Tubulointerstitial Kidney Disease, Cystic Renal Disease Renal Genital Urinary System 2019 TUBULOINTERSTITIAL DISEASE AND POLYCYSTIC KIDNEY DISEASE Biff F. Palmer, MD, Office: H5.112; Phone 87848 Email: [email protected] LEARNING OBJECTIVES • List the pertinent aspects of the history, physical examination, serum and urine electrolytes, and urinalysis that distinguish between acute and chronic interstitial nephritis • 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 chronic kidney disease 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 blood cell casts. Proteinuria, 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 acidosis, glycosuria, aminoaciduria, potassium wasting or retention, and magnesium wasting) and urinary concentrating defects (manifested by nocturia and polyuria). Hypertension is often less severe than it is in the glomerulonephritides. Salt wasting and a predisposition to volume depletion are common findings. Metabolic acidosis, when present, often results from defective ammoniagenesis and is associated with a normal anion gap. Findings typical of glomerular disease (heavy albuminuria (> 2 g/day), red blood cell 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 Nephritic Syndrome Nephrotic Syndrome Primary Na retention Secondary Na retention 1. Impaired urinary concentration 1. Low urinary [Na] 1. Low urinary [Na] 2. Hyperkalemia 2. Hypertension 2. ± Hypertension 3. Renal tubular acidosis 3. Congestive heart failure 3. Edema (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 Nephron Site Functional Defect Manifestation Decreased reabsorption of HCO3, PO4, Proximal Fanconi syndrome amino acids, uric acid, glucose Decreased Na reabsorption and Salt-wasting, type Distal impaired potassium and hydrogen ion IV RTA secretion Salt-wasting, Loop Decreased Na reabsorption nephrogenic diabetes insipidus Interstitium Decreased erythropoietin Anemia 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 protein-creatinine 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 kidney failure, consideration of potentially toxic treatment, or lack of spontaneous recovery following cessation of drug therapy. 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 azotemia 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 acute tubular necrosis that occurs within several days of exposure in patients with a contracted EABV, no predisposing