Improving outcomes in renal disease

CKD often progresses to ESRD despite clinicians’ and patients’ best efforts. But its progression can be delayed, enabling patients to postpone renal replacement therapy and kidney transplantation.

Ray Galley, MPH, PA-C

The author is a physician assistant in family practice at La Familia Medical Center, Santa Fe, NM. He has indicated no relationships to disclose relating to the content of this article.

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End-stage renal disease (ESRD) is defined as chronic renal failure requiring dialysis or renal transplant. Currently, more than 375,000 Americans are being treated for ESRD,¹ at a cost of $17.9 billion a year. More than half of this population (57.5%) has a history of diabetes mellitus and/or hypertension that progressed to ESRD. With 90,000 new cases of kidney failure annually and approximately 19 million Americans with chronic kidney disease (CKD), many physician assistants care for patients with renal disease.^1,2 This article provides an overview of how to monitor and slow the progression of CKD, the comorbidity of cardiovascular disease (CVD), and the preparation for renal replacement therapy.

Early screening and staging

The normal kidney filters blood to remove metabolic waste; produces hormones; and regulates BP, electrolytes, fluids, and acid/base balance. Its functional unit is the nephron (see Figure 1). The histology of CKD shows heterogenous lesions with focal segmental glomerulosclerosis, whether the primary cause is hemodynamic, immunologic, congenital, or attributed to other abnormalities.³ Likewise, the pathophysiology and clinical changes of progressive kidney disease are similar across the etiologic spectrum.⁴ The leading chronic medical conditions that can lead to ESRD are listed in Table 1.¹

In the early stages of renal injury, the kidney adapts by increasing the filtration rate in the noninjured nephrons. This adaptive hyperfiltration allows for normal or near-normal serum creatinine (sCr) levels and is asymptomatic. Historically, indicators for progressing disease were poorly defined and not validated,⁵ further challenging the clinician’s ability to provide care. In 2000, the Kidney Disease Outcomes Quality Initiative (K/DOQI) developed guidelines for identifying the stages of kidney disease and the complications that can lower patients’ quality of life.⁶ The laboratory measurements recommended by the K/DOQI guidelines for determining the presence of CKD are presented in Table 2.

Screening for the earliest signs of CKD includes analysis for albuminuria. Albumin is a more sensitive marker than total protein for CKD due to diabetes, hypertension, and glomerular diseases.⁶ The first morning urine is preferred for testing so as to capture overnight albumin excretion, but random urine specimens are acceptable. The American Diabetes Association defines cutoff values for the spot urine albumin-to-creatinine ratio for microalbuminuria as 30 mg of albumin to 1 g of creatinine and for the spot urine albumin-to-creatinine ratio for albuminuria as 300 mg of albumin to 1 g of creatinine.⁷ The presence of albuminuria or proteinuria indicates the onset of CKD.

A declining glomerular filtration rate (GFR) correlates with decline in renal function. The GFR is the measurement of the total filtration rate of all the renal nephrons. In healthy people aged 30 years or younger, the normal GFR is approximately 125 mL/min/1.73 m² (body surface area).⁸ After age 30, the GFR declines by approximately 10 mL/min per decade of life.

Two equations that accurately estimate the GFR are presented in Figure 2.^8,9 CKD is defined as a GFR less than 60 mL/min/1.73 m² for 3 months or more.^5,6 This GFR corresponds to an sCr concentration higher than 1.5 mg/dL in men and higher than 1.3 mg/dL in women.¹⁰ Progressive decline in renal function occurs when renal injury raises the sCr level to 1.5 to 2 mg/dL.⁵ The action plan recommended in the K/DOQI guidelines is based on the GFR (see Table 3).  

Interventions to prevent progression

CKD often progresses despite early diagnosis and aggressive treatment. Patients with conditions that may result in CKD should be regularly monitored for renal changes. Early referral to a nephrologist and ongoing consultations with renal care specialists are critical in monitoring CKD, managing its complications, and successfully transitioning the patient to dialysis.¹¹

Diabetes The most common cause of ESRD is diabetes mellitus. Hyperglycemia is an independent risk factor for diabetic nephropathy.¹² The pathophysiology of diabetic nephropathy is a process that involves both hemodynamic and glucose-dependent factors, including the accumulation of glycated products, endothelial dysfunction, and loss of intraglomerular BP regulation.¹⁰ Studies have shown that tight glycemic control will delay both the loss of renal function and the progression of CKD.^12,13 The American Diabetes Association recommends a target glycosylated hemoglobin (A1C) of less than 7%.⁷

Hypertension Systemic hypertension is the second leading cause of ESRD. Hypertension damages the small blood vessels in the nephrons, which causes the kidneys to lose their ability to autoregulate glomerular filtration flow and pressure. This results in hyperfiltration that manifests as albuminuria. Excess albumin, a urine protein, is reabsorbed by the proximal convoluted tubule, causing the release of vasoactive substances that further damage the glomerular-tubular complex. Damaged nephrons activate the renin-angiotensin-aldosterone system, resulting in increased sympathetic tone and fluid overload, compounding hypertension and nephron loss.^14,15

Multiple trials demonstrate the benefit of strict BP control in delaying CKD progression.^16,17 ACE inhibitors and angiotensin-II receptor antagonists are more effective than other antihypertensive agents because they selectively lower intraglomerular pressure and reduce proteinuria.^18-20 In patients with CKD, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a target reading of less than 130/80 mm Hg.²¹

Uremia Uremia is defined as elevated serum urea nitrogen level (azotemia) accompanied by renal failure. Although the pathogenesis is not completely understood, three major mechanisms are at work: diminished excretion of electrolytes and water, reduced excretion of the organic solutes (urea and creatinine), and decreased hormone production.⁴ Symptoms of uremia develop when the GFR falls to approximately 20% of normal. At this point, there are so few functioning nephrons that urinary excretion cannot match intake levels. Common symptoms of uremia include cognitive changes, gait disturbances, muscle weakness, peripheral neuropathy, peripheral edema, pericarditis, pruritus, fatigue, anorexia, hiccups, nausea, and vomiting.¹⁰

Malnutrition Serum albumin is a plasma protein essential for maintaining osmotic pressure between intravascular compartments of the body. In addition, it transports bilirubin, fatty acids, metal ions, hormones, and exogenous drugs. Serum albumin is a direct indicator of nutritional status. Normal values range from 3.5 to 4.5 g/dL. These levels depend on the rate of hepatic synthesis, the amount secreted from liver cells, the distribution in body fluids, and the rate of protein degradation.²²

Hypoalbuminemia is associated with increased rates of hospitalization in patients with ESRD. In addition, it is a strong predictor of early death when present at initiation of dialysis.⁵ Hypoalbuminemia develops from multiple physiologic alterations: decreased serum albumin concentration resulting from liver dysfunction, excess protein loss due to nephrotic syndrome, and fluid shifts between intracellular and extracellular compartments. ESRD causes loss of appetite, and this decrease in protein intake triggers changes in protein metabolism. Consequently, diminished lean body mass results in increased requirements for essential amino acids and nitrogen. Finally, a systemic inflammatory response present in ESRD patients lowers serum albumin concentrations.

These patients should be referred to a renal dietitian for ongoing assessment of protein, carbohydrate, lipid, fluid, and sodium and phosphate intake.⁵ K/DOQI recommends a protein intake of 1.2 g/kg/d in patients with ESRD to maintain a serum albumin concentration of 4 g/dL.

Anemia Anemia of CKD results from a decrease in the functioning renal tubular cells that produce erythropoetin, a protein hormone that stimulates erythrocyte production in bone marrow. Fatigue, reduced exercise capacity, decreased cognition, and impaired immunity are common signs and symptoms of this complication. In addition, left ventricular hypertrophy (LVH) may result from increased cardiac workload. LVH is present in 40% to 70% of patients who are starting dialysis, suggesting that anemia may occur in the earlier stages of renal disease.²³

Increased prevalence of anemia is noted when the GFR is lower than 60 mL/min/1.73 m². Patients should be evaluated when the hemoglobin is less than 11 g/dL (hematocrit less than 33%) in premenopausal women and prepubertal patients. In adult men and postmenopausal women, workup is recommended when the hemoglobin is less than 12 g/dL (hematocrit less than 37%). Anemia of CKD has red cell indices that are normocytic and normochromic.¹⁰ Patients suspected of having anemia of CKD should first be evaluated for secondary causes using a CBC, iron studies, and fecal occult blood testing. If results show the sCr to be less than 2 mg/dL and no secondary cause for anemia is found, then erythropoetin deficiency is the likely diagnosis. The target hemoglobin range using epoetin therapy is 11 to 12 g/dL.⁶

Renal osteodystrophy Calcium concentration is regulated by parathyroid hormone (PTH) in healthy people. PTH achieves mineral homeostasis by four mechanisms: modifying the release of calcium and phosphorus into the blood from bone formation and resorption; decreasing renal retention of phosphorus; increasing renal retention of calcium; and indirectly controlling GI absorption of calcium and phosphorus through renal synthesis of calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D.²³

A falling GFR disrupts calcium regulation by decreasing production of calcitriol, resulting in lower serum calcium levels. The loss of kidney function also stimulates renal retention of phosphorus, which further promotes calcium loss. Elevated serum phosphorus concentrations in combination with dietary phosphorus intake appear to increase PTH secretion and proliferation of parathyroid cells.²⁴ This continuous hyperphosphatemia and hypocalcemia lead to sustained elevated PTH levels that result in secondary hyperparathyroidism (HPT).⁵ Bone turnover is excessively rapid in the presence of secondary HPT, resulting in structurally weaker bone replacing the normal lamellar bone. Accelerating osteoblast formation and osteoclast resorption lead to increased peritrabecular fibrosis or osteitis fibrosa cystica, the most common form of renal osteodystrophy.^25,26

In contrast, low levels of PTH in patients with CKD cause adynamic bone disease. This condition results from low rates of bone formation, normal or reduced amounts of osteoid, the absence of peritrabecular fibrosis, and decreased numbers of osteoclasts and osteoblasts. Patients with this skeletal change are generally asymptomatic, but they may have bone or joint pain and are at increased risk for fractures.

Increased PTH levels are noted at a GFR of 60 to 80 mL/min/1.73 m². Early treatment to prevent skeletal changes and parathyroid hyperplasia includes restricting dietary intake of phosphorus (eg, colas, nuts, peas, beans, and dairy products), taking a calcium antacid tablet with meals to bind phosphorus, and administering calcitriol.⁵ However, caution should be used when prescribing vitamin D supplements in CKD because oversuppression of PTH production could accelerate renal disease and adynamic bone disease.^5,24 Serum levels of calcium, phosphorus, and intact PTH must be monitored frequently.

Research is being done on treatments with safer and more effective phosphate binders and vitamin D analogs that maintain the delicate balance of mineral homeostasis in CKD.²⁴ Currently, dosages of calcitriol less than 0.50 mcg/d are considered safe, with a target intact PTH level between 100 and 300 pg/mL.⁵ Patients who continue to have parathyroid hyperplasia should be evaluated for parathyroidectomy or for medical treatment with cinacalcet. This agent sensitizes the chief receptors for calcium on the parathyroid gland, inhibiting the production of PTH. Cinacalcet also is indicated for patients on dialysis.²⁷  

Comorbidity of cardiovascular disease

Patients with CKD are more likely to die from CVD than from chronic renal failure.²⁸ Because dialysis patients have a 10- to 30-fold greater risk for mortality from CVD, they are in the highest risk category for heart disease. Arterial vascular disease and cardiomyopathy are the major causes of death.

Secondary hyperparathyroidism contributes to atherosclerotic lesions that in CKD patients are frequently more calcified and have increased media thickness compared with lesions in members of the general population.^24,28 The clinical presentation of atherosclerosis includes angina, MI, sudden cardiac death, cerebrovascular disease, peripheral vascular disease, and heart failure. Arteriosclerosis often results in decreased arterial compliance, increased systolic BP, and decreased coronary perfusion. Cardiomyopathy is a frequent outcome of arteriosclerosis and untreated hypertension.

Dyslipidemia is a frequent complication of progressive renal disease,^29,30 with an elevated triglyceride level being the most common abnormality. Most patients with CKD also have an elevated LDL-to-HDL cholesterol ratio. LDL promotes atherogenesis, which contributes to CVD. It is critical to screen for and treat dyslipidemia early in CKD. Treatment goals are an LDL level of less than 100 mg/dL and a triglyceride level of less than 200 mg/dL.⁶ Patients who take fibrates to lower their triglyceride levels may be at increased risk for rhabdomyolysis. Statins can safely and effectively lower cholesterol levels in these patients.³¹  

Preparing for renal replacement therapy

Patients have improved outcomes when preparation for transition to the selected renal replacement therapy (RRT) is made in advance.^6,32 Ideally, referral to a nephrologist at least 6 months before starting RRT allows the renal team to assess all the options for dialysis and transplant.⁵ Patients who receive pre-ESRD education and information on their treatment options are more likely to maintain employment, remain compliant with their program, and avoid the need for emergency decisions that may disrupt RRT.

A native arteriovenous fistula (AVF) is the preferred type of permanent vascular access for connection with the dialysis unit.⁵ When compared to arteriovenous grafts, patients with AVFs have fewer complications related to infection and thrombosis and possibly better survival rates. Despite the proven superiority of AVFs, studies indicate that more than half of new dialysis patients have some form of temporary vascular access at the time of their first treatment. Education regarding vascular access should begin when the GFR is 15 to 29 mL/min/1.73 m², while placement of an AVF should be initiated when the GFR falls below 15 mL/min/1.73 m².^5,6 Ideally, a maturation time of at least 3 to 4 months for the AVF is recommended before beginning dialysis.⁵  

Summary

CKD is a silent medical problem that requires laboratory analysis to make an early diagnosis. Early aggressive management of diabetes mellitus, hypertension, and dyslipidemia are vital. Awareness and management of the frequent complications also improve ESRD outcomes. Ongoing consultation with the nephrology team, including a renal dietitian, is important for delaying disease progression and improving patient quality of life.  

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