACEI or ARB therapy should stabilize within 2 to 4 weeks (Figure 1). Moreover, if a significant change in serum creatinine level has not been observed within the first month of therapy and blood pressure has been adequately controlled, the probability of an acute rise in serum creatinine level following this period is unlikely. There are 3 exceptions to this statement: (1) initiation of or increasing the dose of currently prescribed diuretics; (2) initiation by either the patient or physician of a nonsteroidal anti-inflammatory drug; or (3) development of volume depletion from nondiuretic-induced causes such as gastroenteritis.
Bakris, Arch Int Med, 2000