Presentation on theme: "End Organ Damage- The Kidney"— Presentation transcript:
1 End Organ Damage- The Kidney JogiRaju Tantravahi, M.D.Nephrology Fellowship Training Program DirectorDivision of NephrologyUniversity of Florida College of MedicineStaff nephrologist, Malcom Randall VA Medical Center
2 Disclosures of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose.This speaker will not discuss any off-label use or investigational product during the program.This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.
3 Outline The spectrum of renal disease in HIV infection The management of chronic kidney diseaseCurrent methods for measuring renal functionPreserving renal functionManaging the complications of chronic kidney diseaseKidney transplantation in HIV infectionTenofovir (Viread®) nephrotoxicity
4 The nephron…and there’s no need to complicate things. Blood goes inFiltrate of plasma made in the glomerulusBlood comes outThe filtrate of plasma is reabsorbedand modified throughout the nephron.Modified from brutal internet artwork
5 Elevated creatinine or a reduced calculated GFR So how do you know that the patient has a kidney problem (and we’ll see this slide again)?Elevated creatinine or a reduced calculated GFRElectrolyte abnormalities, such as hyperkalemia, metabolic acidosis, or hyperphosphatemiaAbnormal urinalysis, with hematuria, pyuria, proteinuria, or castsDecreased urine output or edema
6 Causes of chronic kidney disease in the HIV population I cannot find significant fault with thespectrum of kidney diseases in patientswith HIV disease outlined by the authors.However, in considering the causes ofrenal disease in the current HIV population,I suggest that more gain will be made ifwe focus on managing the routine causes ofchronic kidney that wee see in the generalpopulation *such as diabetes andhypertension), as I believe that the routinecauses chronic kidney have or will becomemore prevalent than the exotic causes.When I now see chronic kidney disease patient with HIV, I ask how well has the disease been controlled, what drugs does the patient take, and if the patient has diabetes or hypertension.Elewa, U. et a Nephon Clin Prac 118:
7 Normal glomerulus and collapsing glomerulopathy of HIV associated nephropathy Global sclerosisseen in a glomerulusin a patient with thecollapsing glomerulopathyof HIV associatednephropathy. Note that theentire tuft is involuted withno open capillaries withlikely mesangial cellproliferation.The capillaries in theglomerular tuft are open,allowing for glomerularfiltration.ObsolescentglomerulusThin, attenuatedtubulesThe cell numberis appropriate.Dilated tubuleswith microcystsand proteinaceouscastsNormal glomerular structure,from H. Rennke, UpToDateWyatt, C.M, Meliambro, K., and Klotman P.E Ann. Rev. Med. 63:
8 Kidney disease screening algorithm Estrella, M.M., and Fine D. M Adv Chronic Kid Dis 17: 26-35
9 Clinical concepts and entities you need to understand and manage
10 Elevated creatinine or a reduced calculated GFR So how do you know that the patient has a kidney problem (and here’s the slide again)?Elevated creatinine or a reduced calculated GFRElectrolyte abnormalities, such as hyperkalemia, metabolic acidosis, or hyperphosphatemiaAbnormal urinalysis, with hematuria, pyuria, proteinuria, or castsDecreased urine output or edema
11 My chronic kidney disease management paradigm FIGHT FOR EVERY NEPHRON!Measurements of renal functionThe stages of chronic kidney diseaseThe consequences of chronic kidney disease and their managementHypertensionAnemiaBone and mineral metabolismElectrolyte abnormalitiesWhen things fail…replacement therapy with dialysis or transplantation
12 Problems equating elevated creatinine with renal dysfunction Serum creatininea surrogate marker for renal functionnormal range typically 0.6 mg/dl to 1.1 mg/dlhigher values indicate worse renal function.Problems equating elevated creatinine with renal dysfunctionMuscular peopleLarge muscle massHigher creatinine with normal renal functionEmaciated peopleLow/no muscle massFalsely low creatinine in face of renal dysfunction
13 Ways to measure renal function, I 24 hour urineYou need an adequate collectionMen should excrete between 15 mg/kg to 20 mg/kg of creatinine dailyWomen should excrete between 10 mg/kg to 15 mg/kg creatinine dailyIn near end stage renal disease, creatinine secretion is increased, so you need to measure the urea clearance as well and average the values
14 Ways to measure renal function, II Cockroft-Gault formulaCrCl (ml/min)= (140-age) x lean body weight (kg) PCr (mg/dl) x 72MDRD formula170 x [Cr] x [BUN] x [Alb]0.318 x Age x (Female) x (African American)CKD-EPI formulaGFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1) X 0.993Age X [if female] X [if black] where Scr is serum creatinine (mg/dl), κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.Cystatin C, iothalmate clearanceMDRD formula: Levey , A.S.et al Ann Int Med 145:CKD-EPI formula: Levey, A.S. et al Ann Int Med 150:
15 Ways to measure proteinuria Urinary dipstickImprecise and not quantitative24 hour urine collectionThe collection has to be well done, or the result cannot be interpreted.Spot urine for protein and creatinineThe lab reports the value as mg protein/gram creatinine. Since we generally excrete 1 gram creatinine daily, the spot urine ratio is generally reliable.Albuminuria, tubular proteinuria vs. light chainsRole of the urinary albumin to creatinine ratio, serum and urine protein electrophoresis, serum free light chains
16 Communicating with your nephrologist: Stages of chronic kidney disease Stage I: Normal GFR (greater than 90 ml/min) and persistent albuminuriaStage II: GFR between 60 ml/min and 89 ml/min and persistent albuminuriaStage III: GFR between 30 ml/min and 59 ml/min.Stage IV: GFR between 15 ml/min and 29 ml/min.Stage V: GFR less than 15 ml/min or end stage renal disease.As formulated by the National Kidney Foundation
17 What does the kidney do? The major homeostatic organ Electrolyte balance, acid-base balance, salt and water balanceDetoxification and drug metabolismOrganic acids, renal excretion of drugsAn endocrine organTerminal hydroxylation of vitamin D, erythropoietin synthesisGlomerular filtration and reclamation
18 The incredible absorptive capacity of the kidney Substance Filtered Excreted % net reabsorbedWater 180 liters liters %Sodium 26,000 mEq mEq >99%Chloride 21,000 mEq mEq >99%Bicarbonate 4,800 mEq %Individuals with a normal GFR essentially can conserveall the sodium, water, and bicarbonate filtered at theglomerulus. However, fine hormonal control allow us toexcrete sodium, water, or even bicarbonate. Additionally, the kidneys are efficiently excrete potassium in a response to a potassium load.
19 The consequences of chronic kidney disease Beyond the devastating effects of the loss of renal function in an of itself, chronic kidney disease is accompanied by a number of devastating complications.Cardiovascular diseaseHypertension (including volume overload)AnemiaBone diseaseProtein malnutrition not related to cachexiaElectrolyte abnormalitiesMetabolic acidosis
20 General principles regarding the management of chronic kidney disease Hypertension control (target systolic blood pressure of 130 mm Hg or less) using renin-angiotensin system blockade (ACE inhibitor, angiotensin receptor blocker, mineralocorticoid receptor blocker, direct renin antagonist)Diabetes control (target HbA1c of 7.0% or less)Lipid control (target LDL of in the 70 range or a 20% reduction from baseline)Summary of several trials, including UKPDS, IDNT, REIN I and II, RENAAL
21 Cardiovascular complications of chronic kidney disease Accelerated atherosclerotic coronary diseaseLeft ventricular hypertrophyIncreased prevalence of sudden death (especially in the end stage renal disease population)Medial coronary artery calcification
22 Renin-angiotensin system blockade: The mainstay of hypertension management in my practice Clinical trials support the widespread use of renin-angiotensin system blockade for hypertension therapy and renal function preservation.Collaborative Study GroupUKPDSRENAAL TrialIDNT TrialREIN Trials (both REIN I and REIN II)HOPE Trial
23 You have to be braveRenin-angiotensin system blockade abrogates the loss of renal function and prevents cardiovascular mortality.Expect a modest increase in the creatinineTolerate up to a 25% increase in the creatinine as long as the blood pressure comes under control.Risk of hyperkalemia existsManage with potassium lowering drugs rather than stopping the drugRisk of cough or angioedema
24 Hypertension and chronic kidney disease Multi-modal therapy is requiredPolypharmacy is the rule, not the exceptionACE inhibitorAngiotensin receptor blockersDiuretics (loop and thiazide)Sympathetic blockadeCalcium channel blockers (non-dihydropyridines in patient with proteinuria)Aldosterone antagonistsOther second line drugs (clonidine, hydralazine, minoxidil, direct renin antagonists)
25 The ONTARGET studiesONTARGET: Telmisartan, ramipril, or both in patients at high risk for vascular events.NEJM :“Renal” ONTARGET: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multi-center randomized, double blind controlled trial.Lancet :
26 The bottom lineDual renin-angiotensin system blockade might worsen renal disease, especially in patients without proteinuria.I will use dual renin-angiotensin blockade, but mainly in patients with proteinuria (greater than 1 g protein/gram creatinine) and only as a last resort in patients without proteinuria.
27 Common electrolyte abnormalities seen in the outpatient setting Hyperkalemia(you’ll need to manage this)Metabolic acidosisHyperphosphatemia(not really your problem)Hypocalcemia(only your problem if the patient has symptoms like paresthesias)
28 Hyperkalemia, I Potassium value greater than 5.0 mEq/l. Patients who are in a steady state with modestly elevated potassium are usually in no danger.However, hyperkalemia can be a silent killer and should not be ignored.Main symptom of hyperkalemia is profound weakness with arrhythmia as the mode of death
29 ECG findings in hyperkalemia The ECG shows stereotypical findings including a first degree AV block, a widened QRS, and a ”sine wave” pattern in the terminal state.
30 Hyperkalemia, II Causes Treatment Decreased GFR Drugs ACE inhibitors, ARBs, beta-blockersDietTreatmentDietary restrictionDiuretic therapy (mainly loop diuretic therapy)Daily low dose sodium polystyrene sulfonate (Kayexelate®)Modification of drug regimen
31 Metabolic acidosis, IWhere a metabolic acidosis defined as a bicarbonate level less than 22 mEq/l.
32 Bicarbonate treatment of metabolic acidosis protects against deterioration of renal function de Brito-Ashurst, I., et al JASN 20:
33 Clinical concepts you need to understand but not necessarily manage
34 Anemia: The causes Decreased red blood cell half-life (important)Malabsorption of iron and folateChronic bleeding related to platelet dysfunction from uremia(not important)Severe hyperparathyroidismErythropoietin deficiency(very important)
35 As the GFR falls, anemia worsens 9190–4039–3029–2019–10 10GFR (mL/min/1.73 m2)Mean Hgb* (g/dL)n = 18n = 59n = 34n = 2956789101112131415Adapted from Foley, R.N., 2002 Clin Nephrol 58 Supp 1: S58-S61.
36 Anemia management in chronic kidney disease Rule out iron deficiency anemia, determine the cause if presents, and restore iron storesRule out folate or B12 deficiencyUse an erythropoiesis stimulating agentErythropoietin-alpha (Procrit®) or darbepoietin (Aranesp®) in pre-ESRDThe results from several well done trials (CHOIR, CREATE, TREAT) in pre-ESRD patients have shown that the target hemoglobin should fall between 10 g/dl and 11 g/dl. Normalization of the hemoglobin should not be the goal.CHOIR: Singh, A.K., et al NEJM 355: CREATE: Drueke, T.B. et al NEJM 355: TREAT: Pfeffer, M.A., et al NEJM 361:
37 Vitamin D synthesis and feedback loops (simplified) Too much:Inhibits (parathyroid hormone)PTH gene transcriptionToo little:Induces PTH gene transcriptionThe fewer nephrons available,the less efficiently terminalhydroxylation of 25-hydroxycholecalciferol occurs.
38 Bone disease (or why we’re so obsessed with phosphate binders) In Chronic Kidney Disease:Active vitamin D is not made because of decreased 1-a-hydroxylase activity.Phosphorus levels rise because of the decreased GFRDecreased vitamin D levels and hyperphosphatemia increase PTH levels, and the increase in PTH activity starts several seemingly beneficial compensatory processes.
39 Pathophysiological networks in secondary hyperparathyroidism Decreased GFRHyperphosphatemiaMetabolic acidosisDecreased vitamin D synthesisFGF 23resistanceSecondaryHyperparathyroidismHypocalcemiaDecreased calcium sensingreceptor occupancyOsteitis fibrosa...with involution ofthe bone marrow space
40 Bone disease, ITreatment begins with lowering the phosphate level. Our options include:Non-calcium containing binders:Sevelamercarbonte (Renvela®) 800 mgLanthanum carbonate (Fosrenol®) 500 and 1000 mgAluminum hydroxide (Amphojel®), which should essentially never be usedSome iron based phosphate binders are in preparationCalcium containing bindersCalcium carbonate (TUMS®)Calcium acetate (PhosLo® and PhosLyra®) 667 mg
41 Bone disease, IIThe NKF, through K/DOQI, has established the following PTH goals:Stage III chronic kidney disease: GFR between 30 ml/min and 59 ml/min:Target PTH should be betweenStage IV chronic kidney disease : GFR between 15 ml/min and 29 ml/min.Target PTH should be betweenStage V chronic kidney disease: GFR less than 15 ml/min or end stage renal disease or end stage renal disease.Target PTH should be between
42 Bone disease, IIIVitamin D and vitamin D analogues directly inhibit expression of the PTH mRNA. The options include:1,25-dihydroxy-vitamin D (Calcitriol®, or Rocaltrol®)19-nor-1,25-dihydroxy-vitamin D2 (Paricalcitol®, or Zemplar® )1-a-hydroxy-vitamin D2 (Doxercalciferol®, or Hectorol®)Only one non-vitamin D PTH suppressor, cinacalcet, or Sensipar®, exists. Cincalcet binds to the calcium sensing receptor on the parathyroid gland and prevents release of PTH from storage granules.I find little use for the calcium/vitamin D preparation or for 25-OH-cholecalciferol in advanced stage III or stage IV chronic kidney disease.
43 My office guidelines for chronic kidney disease management, I Blood pressure controlTarget systolic blood pressure of 130 mm Hg or less on an ACE inhibitor or ARB based regimen (which will also reduce proteinuria)Diabetes controlTarget HbA1c less than 7.0%Lipid controlTarget LDL in the 70 range or a 20% reduction from baseline (SHARP study) using statin therapy
44 My office guidelines for chronic kidney disease management, II AnemiaTarget hemoglobin 10 g/dl and 11 g/dl after iron stores have been repletedBoneTarget phosphorus level below 4.5 mg/dl using phosphate binders and achieve appropriate PTH control.Electrolytes and metabolic acidosisLimit potassium, replace bicarbonate
45 When things get worse…and they will Re-double your efforts to make sure that conservative management has been optimized and that the underlying disease states are stable.Has a new drug been started (drug induced allergic interstitial nephritis)?Could the patient have ureteral obstruction?Is there a concurrent severe illness?Discuss dialysis and transplantation.
46 Kidney transplantation: an option in very selected patients, I 40 kidney transplants at a single centerCD4 count greater than 200 cells/mm3, viral load < 400 copies/ml.Induction with basiliximab and intravenous methylprednisone and maintenance with prednisone, tacrolimus, and sirolimus (a regimen now proven to be sub-optimal).Two year overall survival was 82%, graft survival was 71%, and acute rejection occurred in 22% of patients.None of the patients had a reduction in the CD4 count, and no opportunistic infections were noted. By and large the HIV viral load was undectatable.Kumar, M.S. et al Kidney Int 67:
47 Kidney transplantation: an option in very selected patients, II 150 HIV infected patients followed at 19 transplant centers transplanted between 2003 and 2009Patients had a CD4 count greater than 200 cells/mm3, viral load < 50 copies/ml.Immunosuppressive regimen was modern.1 year patient survival was 94.6% and 3 year patient survival was 88.2%1 year graft survival was 90.4% (acceptable) and 3 year graft survival was 73.7% (not great).CD4 counts did not fall, but viremia worsened in patients who received anti-thymocyte globulin induction.But acute rejection rates were unacceptably high.Stock, P.G., et al NEJM 363:
48 So when should you enlist the aid of a nephrologist? Anytime you want…Patients with stage III CKDWhen the velocity of the increase in the creatinine rises above what you would expectBlood pressure becomes more difficult to control.Urinary protein excretion rate rises into the nephrotic or high non-nephrotic range.Electrolyte abnormalities present or more difficult to manage.
49 Two slides regarding tenofovir Izzedine, H., Harris, M., and Perazella, M Nat Rev Neph 9:
50 Tenofovir use in chronic kidney disease Undoubtedly, a measurable incidence of Fanconi syndrome and chronic kidney disease exists in patients receiving tenofovir.However, a recent systematic review (Cooper, R.D. et al 2010 Clin Inf Dis 51: ) noted that the risk was small and perhaps limited to underweight patients or those with a high viral load and low CD4 count.They did not see the need to withhold tenofovir if the drug was needed and if the renal function and electrolytes were monitored carefully.