Figure 67.1. Approximate rates of progression in the different stages of diabetic nephropathy.

    Approximately 25% of type 2 diabetics have microalbuminuria at the time of diagnosis, and 3% of newly diagnosed type 2 DM have clinically apparent nephropathy. The majority of patients with type 2 DM have evidence of cardiovascular and hypertensive complications.

PATHOLOGY

Three cardinal features of renal pathology are basement membrane thickening, accumulation of mesangial matrix (with or without Kimmelstiel-Wilson nodules), and vascular disease (see Figure 67.2 and box 67.2). In addition, there is frequently associated evidence of vascular disease. The renal pathologic changes are very similar in patients with type 1 or type 2 diabetic nephropathy. In approximately 20% of biopsies there is a superimposed glomerular lesion with diabetic kidney disease being present in the background.

Box 67.2 PATHOLOGICAL FEATURES OF DIABETIC NEPHROPATHY

DIAGNOSIS

Patients with diabetic nephropathy usually present with hyperglycemia, hypertension (systolic hypertension in particular), either microalbuminuria or proteinuria, and renal dysfunction. Microscopic hematuria may be seen but is unusual. In approximately 10% of patients, red cell casts in the urine sediment have been reported. Patients will frequently have evidence of other complications of DM, such as retinopathy, peripheral vascular disease, and a sensory neuropathy. Patients with more advanced diabetes may have the Charcot foot (increased warmth, erythema, swelling, absence of pain in the lower extremity or foot), diabetic ulcers, skin disease including acanthosis nigricans (darkening and thickening of certain areas of the skin especially in the skin folds) or scleroderma diabeticorum (thickening of the skin on the back of the neck and upper back; see Figure 67.3).

Treatment and Prognosis

Treatment is summarized in box 67.3. Both the Diabetes Control and Complications Trial (DCCT) study for type 1 diabetics and the United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetics demonstrate unequivocally that tight control of blood sugar (aiming for a HbA1c of <7%) is associated with reduced micro- and macrovascular damage. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are drugs of choice as they control both systemic hypertension and intraglomerular hypertension by inhibiting the actions of angiotensin II on the systemic vasculature and renal efferent arterioles. ACE or ARBs inhibitors are effective in delaying the progression of the renal disease in patients with DM. Dual blockade (with both an ACE inhibitor and an angiotensin receptor blocker [ARB]) should be avoided based on a higher rate of acute kidney injury and hyperkalemia reported in the NEPHRON-D study as well as results from the ONTARGET study.

    The blood pressure target in patients with diabetic nephropathy is evolving. The Joint National Committee 7 (JNC7) guidelines recommend a blood pressure target of <130/80 mm Hg using ACE inhibitors or ARBs as first-line therapy. However, these guidelines have now been replaced by JNC8, which recommends a blood pressure target of <140/90 mm Hg. The 2013 American Diabetes Association (ADA) guidelines reflecting results from the ACCORD study also recommends a less aggressive blood pressure target (<140/80 mmHg) in diabetic patients (with or without kidney disease). However, the ADA guidelines do point out that a lower systolic target (<130 mm Hg) may be appropriate in certain patients if tolerated. Blood pressure control in patients with diabetic kidney disease frequently requires more than one drug is needed to control blood pressure; consequently, diuretics, long-acting calcium channel blockers (CCBs), and beta blockers are reasonable adjuncts. Other important interventions in DN that should be considered are dietary protein restriction (0.8 g/kg/day of protein)—recommended by the American Diabetes Association, cessation of smoking, and control of lipids—a target low-density lipoprotein (LDL) of 100 mg/dL is recommended by the ATPIII/NCEP guidelines.

Box 67.3 TREATMENT STRATEGY FOR DIABETIC NEPHROPATHY

HYPERTENSIVE NEPHROPATHY/NEPHROSCLEROSIS

Hypertension affects the majority of the U.S. population. By the age of 60 years, over 50% of the U.S. population will be hypertensive (defined as having a repeatedly elevated blood pressure of ≥140/90 mm Hg). The causes are many and include idiopathic or secondary factors. Secondary factors include renal disease, endocrine causes such as Cushing disease and hyperparathyroidism, hypercalcemia, and pheochromocytoma, and primary hyperaldosteronism. Vascular causes include renovascular disease. Hypertension can result from renal failure; studies suggest that in stage 4 CKD over 75% of patients have evidence of hypertension. Less commonly, renal failure can result from hypertension.

    Renal disease due to chronic hypertension is seen primarily in the black population with a ratio of eight to one, but it can be observed in whites as well. Approximately 5% of patients have accelerated or malignant hypertension (diastolic pressure >120 mm Hg), which may be associated with renal failure and retinal hemorrhages and exudates, with or without papilledema.

CLINICAL FEATURES

Patients with renal disease secondary to hypertension usually describe a long antecedent history of hypertension that is evidenced by a slow rise in BUN and creatinine. Retinopathy and left ventricular hypertrophy will be present in a majority of these patients. Depending on the severity of the renal damage, there may be either microalbuminuria or overt albuminuria. The risk for hypertensive renal disease is increased among individuals of black race, those with underlying renal disease, and those with chronically elevated blood pressure. Benign hypertensive nephrosclerosis is the most common clinical presentation.

PATHOGENESIS

The vascular response to hypertension is intimal thickening with medial hypertrophy and resultant luminal narrowing. This response minimizes the pressure variations in the arterioles and capillaries. With chronicity, the autoregulatory mechanisms of the arterioles fail, and vascular damage ensues. This results in increased permeability, platelet deposition, and deposition of hyaline-like material in the damaged vessels, leading to a permanent lesion of fibroelastic hyperplasia and fibrinoid necrosis. Often hyaline arteriolosclerosis accompanies these changes. Plasma renin, secreted by the kidney in the presence of vascular compromise, is markedly elevated. A self-perpetuating cycle of increasing angiotensin II/intrarenal vasoconstriction becomes established, leading to ischemia and renin secretion. The influence of increased levels of vasoconstrictors (e.g., endothelin) and decreased levels of vasodilators (nitric oxide) may also contribute to vasoconstriction. Aldosterone levels are also elevated and salt retention undoubtedly contributes to the elevation of blood pressure. The increased incidence in the black population is attributed to poorly defined environmental and genetic factors. Often hypertension in blacks is not associated with high renin secretion.

PATHOLOGY

Hypertensive nephropathy may involve the glomerulus, the vessels, and the tubulointerstitial tissue. In patients with advanced disease there may be marked nephron loss in the injured portions of the kidney with hypertrophic enlargement of the remaining segments. The entire glomerular tuft may be involved in a focal segmental fashion or a global segmental fashion. Tubular atrophy may be similar to ischemic type of renal injury. With severe disease, a chronic interstitial nephritis with hyperplastic arteriolitis (onion-skinning), fibrinoid necrosis of arterioles, and necrotizing glomerulitis is apparent.

DIAGNOSIS

A detailed history and the clinical presentation are usually sufficient for the diagnosis. In severe cases patients may have papilledema, retinopathy, encephalopathy, and cardiovascular abnormalities. Urinalysis may show nonnephrotic-range proteinuria. A renal biopsy is rarely indicated.

TREATMENT AND PROGNOSIS

Patients who present with hypertension should always be evaluated for reversible causes of hypertension. The goal of treatment is aimed at normalizing the blood pressure.

    The target blood pressure based on JNC7 recommendations is ≤130/80 mm Hg. However, recent data point to a goal blood pressure of <140/90 mm Hg for nonproteinuric hypertensive patients.

    A similar goal is proposed in the National Kidney Foundation (NKF) guidelines on hypertension. The 2003 NKF Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for antihypertensive therapy recommend:

• Blood pressure measurement at each health care encounter.

• Target blood pressure of <130/80 mm Hg for all patients with kidney disease, including those with diabetic kidney disease and nondiabetic kidney disease, regardless of degree of proteinuria, and in renal allograft recipients.

• Use of an ACE inhibitor/ARB in patients with diabetic kidney disease, and use of ACE inhibitor in nondiabetic kidney disease with proteinuria (spot U_p/U_cr ratio of ≥200 mg/g), to retard progression of kidney disease, irrespective of the presence of hypertension.

• Adjunctive antihypertensive agents: NKF guidelines suggest diuretics followed by either beta blockers or calcium channel blockers in diabetic kidney disease as well as in nondiabetic proteinuric kidney disease (spot U_p/U_cr ratio of ≥200 mg/g). In patients with kidney disease in the absence of significant proteinuria, as defined by spot U_p/U_cr ratio of <200 mg/g, diuretics are the preferred agent, followed by ACE inhibitor, ARB, beta blocker, or calcium channel blocker. In recipients of renal allografts, calcium channel blockade, diuretic therapy, and beta blockade, ACE inhibitor, or ARB are recommended.

CYSTIC DISEASES OF THE KIDNEY

Simple renal cysts are common, occurring in 50% of patients older than 50 years of age.

    The widespread use of ultrasonography (US) and computed tomography (CT) scan has led to an increased detection of simple cysts. Ultrasound criteria for the classification of simple renal cyst include (1) spherical or ovoid shape, (2) absence of internal echoes, (3) presence of a thin, smooth wall that is separate from the surrounding parenchyma, and (4) enhancement of the posterior wall, indicating ultrasound transmission through the water-filled cyst. If all of these criteria are satisfied and the patient is asymptomatic, no further evaluation of the cyst is necessary since the likelihood of a malignancy is very small. Symptomatic patients with the same ultrasound findings should undergo CT scanning with contrast. The gold standard for evaluating renal masses requires CT images <5 mm in thickness before and after contrast is given. The criteria for diagnosing a benign cyst on CT scan include (1) a homogeneous attenuation value near that of water, (2) no enhancement with intravenous contrast material, (3) no measurable thickness of the cyst wall, and (4) smooth interface with renal parenchyma. Magnetic resonance imaging (MRI) is typically used to evaluate patients with indeterminate lesions. MRI does not detect calcifications. The suspicion for malignancy should be raised if the benign criteria are not met, calcification is present within a cyst, or repeat studies show an enlarging lesion. CT scan has a sensitivity of 94% for detection of renal parenchymal masses, but MRI is statistically superior to CT scan in the correct characterization of benign lesions. If a cyst meets the criteria for being benign, periodic reevaluation is the standard of care. If the lesion is not consistent with a simple cyst, surgical exploration is recommended.

    Acquired renal cystic disease occurs in as many as 90% of patients who receive dialysis for 5–10 years. The cysts develop as a consequence of chronic renal insufficiency and may be clinically apparent long before dialysis is instituted. Malignancy and metastases can develop in a small percentage of cases. Screening of all dialysis patients by renal US is recommended after 3 years of dialysis at 1- to 2-year intervals. Major clinical manifestations of acquired cystic disease include flank pain and hematuria in association with rupture of hemorrhagic cysts into the urinary tract or into the perinephric region. Cysts often resolve after successful renal transplantation.

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disease, and that affects 1 in 400 to 1000 live births. ADPKD is usually recognized in adults between the third and fourth decades of life. Adult PKD causes renal insufficiency in 50% of individuals by the age of 70 years, and it accounts for 10% of dialysis patients in the United States. ADPKD is caused by a defective PKD1 gene on chromosome 16p in 85% of cases. A positive diagnosis requires (1) at least two cysts (unilateral or bilateral) in patients younger than 30 years of age; (2) at least two cysts in each kidney in patients aged 30 to 59 years; or (3) four or more cysts in each kidney in patients over age 60 years. These age-specific data have been developed in reference to PKD1 patients. Pathology of ADPKD is characterized by massive enlargement of the kidneys secondary to cyst growth and development. The liver also contains cysts in about 40% of patients with ADPKD. Arterial aneurysms of the circle of Willis are found in about 10% of patients. Diagnosis by US is straightforward in advanced disease, but it may be less reliable in the early stages. CT scan and MRI are more informative, and genetic testing may be required when greater certainty is needed for ADPKD diagnosis.

MEDULLARY CYSTIC KIDNEY DISEASE

Medullary cystic kidney disease is a rare autosomal dominant cystic disease characterized by normal- to small-sized kidneys. When cysts are found, they are located at the corticomedullary junction and in the medulla. Diagnosis relies on clinical features with a thorough family history. CT scan is the most sensitive test for cyst detection. The first signs are inability to concentrate the urine and salt wasting, leading to polyuria and polydipsia. Medullary cystic disease progresses inevitably to ESRD by the age of 20–40 years. Transplantation is the treatment of choice.

MEDULLARY SPONGE KIDNEY

Medullary sponge kidney is usually not diagnosed before the fourth or fifth decade of life, when patients have secondary calcifications with passage of urinary stones or frequent urinary tract infections. This is a benign disorder with incidence of 1 in 5000 in the general population. The diagnosis is made by intravenous urography, which shows irregular enlargement of the medullary and interpapillary collecting ducts bilaterally. There is no specific therapy for medullary sponge kidney disease. The patients should be to excrete over 2 L of urine a day and may benefit from a thiazide diuretic for hypercalciuria, allopurinol for hyperuricosuria, or potassium citrate for hypocitraturia.

RENAL CELL CANCER

Renal cell cancer occurs at a rate of 7.5 cases per 100,000 population annually. It accounts for >80% of renal malignancies in adults and occurs more frequently in men. Risk factors for renal cell carcinoma are smoking, chemicals such as cadmium and nitrosohydrocarbons, acquired cystic disease in ESRD, and von Hippel-Lindau disorder. Patients may present with hematuria, abdominal mass, flank pain, fever, weight loss, or varicocele, but many patients are asymptomatic until the disease is advanced. Laboratory findings include anemia or erythrocytosis, hepatic dysfunction, and hypercalcemia. CT scan with radiographic contrast is currently the most widely available, sensitive, and accurate nonoperative method available for making a presumptive diagnosis of renal cancer and its staging. MRI is used over CT scanning (1) when detecting tumors in regional lymph nodes and extension into the renal veins and inferior vena cava; (2) in patients with radiographic contrast allergy; and (3) when CT results are equivocal. For patients without distant metastases the treatment of choice is radical nephrectomy. The average survival of patients with metastases is only 6–9 months. Postoperative adjuvant radiation, hormonal therapy, and chemotherapy are not proven to prolong survival.

KIDNEY STONES

Kidney stone disease is a common cause of morbidity in the Western world. It affects 10–20% of the population and leads to hospitalization in 1 in 1000 individuals each year. In excess of 80% of kidney stones occur in white males. White males have a lifetime risk of stone formation approximating 20%. In contrast, the lifetime risk in white females is much lower—approximately 5–10%. There is also clear racial preponderance of stone disease among whites—blacks have an incidence rate of stone disease that is 25% that of whites. The peak age of onset for kidney stone formation is 20–30 years. However, there is a high recurrence rate—as high as 50% in 5 years among white males.

    Kidney stones form in the renal tubule or collecting duct and arise when urine is supersaturated with insoluble materials. The nidus is usually a crystal or foreign object. Seventy-five percent of stones are primarily composed of calcium phosphate or calcium oxalate, 10–20% are struvite stones, 5% urate, and 1–2% cystine. Kidney stones can be found throughout the length of the urinary tract system. Symptoms depend on the type, location, and duration of kidney stones. Patients may be asymptomatic or have renal colic, hematuria, dysuria, frequency, or urinary tract infections. Symptoms associated with renal failure may arise when patients suffer from large staghorn calculi that impair renal function. The incidence and prevalence of kidney stones vary by region, age, sex, and race, but approximately 5% of American women and 12% of men will develop stones in their lifetime. The goals of management are to treat complications and symptoms, remove any stones, and prevent recurrences.

    The clinical presentation varies depending on the location, size, and number of the stones. The majority of kidney stones occur in the upper tracts. The most common presentation is renal colic—the sudden onset of severe pain due to the presence of an obstructive renal or ureteral stone. Renal colic is typically spasmodic in character, lasting several minutes, typically localized to the flank, and often radiating down to the groin. Nausea and vomiting frequently accompany renal colic. Renal colic often occurs in the middle of the night or early morning while the patient is sedentary, and its severity has been described as akin to or worse than childbirth. The severity of pain is a common cause of patients coming to the emergency room. On the other hand, larger stones may present with painless obstruction or back pain. Stones that reach the ureterovesical junction often present with renal colic accompanied by urgency and frequency. Alternatively, stones that are located in the calyces may be completely asymptomatic. The general appearance of a patient with renal colic is of someone writhing in excruciating pain. Sometimes the patient presents with restlessness, and pacing about the room. The presence of fever usually heralds an accompanying urinary tract infection. Otherwise the physical examination may be completely negative. The laboratory evaluation should comprise a complete blood count, blood chemistries including measurement of urea (BUN) and creatinine, and a urinalysis. The presence of a urinary tract infection, particularly with pyelonephritis, will be associated with a leukocytosis. An elevated BUN and creatinine would suggest dehydration and/or the presence of an obstructing stone in a patient with a single kidney or bilateral obstructing stones. The urine usually demonstrates hematuria and pyuria. Assessment of urine pH is critical because an acid urine with a radiolucent stone will suggest a uric acid stone, whereas a very alkaline urine (pH >8.0) would suggest an infection with a urease-splitting organism (example.g., Proteus, Pseudomonas, and Klebsiella species). The initial radiologic workup should comprise of a kidney-ureters-bladder (KUB) radiograph and an ultrasound or a noncontrast CT scan.

MANAGEMENT OF KIDNEY STONES

The management of kidney stones can be divided into the management of the acute stone episode, and if the stone is nonobstructing, management of the prevalent stone medically and/or surgically, and prevention of further stones. Management of the acute stone episode rests on optimal pain control using parenteral narcotic agents, hydration, and urologic consultation for potential removal of an obstructing stone. Medical management of a nonobstructing stone comprises increasing fluid intake to cause a urine output of >2 L/day, modification in diet, treatment targeted at changing urinary pH, and strategies to prevent further stones from forming. Surgical management depends on the size, location, and number of stones. Surgical options include extracorporeal shock wave lithotripsy (ESWL) and lithotripsy (percutaneous or transurethral). General rules of thumb are that cystine stones and calcium oxalate monohydrate stones are generally poorly broken up by ESWL, and percutaneous or transurethral lithotripsy for removal are favored. On the other hand, other calcium oxalate stones, struvite stones, and uric acid stones are generally amenable to ESWL, as well as to either percutaneous or transurethral routes for removal depending on the size and location of the stones.

ACUTE KIDNEY INJURY (ACUTE RENAL FAILURE)

Acute kidney injury (AKI) has replaced the use of the term “acute renal failure.” AKI is defined as a reduction in renal function manifest by a rise in serum creatinine over a period of hours to days. AKI is frequently accompanied by dysregulation of extracellular fluid volume and electrolytes and marked increase in the retention of nitrogenous and nonnitrogenous waste products over a period of hours to weeks. Acute kidney injury may be oliguric (<400 mL/day) or nonoliguric (>400 mL/day). AKI can also be defined as an acute and sustained increase in serum creatinine of 0.5 mg/dL (44.2 µmol/L), if the baseline is <2.5 mg/dL (221 µmol/L), or an increase in serum creatinine >20% if the baseline is >2.5 mg/dL (221 µmol/L).

    There have been several attempts to achieve consensus between intensivists and nephrologists on the definition of AKI. The Acute Dialysis Quality Initiative (ADQI) group published the RIFLE classification of AKI in 2004 based on three severity categories (risk, injury, and failure) and two clinical outcome categories (loss and ESRD) (box 67.4). The parameters assessed in the RIFLE classification are changes in serum creatinine level or glomerular filtration rate (GFR) or urine output (UO) from the patient’s baseline. The baseline serum creatinine level and GFRs may not be readily available. Hence, the consensus committee recommends the use of the Modification of Diet in Renal Disease (MDRD) equation to estimate the patient’s GFR/1.73 m². The proportional decrease in GFR is calculated from 75 mL/min/1.73 m², the agreed-on lower limit of normal.

Box 67.4 “RIFLE” CLASSIFICATION FOR AKI

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