Chronic Kidney Disease (CKD)

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In Process

Author / Curator: Justin Berk, MD


Faculty Advisor: TBD
Chronic Kidney Disease, The Basics

Learning Objectives

  • Define chronic kidney disease (CKD) and understand the basic epidemiology and common causes of this condition.
  • Understand how to diagnose CKD and what calculators and blood tests are available to help aid in this process.
  • Identify additional workup that should be completed for someone with newly or long-standing CKD, including when to refer to a nephrologist.
  • Achieve comfort managing patients with CKD, including ways to prevent further progression of disease and treat other secondary complications such as anemia, or hyperparathyroidism.

Key Teaching Points

  • Chronic kidney disease (CKD) is defined as an estimated glomerular filtration rate (eGFR) mL/min < 60 for at least 3 months OR higher GFR with signs of kidney disease in urine or on imaging.[1]
  • The CKD-Epi equation is the most accurate for estimating GFR. Risk of 5 year kidney failure can also be predicted with GFR, proteinuria quantification, and epidemiology (North American vs. non-North American).[2]
  • CKD can be staged using the GFR Clock below.
  • ACE-inhibitors are shown to decrease the progression of proteinuria in chronic kidney disease.[3]

Background

Epidemiology and Pathophysiology

Approximately 1 in 6 adults in the United States have CKD.[4] Patient with acute kidney injuries are at higher risk for future CKD, particularly if requiring inpatient dialysis. [5][6] Recent evidence suggests pediatric kidney disease may also be associated with adult ESRD.[7]

Primary Causes of ESRD
Primary Causes of ESRD

The most common cause of ESRD is diabetes (44%), followed by hypertension (29%). [8] Other etiologies include: autoimmune disease (e.g. SLE, vasculitis, scleroderma), polycystic kidney disease, HIV, Hepatitis C, amyloidosis, obstructive nephropathy(e.g. from nephrolithiasis), and certain medications (PPIs, immune suppressants, HIV medications).[8]

Diagnosis

Definition of CKD

Glomerular filtration rate (GFR) in simplistic terms is an estimate of how well your kidneys are working. GFR is equal to the total of the filtration rates of the functioning nephrons in the kidney. GFR is considered the optimal way to measure kidney function.[9]

The definition of Chronic Kidney Disease (CKD) is defined as:
- The presence of markers of kidney damage for > 3 months in blood, urine, or on imaging (e. g proteinuria, non-urological hematuria, polycystic kidney disease, horseshoe kidney)
OR
- The presence of a GFR < 60 mL/min for > 3 months.[1]

Staging and Prognosis of CKD

The CKD-EPI equation is the most accurate at predicting mortality and ESRD.[2]

Anti-clockwise Model: Strategies for active management of chronic renal disease (Parmar, Malvinder. (2002). Chronic renal disease. BMJ (Clinical research ed.). 325. 85-90.)
After calculating the estimated glomerular filtration rate (eGFR), CKD can be staged into 1 of 5 stages. Using the "anti-clockwise [GFR clock] model[10]" is one way to remember the eGFR cut-offs for each CKD stage.
By drawing a clock, one can visualize the cut-offs for CKD staging based on eGFR
Creatinine clearance can also be used to measure glomerular function, particularly in patients with abnormal body habitus (e.g. bodybuilders, sarcopenic patients).
Creatine Clearance (eGFR) = Urine Cr (mg/dl) * Urine volume (ml)] / [Plasma Cr (mg/dl) * Time (min)

Cystatin C can also be used to confirm CKD staging or improve accuracy when used with other eGFR calculations.[11]

Heat Map: CKD Staging based on eGFR and level of proteinuria

CKD Staging is also based on the level of proteinuria seen in the patient. See Heat Map image.

Risk of ESRD can be predicted using the Tangri formula.[12] In general, lower GFR is associated with higher risk of death, cardiovascular events, and hospitalization. [13]

Initial Work-up

Recommended workup for new diagnosis of CKD[14]:

  • BMP for eGFR and electrolyte abnormalities (e.g. metabolic acidosis)
  • Complete Blood Cell Count (Anemia)
  • Lipid profile
  • Uric Acid
  • Serum albumin
  • Renal ultrasound
    • to look for hydronephrosis, obstruction, cysts, stones, athlerosclerotic disease and assess kidney size and symmetry
  • Urinalysis
    • Quantify proteinuria with urine protein-to-creatinine ratio (Urine Albumin-to-creatinine will miss multiple myeloma Bence-Jones proteins)
    • Look for hematuria or other signs of glomerulonephritis
  • Consider biopsy if significant unexplained proteinuria and no history of diabetes or atypical presentation of renal disease in diabetic patients (cf. [15])

In patients with CKD3 (eGFR < 60 mL/min):

  • Serum calcium, phosphorus, PTH, Vitamin D to assess for Bone Mineral Disease.

If suggested by the history and physical examination:

  • Antinuclear antibody testing to evaluate for lupus
  • Hepatitis B and C, and HIV serology
  • Serum antineutrophil cytoplasmic antibodies to evaluate for ANCA-associated vasculitis
  • Serum and urine protein immunoelectrophoresis to test for multiple myeloma

Nephrology consult recommended if: eGFR < 30 mL/min/1.73 m2, proteinuria > 3.5g / 24 hr, evidence of glomerulopnehritis (hematuria, proteinuria, and hypertension), uncontrolled hypertension, pregnancy, anemia of CKD, bone disorder of CKD, or a rapid decline in GFR (> 4 ml/min/1.73 m2 per year)[16]

Management

General management should prioritize treatment of the underlying condition (i.e. hypertension and diabetes) to stabilize the progression of CKD. Additional efforts should also be taken to reduce cardiovascular risks that are associated with CKD.[17]

Medications

ACE-inhibitors / ARBs demonstrate a significant reduction in proteinuria though no mortality benefit has been observed. [18][19][20][21]

ACE-inhibitors are expected to cause an increase in serum creatinine. Such increase, however, may be associated with risk of mortality.[22] The medication should only be discontinued if the creatinine increases by > 30%.[23]

Blood Pressure Treatment

Per KDOQI 2012 guidelines, the target blood pressure in CKD is <130/90. [24] New AHA guidelines recommend target BP <130/80 for all patients.[25] ACE-inhibitors are first line if there is proteinuria. [3]

Diabetes Management

Metformin is likely OK to use in patients with CKD with eGFR >30. [26][27] There appears to be a difference in expert opinion and lack of guidelines on initiation of metformin at GFR 31-44.[28]

SGLT2 inhibitors (i.e. Empagliflozin and Canagliflozin) are associated with lower rates of worsening nephropathy, progression to albuminuria, initiation of renal replacement therapy and mortality. [29][30][31]

Anemia

There are multiple causes of anemia in patients with CKD including iron deficiency.[32] KDIGO recommends PO (or IV) iron for anemic, non-dialysis, patients with CKD with transferrin saturation <30% and ferritin <500. [33]

Depression Screening

Depression in patients with CKD affects approximately 20% of all patients with CKD.[34]

Nutrition

Guidelines remain controversial but a full discussion can be found at the AKJD Blog or in a 2017 NEJM Review. [35]

Medications to Avoid

Bactrim (trimethoprim-sulfamethoxazole)

  • Use of Bactrim (trimethoprim-sulfamethoxazole) was associated with 3 excess cardiac deaths per 1,000 prescriptions presumably due to hyperkalemia (i.e. patients with CKD at risk). [36]

Proton Pump Inhibitors

  • Observational data demonstrates a link between proton pump inhibitors and CKD. [37]

NSAIDS

  • Numerous retrospective reviews have noted that NSAIDs leads to potential AKI and should be avoided in CKD and/or elderly patients if possible. [38] [39]

Renal Excreted Medications

  • Certain medications, such as gabapentin [40] and baclofen[41][42] also will require renal adjustment for dosing or may not be appropriate in ESRD. It is strongly recommended to look up any new medication to make sure it is renally adjusted to prevent adverse events.

Trial Summaries

CHOIR - A higher target Hgb (>13.5 rather than >11.3) is associated with higher risk of death and hospitalizations for CHF among patients with non-dialysis–dependent CKD and anemia.[43] WJC:CHOIR

TREAT - A higher target Hgb of >13 g/dL with darbopoeitin does not confer a survival benefit in T2DM with CKD, but does increase the risk of stroke.[44] WJC:TREAT

RENAAL - Among patients with diabetic nephropathy, losartan reduced doubling of serum creatinine and progression to ESRD but provided no mortality benefit.[45] WJC:RENAAL

CANVAS - Canagliflozin slows progression of nephropathy (and reduced CVD events and heart failure hospitalizations).[46]  WJC:CANVAS

IDNT- Among patients with diabetic nephropathy, irbesartan slows the progression of nephropathy independent of its antihypertensive effects. [47] WJC:IDNT

EMPA-REG -  Empagliflozin reduced the rate of CV events and slowed the progression of kidney disease among patients with T2DM and high CV risk.[48] WJC:EMPA-REG

EMPA-REG (ESRD) - Empagliflozin is associated with lower rates of worsening nephropathy, progression to macroalbuminuria, initiation of renal replacement therapy and mortality.[49] WJC:EMPA-REG(ESRD)


Visual Abstract Gallery

Ongoing controversies / New updates

Should we use Cystatin C as biomarker for CKD?

It may be better than the current CKD-EPI standard calculator. [50][51]

Should we worry about Contrast-Induced Kidney Injury?

Contrast-induced kidney injury (CIN) may be overestimated in literature. [52] The AMACING trial shows that pre-hydration does not reduce kidney injury in those exposed to contrast, perhaps suggesting less nephrotoxic properties of contrast than previously thought.[53]

Should we worry about giving patients with CKD NSAIDS?

Patients with CKD depend on prostaglandins for vasodilation of afferent arterioles and renal blood flow. [54] NSAIDs block prostaglandin activity and can cause acute kidney injury.  KDIGO Guidelines recommend avoiding NSAIDS in patients with CKD [55], but the evidence suggests that risk of NSAID use in patients with CKD is pretty low (The Male Physician Study showed no elevation in serum creatinine with consistent NSAID use[56] and the PRECISION Trial showed only ~1% risk of kidney events in CKD patients with daily high-dose NSAIDs.[57])

Teaching Resources

KidneyWise Clinical Tool - An evidence-based Clinical Algorithm that helps with identification, detection, and management of patients with CKD. App available online or on iTunes and Google Play.

Nephrology referral form with indications for consultation

CKDPathway.ca - a resource for primary care providers to aid in the diagnosis, medical management, and referral of adults with CKD.

Anemia in CKD Visual Guideline

References

  1. 1.0 1.1 KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. National Kidney Foundation KDOQI Guidelines. Accessed on Mach 16, 2018: http://www2.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm
  2. 2.0 2.1 Michels et al.: Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size. Clin J Am Soc Nephrol 2010;5:1003-9.
  3. 3.0 3.1 Carey & Whelton: Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline. Ann. Intern. Med. 2018;168:351-358.
  4. Centers for Disease Control and Prevention (CDC): Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004. MMWR Morb. Mortal. Wkly. Rep. 2007;56:161-5.
  5. Wald et al.: Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. JAMA 2009;302:1179-85.
  6. Chawla et al.: Acute kidney injury and chronic kidney disease as interconnected syndromes. N. Engl. J. Med. 2014;371:58-66.
  7. Calderon-Margalit et al.: History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. N. Engl. J. Med. 2018;378:428-438.
  8. 8.0 8.1 https://www.usrds.org/2015/download/vol2_USRDS_ESRD_15.pdf
  9. National Kidney Foundation. GFR.https://www.kidney.org/kidneydisease/siemens_hcp_gfr
  10. Parmar &: Chronic renal disease. BMJ 2002;325:85-90.
  11. Peralta, CA, Shlipak, MG, Judd, S. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA 2011; 305, 1545–1552. 
  12. Tangri et al.: Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis. JAMA 2016;315:164-74.
  13. Go et al.: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 2004;351:1296-305.
  14. Drawz & Rahman: Chronic kidney disease. Ann. Intern. Med. 2015;162:ITC1-16.
  15. Espinel et al.: Renal Biopsy in Type 2 Diabetic Patients. J Clin Med 2015;4:998-1009.
  16. Agrawal et al.: Perception of indications for nephrology referral among internal medicine residents: a national online survey. Clin J Am Soc Nephrol 2009;4:323-8.
  17. Sarnak et al.: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension 2003;42:1050-65.
  18. Lewis et al.: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N. Engl. J. Med. 1993;329:1456-62.
  19. Hou et al.: Efficacy and safety of benazepril for advanced chronic renal insufficiency. N. Engl. J. Med. 2006;354:131-40.
  20. Lewis et al.: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 2001;345:851-60.
  21. Brenner et al.: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 2001;345:861-9.
  22. Schmidt et al.: Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ 2017;356:j791.
  23. Bakris & Weir: Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?. Arch. Intern. Med. 2000;160:685-93.
  24. http://www2.kidney.org/professionals/KDOQI/guidelines_bp/guide_7.htm
  25. Whelton et al.: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2017;:.
  26. Lalau et al.: Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care 2018;41:547-553.
  27. Lazarus et al.: Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA Intern Med 2018;178:903-910.
  28. UpToDate. "Metformin in the treatment of adults with type 2 diabetes mellitus" Accessed 15 Jul 2018.
  29. Neal et al.: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017;377:644-657.
  30. Wanner et al.: Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N. Engl. J. Med. 2016;375:323-34.
  31. Zinman et al.: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015;373:2117-28.
  32. Babitt & Lin: Mechanisms of anemia in CKD. J. Am. Soc. Nephrol. 2012;23:1631-4.
  33. Drüeke & Parfrey: Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s). Kidney Int. 2012;82:952-60.
  34. Shirazian et al.: Depression in Chronic Kidney Disease and End-Stage Renal Disease: Similarities and Differences in Diagnosis, Epidemiology, and Management. Kidney Int Rep 2017;2:94-107.
  35. Kalantar-Zadeh & Fouque: Nutritional Management of Chronic Kidney Disease. N. Engl. J. Med. 2017;377:1765-1776.
  36. Fralick et al.: Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ 2014;349:g6196.
  37. Toth-Manikowski & Grams: Proton Pump Inhibitors and Kidney Disease - GI Upset for the Nephrologist?. Kidney Int Rep 2017;2:297-301.
  38. Dixit M, DOan T, Kirschner R and Dixit N. Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting. Pharmaceuticals (Basel). 2010 Apr; 3(4): 1279–1285.
  39. Murray MD et al. Acute and chronic effects of nonsteroidal antiinflammatory drugs on glomerular filtration rate in elderly patients. Am J Med Sci. 1995 Nov;310(5):188-97.
  40. Zand et al.: Gabapentin toxicity in patients with chronic kidney disease: a preventable cause of morbidity. Am. J. Med. 2010;123:367-73.
  41. Wolf et al.: Baclofen Toxicity in Kidney Disease. Am. J. Kidney Dis. 2018;71:275-280.
  42. Chen et al.: Baclofen toxicity in patients with severely impaired renal function. Ann Pharmacother 1997;31:1315-20.
  43. Singh et al.: Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 2006;355:2085-98.
  44. Pfeffer et al.: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med. 2009;361:2019-32.
  45. Brenner et al.: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 2001;345:861-9.
  46. Neal et al.: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017;377:644-657.
  47. Lewis et al.: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 2001;345:851-60.
  48. Zinman et al.: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015;373:2117-28.
  49. Wanner et al.: Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N. Engl. J. Med. 2016;375:323-34.
  50. Levey et al.: Comparing Newer GFR Estimating Equations Using Creatinine and Cystatin C to the CKD-EPI Equations in Adults. Am. J. Kidney Dis. 2017;70:587-589.
  51. Shardlow et al.: The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study. PLoS Med. 2017;14:e1002400.
  52. Wilhelm-Leen et al.: Estimating the Risk of Radiocontrast-Associated Nephropathy. J. Am. Soc. Nephrol. 2017;28:653-659.
  53. Nijssen et al.: Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 2017;389:1312-1322.
  54. Kim &: Renal effects of prostaglandins and cyclooxygenase-2 inhibitors. Electrolyte Blood Press 2008;6:35-41.
  55. http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf
  56. Rexrode et al.: Analgesic use and renal function in men. JAMA 2001;286:315-21.
  57. Nissen et al.: Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N. Engl. J. Med. 2016;375:2519-29.

Contributors

Justin Berk