Urology/Renal Medicine

Canine Chronic Kidney Disease: Current Diagnostics and Goals for Long-Term Management

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JD Foster, VMD, Diplomate ACVIM

Chronic kidney disease is an irreversible and progressive deterioration of renal function; however, through early diagnosis and staging, prompt management can delay disease progression. Each aspect of treatment is comprehensively covered in this article.


Chronic kidney disease (CKD) is an irreversible and progressive deterioration of renal function, resulting from a decreased number of functional nephrons. Unfortunately, the compensatory mechanisms that respond to nephron loss (glomerular hypertension, hyperfiltration) help facilitate progression of CKD, potentially contributing to it more so than the original injury (Table 1).

f02-table1

Patients of any age may develop CKD, but the greatest incidence is in geriatric patients. However, congenital renal diseases, including dysplasia and various glomerulopathies, may produce CKD at very early ages. Once diagnosed, CKD typically remains a life-long condition.

PRESENTATION

Medical History

A thorough medical history plays 2 essential roles; it:

  1. Helps determine a management plan by assessing severity of polyuria and polydipsia, diet, appetite, change in body mass, and energy level.
  2. Provides a baseline—the degree of illness related to CKD at presentation—to use for comparison after therapeutic interventions have been implemented.

Clinical Signs

Early signs of CKD may be mild, even inapparent to the pet owner. Because isosthenuria and azotemia do not develop until 66% and 75% nephron loss, respectively, most renal function has been lost by onset of clinical signs.

Common clinical signs include:

  • Polyuria and compensatory polydipsia
  • Decreasing appetite, weight loss, and lethargy
  • Gastrointestinal (GI) signs, which may be present in early CKD, but are very common in moderate to advanced CKD.

Physical Examination

During a physical examination in patients with suspected or confirmed CKD, pay particular attention to body condition scoring, cardiovascular status, evidence of dehydration, and renal palpation.

  • Muscle wasting may indicate poor nutritional status.
  • New heart murmurs may indicate a physiologic flow murmur due to anemia or hypertension (however, sick or febrile patients should also be evaluated for endocarditis).
  • Dehydration is common in CKD, typically resulting from patients’ inability to ingest enough water to compensate for increased urinary losses.
  • Assessment of renal size and shape, and for the presence of pain, should always be performed, but may be difficult in medium or large breed dogs.

Specific system examinations include:

  • Fundic examination to assess for vessel tortuosity and retinal detachment, which may suggest systemic hypertension
  • Rectal examination to evaluate for evidence of melena or hematochezia, which may indicate uremic ulcers.

DIAGNOSTICS

A thorough diagnostic evaluation (Table 2) can confirm the diagnosis of CKD. These tests may identify underlying causes, ongoing renal injury, and consequences of CKD, providing information about prognosis and treatment goals.

f02-tabler2

Azotemia Interpretation

  • Persistent azotemia (despite normal hydration status) can confirm CKD. However, since 75% nephron loss occurs before azotemia, this criteria only identifies the most advanced cases.
  • Isosthenuria may be seen earlier (66% nephron loss); however, without azotemia, all other causes of isosthenuria need to be excluded before attributing it to CKD.
  • Extrarenal factors may alter creatinine or blood urea nitrogen (BUN) when interpreting azotemia:
    • Creatinine: Decreased in patients with muscle wasting
    • BUN: Increased in patients with GI bleeding or those consuming a high-protein diet; decreased with malnutrition, severe protein restriction, or synthetic liver failure
  • Prerenal or postrenal factors may concurrently contribute to azotemia:
    • Prerenal factors: Consider decreased renal perfusion, most commonly seen in dehydrated, hypovolemic, or hypotensive patients
    • Postrenal factors: Consider unilateral ureteral obstruction, which can be ruled out by abdominal radiographs and ultrasound; may also manifest with renal pain and abnormal renal palpation.

Glomerular Filtration Rate

Glomerular filtration rate (GFR) is the gold standard measurement of renal function; however, its measurement is rarely indicated in patients with CKD. Creatinine and, to a lesser extent, BUN are correlated with GFR, but, as noted earlier, GFR must be reduced by 75% before azotemia is seen. However, measurement of GFR (typically through iohexol or creatinine clearance testing) may confirm reduced renal function in isosthenuric patients.

IRIS STAGING SYSTEM

A tiered stratification system has been proposed by the International Renal Interest Society (IRIS) to help provide guidelines for clinical management of CKD. Staging is based on serum creatinine values, with substages identified for blood pressure and proteinuria (Table 3).

f02-table3

Importance of Hydration

Treatment goals and recommendations are specific to IRIS CKD stage. Since prerenal contributions will often increase the degree of azotemia to the next stage, normal renal perfusion (adequate patient hydration and effective circulating volume) should be restored before determining the patient’s stage of CKD.

Stage Determination

Including the IRIS CKD stage in the medical record relays important information about the severity of CKD. For example, if a dog has a creatinine of 2.5 mg/dL, urine protein:creatinine (UPC) ratio of 1, and arterial blood pressure of 155 mm Hg, its IRIS CKD stage would be considered IRIS 3 P AP 1, or:

  • Serum creatinine: IRIS 3 (Stage 3)
  • Proteinuria substaging: P (Proteinuric)
  • Blood pressure substaging: AP I (Arterial Pressure Stage 1).

TREATMENT GOALS

Treatment of CKD should be individually tailored to each patient. Although not all interventions have been evaluated by clinical trials, some evidence-based information supports their role in management of CKD. IRIS CKD stage management guidelines are listed in Table 4; medications to help achieve treatment goals are listed in Table 5.

f02-table4

Uremia

As stated earlier, IRIS CKD staging should be applied to patients only after exclusion of pre- and postrenal contributions.

Uremic toxins, many of which are byproducts of protein metabolism, are solutes that accumulate due to decreased renal clearance, causing detrimental effects. Urea and creatinine are not significant uremic toxins; however, they serve as surrogate markers, providing some information on renal function and degree of uremic toxin retention.

Hydration

As CKD is irreversible, decreased GFR caused by intrinsic renal dysfunction cannot be improved. Hypovolemic or dehydrated patients will have decreased renal perfusion, causing prerenal reduction in GFR, which is complicated if patients cannot voluntarily maintain hydration.

Measures should be taken to prophylactically maintain hydration in patients that cannot do so on their own (urine output exceeds fluid intake).

THERAPEUTIC GOAL: Maintain Hydration

  • Feed canned food diets; many patients will tolerate additional water added to canned food.
  • Offer low- or no-sodium chicken broth.
  • Feeding tubes (esophagostomy, gastric) can provide access for water, medication, and nutrition delivery.
  • Subcutaneous fluids can be helpful, but contain large amounts of sodium, which some CKD patients may not tolerate, contributing to hypertension.
  • Consider feeding prescription renal diet (see Nutritional Therapy).

Nutritional therapy is a cornerstone of CKD management.

Prescription renal diets typically have:

  • Reduced protein, phosphorus, and sodium concentrations
  • Increased B-vitamins, fiber, and omega-3 fatty acids.

Prescription renal diet reduced the risk of uremic crisis by 72% in study dogs when compared to those fed a maintenance diet.1 Other benefits demonstrated by this study included prolonged median survival time, slower progression of CKD, and improved quality of life.

Lower protein diets, such as senior diets, often do not have the appropriate alterations in phosphorus and electrolyte concentrations recommended for management of CKD; therefore, these diets should NOT be considered acceptable alternatives.

A future article in the Nutrition Notes column will address dietary therapy for renal disease in dogs and cats.

GI Complications

Antacids and antiemetics are useful for managing GI complications of uremia. Due to diminished ability to produce erythropoietin, dogs with CKD take longer to normalize anemia related to GI ulcers.

THERAPEUTIC GOAL: Manage GI Complications of Uremia

  • Proton pump inhibitors: More effective than histamine antagonists for neutralizing gastric acid secretion; no dose adjustment is required in patients with CKD
  • H2-receptor antagonists: Require dose adjustment with renal impairment; are less effective in neutralizing gastric pH.
  • Sucralfate: Helps facilitate GI ulceration healing; may impair absorption of numerous drugs and should be administered alone and without food.
  • Antiemetics: May be given as needed or as daily therapy.

Hyperphosphatemia

Plasma phosphorus concentrations are inversely proportional to GFR; therefore, as renal function declines, phosphate retention occurs. Hyperphosphatemia increases the production of parathyroid hormone (PTH) by the parathyroid glands, one of the key steps in development of renal secondary hyperparathyroidism.

THERAPEUTIC GOAL: Treat Hyperphosphatemia

Phosphate binders are used in combination with a prescription renal diet when diet alone is insufficient to control hyperphosphatemia, and form nonabsorbable complexes with dietary phosphate within the GI tract.

  • Aluminum hydroxide: Often used as first-line drug; however, toxicity has been reported in dogs when administrated above recommended doses.
  • Calcium salts: Must be avoided in patients with hypercalcemia and used cautiously in those with calcium-phosphorus products significantly exceeding 70.
  • Lanthanum carbonate: Compounding may be required to obtain appropriately sized capsules; can be used in combination with aluminum hydroxide (dose of latter may need to be decreased due to synergistic effects).
  • Sevalamer hydrochloride: Expands when it contacts water; tablets or capsules should be administered intact.

Dose of phosphate binders can be titrated up to produce more pronounced effects. Generally, the more severe the hyperphosphatemia, the higher the dose (kept within the recommended dosage range) of phosphate binder required for successful correction. Treatment should be targeted to achieve recommendations according to IRIS CKD stage.

These drugs must be administered with food; feeding meals or phosphate-rich treats without using a phosphate binder lessens their efficacy.

Acidemia

Patients with CKD have metabolic acidosis due to accumulation of acidic uremic toxins; patients with hypoperfusion may additionally have lactic acidosis. If venous blood gas assessment is unavailable to evaluate patient acid—base status, a serum total carbon dioxide level (TCO2) can be used as an estimate of serum bicarbonate concentration. Falsely decreased TCO2 levels occur when blood collection tubes are exposed to air or are not fully filled.

THERAPEUTIC GOAL: Treat Acidemia

Feed a diet that produces a neutral pH, which prescription renal diets are designed to achieve (but not a feature of some urolithiasis diets). Use alkali therapy (Table 5) for patients with persistent acidemia despite appropriate diet. The goal is to maintain a bicarbonate (TCO2) level between 18 and 25 mmol/L.

f02-table5

  • Sodium bicarbonate: Administer as a whole tablet as some dogs find it unpalatable when mixed with food.
  • Potassium citrate: Each 540-mg tablet yields 5 mEq of potassium and 1.7 mEq of citrate, which is metabolized to 420 mg of bicarbonate.

 

While potassium citrate provides some potassium supplementation, which is beneficial to hypokalemic patients, it may exacerbate hyperkalemia in patients with normal or mildly increased serum potassium concentrations. In addition, angiotensin-converting enzyme inhibitor (ACE) inhibitor therapy may also result in mild to moderate hyperkalemia. Use potassium supplementation cautiously in patients receiving such medications, and avoid use in hyperkalemic patients.

Hypokalemia & Hyperkalemia

Hypokalemia is more commonly seen in cats than in dogs. Severe hyperkalemia may be life threatening, and is more often associated with oliguric or anuric acute kidney injury, rather than CKD.

Patients with end-stage CKD and marked reduction in GFR may also demonstrate hyperkalemia, regardless of degree of urine output. By inhibiting the production of angiotensin II, which causes urinary potassium excretion, ACE inhibitor drugs may also produce mild to moderate hyperkalemia as a side effect.

f02-box1

THERAPEUTIC GOAL: Treat Hypokalemia or Hyperkalemia

  • For hypokalemia, oral supplementation is the preferred treatment.
  • For mild hyperkalemia, a prescription renal diet with the lowest potassium content can be useful. Oral potassium binders (sodium polystyrene) can prevent absorption of dietary potassium. Rare GI adverse effects are reported in humans and are possible in dogs.
  • Monitor hyperkalemic patients receiving ACE inhibitors; reduce dose if ACE inhibitors produce significant hyperkalemia.
  • Discontinue potassium supplementation in all hyperkalemic patients.

Anemia

Lack of erythropoietin is the driving force behind the chronic, progressive, nonregenerative anemia of CKD. Always consider GI ulceration resulting in blood loss if CKD patients have new or worsened anemia.

THERAPEUTIC GOAL: Treat Anemia

  • • For moderate to advanced anemia anemia (packed cell volume [PCV] <= 20%):
    • Consider hormone supplementation with darbepoietin.
    • Monitor PCV weekly until target PCV is obtained; then taper frequency of administration.
    • Monitor blood pressure as some patients may develop hypertension after initiation of darbepoietin therapy.
  • For severe anemia, proceed with a blood transfusion.

Darbepoietin, a synthetic form of erythropoietin, is thought to be less antigenic than human erythropoietin, which can cause development of anti-erythropoietin antibodies that crossreact and potentially destroy the patient’s endogenous erythropoietin, leaving the patient dependent on transfusions. Failure to respond to darbepoietin may indicate formation of antidarbepoietin/anti-erythropoietin antibodies; however, concurrent inflammatory disease can also result in diminished response to darbepoietin.

Hypertension

Blood pressure is routinely evaluated throughout treatment of CKD. Normotensive patients may develop hypertension as renal disease progresses. Ideally, assess blood pressure early in the visit before additional stress accrues, leading to nonpathologic increases in blood pressure (“white coat hypertension”). Perform fundic examination to investigate for retinal damage.

THERAPEUTIC GOAL: Treat Hypertension

  • ACE inhibitors are first line therapy for hypertension, and crucial to blunting the renin—angiotensin—aldosterone system (RAAS); however, they are weak antihypertensives, only reducing blood pressure approximately 10 mm Hg.
  • The calcium channel blocker amlodipine is more effective, but should be used with an ACE inhibitor.

Following initiation or increase of ACE inhibitor dosage, mild increases in BUN and creatinine may be noted. Monitor mild increases that do not cause uremia; however, reduce or discontinue the dosage if azotemia, accompanied by uremia, significantly increases, which suggests the ACE inhibitor has caused a significant decrease in GFR.

Proteinuria

Renal protein loss may be due to glomerular or tubular lesions, but glomerular lesions more likely result in greater magnitude of proteinuria and hypoalbuminemia. Proteinuria is a risk factor for progression of CKD; however, only weak evidence suggests that reducing proteinuria slows progression of canine CKD.

THERAPEUTIC GOAL: Treat Proteinuria

The first step in therapy is a protein-restricted renal diet. In addition, managing hypertension also helps minimize proteinuria. ACE inhibitors may cause hyperkalemia due to RAAS blockade, reduce GFR, and increase azotemia; therefore, use these drugs cautiously in IRIS CKD stage 3 and 4 patients.

For persistent proteinuria, therapeutic intervention is recommended:

  • ACE inhibitor: Increase hypertension dosage to help minimize proteinuria; however, contraindicated in hypotensive or dehydrated patients.
  • Omega 3-polyunsaturated fatty acids: Shown to lessen proteinuria.
  • Losartan: Consider this angiotensin receptor blocker for proteinuria refractory to ACE inhibitors; veterinary use has been limited, with contradicting opinions regarding efficacy.

Anticoagulants can be considered when proteinuria is present; however, serum albumin, UPC, or antithrombin levels do not adequately predict hypercoagulability.

Renal Secondary Hyperparathyroidism

Consequences of CKD, including phosphorus retention and decreased synthesis of calcitriol, establish renal secondary hyperparathyroidism.

  1. In response to hyperphosphatemia, parathyroid glands increase PTH—a uremic toxin—synthesis
  2. Calcitriol inhibits PTH release, but hyperphosphatemia inhibits synthesis of calcitriol, creating a feedback loop that results in elevated phosphorus and PTH levels (Figure).
  3. Due to decreased renal function, PTH activity is diminished, resulting in inadequate excretion of phosphorus and suboptimal production of calcitriol.
f02_figure

Serum calcium is regulated by PTH; however, normal calcium handling does not occur in renal secondary hyperparathyroidism due to altered renal handling of calcium, deficiency in calcitriol production, and skeletal resistance to the effects of PTH. While most dogs with CKD have normal to decreased ionized calcium concentrations, about 15% have ionized hypercalcemia. Serum total calcium is often discordant with ionized calcium measurements; therefore, do not use it to predict levels of ionized calcium.

THERAPEUTIC GOAL: Treat Renal Secondary Hyperparathyroidism

Because calcitriol increases GI calcium and phosphorus absorption, make sure to achieve tight phosphorus control before initiating calcitriol therapy.

  • Control hyperphosphatemia to achieve IRIS CKD stage goal (Table 5).
  • Then measure PTH and ionized calcium to document inappropriate PTH levels and low or normal ionized calcium concentration.
  • Begin calcitriol therapy; administer on an empty stomach.
  • Monitor monthly for hyperphosphatemia, hypercalcemia, and alterations in renal function.

MONITORING

Follow-up care is one of the most important aspects of a successful treatment plan.

  • As CKD progresses, determine whether new treatments or dosage adjustments to current medications are needed.
  • Evaluate physical condition, blood pressure measurement, urinalysis (with sediment evaluation), renal values with electrolytes, and PCV every 4 months minimum.
  • Perform urine culture whenever CKD acutely worsens to investigate for pyelonephritis. Due to obligatory polyuria in CKD, patients can have an active infection without lower urinary symptoms.
  • Effect of therapeutic interventions should be monitored, and medications adjusted to achieve IRIS CKD stage goal.

PROGNOSIS

Prognosis is associated with severity of disease. Studies have shown shorter median survival times in dogs with higher IRIS stages. Median survival time for IRIS Stage 1 dogs was over 400 days, Stage 2 ranged from 200 to 400 days, Stage 3 ranged from 110 to 200 days, and Stage 4 ranged from 14 to 80 days.2,3 Successful treatment of CKD delays disease progression, likely provides greater survival times, and increases patient quality of life.

ACE = angiotensin-converting enzyme; BUN = blood urea nitrogen; CKD = chronic kidney disease; GFR = glomerular filtration rate; GI = gastrointestinal; iCa = ionized calcium; IRIS = International Renal Interest Society; PCV = packed cell volume; PTH = parathyroid hormone; RAAS = renin—angiotensin—aldosterone system; TCO2 = total carbon dioxide; UPC = urine protein:creatinine

References

  1. Jacob F, Polzin DJ, Osborne CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs. JAVMA 2002; 220(8):1163-1170.
  2. O’Neill DG, Elliott J, Church DB, et al. Chronic kidney disease in dogs in UK veterinary practices: Prevalence, risk factors, and survival. J Vet Intern Med 2013; doi:10.1111/jvim.12090.
  3. Parker VJ, Freeman LM. Association between body condition and survival in dogs with acquired chronic kidney disease. J Vet Intern Med 2011; 25(6):1306-1311; doi:10.1111/j.1939-1676.2011.00805.x.

Suggested Reading

  • Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012; 42(4):669-692.
  • Harley L, Langston C. Proteinuria in dogs and cats. Can Vet J 2012; 53(6):631-638.
  • Polzin DJ. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract 2011; 41(1):15-30.
  • Polzin DJ. Evidence-based step-wise approach to managing chronic kidney disease in dogs and cats. J Vet Emer Crit Care 2013; 23(2):205-215.

Resource

International Renal Interest Society webpage: iris-kidney.com

f02_FosterJD Foster, VMD, Diplomate ACVIM, is a staff veterinarian and director of the hemodialysis and extracorporeal therapy program at University of Pennsylvania’s Ryan Veterinary Hospital. His clinical specialty is evaluating and treating patients with all aspects of kidney and urinary tract disease. Dr. Foster performed prior research on immune-mediated polyarthritis and is currently investigating new therapies for renal disease, biomarkers of renal injury, and nontraditional uses of hemodialysis. He received his degree from University of Pennsylvania.

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id='input_6_10_5_label' >ZIP / Postal Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' >Zimbabwe</option></select> <label for='input_6_10_6' id='input_6_10_6_label' >Country</label> </span> <div class='gf_clear gf_clear_complex'></div> </div></li> </ul></div> <div class='gform_footer top_label'> <input type='submit' id='gform_submit_button_6' class='gform_button button' value='Sign Up' onclick='if(window["gf_submitting_6"]){return false;} window["gf_submitting_6"]=true; ' onkeypress='if( event.keyCode == 13 ){ if(window["gf_submitting_6"]){return false;} window["gf_submitting_6"]=true; jQuery("#gform_6").trigger("submit",[true]); }' /> <input type='hidden' class='gform_hidden' name='is_submit_6' value='1' /> <input type='hidden' class='gform_hidden' name='gform_submit' value='6' /> <input type='hidden' class='gform_hidden' name='gform_unique_id' value='' /> <input type='hidden' class='gform_hidden' name='state_6' value='WyJbXSIsIjNkNTNhNjhlOThlOGY4N2JlZWZiNTRmZDhlZDQ5OWI3Il0=' /> <input type='hidden' class='gform_hidden' name='gform_target_page_number_6' 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