Introduction to Chronic Kidney Disease epidemiology, diagnosis, treatment of complications and system issues (e.g. interface between nephrology and primary care, specialty referrals) for medical students

1. Chronic Kidney Disease
Christos Argyropoulos MD, PhD
University of New Mexico School
of Medicine
An Introduction

2. Overview – Learning Objectives
• Chronic Kidney Disease Basic
• Guidelines for CKD care
• Interface between Primary Care and
Nephrology
• CKD referrals

3. CKD BASICS

4. 1. Definition of Chronic Kidney Disease (CKD)
2. Burden of CKD and kidney failure
3. Back to the basics
 Renal anatomy, physiology, functional assessment
 Physiology of adaptation and clinical manifestations
 “Numerology” of Nephrology (eGFR/proteinuria)
 Identify and monitor CKD progression
Chronic kidney disease basics

5. BURDEN OF CKD

6.  Chronic Kidney Disease
− Kidney function
 Glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 for > 3
months with or without kidney damage
AND/OR
− Kidney damage
 > 3 months, with or without decreased GFR, manifested by either
− Pathological abnormalities
− Markers of kidney damage, i.e., proteinuria (albuminuria)
» Urine albumin-to-creatinine ratio (UACR) > 30 mg/g
CKD is reduced kidney function
and/or kidney damage
Reference: National Kidney Foundation Kidney Disease Outcome Quality Initiative
(KDOQI). Clinical practice guidelines for chronic kidney disease: evaluation,
classification, and stratification. Amer J Kid Dis 2002; 39(2 suppl 1):S18–S266.

7.  Severe form of CKD : Kidney failure (eGFR < 15)
 Kidneys cannot maintain homeostasis.
 Kidney failure is associated with fluid, electrolyte, and
hormonal imbalances and metabolic abnormalities.
 Certain abnormalities may appear at earlier stages
 ESRD means the patient is on dialysis or has a kidney
transplant.
 Uremia is the term used to describe the symptoms or
symptom complex attributable to advanced renal failure
or end-stage renal disease.
CKD vs Kidney failure v.s. ESRD v.s. uremia

9. Adverse
Clinical
Outcomes in
patients with
CKD

10. Diabetes is the leading cause
of ESRD, followed by hypertension
Reference: Adapted from USRDS Annual Data Report (NIDDK, 2011)

11. CKD (And ESRD) are costly
• Cost of treating ESRD : almost $50B/year
• Cost of treating all CKD: $45.5B/year
• Cost of treating diabetic CKD: $24.6B/year
Reference: Adapted from USRDS Annual Data Report (NIDDK, 2013)

12. New Mexico And Hawai Are Sister States
(for Diabetic ESRD)
Ground Zero for
the epidemic of
diabetic CKD &
ESRD

13.  Diabetes
 Hypertension
 Family history of kidney disease
 Cardiovascular disease
 Recurrent urinary tract infections
 HIV infection
 Autoimmune diseases
Risk factors for CKD

14. BACK TO THE BASICS
Why we still teach physiology in Med
School

15. The functions include:
 Filtration
− Glomeruli generate
ultrafiltrate of the plasma.
 Reabsorption
− Tubules selectively
reabsorb substances from
the ultrafiltrate.
 Secretion
− Tubules secrete
substances into the urine.
The nephron functions to maintain balance

16.  Regulatory function
− Control composition and volume of blood
 Maintain stable concentrations of inorganic anions such as
sodium (Na), potassium (K), and calcium (Ca)
− Maintain acid-base balance
 Excretory function
− Produce urine
− Remove metabolic wastes
 Including nitrogenous waste
The kidneys maintain homeostasis

17.  Hormone function
− Produce renin for blood pressure control
− Produce erythropoietin which stimulates marrow
production of red blood cells
− Activate 25(OH)D to 1,25 (OH)2D (active vitamin D)
 Metabolic function
− Gluconeogenesis
− Metabolize drugs and endogenous substances
(e.g., insulin)
The kidneys have other functions

18. Mechanisms of Progression of
Chronic Kidney Disease
Structural events in nephron loss Nephron loss as a self-fulfilling prophecy
Pediatr Nephrol. 2014 Feb; 29(2):
10.1007/s00467-013-2494-8.

19.  We have a large physiologic reserve of renal functional mass
 Each kidney has about 1 million nephrons; slow loss may not be
noticeable
 Slow, progressive loss of functioning nephrons may not be
noticeable.
 The slow, progressive loss of function triggers a number
of maladaptive compensatory mechanisms
 Either the loss of renal function or the adaptations to
reduced renal function lead to the manifestations of
uremia
 The person with CKD may not feel different (silent killer).
Pathogenesis of the manifestations of CKD

20.  Urine volume may not change
− Composition of the urine changes
 Reduced waste excretion
− May not be apparent until CKD is advanced
 Altered hormone production
− Anemia (erythropoietin) and mineral & bone disorders
(vitamin D)
 Reduced catabolism
− Examples: Insulin, glucagon, drugs
Physiological basis of clinical manifestations
of CKD: Fewer nephrons disrupt the balance

21.  Reduced renal clearance and accumulation of:
− Advanced glycation end products
− Pro-inflammatory cytokines
− Reactive oxygen species (oxidation)
− Metabolic acids
 Insulin resistance (even in people without diabetes)
− Reduces insulin-mediated glucose uptake in skeletal
muscles
− May be associated with inflammation as well
Physiological basis of clinical manifestations
of CKD: Fewer nephrons disrupt the balance

22. Mechanisms of adaptation
• Intact nephron
hypothesis
– more work per
nephron to
maintain
homeostasis
• Osmotic diuresis
– urea
• Functional reserve
• Hyperfiltration
• Trade-off
hypothesis
Kidney Int 2011; 79 (Suppl 121): S3–S8.
Am J Physiol. 1985 Sep;249(3 Pt 2):F324-37.
Price to pay for maintaining external
solute balance is the induction of one
or more abnormalities of uremia

23. Physiologic Basis of Adaptation
• Increased solute excretion per remaining
functional nephron
Fractional excretion increases as
GFR decreases

24. Sodium Retention in CKD
• The Input Solution
– Dietary Na Restriction in proportion to the decrement
in GFR
• The output solution
Decreased Na Reabsorption
Increased Fractional Na Excretion
Adaptive Natriuresis

25. Not all solutes are regulated to the
same extent
Little regulation: Plasma concentrations
increase as nephrons are lost.
Creatinine
Urea
Partial regulation: Plasma
concentrations maintained until 50% lost.
HCO3-
Ca++
Pi
Near complete regulation: Plasma
concentration can be maintained until
approximately 90% nephron loss.
Water
Na+
K+

26. Regulation of solutes with progressive
nephron loss: Plasma concentration and
urine concentrating ability by GFR
100 % 65 % 33 % 20 % 10 %
Cr 1 1.3 3.1 5 10.4
BUN 14 18 29 46 82
[Pi] 4 4.2 4.3 5.2 5.8
[HCO3] 24 24 22 16 13
[Na+] 140 140 140 138 136
[K+] 4 4 4 4.5 5.5
pH 7.4 7.4 7.37 7.3 7.26
Max Uosm 1200 1000 500 350 310
Min Uosm 50 50 70 200 310

27. Trade-off among renal function, PTH and
FGF23 on phosphorus homeostasis
PTH FGF23
Judith Blaine et al. CJASN doi:10.2215/CJN.09750913
Kidney International (2011) 80, 443 – 445. doi: 10.1038/ki.2011.146

28. Putting it all together
Normal Kidney
Function
Chronic Kidney
Disease
doi: 10.2215/​CJN.06040710
28

29. Disorders of erythropoiesis in CKD
• EPO is produced by the kidney
peritubular interstitial fibroblasts
• Renal EPO Producing Cells
• In CKD, REPC undergo
transdifferentiation to
myofibroblasts losing the ability
to produce EPO (erythropoietin)
• In CKD kidneys, the number of
REPC is reduced, which results in
inadequate EPO production in
response to hypoxic stimuli and
leads to the development of
anemia
Blood Rev. 2013 Jan; 27(1): 41–53.

30. Hypoxia Inhibitor Factors, EPO and Iron metabolism
EPO regulation by HIF & O2 in REPC Iron metabolism & HIF pathways
Blood Rev. 2013 Jan; 27(1): 41–53.
In CKD, decreased HIF activation may
contribute to the apparent iron deficiency and
iron resistance noted in patients

31. Uremia: Common Symptoms
• GI Nausea, vomiting, diarrhea
• CVS Dyspnea, edema, chest pain
• Neuro Restless legs, twitching, confusion
• Skin Pruritus, bruising, uremic frost
• MSK Bone pain, arthritis

32. Uremia: signs and symptoms of
the later stages
• Sallow pallor, bruising
• Uremic fetor
• Hypertension
• Pericardial rub
• Alteration of consciousness
• Neuropathy
• Hyperkalemia and acidosis that are refractory
to dietary interventions and medical
management

33. Clinical Manifestation of Sodium
Balance in CKD
These appear across all stages
• Common
– Weight gain
– Peripheral edema
– Pulmonary edema
• Uncommon
– Renal Na wasting (ECF volume depletion)
– Weight loss
– Systemic hypotension

34. Ca abnormalities in CKD (Chronic Kidney Disease)
•In CKD stages 2-3 (renal fx >30% of nl), serum calcium levels are
maintained by ↑ PTH levels because of reductions in calcitriol
•Intestinal calcium absorption is impaired in CKD due to decreased
calcitriol levels
•Urinary calcium excretion decreases as CKD progresses due to ↑
PTH:
•In CKD, intestinal absorption is not equal to urinary excretion
•The ability of bone to take up calcium depends on bone turnover
•Higher PTH levels but also increased resistance to its action
•Late stage CKD patients have a net positive calcium balance
•This leads to extraosseal calcification – a cardiovascular disease risk factor in these
patients
•Note that this positive calcium balance is not associated with
high but rather low-normal calcium levels (Secondary
Hyperparathyroidism – SHPT) 34

35. Phosphorus abnormalities in CKD
•Phosphorus homeostatic control is impaired at a GFR as high as 60
mL/min
•As GFR decreases to <60 mL/min, there is a gradual increase in serum
phosphorus levels
•During this period, “normal” phosphorus levels are maintained by
continual increases in FGF-23 and PTH levels
•Eventually, this compensatory mechanism is overwhelmed when GFR
decreases to <30 mL/min, and measured serum phosphorus levels may
increase to higher than the reference range
•Hyperphosphatemia also leads to inhibition of calcitriol synthesis,
which stimulates further PTH production; together, these processes
trigger secondary hyperparathyroidism in CKD to develop
•Observational data suggest that hyperphosphatemia is connected to
increased morbidity and mortality (all cause and cardiovascular) in CKD
(>5.5 mg/dl) and non CKD populations (in the normal range)

36. Biochemical abnormalities, Bone Disease and
Extraskeletal Calcification in CKD-MBD
Adv Chronic Kidney Dis 2007 14 3-12
Multifactorial Pathogenesis:
•Phosphorus retention
•Hypocalcemia
•↑ FGF-23
•↑ PTH
•↑ Resistance to the action of
hormones (VDR,PTH,FGF-
23/klotho)

37. Coronary Calcification in Young
Adults with ESRD
Goodman, et al NEJM 2000
Elevated Ca x P product
and cumulative use of
calcium-containing P-
binders are correlated
with coronary
calcification

38. CKD leads to many bone diseases
Cardiovascular disease correlates with the presence of these
bone disorders: bones hurt and heart suffers

39. Dyslipidemia
Traditional Risk Factors Non-traditional Risk Factors
Abnormal bone
Age
Oxidation (OxLDL)
Diabetes
HTN
Advanced glycation
end-products
Smoking
Genetics
Carbonyl stress
Low fetuin-A
Elevated IL-1, Il-6, TNFa
Homocysteine
Abnormal mineral metabolism
Fractures
Cardiovascular
disease in CKD

40. NUMEROLOGY
eGFR and Albuminuria

41.  GFR is equal to the sum of the filtration rates in all
of the functioning nephrons.
 GFR is not routinely measured in clinical settings.
 Estimation of the GFR (eGFR) gives a rough measure
of the number of functioning nephrons.
What is the glomerular filtration rate (GFR)?

42.  eGFR is not the measured GFR.
 The formula to estimate GFR was derived from a population-
based study.
 MDRD, CKD-Epi, etc www.kidney.org/GFR.
 eGFR is based on serum creatinine levels.
 Previous methods to estimate kidney function also are based
on serum creatinine.
 Creatinine assays are now standardized.
− Isotope Dilution Mass Spectrometry (IDMS)
eGFR estimates the measured GFR

43.  Do not use with:
− Rapidly changing creatinine levels
 Example: acute kidney injury
− Extremes in muscle mass, body size, or altered diet
patterns
− Medications that interfere with the measurement of
serum creatinine
 Not all estimating equations are created equal
− MDRD is “blind” above 60 ml/min/1.73m2
Creatinine-based estimates of kidney
function have limitations

44.  Glomerular Basement Membrane retains (large) proteins
into the blood stream
 Damage to the filter allows larger molecular weight
substances such as albumin into the ultrafiltrate.
 Tubular damage may result in decreases in the tubular
absorption of proteins in the proximal tubule
 More proteins appear in the urine
 Increased urine protein may be a cause as well as a sign
of kidney injury.
Physiological basis of
proteinuria/albuminuria

45.  Standard of diabetes care (annual screen)
 Diagnosis
− Forty percent of people are identified with CKD on the basis of
urine albumin alone.
− 50% of pts with DM & CKD will NOT have abnormal albuminuria
 Prognosis
− Important prognostic marker, especially in diabetes mellitus
(DM)
− Used to monitor and guide therapy (but note ACP guidelines)
 Tool for patient education and self-management (such as
A1C or eGFR)
Urine albumin results are used for screening,
diagnosing, and treating CKD

46. Definition of Albuminuria
Method Normal
Micro-
albuminuria
Overt/Macro-
albuminuria
24 hour excretion <30 mg/day 30-300 mg/day >300 mg/day
Timed urine specimen <20 g/min 20-200 g/min >200 g/min
Spot-urine albumin
specific dipstick
(screening)
<3 mg/dl >3 mg/dl N/A
Spot urine albumin/
creatinine ratio (ADA)
< 30 mg/g 30-300 mg/g >300 mg/g
Spot urine albumin/
creatinine ratio (gender
specific) (K/DOQI)
<17 mg/g (men)
<25 mg/g (women)
17-250 (men)
25-355 (women)
>250 (men)
>355 (women)
K/DOQI and ADA

47.  Dipstick
− Semi-quantitative, screening only
 Affected by urine concentration, highly variable
− Detection of urine albumin > 300 mg/day
(1+ approximates albumin excretion of 30 mg/day)
 Urine protein/creatinine ratio
‒ All proteins, not just albumin (myeloma/CIN)
 Urine albumin-to-creatinine ratio (UACR)
‒ Quantifies urine albumin
− Steps toward standardization currently in progress
− Standard for public health, clinical care, and research
Which urine test to use?
ACR > PCR > Auto strip > Manual strip (KDIGO 2012)

48. Urinary ACR is NOT perfect

49. GUIDELINES
ACP and KDIGO Guidelines for CKD and its complications

50. ACP Guidelines
• Recommendation 1: ACP recommends against screening for chronic kidney
disease in asymptomatic adults without risk factors for chronic kidney disease.
– (Grade: weak recommendation, low-quality evidence)
Ann Intern Med. 2013;159(12):835-847.

51. • Recommendation 2:
ACP recommends against
testing for proteinuria in
adults with or without
diabetes who are currently
taking an angiotensin-
converting enzyme inhibitor
or an angiotensin II–receptor
blocker.
– (Grade: weak
recommendation, low-quality
evidence)
– Nephrologists disagree:
Residual albuminuria in fixed
dose ARB trials: increased renal
risk
ACP Guidelines
Ann Intern Med. 2013;159(12):835-847.

52. ACP Guidelines
• Recommendation 3:
ACP recommends that clinicians select pharmacologic therapy
that includes either an angiotensin-converting-enzyme
inhibitor (moderate-quality evidence) or angiotensin II–
receptor blocker (high-quality evidence) in patients with
hypertension and stage 1 to 3 chronic kidney disease.
– (Grade: strong recommendation)
• The risk for ESRD was not reduced in patients with only microalbuminuria or
impaired GFR.
• Pooled data from 10 trials showed that mortality risk was reduced in patients
with microalbuminuria, although most of the data were derived from a large
study that showed no difference in mortality between patients with and without
microalbuminuria.
• Therapy with ACE inhibitors did not reduce the risk for cardiovascular mortality,
myocardial infarction (MI), stroke, or other vascular outcomes.

53. ACP Guidelines
• Recommendation 4: ACP recommends that clinicians
choose statin therapy to manage elevated low-
density lipoprotein in patients with stage 1 to 3
chronic kidney disease.
– (Grade: strong recommendation, moderate-quality evidence)
• Nephrology guidelines (KDIGO) suggest that one does not
start statins, but do not stop either in CKD stages 4,5 & ESRD

54. KDIGO Guidelines
CKD-MBD/SHPT
1. Assess calcium, phosphorus, PTH
and vitamin D
2. Correct these abnormalities
before treating elevated PTH
3. Dietary intervention and
phosphate binders for
hyperphosphatemia
4. If PTH > UNL in CKD 3-5 use
vitamin D analogs or calcitriol
5. In ESRD, use vitamin D analogs,
calcitriol, calcimimetics or
combination
Anemia
1. Investigate anemia using
Hb, red cell indices, WBC &
PLTs, absolute retic count,
ferritin, TSAT, B12, folate
2. Address iron deficiency
(TSAT< 30%, ferritin < 500
ng/ml) before using ESA
3. ESAs are started when
hemoglobin < 10 g/dl
4. Do not use to maintain Hb
>11.5 g/dl

55. INTERFACE BETWEEN PRIMARY CARE
AND NEPHROLOGY
PRIMARY CARE PHYSICIANS ARE THE FIRST LINE OF DEFENSE AGAINST CKD

56. Lifestyle modifications which help lower
blood pressure in the general population
have not been studied in ESRD
References: Chobanian et al. J Am Med Assoc 2003; 289(19):2560–2571;
Neter et al. Hypertension 2003; 42(5):878–884; Dietary Guidelines, 2010
Modification Recommendation Lowers Systolic Blood
Pressure by (Range)
Weight reduction •Maintain normal body weight
•Body mass index (BMI) 18.5–24.9
kg/m2
5–20 mm Hg /  10 kg
 4 mm Hg /  5 kg
DASH •Increase potassium (fruits and
vegetables) and calcium (dairy)
•DASH may be too high in protein,
potassium and phosphorus for CKD
8–14 mm Hg
Physical activity •At least 30 minutes most days 4–9 mm Hg
Moderate alcohol
consumption
•Women: ≤ 1 drink per day
•Men: ≤ 2 drinks per day
2–4 mm Hg
Sodium restriction •2,300 mg per day
•1,500 mg per day for hypertension,
diabetes, and CKD
2–8 mm Hg
Modification Recommendation Lowers Systolic Blood
Pressure by (Range)
Weight reduction •Maintain normal body weight
•Body mass index (BMI) 18.5–24.9
kg/m2
5–20 mm Hg /  10 kg
 4 mm Hg /  5 kg
DASH •Increase potassium (fruits and
vegetables) and calcium (dairy)
•DASH may be too high in protein,
potassium and phosphorus for CKD
8–14 mm Hg
Physical activity •At least 30 minutes most days 4–9 mm Hg
Moderate alcohol
consumption
•Women: ≤ 1 drink per day
•Men: ≤ 2 drinks per day
2–4 mm Hg
Sodium restriction •2,300 mg per day
•1,500 mg per day for hypertension,
diabetes, and CKD
2–8 mm Hg

57. Goals of Hypertension
Treatment in CKD
• Slow decline in kidney function
• Blood pressure control1
– ACR <30 mg/g: ≤140/90 mm Hg
– ACR 30-300 mg/g: ≤130/80 mm Hg*
– ACR >300 mg/g: ≤130/80 mm Hg
– Individualize targets and agents according to age,
coexistent CVD, and other comorbidities
– ACEi or ARB
*Reasonable to select a goal of 140/90 mm Hg, especially for moderate albuminuria (ACR 30-300 mg/g.)2
1) Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney Int Suppl.
(2012);2:341-342.
2) KDOQI Commentary on KDIGO Blood Pressure Guidelines. Am J Kidney Dis. 2013;62:201-213.

58. Slowing CKD Progression: ACEi or ARB
• Risk/benefit should be carefully assessed in the elderly and
medically fragile
• Check labs after initiation
– If less than 25% SCr increase, continue and monitor
– If more than 25% SCr increase, stop ACEi and evaluate for RAS
• Continue until contraindication arises, no absolute eGFR cutoff
• Better proteinuria suppression with low Na diet and diuretics
• Avoid volume depletion
• Avoid ACEi and ARB in combination1,2
– Risk of adverse events (impaired kidney function,
hyperkalemia)
1) Kunz R, et al. Ann Intern Med. 2008;148:30-48.
2) Mann J, et al. ONTARGET study. Lancet. 2008;372:547-553.

59. Medications that increase risk for
hyperkalemia in CKD
Referece: Chobanian et al. J Am Med Assoc 2003; 289(19):2560–2571
Commonly prescribed
 Angiotensin-Converting
Enzyme Inhibitor (ACEi)
 Angiotensin Receptor
Blockers (ARB)
Used cautiously in CKD
 Aldosterone antagonists
 Renin inhibitors
 Potassium-sparing
diuretics
 NSAIDS
Whenever an ACEi/ARB/Aldo antagonist/DRI is started
check K within 7-10 days (but not sooner than 7 or >14)
K-sparing diuretics in CKD or diabetes (with normal
eGFR/proteinuria): check K within 3-7 days (but not later)

60.  Renal threshold for glucose is 180–200 mg/dL.
 Sugars cross-linking to proteins changes their shapes and
functions (AGEs).
 A1C goal is individualized (≤ 7% in ADA 2014).
 Spontaneous improvement in glycemic control may
indicate CKD progression and medications may change.
 Risk for hypoglycemia occurs with CKD (insulin is cleared
from the kidneys, 20% of gluconeogenesis occurs in the
kidney); risk for hyperkalemia occurs with ACEi and
ARBs.
− Use low-potassium juice to treat hypoglycemia.
− Light-colored soda pop is lower in phosphorus than cola.
CKD and diabetes I

61.  Urine albumin excretion is associated with diabetic kidney
disease, but not all people will have high urine albumin
levels.
 High levels of urine albumin may mean more rapid
progression of CKD.
 Good control of diabetes early may help reduce the risk of
albuminuria later.
 Tight versus good control may not slow progression
 Potential dangers associated with very tight control and
sodium restriction
CKD and diabetes II

62.  Control blood pressure (ACEi/ARB)
 Reduce sodium intake (but note emerging data
about possible harms in patients with diabetes)
 Achieve good control of diabetes early; may help
prevent albuminuria
 Reduce weight (if obese)
 Reduce protein intake, if excessive
 Achieve tobacco cessation
Interventions for reducing urine albumin

63.  Glyburide
 Metformin (US label SCr>1.4-
1.5 ex-US eGFR>30)
 Alpha-glucosidase inhibitors
 Exenatide
 Glimepiride
 Sitagliptin
 Repaglinide
 Insulin (dose decrease)
 Glipizide
 Pioglitazone
− Fluid retention (bladder cancer, ↑
risk of CKD?)
 Nateglinide
 Pramlintide
 SGLT2 inhibitors:
− Canaglifozin
(Invokana)/empaglifozin
(Jardiance) (stop if eGFR<45)
− Dapaglifozin(Farxiga) (stop if
eGFR<60)
Diabetes medications may be
discontinued or dose-adjusted in CKD
Reference: Reilly & Berns Seminars in Dialysis 2010; 23(2):163–168.
Farxiga/Invokana/Jardiance PIL

64. Detect and Manage Metabolic CKD
Complications
• Metabolic acidosis
o Usually occurs later in CKD
o Serum bicarb >22mEq/L
o Correction of metabolic acidosis may slow CKD progression
and improve patients functional status1,2
• Hyperkalemia
o Reduce dietary potassium
o Stop NSAIDs, COX-2 inhibitors, potassium sparing diuretics
(aldactone)
o Stop or reduce beta blockers, ACEi/ARBs
o Avoid salt substitutes that contain potassium
1) Mahajan, et al. Kidney Int. 2010;78:303-309.
2) de Brito-Ashurst I, et al. J Am Soc Nephrol.
2009;20:2075-2084.

65. Drug Dosing Considerations
• Renal impairment may alter both pharmacodynamics and
pharmacokinetics
• There is a higher risk for Adverse Drug Reactions as a result of
renal functional impairment AND comorbidities in CKD
patients
• Drug development programs and the FDA lag behind clinical
practice when quantifying renal function and risk (MeDRA
uses creatinine elevation, studies are designed based on
Cockroft Gault)
• MOST DRUGS HAVE NEVER BE TESTED IN CKD POPULATIONS
• Dosing recommendations are often based on post-hoc
analyses or PK/PD modeling using “general population”
relationships
• One is often conducting an RCT n=1 when prescribing a
medication in CKD

66. Common Non-DM Medications Requiring Dose
Reduction in CKD
• Allopurinol
• Gabapentin
– CKD 4- Max dose 300mg qd
– CKD 5- Max dose 300mg
qod
• Reglan
– Reduce 50% for eGFR< 40
– Can cause irreversible EPS
with chronic use
• Narcotics
– Methadone and fentanyl
best for ESRD patients
• Lowest risk of toxic
metabolites
• Renally cleared beta blockers
o Atenolol, bisoprolol, nadolol
• Digoxin
• Some Statins
o Lovastatin, pravastatin,
simvastatin. Fluvastatin,
rosuvastatin
• Antimicrobials
o Antifungals, aminoglycosides,
Bactrim, Macrobid
• Enoxaparin
• Methotrexate
• Colchicine

67. The
cautious
approach
to drug
dosing in
CKD
Pharmacotherapy. 2011;31(11):1130-1144.

68. CKD REFERRALS

69. *Significant albuminuria is defined as ACR ≥300 mg/g (≥30 mg/mmol) or AER ≥300 mg/24 hours, approximately
equivalent to PCR ≥500 mg/g (≥50 mg/mmol) or PER ≥500 mg/24 hours
**Progression of CKD is defined as one or more of the following: 1) A decline in GFR category accompanied by a 25%
or greater drop in eGFR from baseline; and/or 2) rapid progression of CKD defined as a sustained decline in eGFR of more than
5ml/min/1.73m2/year. KDOQI US Commentary on the 2012 KDIGO Evaluation and Management of CKD
Indications for Referral to Specialist Kidney Care
Services for People with CKD
• Acute kidney injury or abrupt sustained fall in GFR
• GFR <30 ml/min/1.73m
2
(GFR categories G4-G5)
• Persistent albuminuria (ACR > 300 mg/g)*
• Atypical Progression of CKD
**
• Urinary red cell casts, RBC more than 20 per HPF sustained and not
readily explained
• Hypertension refractory to treatment with 4 or more
antihypertensive agents
• Persistent abnormalities of serum potassium
• Recurrent or extensive nephrolithiasis
• Hereditary kidney disease

70. Observational Studies of Early vs. Late
Nephrology Consultation
Chan M, et al. Am J Med. 2007;120:1063-1070.
http://download.journals.elsevierhealth.com/pdfs/journals/0
002-9343/PIIS000293430700664X.pdf
KDIGO CKD Work Group. Kidney Int Suppls. 2013;3:1-

71. Interface between
PC and Nephrology
KDIGO guidelines

72. Why should we refer at later stages?
Complications may increase as estimated
glomerular filtration rate (eGFR) decreases
Reference: Adapted from USRDS 2010 Annual Data Report (NIDDK, 2010)

73. The role of the nephrologist outside the
dialysis unit
• Treating complications of CKD
• Slowing progression
• Preparation for renal replacement therapy:
– Outpatient hemodialysis
– Home hemodialysis
– Peritoneal dialysis (home therapy)
– Pre-emptive renal transplantation

74. Collaborative Care Agreements Between
PCPs & Nephrologists
• Soft Contract between primary care and nephrologist
• Defines responsibilities of primary care
– Provide pertinent clinical information to inform the
consultation prior to the scheduled visit.
– Initiate a phone call if the condition is emergent
– Provide timely referrals with adequate number of visits to
treat the condition.
• Defines responsibilities of nephrologist
– Timely communication of consultation (7 days routine & 48
hours emergent) – fax if no electronic information sharing
– No consultation to other specialist initiated without primary
care input

75. • Delivered by a CKD educator (usually a RN) meeting
face to face with the patient
• Increase number of pts. receiving early (stage 3 & 4)
CKD education statewide.
• Prevent “traumatic dialysis starts”: decrease catheter
placement rate, increase fistula placement and PD
catheter placement rate.
• Increase number of pts. choosing Home Dialysis.
• Slow progression of CKD and delay need for dialysis.
• Prevent dialysis through pre-emptive transplant.
IT IS NOT JUST ABOUT THE
NEPHROLOGIST: CKD EDUCATION
PROGRAM OBJECTIVES

76. SUMMARY
Things to remember even if you do not become a nephrologist

77.  The composition of the urine changes to ensure that
plasma values do not change (much).
 Most people do not notice any difference in urine
volume.
 CKD has to be pretty advanced and patient near
dialysis before decreases in the amount of urine are
noticed
 Increases in the frequency of urination (nocturia)
may be a clue to renal disease
Don’t be fouled by the urine:
People with CKD still make urine

78.  Certain blood based tests (eGFR) will reveal loss of
renal function
 Based on creatinine but clinicians tend to
underestimate (higher levels of renal function) and
overestimate (lower levels of renal function) the same
absolute change in creatinine values
 Slow, progressive loss of function may not be
noticeable.
 May have to monitor trends of labs over time to
identify slow progressors
Estimated glomerular filtration rate

79. Proteinuria/Albuminuria
• Though not a measure of GFR, it is a marker of kidney damage
that independently predicts cardiovascular disease.
• Higher urinary albumin-to-creatinine implies worse prognosis
for the same level of eGFR
• Controversial whether microalbuminuria always represents
kidney disease (CKD stage 1) or whether it could reflect
endothelial dysfunction without kidney damage.
• Generally use spot urine for albumin/creatinine ratio- but can
use total protein/creatinine for significant proteinuria (>500-
1000 mg/g).

80. CKD Checklist for PCPs
• Slowing Progression
– BP < 140/90 (UACR < 30 pr
130/80 UACR>30)
– HBA1c ≤ 7% within 6 mos
– On ACEi/ARB if DM or microalb
> 30mg/g
– Smoking cessation
– Discuss avoidance of
NSAIDs/nephrotoxins
• Tx of Complications
– CBC, iron studies within the
year
– Ca, P, PTH (q 6 mo if eGFR <
60, q 3 mo if eGFR < 30)
• Nephrology Referral
– GFR < 30
– Persistent proteinuria despite
ACEi
– Persistent hyperK
– Resistant HTN (≥4 meds)
– ↓GFR by 30% (“certain drop”)
irrespective of eGFR
– Unclear etiology of CKD
– Anemia requiring ESAs
– ↑ P, PTH
– Recurrent nephrolithiasis
– Genetic renal disease
• Health Maintenance
– Annual screen for
proteinuria
– LDL < 100 within the last
year
– Both Pneumococcal
vaccines
– Yearly flu shot