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Interstitial & Polycystic Disease

Interstitial & Polycystic Disease

Tubulointerstitial Disease, Cystic Renal Disease Renal Genital Urinary System 2019

TUBULOINTERSTITIAL DISEASE AND POLYCYSTIC

Biff F. Palmer, MD, Office: H5.112; Phone 87848 Email: [email protected]

LEARNING OBJECTIVES

• List the pertinent aspects of the history, , serum and electrolytes, and urinalysis that distinguish between acute and chronic interstitial • List the common clinical entities that can give rise to acute or chronic tubulointerstitial renal disease • List the common clinical characteristics of polycystic kidney disease. • Delineate the features that one can utilize to distinguish glomerular versus interstitial renal disease

Tubulointerstitial Kidney Disease

Tubulointerstitial renal disease involves the tubules and the interstitium rather than the glomeruli and the vasculature of the kidney. Tubulointerstitial disease may be acute or chronic and may present as a primary renal disease or may occur as part of a systemic disorder. Patients may present with subtle tubular defects or fulminant renal failure and can develop renal structural and functional changes that are either reversible or permanent. Although tubulointerstitial renal disease makes up only a small percentage of the cases of and end-stage renal disease in the United States, damage to the tubulointerstitium of the kidney contributes significantly to the progression of most of the important forms of renal disease.

Specific laboratory findings in patients who have tubulointerstitial disease reflect the underlying etiology; the extent of injury, and the chronicity of the insult. The urinary sediment often contains erythrocytes, leukocytes, and white casts. , when present, predominantly results from loss of low-molecular-weight proteins (e.g., ß2-microglobulin) rather than loss of albumin. Common defects in tubulointerstitial diseases include isolated tubular defects (e.g., renal tubular , , , wasting or retention, and magnesium wasting) and urinary concentrating defects (manifested by nocturia and ). is often less severe than it is in the glomerulonephritides. Salt wasting and a predisposition to volume depletion are common findings. , when present, often results from defective ammoniagenesis and is associated with a normal . Findings typical of glomerular disease (heavy (> 2 g/day), casts, and deformed erythrocytes in the urine sediment) are usually absent in tubulointerstitial disease unless there is an associated glomerular pathology.

Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

Urinalysis in Glomerular vs Interstitial Kidney Disease Glomerular Disease Interstitial Disease Nephritic Sediment Nephrotic Sediment 1. WBC casts 1. Heavy proteinuria, 1. RBC’s 2. Sterile pyuria > 3.5 g/d 2. RBC casts 3. Eosinophiluria 2. Oval fat bodies 3. Variable proteinuria 4. Low grade proteinuria 3. Fatty casts 4. Granular casts (< 2 g/d) 4. Free fat droplets 5. ± Hematuria

Renal Function in Glomerular and Interstitial Kidney Disease Glomerular Disease Interstitial Disease Primary Na retention Secondary Na retention 1. Impaired urinary concentration 1. Low urinary [Na] 1. Low urinary [Na] 2. 2. Hypertension 2. ± Hypertension 3. 3. Congestive 3. (type IV RTA) 4. Edema 4. Less reduction in GFR 4. Sodium wasting 5. Severe reduction in GFR

The hallmark of interstitial renal disease is evidence of tubular dysfunction. As a result, characteristic findings include an inability to concentrate the urine, the development of hyperkalemia out of proportion to any reduction in GFR, early development of a normal anion gap acidosis, and a tendency towards salt wasting.

Renal Function Tests in Interstitial Kidney Disease Clinical Site Functional Defect Manifestation Decreased of HCO3, PO4, Proximal amino , uric , glucose Decreased Na reabsorption and Salt-wasting, type Distal impaired potassium and hydrogen ion IV RTA secretion Salt-wasting, Loop Decreased Na reabsorption nephrogenic insipidus Interstitium Decreased

I. Acute Interstitial Nephritis

Acute interstitial nephritis is most commonly caused by a hypersensitivity reaction to a medication such as a beta-lactam or sulfa-containing antibiotic. Proton pump inhibitors are now believed to be a common cause of drug-induced acute interstitial nephritis. Acute interstitial nephritis also may be caused by certain infections or autoimmune conditions. Drug-induced acute interstitial nephritis may manifest as a rash, pruritus, eosinophilia, and fever; however, these features may be absent, particularly in acute interstitial nephritis due to use of NSAIDs and proton pump inhibitors. Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

Urinalysis findings in patients with acute interstitial nephritis may include leukocyte casts, eosinophils, and a urine - ratio less than 2.5 mg/mg (predictive of <2.5 gm/24h).

Kidney biopsy is often required to establish a definitive diagnosis because of the lack of sensitivity and specificity of eosinophiluria. In patients with suspected drug induced acute interstitial nephritis, discontinuing the inciting agent and monitoring for improvement in kidney function over the next 2 to 3 weeks is often sufficient. Indications for biopsy generally include diagnostic uncertainty, advanced , consideration of potentially toxic treatment, or lack of spontaneous recovery following cessation of drug .

Management of drug-induced interstitial nephritis includes withdrawing the inciting medication. Corticosteroids may be used in patients with aggressive disease, such as those with persistent or worsening despite discontinuation of the inciting agent, and biopsy may be particularly warranted if this therapy is being considered. Patients demonstrating active inflammation in the absence of significant chronic damage seen on biopsy are more likely to benefit from corticosteroids. However, data regarding the efficacy of corticosteroids in this setting have been limited to retrospective trials.

Patients with acute interstitial nephritis typically present with the following findings:

• An acute rise in the plasma creatinine concentration temporally related to an offending drug or infection. • Fever in most cases, which may be accompanied by a rash. • A urine sediment that usually reveals white cells, red cells, and white cell casts. • Eosinophilia and eosinophiluria • Normal or only mildly increased protein excretion (less than 1-2 g/day) in most patients. However, concurrent nephrotic syndrome due to minimal change disease is often seen with NSAIDs. It is presumed that the increase in glomerular permeability in this setting is induced by cytokines released by the infiltrating T cells. • Signs of tubulointerstitial damage such as the Fanconi syndrome and renal tubular acidosis.

Case presentation:

History: A 50 year old man is admitted to the hospital with right foot pain thought secondary to arterial insufficiency. A CXR reveals an apical cavitary lesion and the patient is started on INH, Rifampin, PZA, and ethambutol for presumed tuberculosis. On the third hospital day, an aortogram is performed to evaluate the ischemic right foot. On hospital day 7, the serum creatinine was noted to be increased.

Physical examination: Well-developed, slightly emaciated; BP 110/60, pulse 90 bpm, respiratory rate 20 breaths per min, temperature 38° C. Normal ocular exam, upper lobe wheezes, cool right foot with poor capillary refill. No skin rash.

+ + - Laboratory examination: (mEq/L): Na 136, K 5.8, Cl 106, HCO3 19, creatinine 3.2 mg/dl, BUN 48 mg/dl, glucose 88 mg/dl, UA: SG 1.005, 1+ glucose, 2+ protein, 10-15 WBC/hpf, 5-10 RBC/hpf, FENa 3%, 24 hour urine: 820 mg protein

Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

Case presentation:

History: 28 year old black woman presents with a 2 week history of lower extremity edema and facial puffiness. She has had generalized headaches and has been treating herself with ibuprofen for the last 3 months. There was no history of fever, rash, or joint pain.

Physical examination: Well-developed, well-nourished black woman, BP 130/74, pulse 76 bpm, respiratory rate 18 breaths per minute, afebrile. The remainder of the examination is only remarkable for 2+ lower extremity edema.

+ + - Laboratory examination: (mEq/l): Na 136, K 5.4, Cl 103, HCO3 22, creatinine 1.8 mg/dl, BUN 24 mg/dl, albumin 1.7 g/dl, cholesterol 422, Urine: SG 1.017, 4+ protein, 2-4 WBC/hpf, oval fat bodies, 24 hour urine 8.5 gm protein

NSAID-Induced Tubulointerstitial Nephritis

NSAIDs on occasion can give rise to a form of tubulointerstitial renal disease. Unlike other forms of TIN, these patients present with large amounts of proteinuria. Minimal change histology is most commonly seen in the glomerulus although membranous glomerulapthy can occasionally be seen. In addition to the glomerular changes, there is evidence of tubulointerstitial inflammation (findings notably absent in idiopathic minimal change disease and membranous GN). Unlike NSAID-induced that occurs within several days of exposure in patients with a contracted EABV, no predisposing condition can be found in patients who develop this condition. In addition, the development of NSAID-induced TIN can present after months of chronic therapy.

As a reminder: NSAIDS can be associated with two renal syndromes. First, these agents can cause acute tubular necrosis when given to patients with a decrease in absolute or effective arterial blood volume. In this setting the kidney is dependent upon vasodilatory prostaglandins. Second, NSAIDs can be associated with a form of tubulointerstitial renal disease that is unusual in that it is characterized by nephrotic range proteinuria as discussed above.

II. Chronic Tubulointerstitial Nephritis (TIN)

Chronic tubulointerstitial renal disease is characterized by a syndrome of chronic kidney disease (CKD) that slowly progresses to ESRD. Patients with primary chronic tubulointerstitial disease also may have polyuria and nocturia. Older patients and women have an increased risk for the development of CKD. The diagnosis of tubulointerstitial disease can be established in patients with slowly progressive CKD associated with a bland urine sediment and urine protein excretion that is typically less than 2-g/24 h. Low molecular weight tubular proteins such as beta 2 microglobulin, uromodulin (Tamm-Horsfall mucoprotein), and light chains are primarily excreted in these patients; urine albumin excretion is only minimally elevated.

Patients with tubulointerstitial disease also may have a decreased estimated glomerular filtration rate (eGFR) and a non-anion gap (hyperchloremic) metabolic renal tubular acidosis. Ultrasonography of the kidneys in patients with chronic tubulointerstitial disease reveals atrophic, echogenic kidneys consistent with CKD. Characteristic kidney biopsy findings in patients with tubulointerstitial disease include lymphocytic infiltration and in the interstitium with tubular atrophy, arteriosclerosis, and global glomerulosclcrosis. Various causes of chronic TIN are listed below:

Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

• Drugs: analgesics, , cyclosporin A, Chinese herb nephropathy (aristolochic acid) • Metabolic: and oxalate deposition, chronic , • Metals: lead, cadmium, mercury • Immunologic: Sjögren's syndrome, systemic erythematosus • Neoplastic: • Obstructive uropathy and • Miscellaneous: sarcoidosis, Balkan nephropathy (now thought to be due to aristocholic acid), radiation

Case presentation:

History: A 38 year-old woman presents with a three month history of and progressive . Her past medical history is positive for frequent headaches and occasional body aches for many years. She admits to taking an occasional over-the-counter pain pill.

Physical examination: Well-developed, thin chronically ill appearing white woman; BP 150/90, pulse 92 bpm, respiratory rate 20 breaths per min, afebrile, JVD of 6 cm, basilar rales, 2+ edema.

+ + - Laboratory examination: (mEq/L) Na 137, K 5.7, Cl 105, HCO3 19, glucose 96 mg/dl, creatinine 5.7 mg/dl, BUN 69 mg/dl, WBC 8.8, hematocrit 20, platelets 380K, Urine: SG 1.015, 1+ glucose, 15- 20 WBC/hpf, cultures negative for bacteria and acid-fast bacilli, 24 hour urine 1.8 gm/24h, renal sonogram R kidney 8.8 cm, L kidney 9.0 cm

Analgesic Nephropathy

Analgesic nephropathy is a chronic form of tubulointerstitial nephritis. The development of analgesic nephropathy (which is characterized by vascular lesions and areas of papillary necrosis) requires the prolonged ingestion of analgesic mixtures, particularly compounds containing both phenacetin and .

It should be emphasized that patients taking analgesic mixtures appear to be at particular risk for analgesic nephropathy. It is still controversial as to whether chronic and prolonged monotherapy with acetaminophen is nephrotoxic. Aspirin alone does not appear to induce renal injury although it potentiates the toxicity of phenacetin and probably acetaminophen. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is also generally safe when used as monotherapy. However, papillary necrosis can occur with these agents, particularly in patients consuming excessive amounts over a prolonged period of years.

The renal manifestations of analgesic nephropathy are usually nonspecific: slowly progressive chronic kidney disease (with some patients presenting with end-stage renal disease) with a urinalysis that may be normal or may reveal sterile pyuria and/or mild proteinuria (less than 1-2 g/day). Hypertension and anemia are commonly seen with moderate to advanced disease. Most patients have no symptoms referable to the urinary tract, although flank pain or from a sloughed or obstructing papilla may occur. is also somewhat more common in women with this disorder.

Despite the nonspecific nature of the renal presentation, there are frequently other findings that point toward the presence of analgesic nephropathy. Most patients are women between the ages of 30 to 70. Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

Careful questioning often reveals a history of chronic headaches or low back pain that leads to the analgesic use. Also common are other somatic complaints (such as and weakness), and ulcer- like symptoms or a history of peptic ulcer disease due in part to chronic aspirin ingestion.

Lead Nephropathy

Chronic lead exposure can affect a variety of organ systems, including the kidney where it can produce a chronic interstitial nephritis. The pathogenesis of the renal disease may be related to the reabsorption of filtered lead, with subsequent accumulation in the proximal tubule cells. The histologic findings are compatible with this hypothesis, with the earliest change being proximal tubular injury with intranuclear inclusion bodies composed of a lead-protein complex that may reflect lead sequestered in a nontoxic form.

Clinical manifestations at this time are limited to findings of impaired tubular function such as (saturnine gout) due to diminished urate secretion and, in some cases, aminoaciduria or renal glucosuria due to diminished reabsorption. Continued lead exposure over 5 to 30 years can induce progressive tubular atrophy and interstitial fibrosis. Affected patients typically present at this later stage with chronic kidney disease, a relatively normal urinalysis, hypertension, and gout. Thus, all patients with prominent hyperuricemia and renal insufficiency should be questioned about occupational lead exposure (including the manufacture or destruction of lead-containing batteries or lead-containing aerosols in the workplace), the ingestion of moonshine whiskey, or, in children, the ingestion of paint or residence near a major highway (when leaded gasoline was in widespread use).

Sjögren's Syndrome

Sjögren's syndrome is typically associated with a lymphocytic and plasmacytic infiltrate in the salivary, parotid, and lacrimal glands, leading to a sicca syndrome. This immune process can also affect non-exocrine organs, including the kidneys, producing an interstitial nephritis and defects in tubular function. The interstitial nephritis in Sjögren's syndrome is characterized histologically by an interstitial infiltrate that can invade and damage the tubules. More chronic disease is associated with tubular atrophy and interstitial fibrosis. The glomeruli are usually normal, although an immune complex-mediated has rarely been described. The clinical manifestations of the interstitial nephritis include a variable, but generally mild elevation in the plasma creatinine concentration, a relatively benign urinalysis, and abnormalities in tubular function. Type I distal renal tubular acidosis and/or nephrogenic are commonly present in these patients.

Myeloma Kidney

Renal disease is a common problem in multiple myeloma, although a variety of different mechanisms may be involved. Most of the renal diseases in multiple myeloma are related to the overproduction of monoclonal immunoglobulin light chains. Myeloma kidney (or cast nephropathy) refers to acute or chronic renal failure that results from the filtration of toxic light chains, leading to both tubular injury and intratubular cast formation and obstruction. One important characteristic of light chains that induce cast nephropathy is specific binding to Tamm-Horsfall mucoprotein, a protein normally synthesized by the tubular cells in the thick ascending limb of the loop of Henle. Volume depletion is an additional risk factor, both by slowing flow within the tubules and by increasing the light chain concentration, thereby promoting the formation of large aggregates. A response to this cast formation is the interstitial accumulation of macrophages with subsequent formation of giant cells.

Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

Cast nephropathy occurs in 30% to 50% of patients with multiple myeloma and is particularly associated with severe kidney dysfunction. These patients are particularly susceptible to the development of with development of volume depletion, infection, hypercalcemia, or exposure to radiocontrast agents and NSAIDs.

The urine dipstick does not reveal albuminuria in patients with myeloma-related kidney disorders, but the addition of sulfosalicylic add to the urine will precipitate all nonalbumin proteins, including light chains. Kidney biopsy is recommended to confirm multiple myeloma in the absence of other tissue diagnoses and to exclude other kidney disorders.

In some patients, the toxic effect of filtered light chains is limited to tubular dysfunction, with the glomerular filtration rate being relatively well maintained. The proximal tubules are most prominently affected, due to the reabsorption of filtered light chains and their subsequent accumulation in the proximal cells. The clinical manifestations of tubular dysfunction include signs of the Fanconi syndrome such as proximal renal tubular acidosis and wasting. One should always exclude myeloma in an adult patient who presents with findings of the Fanconi syndrome.

Polycystic Kidney Disease

ADPKD has a high prevalence in whites in the United States, occurring in one in 400 to one in 1,000, and is transmitted to 50% of the offspring of affected persons. ADPKD is an inherited systemic disorder that commonly leads to progressive renal failure but that can also affect a number of other organ systems. Almost 90% of patients with ADPKD have an abnormal gene on the short arm of chromosome 16 (the ADPKD1 locus). This gene encodes for polycystin, a plasma membrane protein that is expressed in most cystic epithelia from patients with PKD1. The physiologic role of polycystin in PKD1 is not fully defined, although it may be involved in cell-cell or cell-matrix interactions.

In most other patients, a locus for this abnormality has been found on chromosome 4 (the PKD2 locus); it encodes for polycystin 2, which may be involved in cell signaling. As many as 75% of all ADPKD patients have a positive family history. In ADPKD, the cysts arise from outpouchings of the renal tubule and Bowman space. They are lined by epithelium and contain fluid derived from the glomerular filtrate and modified by the action of the tubular epithelial lining. The underlying mechanisms of cyst formation in ADPKD are unclear. Cyst formation begins in utero, and cysts increase in size and number as the patient ages. Most patients come to medical attention in middle age. Cyst enlargement and ESRD occur later in life in PKD2. As the cysts enlarge, they compress adjacent normal tissue and lead to interstitial scarring. Although the exact mechanism responsible for this interstitial damage is unclear, increased cyst growth is associated with a decline in the GFR.

Symptoms and signs include flank or back pain, abdominal masses, gross hematuria, urinary tract infections, and stone disease. Patients are typically less anemic than is expected for their degree of renal insufficiency. Hypertension that is related to increased activation of the renin-angiotensin- system is found in 60% to 75% of adults with ADPKD and is an early manifestation of the disease.

The kidneys typically enlarge progressively as the patient ages and the cysts grow. The kidneys may reach massive proportions, causing abdominal distention. Half of affected persons with the ADPKD1 abnormality progress to renal failure by 60 years of age. Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

The mean age of end-stage renal failure in patients with ADPKD1 is 55 to 60 years, compared with 70 years for non-ADPKD1 patients who die of renal failure. Age and total kidney volume (TKV) are the most commonly cited factors associated with a rapid rate of ADPKD progression. Cysts can also occur in the liver, pancreas, and spleen. Hepatic cysts increase with age from 10% of patients younger than 30 years to more than 40% of patients older than 60 years and are more common in women, especially in those who have had several pregnancies. Liver function is typically normal in patients with ADPKD despite the presence of cysts. Other systemic findings that commonly occur in patients with polycystic kidney disease are berry aneurysms of the circle of Willis, which occur in 4% to 10% of patients; mitral valve prolapse, which is revealed by echocardiography in as many as 25% of patients; and colonic diverticula and diverticulitis and hiatal hernias.

Autosomal recessive polycystic kidney disease, formerly called infantile polycystic disease, is a rare disorder, with an incidence of one in 40,000 persons to one in 10,000 persons. It presents as severe cystic involvement in infancy or early childhood; may be associated with hepatic cysts, fibrosis, and portal hypertension; and leads to progressive severe renal failure. Often, occurs at an early age.

Summary of Findings in Kidney Failure Syndromes:

Renal failure syndromes can be divided into pre-renal (e.g. volume depletion) intra-renal (e.g. ATN) and post-renal (obstructive uropathy). The patient's cardiovascular and volume status, urinalysis and serum chemistries are important in determining the cause and prescribing appropriate clinical management.

Kidney Diagnostic Indices Type of Kidney BUN/ [UNa+] FENa+ Uosm Urine Sediment Failure Cr <20 A. Pre-renal >20 <1% >350 Normal mEq/L

B. Post-renal >20 (chronic) <20 >1% <350 Often normal mEq/L <10 RBC casts, granular <1% >350 C. Acute GN >20 mEq/L casts, lipid droplets, (early) (early) (early) oval fat bodies Renal tubular cells D. Tubulo- >20 <20 >1% <350 and casts, white cell interstitial mEq/L casts Pigmented and >20 granular casts, renal E. ATN <20 >1% <350 mEq/L tubular cells, renal tubular casts

The above table lists several renal syndromes and how various diagnostic indices can be used to distinguish between them. It should be noted that these are guidelines and that some overlap does occur. Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019

Glomerular versus Interstitial Kidney Disease Feature Glomerular Interstitial Proteinuria >3 g/24 hr < 2 g/24 hr Many cells, casts, RBC Few cells, pyuria, WBC Sediment casts casts Na handling Normal or Na+ avid Salt wasting Anemia Moderate severity until late Severe early on Hypertension Common Less common Acidosis Not present until late Type IV RTA common Increased (impaired Urine volume Normal concentrating ability)

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