Current Concepts in Management of Kidney Disease

Educational Objectives

The goal of this program is to improve the management of chronic kidney disease (CKD) and renal stones. After hearing and assimilating this program, the clinician will be better able to:

1.   List risk factors that increase mortality in patients with CKD.

2.   Discuss metabolic effects of nitric oxide on the kidneys, based on animal subtotal nephrectomy models.

3.   Describe the role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in CKD.

4.   Identify genetic and environmental factors that increase risk for renal stone disease.

5.   Select appropriate treatment for idiopathic hypercalciuria and medullary sponge kidney.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgements

Dr. Blantz spoke in San Diego, CA, on March 10, 2009, at Topics and Advances in Internal Medicine, presented by the University of California, San Diego, School of Medicine. Dr. Kupin was recorded in Miami Beach, FL, at Advances in Medicine 2009, presented January 25-30, 2009, by the University of Miami Miller School of Medicine. The Audio-Di­gest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Challenges in Kidney Disease

Roland C. Blantz, MD, Professor of Medicine and Head, Division of Nephrology-Hypertension, University of California, San Diego, School of Medicine, and Nephrologist, Veterans Affairs Healthcare System, San Diego, CA

Introduction: 2002  —  according to National Health and Nutrition Examination Survey (NHANES) data, »20 million people in United States have chronic kidney disease (CKD); many patients have moderate stage 3 CKD (glomeru­lar filtration rate [GFR] of 30-59 mL/min); 1997 to 1999  —  fewer than one-third of patients with CKD given angio­tensin-converting enzyme inhibitor (ACEI); ACEI or angiotensin receptor blocker (ARB) given to only 20% of patients with stage 3 CKD discharged after diagnosis of myocardial infarction (MI), coronary event, or congestive heart failure

Barriers to proper delivery of care: limited number of nephrologists; overhead costs (of, eg, back-up system [eg, nurse practitioners, nurse educators, pharmacists] in primary care practices); limited time to see patients; accep­tance of CKD as health care and economic issue; implementation of disease management  —  many CKD clinics minimize time spent with physician and maximize preventive care from, eg, nurse educator; management of CKD clinics difficult

Risk factors: meta-analysis found poor blood pressure (BP) control led to faster decline in GFR; in untreated hyper­tension, GFR decreases 10 to 12 mL/min per year; early therapy can delay chronic kidney failure in patients with CKD; cardiovascular (CV) risk associated with CKD outweighs that associated with hypertension and high choles­terol; mortality rate of patients 25 to 34 yr of age with end-stage renal disease equal to that of persons 75 to 80 yr of age with normal renal function for age; at each stage of decline in renal function, relative risk for mortality in­creases (predominantly due to CV risk, but infection and malignancy also contribute)

Effects of treatment: in animal models, ACEIs shown to delay progression of CKD; in diabetes and CV disease, ACEIs or ARBs can ameliorate progression of CKD; patients treated with ramipril had reduced risk for overall CV disease, MI, stroke, and CV death, compared to those treated with placebo; in patients with GFR <60 mL/min, re­ducing GFR decline by 10% estimated to save health care system $5 billion to $18 billion by 2010; rate of accumu­lation of new dialysis patients appears to be slowing; yearly increase in net effect may be due in part to ACEI and ARB therapy (particularly in diabetic population); 35% to 40% of patients with stage 3 CKD periodically cared for by nephrologists; patients with stages 4 and 5 CKD mainly cared for by nephrologists

Acute renal failure or acute kidney injury: diagnosis increasing; repeated episodes may be risk factor for progres­sion of CKD; normal kidney obligates 20% of cardiac output; in acute kidney injury, countercurrent shunting of O₂ between arteries and veins in kidney results in low Po₂ of kidney (40-44 mm Hg; lower in certain hereditary forms of hypertension and in diabetic kidneys); environment borderline hypoxic; diabetic and hypertensive renal disease characterized by higher than normal O₂ consumption; regulators of vascular resistance and blood flow  —  adenosine triphosphate (ATP) and adenosine  (vasoconstrictors); nitric oxide (NO; vasodilator; decreases O₂ utilization); an­giotensin (vasoconstrictor)

Five-sixths nephrectomy model: nephrectomy of one kidney and removal of two-thirds of other kidney; kidney gradually develops focal sclerosis and CKD; after few weeks, remnant kidney (one-third of normal mass) hypertro­phies, undergoes hyperplasia, and requires twice as much O₂ (associated with increased reactive O₂ generation); hy­poxia (Po₂ in kidney cortex »30 mm Hg) in early phases of remnant kidney

Metabolic effects of NO: decreases pyruvate uptake; inhibits cytochrome C oxidase; decreases O₂ consumption by kidney; NO inhibition with, eg, s-methyl-thiocitrulline (SMTC; NO synthase [NOS] inhibitor) increases O₂ con­sumption; in various models of CKD, amount of NOS markedly declined in cortex and medulla, compared to nor­mal kidney; inhibitors of NOS generated secondary to loss of renal function; reductions in NOS-1 activity correlated with development of glomerular sclerosis (eg, glomerular sclerosis in rat kidneys increased when NOS-1 levels low; implies causality)

Angiotensin blockade studies: based on animal subtotal nephrectomy model (model of hypertension); studied group in which angiotensin system blocked with ACEIs and ARBs, and control group (BP reduced with triple therapy [re­serpine, hydrochlorothiazide, and hydralazine]); findings  —  massive (»80%) increase in O₂ consumption in CKD kidney (normalized with combined angiotensin blockade; did not normalize with GFR control [elevation with amino acids]); in subtotal nephrectomy model, low level of NOS related to high O₂ consumption normalized with angiotensin blockade; molecules important to cell proliferation and fibrosis (eg, mitogen-activated protein [MAP] kinase; extracellular signal-regulated kinase [ERK]) elevated at 1 wk, but normalized with angiotensin blockade; in remnant kidney model, NOS inhibition does not lead to increased O₂ consumption (as in normal kidney), but treat­ment with angiotensin blockers for 1 wk restores normal response; feedback system  —  in normal kidney, increased flow to macula densa (distal tubule) leads to decrease in GFR; in 5/6 nephrectomy model, no feedback activity oc­curs, but it can be restored by inhibiting angiotensin II

Conclusions: recognize possibility of angiotensin as growth factor; proteinuria not cause of increased O₂ consump­tion; low NO status in CKD contributes to increased O₂ consumption; insulin resistance  —  application of insulin to kidneys with high O₂ consumption can lower O₂ costs; angiotensin may be contributing to high metabolic rate; con­tinue therapy with ACEIs and ARBS; correction of metabolic abnormality may be beneficial in slowing progres­sion of CKD; consider possible contribution of  hypoxia to transformation of epithelial cell to fibroblast and scar

Questions and answers: dietary management in chronic renal failure  —  management of calcium, phosphate, and protein intake important; control metabolic acidosis and phosphates; 24-hr urine collection  —  estimated GFR (eGFR) adequate for categorizing patients; consider errors  in clearances; when looking at protein excretion, albu­min to creatinine ratio or total protein to creatinine ratio performed at specific time of day likely adequate; GFR in patients >65 yr of age  —   fewer glomeruli per kidney; smaller surface area of kidneys; older literature suggests de­cline in renal function in women occurs after menopause (in men, at age »25 yr); exercise and high maintenance of creatinine mass reduce severity of decline; decline in renal function more related to sedentary behavior; single kid­ney vs remnant kidney  —  absolute GFR similar, but environment of kidney different (fewer nephrons in remnant kidney); ACEIs and ARBs  —  in animal models, use of ACEIs several weeks after institution of reasonable therapies associated with fairly normal plasma levels of angiotensin; other angiotensin receptors, when stimulated, may pro­vide benefit to kidney and cardiovascular system; increasing evidence of added benefit in certain circumstances (eg, diabetes)

Renal Stones

Warren L. Kupin, MD, Professor of Medicine, University of Miami Miller School of Medicine, Miami, FL

Types of renal stones: calcium oxalate stones (found in 60%-65% of patients); infection stones (struvite); calcium phosphate stones; other (eg, drug-induced stones)  —  incidence increasing; drug-induced nephrolithiasis most com­monly caused by indinavir; can be caused by ciprofloxacin, phenytoin (Dilantin), aminophylline, triamterene, and trimethoprim-sulfamethoxazole (eg, Bactrim); must analyze every stone to rule out drug-induced nephrolithiasis

Cost of kidney stone disease: single episode causes 2.5 missed days of work; economic effect »$3500/patient;  $2 billion economic burden; incidence (1 in 1000) and cost increasing

Prevalence and influential factors: in United States, 8% to 12% prevalence overall; more common in men (»15% chance);  »6% in women; more common in whites; typically affects men 50 to 60 yr of age; more common in areas of high ambient temperature (eg, southeastern United States); genetics  —  higher incidence in monozygotic twins than in dizygotic twins from same household environment; may be associated with hereditary nature of certain met­abolic defects (eg, hypercalciuria); associated with positive family history; obesity considered risk factor

Characteristics of stones: radio-opaque  —  most stones show opacification on computed tomography (CT), intrave­nous pyelography (IVP), or x-ray; radiolucent  —  uric acid stones; not visible on x-ray; drug-induced stones; uri­nary pH  —calcium oxalate, uric acid, and cystine stones crystallize in acidic (pH 5-6) urine (treatment focuses on alkalinizing diet); stones that form in alkaline urine (eg, infection stones and calcium phosphate stones) rare; rec­ommend diet that acidifies urine

Typical presentation: white man, 50 to 60 yr of age with acidic urine and calcium oxalate stone; symptoms  —  pain; unlike patients with acute appendicitis (who usually lie rigid), those with renal colic  tend to roll around on bed due to cramping; microhematuria from laceration of ureter as stones travel

Appearances of crystals: calcium oxalate  —  appear as “envelopes” or squares under microscope; uric acid  —  smooth surface with lamellar appearance; appear rhomboid and stellate; cystine  —  cystinuria rare hereditary dis­ease; hexagonal crystals; triple phosphate  —  often seen in conjunction with infection; rectangular crystals; “legal envelopes” or coffin-shaped crystals; form staghorn calculi; can completely obstruct kidney

Calcium oxalate stone disease: without intervention, recurs in 5 to 15 yr; stones damage kidneys and ureter, creating nidus for further stone formation; greater number of episodes results in faster recurrence

Formation of stones: promoters  —  calcium; oxalate; uric acid; inhibitors  —  citrate, magnesium, and phosphate; ci­trate and magnesium compete with calcium to bind with oxalate, and thereby prevent stone formation; stones form while attached to small nidus at tip of papilla; stone enlarges, breaks off, and enters urine; crystals grow on Ran­dall's plaques (calcification front at tips of each papilla) and fall off; Randall's plaque remains, allowing for recur­rences; Randall's plaques found only in patients who form stones

Idiopathic hypercalciuria: most common cause of calcium oxalate stone disease; does not always lead to stone for­mation; urine screening test never used to identify risk in patients with no history of stone disease (used only to identify risk for recurrence); silent in many patients; causes  —  1) overabsorption of dietary calcium; 2) renal leak of calcium in urine; “everyone does a little bit of each”; every patient with hypercalciuria has lower total body calcium load, resulting in osteopenia and osteoporosis; calcium restriction increases risk for worsening bone disease; check bone mineral density; dietary causes  —  high dietary sodium and protein intake; oxalate intake (from, eg, vitamin C, green leafy vegetables, chocolate); >500 mg/day of vitamin C increases risk for stone disease by nearly 25%; pa­tients with stone disease should not take excess vitamin C

Oxalobacter formigenes: bacteria in colon; metabolizes oxalate; patients with stone disease have low population of O formigenes (supplementation may reduce risk for stone disease; Food and Drug Administration approval pending)

Clinical approach: determine composition of stone; check whether any stones remain in patient; kidney, ureter, blad­der (KUB) film; CT most sensitive for identifying residual stone particles and checking renal anatomy and mor­phology; electrolytes; calcium and phosphorus levels; consider work-up for hyperparathyroidism; urine culture; standard work-up of first episode does not include 24-hr urine analysis; give dietary advice; look for congenital malformations of kidneys (eg, horseshoe kidneys, bifid kidneys, duplicated kidneys; affect stagnation and risk for stones)

Medullary sponge kidney (MSK): common in patients who form stones; not hereditary; does not lead to kidney fail­ure; physical developmental abnormality of collecting ducts; incurable; associated with high risk for stone disease; patients usually do not respond to dietary intervention;  medication required immediately after first episode; flecks of calcification located around collecting ducts recognized on CT; difficult to treat

24-hr urine analysis: recommended for complicated or recurrent disease, and patients with recurrences, single kid­ney, or high-risk occupation (eg, airline pilots); check citrate, magnesium, phosphate, and uric acid; perform after patient has resumed normal diet (can be 2-3 mo after patient passes stone); 2 to 3 samples recommended

Intervention: volume  —  need to drink 2.5 to 3 L daily to produce >2 L of urine; dilution of urine dramatically de­creases risk for stone disease; citrus products (eg, lemon juice, lemonade) recommended because of high citrate content; if patient has hypercalciuria, maintain adequate calcium intake; thiazide diuretics reduce urinary calcium; reduce animal protein intake (1 g/kg per day of protein from nonanimal source adequate); potassium citrate in­creases alkalinity and concentration of citrate in urine; thiazide diuretics and potassium citrate reserved for patients with MSK, recurrences, and high-risk occupations

Suggested Reading

Bakris GL et al: Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Disease 36:646, 2000; Blantz RC: Handing out grades for care in chronic kidney disease: nephrologists versus non-nephrologists. Clin J Am Soc Nephrol 2:193, 2007; Blantz RC et al: Regulation of kidney function and metabolism: a question of supply and demand. Trans Am Clin Climatol Associate 118:23, 2007; Daudon M et al: Stones in primary hyperoxaluria—a clarifi­cation. N Engl J Medicine 360:1680, 2009; Deng A et al: Regulation of oxygen utilization by angiotensin II in chronic kidney disease. Kidney Int 75:197, 2009; Erdely A et al: Resistance to renal damage by chronic nitric oxide synthase in­hibition in the Wistar-Furth rat. Am J Physiol Regul Integr Comp Physiol 290:R66, 2006; Escribano J et al: Pharmaco­logical interventions for preventing complications in idiopathic hypercalciuria. Cochrane Database Syst Rev (1):CD004754, 2009; Go AS et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitaliza­tion. N Engl J Med 351:1296, 2004; Harris DC et al: Remnant kidney hypermetabolism and progression of chronic re­nal failure. Am J Physiol 254:F267, 1988; Kupin WL: A practical approach to nephrolithiasis. Hosp Pract (Off Ed) 30:57, 1995; Kupin WL et al: Effect on renal function of change from high to moderate protein intake in type I diabetic patients. Diabetes 36:73, 1987; Lebovitz HE et al: Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int Suppl 45:S150, 1994; Nath KA et al: Oxygen consumption and oxidant stress in sur­viving nephrons. Am J Physiol 258: F1354, 1990; Nouvenne A et al: Diet to reduce mild hyperoxaluria in patients with idiopathic calcium oxalate stone formation: a pilot study. Urology 73:725, 2009; Stratta P et al: Medullary sponge kid­ney. Am J Kidney Disease 48:e87, 2006.