CKD for Medical Students

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. Definition of Chronic Kidney Disease (CKD) Burden of CKD and kidney failure 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 m 2 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

8. 6.7% 6.6%

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) 2 D (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 [HCO 3 ] 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 U osm 1200 1000 500 350 310 Min U osm 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 R enal E PO P roducing 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, TNF a 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/1.73m 2 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 Assess calcium, phosphorus, PTH and vitamin D Correct these abnormalities before treating elevated PTH Dietary intervention and phosphate binders for hyperphosphatemia If PTH > UNL in CKD 3-5 use vitamin D analogs or calcitriol In ESRD, use vitamin D analogs, calcitriol, calcimimetics or combination Anemia Investigate anemia using Hb , red cell indices, WBC & PLTs, absolute retic count, ferritin, TSAT, B12, folate Address iron deficiency (TSAT< 30%, ferritin < 500 ng/ml) before using ESA ESAs are started when hemoglobin < 10 g/dl 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/m 2 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/m 2 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 control 1 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 Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney Int Suppl . (2012);2:341-342. 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 combination 1,2 Risk of adverse events (impaired kidney function, hyperkalemia) Kunz R, et al. Ann Intern Med . 2008;148:30-48. 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 Usually occurs later in CKD Serum bicarb >22mEq/L Correction of metabolic acidosis may slow CKD progression and improve patients functional status 1,2 Hyperkalemia Reduce dietary potassium Stop NSAIDs, COX-2 inhibitors, potassium sparing diuretics ( aldactone ) Stop or reduce beta blockers, ACEi /ARBs Avoid salt substitutes that contain potassium Mahajan, et al. Kidney Int . 2010;78:303-309. 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 Atenolol, bisoprolol , nadolol Digoxin Some Statins Lovastatin, pravastatin, simvastatin. Fluvastatin , rosuvastatin Antimicrobials 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/1.73m 2 /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/0002-9343/PIIS000293430700664X.pdf KDIGO CKD Work Group. Kidney Int Suppls . 2013;3:1-150.

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