Renal Tubular & Interstitial Disease PDF

Renal Tubular & Interstitial Disease Benito K. Lim Hong III, M.D.  Objectives 1. To know & understand the pathophysiology of Acute Renal Failure, Tubulointerstitial Diseases, Renal Blood Vessel Diseases, & Obstuctive Uropathy. 2. To know the causes of Acute Renal F...

Renal Tubular & Interstitial Disease Benito K. Lim Hong III, M.D.  Objectives 1. To know & understand the pathophysiology of Acute Renal Failure, Tubulointerstitial Diseases, Renal Blood Vessel Diseases, & Obstuctive Uropathy. 2. To know the causes of Acute Renal Failure, Tubulointerstitial Diseases, Renal Blood Vessel Diseases, & Obstuctive Uropathy. 3. To know the signs & symptoms of Acute Renal Failure, Tubulointerstitial Diseases, Renal Blood Vessel Diseases, & Obstuctive Uropathy. 4. To know the histopathologic morphology of Acute Renal Failure, Tubulointerstitial Diseases, Renal Blood Vessel Diseases, & Obstuctive Uropathy.  Acute Renal Failure (ARF) Signifies acute suppression of renal function, often with a fall in urine output to < 400 ml in 24 hr. ARF is caused by: 1. Acute tubular necrosis – the most common cause 2. Organic vascular obstruction 3. Severe glomerular disease 4. Acute tubulointerstitial nephritis 5. Massive infection, especially with papillary necrosis 6. Disseminated Intravascular Coagulation (DIC)  Case Scenario A 78 year old female, poorly controlled diabetic, was rushed by her family to the ER due to dyspnea, change in sensorium, & undocumented fever for 1 week. One of the family members claimed that the patient had been poor compliant to her maintenance meds. The patient had less urine output than usual however the exact amount was not measured. V/S: BP=80/40, HR=114 bpm, RR=29 cpm, T=38.5˚C. GCS=8 (M4 V2 E2). Physical Examination: No gangrenous extremities, (+) Kidney Punch Sign on the right lumbar area. Fluid resuscitation was done, FBC was inserted & attached to urobag which revealed 100 ml in 24- hour urine output.  Acute Tubular Necrosis (ATN) Characterized by destruction of renal tubular epithelial cells either from ischemia or nephrotoxins. 1. Ischemic ATN – occurs after shock produced by sepsis, burns, crush injury, or circulatory collapse. (ATN is uncommon after hemorrhagic shock)  Acute Tubular Necrosis (ATN) Characterized by destruction of renal tubular epithelial cells either from ischemia or nephrotoxins. 2. Nephrotoxic ATN – is caused by a wide variety of drugs (Ex: Gentamicin, Cephalosporin, Methoxyflurane, Cyclosporine, Contrast Media) & toxins (Ex: Mercury, Lead, Arsenic, Methyl Alcohol, Ethylene Glycol, & certain Mushrooms, Insecticides, & Herbicides). ATN may also follow massive hemoglobinuria or myoglobinuria (from rhabdomyolysis), usually associated with dehydration & hypoxia.  Acute Tubular Necrosis (ATN) Pathophysiology: Although the exact pathogenesis of ARF in ATN is debated, tubular damage likely leads to: 1. Arteriolar vasoconstriction, probably involving the renin-angiotensin mechanism. 2. Cast formation & tubular obstruction. 3. Back-leak of tubular fluids. 4. Altered glomerular ultrafiltration.  Acute Tubular Necrosis (ATN) Clinical Course: Proceeds through: 1. Initiating Stage (dominated by the inciting event) 2. Maintenance Stage (dominated by persistent renal failure & hyperkalemia) 3. Recovery Stage (dominated by polyuria & perhaps hypokalemia)  Acute Tubular Necrosis (ATN) Although the morphologic abnormalities may be very subtle by light microscopy, careful studies reveal that: 1. Ischemic ATN – shows patchy tubular necrosis mostly in the straight segments of the proximal tubules & ascending limbs of Henle’s loop. 2. Nephrotoxic ATN – shows extensive tubular necrosis mostly in proximal tubules, although other tubular segments can be affected. In both types the distal tubules & collecting ducts contain casts. The recovery phase shows epithelial regeneration (flattened tubular cells & mitotic figures). Acute Tubular Necrosis (Gross) Ischemic ATN (Histopathology) Nephrotoxic ATN (Histopathology)  Acute Tubular Necrosis (ATN) Prognosis: Depends on the cause: Very good for nephrotoxic ATN. Poor for ATN secondary to overwhelming sepsis.  Case Scenario A 28 year old female was brought by her family to the ER due to undocumented fever for 2 days with chills & dysuria. No cough & corzya. Patient self-meds with Bioflu with temporary relief of the fever. V/S: BP=120/80, HR=94 bpm, RR=20 cpm, T=38.5˚C. GCS=15. Physical Examination: (+) Kidney Punch Sign on bilateral flank area. U/A revealed Pyuria (WBC=TNTC).  Pyelonephritis (PN) & Urinary Tract Infection (UTI) Urinary tract infection (UTI) implies involvement of the bladder (cystitis), or the kidney (PN), or both. UTI may be clinically silent (asymptomatic bacteriuria) but more often causes dysuria & frequency, & in PN, flank pain & fever.  Pyelonephritis (PN) & Urinary Tract Infection (UTI) Risk Factors: 1. Females - perhaps due to a shorter urethra & hormonal changes affecting mucosal adherence of bacteria. 2. Long-term Catheterization 3. Pregnancy 4. Diabetes Mellitus 5. Immunosuppression 6. Lower Urinary Tract Obstruction due to Congenital Defects, Benign Prostatic Hypertrophy, Tumors, or Calculi  Pyelonephritis (PN) & Urinary Tract Infection (UTI) PN is most commonly the result of ascending infection, the consequence of vesicoureteral reflux (VUR) through an incompetent vesicoureteral orifice. VUR is most often due to congenital defects in the intravesicular portion of the ureter & may be accentuated by cystitis, allowing retrograde seeding of the renal pelvis & renal papillae (intrarenal reflux). Escherichia coli, Proteus, & Enterobacter are the most frequent culprits.  Pyelonephritis (PN) & Urinary Tract Infection (UTI) Hematogenous seeding of kidneys occurs most often in the setting of septicemia or infective endocarditis, is frequently due to Staphylococcus or Escherichia coli, & is enhanced by urinary obstruction.  Pyelonephritis (PN) & Urinary Tract Infection (UTI) Hematogenous seeding of kidneys occurs most often in the setting of septicemia or infective endocarditis, is frequently due to Staphylococcus or Escherichia coli, & is enhanced by urinary obstruction.  Acute Pyelonephritis Acute infection of the kidney marked by patchy, interstitial, suppurative inflammation, tubular necrosis, & neutrophilic casts. More advanced changes include: 1. Abscesses 2. Necrotizing Papillitis (especially in diabetics & in those with obstruction) 3. Pyonephrosis (pelvis filled with pus) 4. Perinephric Abscesses 5. Renal scars with fibrotic deformation of the cortex & underlying calyx & pelvis (Chronic Pyelonephritis)  Chronic Pyelonephritis (CPN) & Reflux Nephropathy A disorder in which tubulointerstitial inflammation causes discrete, corticomedullary scars overlying dilated, blunted, & deformed calyces. CPN is the cause of 11% to 20% of cases of chronic renal failure.  Chronic Pyelonephritis (CPN) & Reflux Nephropathy It can be divided into 3 forms: 1. Reflux Nephropathy-associated CPN – Most common cause of CPN. Begin in childhood as a result of infection superimposed on congenital vesicoureteral reflux & intrarenal reflux. Whether sterile reflux can cause CPN is controversial. Reflux nephropathy may be silent, insidious onset, often with hypertension & polyuria.  Chronic Pyelonephritis (CPN) & Reflux Nephropathy It can be divided into 3 forms: 2. Obstructive CPN – Chronic destruction predisposes the kidney to infections, & multiple recurrences over time produce CPN. Usually caused by enteric bacteria.  Chronic Pyelonephritis (CPN) & Reflux Nephropathy It can be divided into 3 forms: 3. Xanthogranulomatous PN – an uncommon form of CPN associated with Proteus infections, in which a mixed inflammatory infiltrate with abundant foamy macrophages produces large, yellow-orange nodules that can clinically & radiologically mimic renal cell carcinoma. Acute Pyelonephritis (Gross) Acute Pyelonephritis (Histopathology) Obstructive Chronic Pyelonephritis (Gross) Reflux Nephropathy-associated Chronic Pyelonephritis (Gross) Chronic Pyelonephritis (Histopathology) Xanthogranulomatous Pyelonephritis (Gross) Xanthogranulomatous Pyelonephritis (Histopathology)  Case Scenario A 25 year old male was brought by her family to the ER due to hematuria, skin rashes, & undocumented fever. His wife claimed that patient had an abrasion on his right shin due to motor vehicular accident 1 week ago. Patient self- meds with ampicillin orally without consulting a physician. After 1 week, patient noted gross hematuria & maculopapular skin rashes. V/S: BP=120/80, HR=94 bpm, RR=20 cpm, T=38˚C. GCS=15. Physical Examination: (+) Kidney Punch Sign on bilateral flank area. CBC revealed eosinophilia (Eos=10). U/A revealed Pyuria (WBC=TNTC). Crea=1.8 mg/dl (Normal Values=0.5-1.5 mg/dl) Acute Drug-induced Interstitial Nephritis Occurs most frequently 2 to 40 days after exposure to a variety of drugs (methicillin, ampicillin, rifampicin, thiazides, various NSAIDS, cimetidine, etc.). Withdrawal of drug is followed by recovery in most patients. The syndrome is variably characterized by fever, eosinophilia, skin rashes, hematuria, mild proteinuria, sterile pyuria, azotemia, & even ARF. Acute Drug-induced Interstitial Nephritis Biopsy shows edema, patchy tubular necrosis, & tubulointerstitial infiltrates, with variable combinations of lymphocytes, histiocytes, eosinophils, neutrophils, plasma cells, & occasionally well-formed granuloma. Acute Drug-induced Interstitial Nephritis (Histopathology)  Case Scenario A 75 year old male was brought by her family to the ER due to severe bilateral flank pain, headaches, & undocumented fever. His wife claimed that patient had an arthritis for about 10 years & self-meds with Alaxan FR orally without consulting a physician. This time, patient had epigastric pain (pain score=7/10) & polyuria. V/S: BP=200/130, HR=64 bpm, RR=20 cpm, T=38˚C. GCS=15. Physical Examination: Pale palpebral conjunctiva, (+) Kidney Punch Sign on bilateral flank area. CBC revealed anemia (Hgb=8 g/dl). U/A revealed Pyuria (WBC=90-100). Crea=2.8 mg/dl (Normal Values=0.5-1.5 mg/dl)  Analgesic Abuse Nephropathy Cause by excessive intake of analgesic mixtures & characterized by chronic tubulointerstitial nephritis with papillary necrosis. Most patients consume phenacetin-containing mixtures & cases ascribed to aspirin, phenacetin, or acetaminophen alone are uncommon. The drugs act synergistically to cause papillary necrosis 1st; the tubulointerstitial nephritis is secondary.  Analgesic Abuse Nephropathy Pathophysiology: Proper kidney function depends upon adequate blood flow to the kidney. Kidney blood flow is a complex, tightly regulated process that relies on a number of hormones and other small molecules, such as prostaglandins. Under normal circumstances, prostaglandin E2 (PGE2) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE2 synthesis depends upon the cyclooxygenases.  Analgesic Abuse Nephropathy Pathophysiology: Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE2 concentration causing a reduction in blood flow. Because blood flow to the kidney first reaches the renal cortex (outside) and then the renal medulla (inside), the deeper structures of the kidney are most sensitive to decreased blood flow.  Analgesic Abuse Nephropathy Pathophysiology: Thus the innermost structures of the kidney, known as the renal papillae, are especially dependent on prostaglandin synthesis to maintain adequate blood flow. Inhibition of cyclooxygenases therefore rather selectively damages the renal papillae, increasing the risk of renal papillary necrosis.  Analgesic Abuse Nephropathy Pathophysiology: It is unclear how phenacetin induces injury to the kidney. Bach and Hardy have proposed that phenacetin's metabolites lead to lipid peroxidation that damages cells of the kidney.  Analgesic Abuse Nephropathy Pathophysiology: Paracetamol is the major metabolite of phenacetin and may contribute to kidney injury through a specific mechanism. In cells of the kidney, cyclooxygenases catalyse the conversion of paracetamol into N-acetyl-p- benzoquinoneimine (NAPQI).  Analgesic Abuse Nephropathy Pathophysiology: NAPQI depletes glutathione via non-enzymatic conjugation to glutathione, a naturally occurring antioxidant. With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage.  Analgesic Abuse Nephropathy Pathophysiology: The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy. Found in the renal pelvis, ureter, and capillaries supplying the nephrons, capillary sclerosis is thought to lead to renal papillary necrosis and, in turn, chronic interstitial nephritis.  Analgesic Abuse Nephropathy Signs & Symptoms: 1. Polyuria 2. Headaches 3. Anemia 4. Gastrointestinal Symptoms 5. Pyuria 6. UTI 7. Hypertension  Analgesic Abuse Nephropathy Diagnosis: 1. Clinical findings above in combination with excessive analgesic use - It is estimated that between 2 and 3 kg each of phenacetin or aspirin must be consumed before evidence of analgesic nephropathy becomes clinically apparent. 2. Computed Tomography (CT) imaging without contrast - 92% sensitive and 100% specific  Analgesic Abuse Nephropathy Complications: Chronic renal failure may result, but drug withdrawal often stabilizes renal function. Unfortunately, these patients have an increased incidence of transitional cell carcinoma of the renal pelvis. Renal Papillary Necrosis (Lumbar X-ray) Renal Papillary Necrosis (CT Scan) Renal Papillary Necrosis (Gross) Differentiating Normal Cells from Necrotic Cells Renal Papillary Necrosis (Histopathology)  Case Scenario A 67 year old male was brought by her family to the ER due to severe bilateral flank pain & pitting edema of both lower extremities. His wife claimed that patient had a painful swelling of the right big toe 1 year ago & self-meds with Alaxan FR orally without consulting a physician. The patient claimed that he is fond of eating nuts & internal organs. V/S: BP=240/150, HR=64 bpm, RR=29 cpm, T=36˚C. Physical Examination: Pale palpebral conjunctiva, (+) Kidney Punch Sign on bilateral flank area, (+) pitting edema on both lower extremities. CBC revealed anemia (Hgb=8 g/dl). U/A revealed pH=5.6, Uric Acid Crystals=100-200/LPO, Coarse Granular Cast=5-10/LPO & pyuria (WBC=100-200). Crea=4.8 mg/dl (Normal Values=0.5-1.5 mg/dl). BUA=13 mg/dl (Normal Value=4.0- 8.5 mg/dl for male). Ultrasound-KUB revealed:  Urate Nephropathy Uric acid is the relatively water-insoluble end product of purine nucleotide metabolism. It poses a special problem for humans because of its limited solubility, particularly in the acidic environment of the distal nephron of the kidney. Humans do not possess the enzyme uricase, which converts uric acid into the more soluble compound allantoin.  Urate Nephropathy Can cause acute renal failure or chronic renal failure, depending on the time course of uric acid crystal deposition. Acute renal failure occur in patients who undergoes chemotherapy. Chronic renal failure occur in patients with gout.  Urate Nephropathy Pathophysiology: Acute uric acid nephropathy is caused by deposition of uric acid crystals within the kidney interstitium and tubules, leading to partial or complete obstruction of collecting ducts, renal pelvis, or ureter. This obstruction is usually bilateral, and patients follow the clinical course of acute renal failure.  Urate Nephropathy Causes: 1. Tumour lysis syndrome in patients undergoing chemotherapy or radiation therapy for the treatment of malignancies with rapid cell turnover, such as leukemia and lymphoma. 2. Acute attack of gout  Urate Nephropathy Diagnosis: 1. History & Physical Examination 2. Rapidly rising Serum Creatinine levels 3. Decreased urine production 4. Urine Uric Acid/Creatinine ratio > 1 in a random urine sample Urate Nephropathy (Ultrasound-KUB) Urate Nephropathy (Gross) Urate Nephropathy (Histopathology)  Case Scenario A 37 year old male was brought by her family to the ER due to severe left flank pain & pitting edema of both lower extremities. V/S: BP=190/130, HR=65 bpm, RR=25 cpm, T=37˚C. GCS=15. The patient claimed that he drank less water a day. Physical Examination: Pale palpebral conjunctiva, (+) Kidney Punch Sign on left flank area, (+) pitting edema on both lower extremities. CBC revealed anemia (Hgb=8 g/dl). U/A revealed pH=5.0, Specific gravity=1.000 (Normal=1.002 to 1.030), Calcium Oxalate Crystals=50-100/LPO, Coarse Granular Cast=5-10/LPO & Pyuria (WBC=50-60). Crea=3.4 mg/dl (Normal Values=0.5- 1.5 mg/dl). UTZ-KUB & CT Stonogram revealed: UTZ-KUB CT Stonogram  Nephrocalcinosis A condition in which calcium levels in the kidneys are increased. Most often, the increase in renal calcium is generalized, as opposed to the localized increase observed in calcified renal infarct and caseating granulomas of renal tuberculosis. From whatever cause, hypercalcemia can cause stone (nephrolithiasis) or deposition within the kidney & both may lead to renal insufficiency & failure.  Nephrocalcinosis Pathophysiology: Calcium is a critical divalent cation that is transported, along with sodium, potassium, and water, in a complex and regulated manner along the renal tubular epithelium. The cytoplasmic concentration of calcium is tightly regulated and kept very low, being maintained by active extracellular extrusion of calcium and sequestration into the endoplasmic reticulum and mitochondria.  Nephrocalcinosis Pathophysiology: Increased extracellular calcium leads to impairment of the calcium messenger system with gross tubular impairment. Hypercalcemia results in renal vasoconstriction and a reduced glomerular filtration rate. Impaired renal concentration ability and resistance to vasopressin are the most common defects observed with hypercalcemia.  Nephrocalcinosis Pathophysiology: These changes may be mediated by reduced sodium transport in the loop of Henle and by antidiuretic hormone antagonism via calcium-sensing receptors, or they may be related to medullary prostaglandin synthesis. Maximum diluting capacity remains unimpaired resembling that of nephrogenic diabetes insipidus.  Nephrocalcinosis Pathophysiology: Hypercalcemia increases urinary calcium excretion by increasing the filtered load and reducing tubular absorption. Pure hypercalcemia reduces phosphate excretion in contrast to in certain cancers where it can be associated with increased phosphate excretion probably due to the presence of phosphaturic peptides (phosphatonins), which are secreted in some malignancies.  Nephrocalcinosis Causes of cortical nephrocalcinosis: 1. Acute cortical necrosis. May be caused by: a. Placenta abruptio b. Placenta previa c. Septic abortion d. Transfusion reactions e. Burns f. Snake bite g. Severe dehydration h. Shock i. Severe heart failure j. Abdominal aortic surgery  Nephrocalcinosis Causes of cortical nephrocalcinosis: 2. Chronic glomerulonephritis 3. Alport syndrome 4. Prolonged hypercalcemia and/or hypercalciuria 5. Renal transplant rejection 6. Sickle cell disease (rare) 7. Vitamin B6 (pyridoxine) deficiency (rare)  Nephrocalcinosis Causes of medullary nephrocalcinosis: 1. Medullary sponge kidney 2. Hyperparathyroidism 3. Hypoparathyroidism 4. Renal tubular acidosis (specifically distal RTA) 5. Renal tuberculosis 6. Renal papillary necrosis 7. Hyperoxaluria  Nephrocalcinosis Other causes of hypercalcemia (and thus hypercalciuria): 1. Immobilization (leading to hypercalcemia and hypercalciuria) 2. Milk-alkali syndrome 3. Hypervitaminosis D 4. Sarcoidosis  Nephrocalcinosis Signs & Symptoms: 1. Renal colic 2. Polyuria and Polydipsia  Nephrocalcinosis Morphology: Characterized by the presence of microscopic crystalline calcium precipitates in the form of oxalate or phosphate.  Nephrocalcinosis Prognosis: Depends mainly on the etiology of the nephrocalcinosis. Best prognosis - Idiopathic Hypercalciuria and Medullary Sponge Kidney Worst prognosis - Primary Type 1 Hyperoxaluria The morbidity and mortality associated with nephrocalcinosis depend on the disease associated with the condition rather than on the nephrocalcinosis itself.  Nephrocalcinosis Prognosis: The major long-term complication in patients with medullary nephrocalcinosis is renal failure. Early treatment of reversible causes of renal failure, such as urinary infections, obstruction, and hypertension, is essential. Once chronic renal failure has developed, treatment should focus on appropriate management of chronic kidney disease and its complications. Nephrocalcinosis (Ultrasound-KUB) Nephrocalcinosis (CT Stonogram) Nephrocalcinosis (Histopathology)  Case Scenario A 61 year old male was brought by her family to the ER due to severe lumbar pain & cachexia. V/S: BP=170/100, HR=60 bpm, RR=28 cpm, T=37˚C. GCS=15. The wife claimed the patient to have poor appetite. Physical Examination: Pale palpebral conjunctiva, (+) deformities on the chest & lumbar area. CBC revealed anemia (Hgb=8 g/dl). U/A revealed pH=5.0, Coarse Granular Cast=5- 10/LPO, WBC Cast=5-10/LPO. Crea=3.4 mg/dl (Normal Values=0.5-1.5 mg/dl). CXR-PA View & X-ray of the Lumbosacral, AP View revealed: CXR-PA X-ray, Lumbosacral, AP View  Case Scenario Bone Marrow Aspiration Biopsy of the Rib was done during the course of the admission & revealed: Multiple Myeloma (Plasma Cell Myeloma) A cancer of plasma cells, a type of white blood cell normally responsible for producing antibodies. Initially, often no symptoms are noticed. When advanced, bone pain, bleeding, frequent infections, and anemia may occur. It usually occurs around the age of 61 and is more common in men than women. Multiple Myeloma (Plasma Cell Myeloma) Signs & Symptoms: Mnemonics: CRAB C = Calcium (elevated) (Pathologic Fracture) R = Renal Failure (Bence Jones Proteinuria) A = Anemia (Normocytic, Normochromic) B = Bone Lesions (Pathologic Fracture) Multiple Myeloma (Plasma Cell Myeloma) Pathophysiology: The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome where it stimulates an antibody gene to overproduction. Multiple Myeloma (Plasma Cell Myeloma) Pathophysiology: A chromosomal translocation between the immuno- globulin heavy chain gene (on chromosome 14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. Multiple Myeloma (Plasma Cell Myeloma) Pathophysiology: The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. Production of cytokines (especially IL-6) by the plasma cells causes much of their localized damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Multiple Myeloma (Plasma Cell Myeloma) Pathophysiology: Angiogenesis (the attraction of new blood vessels) is increased. The produced antibodies are deposited in various organs, leading to kidney failure, polyneuropathy and various other myeloma-associated symptoms. Multiple Myeloma (Plasma Cell Myeloma) Diagnosis: 1. CBC 2. Radiologic Imaging – “Punch-out” Lesion 3. ESR - elevated 4. Protein Electrophoresis - paraprotein (peak in the gamma zone) 5. Serum Calcium - elevated 6. Serum Creatinine – elevated 7. Bone Marrow Aspiration Biopsy – elevated Plasmablast Multiple Myeloma (X-ray) Multiple Myeloma (Protein Electrophoresis) Multiple Myeloma (BMAB)