Chronic Kidney Disease (CKD) Shiva Seyrafian IKRC- IUMS 1392/2/19____9/5/2013

The Story of Mr. G. L. 45 yr with Diabetes for 10 yrs, “reasonably well controlled” PMH: Hypertension for 7 yrs..well controlled BMI of 30 Dyslipidemia Fam Hx: Diabetes; Soc Hx: Sedentary; non smoker; Comedian Exam 139/85 – Mild Obesity, rest fairly normal Labs BUN 28, Creatinine 1.8, Urine protein (dipstick) 2+

Chronic Kidney Disease Definition: Chronic, irreversible loss of kidney function attributable to loss of functional nephron mass – pathophysiologic processes for more than 3 months.

Epidemiology CKD affects about 26 million people in the US Approximately 19 million adults are in the early stages of the disease On the rise due to increasing prevalence of diabetes and hypertension Total cost of ESRD in US was approximately $40 billion in 2008

Pathophysiology of CKD Final Common Pathway is loss of nephron mass Diabetes Hypertension Chronic GN Cystic Disease Tubulointerstitial disease Mediated by vasoactive molecules, cytokines and growth factors, renin angiotensin axis

Pathophysiology Repeated injury to kidney The causes of acute or chronic kidney disease are traditionally classified by that portion of the renal anatomy most affected by the disorder The two major causes of reduced renal perfusion are volume depletion and/or relative hypotension. This may result from true hypoperfusion due to bleeding, gastrointestinal, urinary, or cutaneous losses, or to effective volume depletion in heart failure, shock, or cirrhosis Various vascular diseases can also lead to kidney disease. Direct etiologies from kidney: Tubular and interstitial disease, Glomerular disease, Obstructive uropathy Acute tubular necrosis — 45 percent Prerenal — 21 percent Acute or chronic kidney disease — 13 percent (mostly due to acute tubular necrosis and prerenal disease) Urinary tract obstruction — 10 percent (most often older men with prostatic disease) Glomerulonephritis or vasculitis — 4 percent Acute interstitial nephritis — 2 percent Atheroemboli — 1 percent

Staging of Chronic Kidney Disease Stage Description GFR (ml/min/1.73 m2) At increased risk 90 (with CKD risk factors) 1 Kidney damage with normal or increased GFR 90 2 Kidney damage with Mildly decreased GFR 60-89 3 Moderately decreased GFR 30-59 4 Severely decreased GFR 15-29 5 Renal Failure <15 (or dialysis)

Who is at Risk for CKD? Family history of heritable renal disease Diabetes Hypertension Auto-immune disease Old age Prior episode of ARF Current evidence of renal damage, even with normal or increased GFR

Estimation of GFR Modification of Diet in Renal Disease (MDRD) Formula Estimated GFR = 1.86 (Serum Creat) -1.154 X (age) -0.203 Multiply by 0.742 for women Multiply by 1.21 for African Americans Cockroft Gault Formula (140 – age) X Body Weight (Kg) 72 X Serum Creatinine (mg/dL) Multiply by 0.85 for women

MDRD GFR for Mr Lopez Diabetic, Hypertension, Metabolic Syndrome X Stage 3 CKD GFR = 44 ml/min/1.73 m2

Stages in Progression of CKD and Therapeutic Strategies AJKD 2002: 39(2)

Etiology and Epidemiology 6% of the US population has CKD (Stage 1 and 2) Additional 4-5% have Stage 3 and 4 CKD Diabetic nephropathy Hypertension – chronic ischemic nephropathy Very high CV disease burden

Monitoring of CKD Serial measurements of Albumin Creatinine GFR Albumin Albumin-creatinine ratio in the 1st morning sample Electrolytes including HCO3, Ca, Phos; alkaline phosphatase, iron studies, intact PTH Renal sonogram Renal biopsy

Symptoms of CKD Stage 1 and 2 Stage 3 and 4 Stage 5 Asymptomatic, hypertension Stage 3 and 4 Anemia – loss of energy Decreasing appetite; poor nutrition Abnormalities in Calcium, Phosphorus metabolism Sodium, water, potassium and acid base abnormalities Stage 5 All of the above – accentuated; eventually overt uremia

Symptoms Hematuria Flank pain Edema Hypertension Signs of uremia Lethargy and fatigue Loss of appetite If asymptomatic may have elevated serum creatinine concentration or an abnormal urinalysis

Common Causes and Presentation Clinical Presentation Diabetic kidney disease History of diabetes, proteinuria and retinopathy Hypertension Elevated BP, normal UA, family history Non diabetic glomerular disease Nephritic or nephrotic presentations Cystic kidney disease Urinary symptoms, abnormal sediment, radiologic findings Tubulointerstitial disease UTI, reflux, chronic med use, drugs, imaging abnormalities, urine concentrating defects

Risk Factors Age of more than 60 years Hypertension and Diabetes Responsible for 2/3 of cases Cardiovascular disease Family history of the disease. Race and ethnicity Highest incidence is for African Americans Hispanics have higher incidence rates of ESRD than non-Hispanics. _followed by American Indians and Alaska Natives, then Asian Americans and native Hawaiians and other Pacific Islanders, and finally Caucasians.

Convergence of Genetic Factors Genes for heart and vascular disease Genes that maintain ionic balance Genes for glomerulonephritis Genes for diabetes Genes that may be involved in inherited renal diseases

Genetic Considerations Autosomal dominant PKD Alport’s hereditary nephritis Familial FSGS Nephronopthisis Medullary cystic kidney disease Fabry’s disease

Natural History of CKD Most CKD has a logarithmic progression and is predictable

Mr. G. L. – Progressive Decline

Clinical Features of Diabetic CKD

Symptoms of Uremia Organ System Symptoms Signs General Fatigue, weakness Sallow-appearing, chronically ill Skin Pruritus, easy bruisability Pallor, ecchymoses, excoriations, edema, xerosis ENT Metallic taste in mouth, epistaxis Urinous breath / fetor Eye   Pale conjunctiva Pulmonary Shortness of breath Rales, pleural effusion Cardiovascular Dyspnea on exertion, retrosternal pain on inspiration (pericarditis) Hypertension, cardiomegaly, friction rub Gastrointestinal Anorexia, nausea, vomiting, hiccups Genitourinary Nocturia, impotence Isosthenuria Neuromuscular Restless legs, numbness and cramps in legs Neurologic Generalized irritability and inability to concentrate, decreased libido Stupor, asterixis, myoclonus, peripheral neuropathy

Sodium and water Imbalance Sodium retention, contributes to hypertension. Higher than usual doses for diuretics. In situations with volume depletion – can be severe, because of inadequate sodium retention.

Potassium Imbalance Potassium GI excretion is augmented Constipation, dietary intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored blood, metabolic acidosis, Drugs: ACE inhibitors, ARBs, B blockers, K sparing diuretics and NSAIDs Hyporeninemic hypoaldosteronism: Diabetes, sickle cell disease

Acid Base Imbalance Damaged kidneys are unable to excrete the 1 mEq/kg/d of acid generated by metabolism of dietary proteins. NH3 production is limited because of loss of nephron mass Decreased filtration of titrable acids – sulfates, phosphates Decreased proximal tubular bicarb reabsorption, decreased H ion secretion Arterial pH: 7.33 - 7.37; serum HCO3 rarely below 15 – buffering offered by bone calcium carbonate and phosphate Should be maintained over 21

Bone Disease

Young boy on HD several years with 2nd hyperpara, brown tumor and cyst, 91/8

Mineral Metabolism Calciphylaxis PTH, P, Ca x P, Active Vitamin D, Fetuin A, Matrix Gla protein ( warfarin) Calcemic uremic arteriopathy Extraosseous/metastatic calcification of soft tissues and blood vessels Devastating complication

Reza ahmadi niya –alzahra univ. haospit Reza ahmadi niya –alzahra univ. haospit. HD, renal osteodystrophy 91/ 7, 69 Y/O

Reza ahmadi niya –alzahra univ. haospit Reza ahmadi niya –alzahra univ. haospit. HD, renal osteodystrophy 91/ 7, 69 Y/O

Reza ahmadi niya –alzahra univ. haospit Reza ahmadi niya –alzahra univ. haospit. HD, renal osteodystrophy 91/ 7, 69 Y/O

Cardiovascular Abnormalities Leading cause of morbidity and mortality in patients with CKD at all stages Ischemic CAD Hypertension and LVH Congestive heart failure Uremic pericarditis

Cardiovascular risks in CKD Reduced glomerular filtration rate (GFR) and proteinuria are both independently associated with an increased risk of cardiovascular events.  The increase in cardiovascular risk associated with CKD. The risk of death, particularly due to cardiovascular disease, is typically higher than the risk of eventually requiring renal replacement therapy.

Pericarditis Uremic pericarditis:There is a correlation with the degree of azotemia (the BUN is usually >60 mg/dL), Except in the case of systemic immune disorders (such as lupus erythematosus or scleroderma), there is no relationship with the underlying cause of renal failure. Dialysis-associated pericarditis: two causses: inadequate dialysis (ie, the patient has uremic pericarditis) and/or fluid overload.

Pericarditis Unusual feature of uremic pericarditis:  the electrocardiogram does not show the typical diffuse ST and T wave elevations observed with other causes of acute pericarditis.  With the development of cardiac tamponade, typical ECG changes (eg, electrical alternans) may occur

Cardiac Complications

Lipid abnormalities The most common dyslipidemia in CKD patients is hypertriglyceridemia, whereas the total cholesterol concentration can be normal or low, perhaps due in part to malnutrition.  Some have found that low (not high) serum cholesterol values are associated with increased mortality.

Lipid abnormalities Some have found no association between lipid levels and mortality among patients with CKD.  Reflect the adverse effect of malnutrition and chronic inflammation upon mortality.

Hematological Abnormalities Anemia: Chronic blood loss, hemolysis, marrow suppression by uremic factors, and reduced renal production of EPO Normocytic, normochromic Coagulopathy: Clinical bleeding in uremia is typically cutaneous, including easy bruising and mucosal bleeding, or may occur in response to injury or invasive procedures. Less frequent is epistaxis, gingival bleeding, or hematuria. Mainly platelet dysfunction – decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness and impaired thrombin consumption Increased propensity to bleed – post surgical, GI Tract, pericardial sac, intracranial Increased thrombotic tendency – nephrotic syndrome

Other Abnormalities Neuromuscular Central, peripheral and autonomic neuropathy Motor Neuropathy: muscle atrophy, myoclonus, and eventual paralysis. Mononeurpathy: Carpal tunnel syndrome Dysfunction of both the vestibular and cochlear divisions of the eighth cranial nerve  Polyneuropathy: paresthesias, burning sensations, and pain — tend to precede the motor symptoms. The initial finding in uremic polyneuropathy is loss of position and vibration sense in the toes and decreased deep tendon reflexes, beginning with the Achilles reflex. The hands may become involved.  Sensory syndromes: restless leg syndrome, the burning foot syndrome, Paradoxical heat sensation 

Other Abnormalities Gastrointestinal Endocrine Uremic fetor Gastritis, peptic disease, mucosal ulcerations, Endocrine Glucose metabolism Some patients have hyperglycemia in response to oral and intravenous glucose loads, while others are able to maintain normoglycemia by raising plasma insulin levels.  Accumulation of a uremic toxin or toxins and excess parathyroid hormone (PTH), resulting from abnormalities in phosphate and vitamin D metabolism, are thought to be responsible for the insulin resistance

Other Abnormalities HYPOGLYCEMIA   spontaneous hypoglycemia. This complication can be seen in both diabetic and nondiabetic subjects. Estrogen levels – amenorrhea, frequent abortions Male: oligospermia, germinal cell dysplasia, delayed sexual maturation Dermatologic Pallor, ecchymoses, hematomas, calciphylaxis, pruritus, uremic frost

Dermatologic changes of Uremic

Uremic Complications

What Should Patients and Doctors Know In general CKD is characterized by a gradual loss of the kidney’s filtration capacity. Markers Don’t tell everything Source: http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000326901

What Should Patients and Doctors Know Prevention Keep diabetes and blood pressure controlled If at risk perform screening tests Reduce exposure to nephrotoxic drugs Eat right and exercise Know your family history If you have a positive family history ask doctor to perform common screening tests for kidney function.

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