276 Interstitial nephritis and nephrotoxins Interstitial nephritis is an important cause of bot h acute and chronic renal failure. Acute interstitial nephritis (AIN): Typical cause: Aller gic reac- tion to antibiotics: Penicillins/cephalosporins, furosemide (sulfonamides), NSAID s, allopurinol, rifampin; infection (staphylococci, streptococci, Brucella , Leptospira ); systemic disease (sarcoidosis, Sj gren \200\231s syndrome); or no obvious cause. Clinica l features: Fever, arthralgias, rash (especially if drug-related), eosinophilia, eosinophil uria, AKI or CKD, rarely an associ- ated uveitis (tubulointerstitial nephritis uveitis synd rome or TINU). Except for AKI or CKD, other features may be absent. Diagnosis: Biopsy shows mononuclear cell infiltration of the renal interstitium and tubules with eosinophils in dr ug-induced causes. Systemic features of fever, rash, and eosinophilia or eosinophiluria are rarely present wit h NSAIDs, + in 33 \200\22350% of non \200\223penicillin drug induced causes. Treatment: AK I (p. 269); corticosteroids may be used with systemic disease, but use in drug-induced caus es is controversial. Nevertheless, many neph- rologists will attempt its use. CKD: None. Pr ognosis: Favorable in AIN if due to drug or systematic disease. Chronic interstitial nephri tis may be a slowly evolving form of the acute disease or caused by analgesic nephropathy ( below), sickle-cell disease, or chronic pyelonephritis/reflux nephropathy with secondary FS GS . NB: Urine may have few WBC/HPF since this has been chronic. Analgesic nephropathy is a ssociated with the prolonged, heavy ingestion of compound antipyretic analgesics. The incid ence of analgesic nephropa- thy has fallen since the withdrawal of phenacetin. Use of aceta minophen has been associated, but controversial. Signs: Urinary abnormalities (pro- teinuri a, hematuria, sterile pyuria); renal colic/obstruction from sloughed papilla; secondary UTI or pyelonephritis from obstruction; chronic kidney disease; HTN. Diagnosis is based on a h istory of excess analgesic use and demonstrating the characteristic renal lesion. Tests : C T scan reveals papil- lary calcifications, \206\221 renal size, \200\234bumpy \200\235 co ntours. IVP shows cortical scar- ring/clubbed calyces; demonstrates papillary necrosis. Bio psy shows chronic interstitial nephritis or capillary sclerosis. Treatment: Stop analgesics , anti- biotics for infection, drainage for obstruction, dialysis or transplantation for ES RD. Urate nephropathy Acute crystal nephropathy may occur when insoluble purines deposit wi thin the tubules causing blockage or inflammation of the tubules. It is caused by gross uri c acid overproduction (e.g., treatment of myeloid tumors) or by inherited diseases (e.g., L esch \200\223Nyhan syndrome). Diagnosis is by elevated serum uric acid levels of 15 \200 \22320 and urine uric acid/ urine creatinine >1. Treatment : Allopurinol, uricase (rasburic ase) to \206\223 uric acid, good fluid intake, alkalinize urine, HD or CRRT if \206\221 u ric acid levels and poor renal function (especially in cases of ongoing uric acid productio n; e.g., tumor lysis syn- drome). Chronic urate nephropathy typically affects middle-aged m en with gout. May be secondary to lead exposure. Diagnosis : X-ray fluorescence or \206 \221 urine lead levels after EDTA. Histologically, there is interstitial fibro- sis with as sociated vascular changes; crystals are rarely found. Treatment : Allopurinol ( \206\223 d ose in renal impairment); if lead nephropathy, can attempt EDTA to chelate lead with modera te CKD. Hypercalcemic nephropathy is caused by malignancy (most common), hyperparathyroidis m, multiple myeloma, sarcoidosis, vitamin D intoxica- tion. Clinical features: Nephrogenic diabetes insipidus (polyuria, polydipsia, dehydration, uremia), symptoms of hypercalcemia ( nausea, vomiting, con- stipation, lethargy, weakness, confusion, coma), pancreatitis. Inves tigations: Creatinine \206\221 , Ca 2+ \206\221 (1,25 OH vitamin D, intact PTH, PTH-relat ed peptide, SPEP if clinical suspicion), proteinuria, hematuria, pyuria, hypercalciuria. AX R may show renal calculi/nephrocalcinosis. Treatment : IV fluids (3 \200\2236 L 0.9% saline /24 h); loop diuretics; IV bisphosphonates (p. 307). Steroids may be useful in sarcoidosis. Radiation nephritis Acute radiation nephritis (within 1 yr of radiotherapy) Signs: Hematur ia, proteinuria, BP \206\221 , anemia. Chronic radiation nephritis may occur after acute r adiation nephritis or present with HTN, proteinuria, ane- mia, or end-stage renal failure ( ESRD 2 \200\2235 yrs after exposure to radiation). Treatment : Control BP, renal replacemen t therapy for ESRD. Prevention : Exclusion or shielding of renal areas during radiotherapy. e n i c i d e m l a n e R 277 Nephrotoxins Many agents may be toxic to the kidneys and cause ARF (see Table 8.7). Table 8.7 Nephrotoxins Exogenous nephrotoxins include: \212 \212 Analgesics: NSAIDs/cox-2 inhibitors Antimicrobials: ATN : Aminoglycosides, amphotericin, pe ntamidine. AIN (potentially all): Penicillins, cephalosporins, sulfonamides. Tubular obstru ction : Acyclovir, indinavir. RTA : Proximal \200\224tenofovir; distal \200\224am- photeric in; both \200\224ifosfamide. Chemotherapeutic agents: Cisplatin. obstruction : Methotrexate . ACE-inhibitors and angiotensin II receptor antagonists (ARBs) may cause glomerular hemody namic changes. Iodinated contrast agents: Especially in diabetic nephropathy, older patient s: CKD, AKI (myeloma) Organic solvents: Ethylene glycol, hippurate (glue sniffing: Acidosis ) Insecticides, herbicides, Amanita mushrooms, snake venom; all rare Immunosuppressants: Cy closporine, tacrolimus \212 ATN : Mitomycin C-TTP. Tubular \212 \212 \212 \212 \212 Endogenous nephrotoxins include: \212 Pigments (myoglobin, hemoglobin) C rystal deposition/precipitation (urate, phosphate) \212 \212 Tumors (immunoglobulin light chains) Aminoglycosides (e.g., gentamicin, amikacin) are well-recognized nephro- toxins. T he typical clinical picture is of nonoliguric renal failure 1 \200\2232 wks into therapy. T he risk of nephrotoxicity is increased in old age, lowered renal perfusion, preexisting CKD , high dosage or prolonged treatment, and coad- ministration of other nephrotoxic drugs. Th ese circumstances are common in severely ill patients. Recovery may be full, delayed, or in complete. Myoglobin from muscle injury or necrosis (rhabdomyolysis). Causes: Trauma, ischem ia, immobility, excessive exercise, seizures, myositis, meta- bolic (K + \206\223 , \206 \221 phosphate), medications (fibrates, statins), toxins (alcohol, ecstasy, snake bite, car bon monoxide), malignant hyperpyrexia, neuro- leptic malignant syndrome, inherited muscle d isorders. Clinical features: These may be absent or nonspecific (muscle pain, swelling, or tenderness). Tests: Dark brown urine is +ve for blood on dipstick but without RBCs on micro scopy. Blood tests : \206\221 BUN; \206\221 creatinine; \206\221 K + ; \206\223 Ca 2+ ; \206\223 PO 4 3 \200\223 . \206\221 ck; \206\221 ldh; \206\221 urate. Treatment: Large volumes of IV fluids, urinary alkalinization with IV bicarbonate has been used. Hemodialys is/CRRT may be required. 278 Renal vascular diseases/secondary hypertension HTN may be a cause or consequence of renal d isease. Essential HTN : Investigations (p. 132). Treatment (p. 134). Accelerated (malignant ) HTN may cause ARF. Treatment (p. 134). Pregnancy-induced HTN with proteinuria (preeclamps ia): Edema + proteinuria glomerular endotheliosis/oblitera- tion + deposition of fibrin and platelets. May see: Hemolysis, elevated liver enzymes, low platelet counts (HELLP). See Table 8.8. Renal diseases causing HTN Diabetic nephropathy, acute glomerulone- phritis, ch ronic interstitial nephritis, polycystic kidneys, CKD, renovascular disease, acute vasculitis, scleroderma renal crisis, hemolytic uremic syn- drome (TTP; see below). As individuals progress to ESRD, even if no pre- existing HTN, they will develop HT N. Also, as renal function declines, BP is more difficult to control, requiring increased n umber of agents. Renovascular disease Causes: Atherosclerosis (65 \200\22375%, age >50 yrs, vascular disease); fibromuscular dysplasia (suspect in younger women), trauma, aortic diss ection, or medium size vessel vasculitides (Takayasu \200\231s or polyarteritis nodosa [PAN ]). History: Atherosclerotic : Coexistent cardiovascular, cerebrovascular, or peripheral va scular disease; deterioration in renal function after ACE-inhibitor/ ARB, sudden \206\221 in BP after stable baseline, HTN with asymmetric kidney sizes (>2 cm), severe HTN, recurren t unexplained flash pulmonary edema, proven onset later age (>50). FMD : Young onset, sudde n-onset HTN in absence of other risk factors. Examination: Abdominal, carotid, or femoral b ruits; absent leg pulses; grade III \200\223IV hypertensive retinopathy. Tests: Renal angio graphy is gold standard. Other tests : Can be center dependent: MRA (avoid gadolinium if EG FR <30 mL/min), CT angiography, Doppler ultrasound are currently used for screening tests f or atherosclerotic renal artery disease. These test are poor for detecting fibromuscular dy splasia. CT angiography requires a large amount of potentially nephrotoxic contrast dye. Tr eatment: Percutaneous transluminal renal angioplasty stent or renal bypass surgery. Risk of rupture or atheroembolic disease. Recommended for those with refractory disease. Result s variable. Thrombotic microangiopathy Previously thought of as spectrum between hemolytic uremic syndrome (HUS) and thrombotic thrombocy- topenic purpura (TTP). This is a hematologi c emergency: Get expert help . Thrombotic thrombocytopenic purpura is a pentad of: (1) Feve r, (2) fluctuating neurologic signs (microthrombi, e.g., causing seizures, \206\223 consci ous- ness, \206\223 vision), (3) microangiopathic hemolytic anemia, (4) thrombocytopenia, (5) AKI. In TTP, there is decreased ADAMTS13 activity (inherited/Ab), leading to unusually large \206\221 in von Willebrand factor (vWF) with \206\221 platelet clumping. Hemolytic uremic syndrome is characterized by a microangiopathic hemolytic anemia, thrombocytopenia, and AKI. Platelet aggregates stimulated by endothelial damage, causing release of ultra-lar ge multimers of vWF. Thrombotic angiopathy other features: Purpura, GI or intracerebral ble eds, hematuria, proteinuria, BUN/CR \206\221 . Causes of thrombotic microangiopathy: Idiop athic, medications (cyclosporine, tacrolimus, OKT3, mitomycin C, 5-fluorouracil, ticlopidin e, clopidogrel, quinine, gemcitabine), malignancy (adenocarcinomas), SLE, HIV, pregnancy, b one marrow transplant. Shigatoxin-associated HUS : E. coli 0157; Shigella dysenteriae; Stre ptococcus pneumoniae). Atypical HUS : Complement fac- tor mutations). Tests: Key test: Look at the peripheral smear(fragmented RBC-schistocytes). \206\223 Hb, \206\223 platelets, \206\221 reticulocytes), \206\221 creatinine, \206\221 bilirubin, \206\221 LDH, \206 \223 haptoglobin, hematuria, proteinuria. Treatment : Plasma exchange may be life-saving wi th fresh frozen plasma (FFP) for idiopathic TTP, pregnancy, autoimmune disorders, acute dru g-induced (quinine, clopidogrel). Cancer-associated and post bone marrow transplant thrombo tic microangiopathy is less likely to respond. Immunosuppressive treatment may be used in s ome cases (idiopathic, autoimmune-associated, adults with severe Shigatoxin-induced cases). Prognosis: TTP may relapse (depends on underlying cause). Mortality is high, therefore imm ediate workup is key. Cholesterol emboli Suspect in any patient with diffuse atherosclerosi s, recent arterial procedures or anticoagulation. Can be spontaneous if high ath- erosclero tic burden. Prevalence: 0.3% in unselected autopsies. Signs: Livedo reticularis, distal gan grenous lesions, abdominal pain, Hollenhorst plaques in retinal vessels, progressive renal failure, eosinophilia, eosinophiluria, hypo- complementemia. Urinalysis may be bland. Chole sterol clefts seen in renal e n i c i d e m l a n e R 279 Table 8.8 Diabetes mellitus (type 2) and the kidney Diabetes is a vascular disease, with the kidney as one of its chief targets for end-organ d amage. An important intervention in the long-term care of DM is the control of BP, to prote ct the heart, the brain, and the kidney. Hypertensive type 2 DM patients with microalbuminu ria (30 \200\223300 mg albumin excreted per day)/overt nephropathy should either be on an A RB or ACE-inhibitor. Microalbuminuria gives early warning to possible nephropathy. SES of A RBs and ACE-inhibitors : \206\221 K + and \206\221 creatinine (close monitoring after sta rting/ increasing dose); dry cough with ACE-inhibitor >> ARB (rare). ARB or ACE-inhibitors are first-line. ARB is used with ACE-inhibitor intolerant individuals. Occasionally, they m ay be combined, but only by specialists. Example of target BP in DM if no proteinuria: 130/ 80 mm Hg; if proteinuric , aim for <120/75 mm Hg. Do targets work? Target-driven, long-term , intense therapy (including pro- phylactic aspirin) revolving around microalbuminuria and other risk fac- tors can halve the risk of macro- and microvascular events (MI etc.). Is mi croalbuminuria reversible? Answer: Sometimes, and more likely if: \212 \212 \212 Recent onset HbA1c <8% Systolic <115 mm Hg biopsies; they induce inflammation, ischemia, and then fibrosis. Treatment: No proven medic al therapy; avoid anticoagulants and instrumentation, HMG-CoA reductase inhibitors. Prognos is: Often progressive and fatal. A few have regained renal function after dialysis. Renal tubular disease (see Table 8.9) Nephrogenic diabetes insipidus is characterized by re nal insensitivity to vasopressin, decreased urinary concentration, polyuria, hypernatremia (if water access limited), and, potentially, CKD. It may be primary (familial X-linked) or secondary to a number of causes: \212 \212 \212 280 Drugs (lithium, ifosfamide, cidofovir, foscarnet, Amphotericin, demeclocycline) Metabolic ( hypercalcemia, hypokalemia) Tubulointerstitial disease (partial obstruction, renal amyloid, Sj gren \200\231s, sickle-cell disease) Fanconi syndrome is a disturbance of proximal renal tubular function resulting in: \212 \212 \212 \212 \212 Generalized aminoaciduria Phosphaturia Glycosuria Rickets (children) or osteomalacia (adult s) Renal tubular acidosis type 2 (proximal); proximal tubular defect leads to inability to reclaim filtered bicarbonate Inherited causes: Cystinosis, galactosemia, glycogen storage disease type 1, fructose intol erance, Lowe \200\231s syndrome, tyrosinemia type 1, Wilson \200\231s dis- ease. Idiopathic . Acquired causes: Myeloma, medications (ifosfamide, tenofovir). Hereditary hypokalemic tub ulopathies Bartter \200\231s syndrome: Sodium reabsorption defect in ascending limb with mu tations in the Na \200\223K \200\2232Cl co-transporter (NKCC2) ROMK channel. (Behaves like a loop diuretic.) May have growth/mental retardation. Gitelman syndrome: Sodium reabsorp- t ion defect in distal convoluted tubule. Cause: Mutations in the distal tubular Na \200\223C l co-transporter gene (like a thiazide diuretic). Autosomal recessive. Diagnosed later in l ife, may be asymptomatic. Table 8.9 Type Type I Distal Type II Proximal Type IV Characterization Inability to generate acidic urine in Alone or with Fanconi \200\231s syndrome. Defect in H+ secretion, defective HCO3 reabsorp- tion in proximal tubule and loss of bicarb in urine Hypoaldosteronism or failure of aldosterone metabolism; Mineralocorticoid deficiency \206 \222 increased H secretion in distal nephron resulting in NH4 excretion distal nephron Sjogren \200\231s, amphotericin, SLE, RA, lithium, renal txplt, obstruction, sickle cell di sease Idiopathic, sporadic, multiple myeloma, Addison \200\231s; inborn error of Cause carbonic anhydrase inhibitors, ifosfamide, tenofovir, heavy metals, renal transplant metabolism; DM, chronic inter- stitial disease; drugs (NSAIDs, K sparing diuretics, ACEi); mineralocorticoid deficiency Hyperventilation, low K, Polyuria, polydipsia, proximal myopathy, osteomalacia, rickets, rare stones and nephrocalci nosis Hyperkalemia Sign nephrocalcinosis Urinary ph>5.3, hyperchlo- remic metabolic acidosis; hypercalciuria Hypokalemic Hyperchloremic metabolic acidosis Acidic urine Urinary ph <5, hyperkalemia, hyperchloremic metabolic acidosis Diagnosis Correct hypokalemia; Oral bicarb (1 \200\2232 meq/kg/d) High doses of bicarbonate replacement 3 meq/kg/day Florinef if acidotic or hyperkalemia Treatment 2 8 1 Renal medicine Both are associated with hypokalemia and metabolic alkalosis, hypercalciu- ria with Bartter \200\231s and hypocalciuria with Gitelman \200\231s. Inherited kidney diseases Autosomal dominant polycystic kidney disease (APKD) Prevalence: 1 :1,000. Inheritance: Autosomal dominant. Genes on chromosomes 16 (PKD1) (accounts for 85%) and 4 (PKD2). Signs: Renal enlargement with cysts, abdominal pain, hematuria, UTI, renal ca lculi, BP \206\221 , CKD. Extrarenal : Liver cysts, intracranial aneurysms, subarachnoid h emorrhage, mitral valve prolapse, abdominal hernias. Diagnosis : Ultrasound criteria: Betwe en age 15 \200\22330, two unilateral or bilateral cysts; age 30 \200\22359, two cysts per k idney; >60, four cysts per kidney. Treatment: Monitor U&E and BP; treating \206\221 BP is most important. Treat infections; dialysis or transplantation for ESRD; genetic counseling. Screening for intracranial aneu- rysms: mra without gadolinium, if positive family history of aneurysms. Infantile polycystic kidney disease Prevalence 1:40,000. Autosomal recessive (chromosome 6). Signs : Renal cysts; congenital hepatic fibrosis. Nephronophthisis An inhe rited medullary cystic disease. The juvenile form (autosomal recessive) accounts for 10 \200\22320% of ESRD in children. Signs: Polyuria, polydipsia, enuresis, renal impairment, m etabolic acidosis, anemia, growth retardation, ESRD. Extrarenal signs : Retinal degeneratio n, retinitis pigmentosa, skeletal changes, cerebellar ataxia, liver fibrosis. The adult for m (autosomal dominant; restricted to the kidney) is rare. Renal phakomatoses Tuberous scler osis: Complex disorder with hamar- toma formation in skin, brain, eye, kidney, and heart ca used by autosomal dominant genes on chromosomes 9 (TSC1) and 16 (TSC2). Signs: Skin: Adenom a sebaceum, angiofibromas, \200\234ash leaf \200\235 hypomelanic macules, sacral plaques o f shark-like skin (shagreen patch), periungual fibromas; IQ \206\223 ; sei- zures. von Hip pel \200\223Lindau syndrome is the chief cause of inherited renal can- cers. Cause: Germlin e mutations of the VHL tumor-suppressor gene (also inactivated in most sporadic renal cell cancers). Anderson \200\223Fabry disease is X-linked recessive; intralysosomal deposits of tri- hexoside causing burning pain/paresthesia in the extremities and angiokeratoma corpori s diffusum (blue-black telangiectasia in bathing trunk distribution). Hyperoxaluria Primary hyperoxaluria is due to an autosomal recessive inherited enzyme defect (types I and II). M easure 24 h urinary oxalate excre- tion and creatinine clearance (excretion \206\223 in re nal failure) for unexplained recurrent calcium oxalate stones. Secondary hyperoxaluria is d ue to small intestine disease/resection, \206\223 calcium intake, \206\221 \206\221 oxala te intake (diet, ethylene glycol poisoning), pyridoxine deficiency. Signs: Oxalate stones, nephrocal- cinosis, renal failure, cardiac conduction defects, cardiomyopathy, subcu- taneo us calcinosis, peripheral neuropathy, mononeuritis multiplex, retinal changes, synovitis, o steodystrophy. Treatment: High fluid intake, restrict dietary oxalate (tea, chocolate, stra wberries, rhubarb, beans, celery, nuts), pyridoxine ( \206\223 urinary oxalate excretion), hepatic renal transplantation. Cystinuria is the commonest aminoaciduria. Clinical feat ures: Cystine stones, abdominal pain, hematuria, renal obstruction, UTI. Treatment: \206 \221 Fluid intake, NaHCO 3 \200\223 supplements (alkalinizes urine), penicillamine tio- pr onin ( \206\223 cystine excretion). 282 Renal manifestations of systemic disease Amyloidosis AL (primary) or AA (secondary) Protein uria, nephrotic syn- drome, progressive renal failure, renal tubular dysfunction. Diagnosis (p. 635): For secondary amyloidosis, treat underlying cause (e.g., rheumatoid arthritis). Diabetes 30 \200\22340% of patients on dialysis have diabetic nephropathy. Pathology: Nodul ar capillary glomerulosclerosis (Kimmelstiel \200\223Wilson lesion). Early on, there is renal hyperperfusion associated with \206\221 GFR and \206 \221 renal size. Microalbuminuria (albumin excretion 30 \200\223300 mg/d or 30 \200\223300 mg/g Cr) occurs 5 \200\22315 yrs postdiagnosis and is associated with a normal GFR and a no rmal but rising BP. Type 1 DM nephropathy occurs 10 \200\22315 yrs postdiagnosis and is cha racterized by macroalbuminuria (albumin excretion >300 mg/d or 30 \200\223300 mg/g Cr), \206\223 GFR, and \206\221 BP. Renal failure occurs 15 \200\22330 yrs postdiagnosis (rare after 30 yrs); there may be nephrotic-range proteinuria (>3 g/d). Type 2 DM ( \200\234matur ity onset \200\235) nephropathy (see p. 280): >10 \200\22330% have neph- ropathy at diagnos is, and its prevalence rises linearly with time. Treatment: Good glycemic control delays on set and progression of microal- buminuria but has little effect on established proteinuria. Reducing BP reduces microalbuminuria and attenuates loss of GFR. ACE-inhibitors ARBs re duce microalbuminuria and slow progression to CKD, even if normotensive. Infection-associat ed nephropathies are common causes of renal dis- ease. Infection-related GNs are characteri zed by proteinuria/hematuria are associated with endocarditis, bacteremia, shunt nephritis. Other associ- ated glomerular diseases : Hepatitis C-membranoproliferative GN; hepatitis B / \200\223syphilis-membranous; HIV/parvovirus-collapsing FSGS. Vasculitis (p. 416) occurs w ith HBV, post-streptococcal, staphylococcal, or streptococcal septicemia. Interstitial neph ritis is seen with E. coli, Staphylococcus aureus, Proteus , lep- tospirosis, hantavirus, a nd schistosomal infections. Malignancy Direct effects: Renal infiltration (leukemia, lympho ma), obstruction (pelvic tumors), metastases. Indirect: Hypercalcemia, neph- rotic syndrome (membranous nephropathy- solid tumors, minimal change disease-hematologic malignancies), AK I, amyloidosis, glomerulonephritis. Treatment-associated: Nephrotoxic drugs, tumor lysis sy ndrome, radiation nephritis. Multiple myeloma is characterized by excess production of mono clonal antibody and/or light chains. Bence Jones proteinuria is common. Myeloma kidney is c haracterized by accumulation of distal nephron casts. Light-chain nephropathy is caused by direct toxic effects of light chains on nephrons. Clinical features: AKI, CKD, amyloidosis, nephrotic syndrome, tubular dys- function, hypercalcemic nephropathy. Treatment: Treat AKI (p. 269) and hypercalcemia (p. 675); chemotherapy, dialysis. Rheumatological diseases Rheu matoid arthritis (RA) tends to have renal complications as result of medications or long-st anding inflammation. NSAIDs may cause \206\223 GFR or interstitial nephritis. Penicillamin e and gold may induce membranous nephropathy. Tumor necrosis factor (TNF)- agents may in duce crescentic GN. Methotrexate- interstitial disease. Secondary amy- loidosis occurs in 1 5% of RA patients. SLE involves the kidney in 40 \200\22360% of adults. Clinical features : Proteinuria, hematuria, \206\221 BP, renal impairment, ARF. Lupus nephritis shows a wide variety of histological patterns (p. 264). Treatment : Corticosteroids; immunosuppressive m eds (cyclophosphamide/ mycophenolate mofetil). Systemic sclerosis (p. 412) involves the kid ney in 30% of patients. Clinical features : Proteinuria, hematuria, \206\221 BP, renal imp air- ment, \200\234scleroderma crisis \200\235 (AKI + malignant HTN) Treatment : Control B P (ACE inhibitors); dialysis; transplantation. Hyperparathyroidism Nephrocalcinosis: Deposi tion of calcium in the renal medulla (seen on plain x-ray). Renal stones from associated hy percalciuria. Sarcoidosis may involve the kidney in a number of ways. Abnormal Ca2+ metabol ism may cause hypercalciuria, nephrocalcinosis, or nephrolithiasis. Interstitial nephritis may present with CKD or AKI. Glomerular involvement usually presents with the nephrotic syn drome and is due to membranous glomerulonephritis, other glomerulopathies, or amyloidosis. e n i c i d e m l a n e R 283 Endocrinology Kendall F. Moseley , M.D. y g o o n i r c o d n E l Contents The essence of endocrinology 285 Diabetes mellitus Type 1 diabetes mellitus 286 Type 2 diabetes mellitus 288 Diabetic retinopathy 291 Diabetic nephropathy 292 Diabetic neuropathy 293 The diabetic foot 294 Hypoglycemia 295 9 Thyroid, parathyroid, and metabolic bone disease Thyroid function tests 297 Hyperthyroidism 298 Hypothyroidism 301 Nonthyroidal illness 302 Hyperparathyroidism 303 Hypoparathyroidism 305 Osteoporosis 305 Paget \200\231s disease of the bone 306 Osteomalacia 308 The adrenal gland Cushing \200\231s syndrome 309 Adrenal insufficiency 312 Hyperaldosteronism 313 Pheochromoc ytoma 315 Hirsutism 316 Gynecomastia 319 284 The pituitary gland Pituitary adenomas 320 Hypopituitarism 321 Hyperprolactinemia 322 Acromegaly 324 Diabetes i nsipidus 325 The essence of endocrinology See Table 9.1. y g o o n i r c o d n E l Table 9.1 The essence of endocrinology \212 Involves the study of hormones, the many glands that secrete them, and the multiple functio ns of these hormones on target tissues. Endocrine glands include the pancreas, thyroid, par athyroids, adrenals, pituitary and gonads; kidney, bone, and adipose tissue also have endo- crine functions. Clinical syndromes and endocrine diseases result from deficiencies of hor mones ( hypo- syndromes) and corresponding clinical syndromes associated excessive amounts of hormones ( hyper- syndromes). Primary endocrine disease involves dysfunction of the endo crine gland itself (i.e., primary hypothyroidism = overactive/underactive thyroid gland); c entral (or secondary) endocrine disease involves dysfunction of the hypothalamus/pituitary with resultant inappropriate signaling to the target endocrine gland (i.e., Cushing \200 \231s disease). Endocrine diseases are identified and diagnosed by measuring levels of horm ones or metabolites of hormones in blood or urine samples at the appropriate time of day. M easurement of stimulating hormones secreted by the pituitary may be used to distinguish pri mary from central (secondary) disease (i.e., thyroid-stimulating hormone (TSH) to diagnose primary hypothy- roidism and hyperthyroidism; adrenocorticotropic hormone (ACTH) to disting uish between primary and central (secondary) adrenal insufficiency). To confirm suspected d eficiency of a hormone, administer an agent that stimulates secretion of that hormone befor e drawing samples for measurement. To confirm suspected secretion of excessive amounts of a hormone, administer an agent that suppresses secretion of that hormone before drawing samp les for measurement. Use radiographic studies to evaluate the anatomic structure and physi- ologic function of specific endocrine glands only after gland dysfunction has been confirm ed by biochemical testing. Treat conditions associated with deficiencies of hormones by adm in- istering (a) pharmacologic preparations of hormone and hormone analogs, or (b) agents t hat stimulate secretion of hormones from func- tional tissue. Treat conditions associated w ith secretion of excessive amounts of hormones by (a) surgically resecting hyperfunctioning tissue, (b) administering agents that target and destroy hyperfunctioning tissue, or (c) a dministering agents that suppress secretion of hormones from hyperfunctioning tissue. \212 \212 \212 \212 \212 \212 \212 285 \212 \212 \212 Type 1 diabetes mellitus Definition Clinical disease caused by autoimmune destruction of pa ncre- atic islet cells required for secretion of endogenous insulin. Type 1 diabetes mellit us (T1DM) is a disease of insulin deficiency. T1DM usually presents during childhood or ado lescence, but may occur at any age (see latent auto- immune diabetes in adulthood [LADA], b elow). Patients require lifelong treatment with insulin and are prone to developing extreme fluctuations in blood glucose levels (hypoglycemia and hyperglycemia with ketoacidosis). M ay be associated with specific HLA types (DR3 and DR4) and other auto- immune disorders. An ti-glutamic acid decarboxylase antibodies (anti-GAD) and anti-islet cell antibodies may be detectable at the time of diagnosis and confirm T1DM, if present.Antibody levels may be too low to detect in later-stage T1DM; their absence does not rule out disease. Concordance is >30% in identical twins. Presentation Usually acute, with ketoacidosis characterized by pr ogres- sive polyuria, polydipsia, weight loss, fatigue, lethargy, hyperventilation, and a d istinctive odor of acetone on the breath. Subacute cases may present with more protracted c ourses of variable polyuria, polydipsia, and weight loss with associated lethargy and frequ ent infection(vaginal candidiasis, furunculosis). In adults who present with these symptoms and hyperg- lycemia, LADA should be suspected.Adults with LADA have T1DM and should be tre ated, as below.Early in the course of treatment, patients may experience a transient \200 \234honeymoon phase \200\235 characterized by improved con- trol with reduced daily insulin requirements.Destruction of islet cells will resume and be permanent. Diagnosis A suspecte d diagnosis may be confirmed on the basis of (1) hemoglobin A1c (HbA1c) > 6.5% in a certifi ed laboratory, (2) a random plasma glucose > 200 mg/dL with associated symptoms (polyuria, polydip- sia, weight loss), (3) a fasting plasma glucose > 126 mg/dL, or (4) a 75 g oral gl ucose tolerance test with a 2 h plasma glucose > 200 mg/dL. 1 Positive results from tests 2 \200\2234 should be verified with repeat testing. Treatment Insulin, administered as multi ple daily injections or through a pump delivering a continuous subcutaneous infusion. Oral medications are not effective in T1DM.Insulin doses should be timed to reproduce normal pat terns of basal and postprandial insulin secretion. Monitoring requires frequent self-measur ement of blood glucose levels throughout the day (fast- ing and mealtimes). Intensive contr ol targeting normoglycemic preprandial and postprandial blood glucose levels reduces the ri sk of developing micro- vascular complications (described below), but may be associated wit h more frequent episodes of hypoglycemia. Continuous glucose monitoring (CGM) devices may b e helpful in patients with extreme fluctuations in blood glu- cose ( \200\234brittle diabet es \200\235), frequent or dangerous hypoglycemia, or to opti- mize insulin regimen.See Tabl e 9.2. Clinical guidelines recommend intensifying treatment to target HbA1c levels <7% to m inimize diabetic complications.Aggressive glucose control (HbA1c <6%) is not recommended an d may be associated with increased mortality. Note that HbA1c levels reflect average blood glucose control over the course of the previous 8 \200\22312 wks. See Table 9.3. 286 1 American Diabetic Association. American Diabetic Association Clinical Practice Recommenda tions. Diabetes Care. January 2011; 34 (suppl 1). y g o o n i r c o d n E Table 9.2 Insulin l Available in 100 U/mL preparations. May be drawn up and injected using special syringes (ma rked in units) or directly injected from preloaded adjustable pen injectors. Five major typ es available for use. Rapid-acting insulin analogs Insulin lispro (Humalog ), insulin aspa rt (NovoLog ), modified to promote rapid absorption, must be injected immediately before o r after eating to cover prandial spike in glucose levels. Dosing schedule: With meals. Shor t-acting insulin Regular insulin , must be injected 15 \200\22330 min before eating. Less c ommonly prescribed given challenges with timing of insulin and onset of insulin action. Int ermediate-acting insulin ( NPH insulin), peak effect at 4 \200\22310 h, effec- tive duratio n is 10 \200\22316 h. Dosing schedule: Twice daily. Long-acting insulin analogs Insulin gla rgine (Lantus ), insulin detemir (Levemir), modified to promote steady absorption and cont inuous cov- erage of glucose levels without peaks. May not be mixed with other types of ins ulin or insulin analogs. Dosing schedule: Once daily (morning or night), although consider twice-daily dosing for total insulin >40 units to ensure absorption of full dose. High conc entration insulin analogs should only be used in cases of extreme insulin resistance. Humul in R U-500 is only available as a regular form of insulin. Peak effect 2 \200\2234 h after administration, duration of action 5 \200\2237 h. Should only be prescribed by a diabetolog ist. Premixed preparations combine intermediate-acting insulin with short-acting insulin or rapid-acting insulin analogs in specified fractions (i.e., 70/30 NPH insulin/regular insul in, 75/25 NPH/insulin lispro). May be used to minimize daily injections. Table 9.3 Insulin regimens used to treat type 1 diabetes General Ideal insulin administration consists of \200\234basal \200\235 coverage for 24 h man- agement of blood glucose and \200\234bolus \200\235 or \200\234prandial \200\235 cov erage to manage blood glucose spikes during meals. Persons with T1DM require exogenous insu lin at all times given insulin deficiency and risk of diabetic ketoacidosis (DKA). Continuo us insulin administration Available through insulin pumps dosed for time of day, meal intak e, and correction of elevated blood glu- cose levels. Insulin cartridges filled with rapid- acting insulin analogs. Two daily injections Comprised of (1) intermediate-acting insulin m ixed with a rapid-acting insulin analog (or short-acting insulin) before breakfast; and (2) intermediate-acting insulin mixed with a rapid-acting insulin analog (or short-acting insu lin) before dinner. Often started by administering two-thirds of the estimated daily dose b efore breakfast and one-third before dinner. Three daily injections Comprised of (1) interm ediate-acting insulin mixed with a rapid-acting insulin analog (or short-acting insulin) be fore breakfast; (2) a rapid-acting insulin analog (or short-acting insulin) before dinner; and (3) intermediate-acting insulin at bedtime. May reduce the frequency and severity of ov ernight hypoglycemia. Four daily injections Comprised of (1 \200\2233) a rapid-acting insul in analog (or short-acting insulin) before breakfast, lunch, and dinner; and (4) a long-act ing insulin analog at bedtime. Preprandial doses of rapid-acting insulin analogs may be adm inistered as fixed doses or may be adjusted to account for (a) estimated grams of carbohydr ate to be eaten or (b) sliding scale correction formulas based on preprandial blood glucose levels. 287 (Continued) Table 9.3 (Continued) Intercurrent illnesses may increase daily insulin requirements despite diminished appetite and reduced caloric intake. During the course of any moderate to severe illness, patients s hould be instructed to (a) maintain caloric intake, (b) drink large volumes of fluids, (c) check blood glucose levels at least four times daily, and (d) check for urine ketones with home dipstick tests if blood glucose levels are noted to be persistently elevated. Insulin doses may need to be transiently increased to prevent the onset of hyperglycemia, volume de pletion, and ketoacidosis. Type 2 diabetes mellitus Definition Clinical syndrome characterized by insulin resistance l eading to endogenous hyperinsulinemia with eventual -cell failure and relative insulin d eficiency. Over time, the combined effects of insulin resistance and inade- quate insulin s ecretion lead to persistent hyperglycemia. Strongly associated with obesity, physical inact ivity, and positive family history. Higher preva- lence among certain ethnic groups includi ng African Americans, Latinos, Native Americans, Asian Americans, and Pacific Islanders. Al though once considered a disease of adults, incidence of confirmed diagnoses of type 2 diab etes mellitus (T2DM) in children and adolescents is increasing with the obesity epidemic. C oncordance is >80% in identical twins. Presentation Highly variable. At one end of the spec trum, patients may present with mild asymptomatic hyperglycemia identified on routine labor a- tory testing. At the other extreme, patients with unsuspected and untreated disease may present in advanced, decompensated, hyperosmolar states. Known as the hyperosmolar hypergly cemic state (HHS), it is characterized by severe hyperglycemia, volume depletion, and menta l status changes. Metabolic syndrome is defined by high-density lipoprotein (HDL) cho- lest erol <40 mg/dL (men) or <50 mg/dL (women), waist circumference >102 cm (men) or >88 cm (wom en), blood pressure (BP) > 130/85 mmHg or active treatment for hypertension, and fasting bl ood glucose >100 mg/dL or active drug treatment for elevated blood glucose.Persons with any three of the five criteria have metabolic syndrome. There is a strong link between the met abolic syndrome and subsequent risk of developing T2DM. Diagnosis Suspected diagnosis. 2 ma y be confirmed on the basis of (1) HbA1c >6.5% in a certified laboratory, (2) a random plas ma glucose >200 mg/dL with associated symptoms (polyuria, polydipsia, weight loss), (3) a f asting plasma glucose >126 mg/dL, or (4) a 75 g oral glucose toler- ance test with a 2 h pl asma glucose >200 mg/dL. Positive results should be verified with repeat testing. \200\234 Pre-diabetes \200\235 may be diagnosed when testing reveals (a) HbA1c 5.7 \200\2236.4%, (b) a fasting plasma of 100 \200\223125 mg/dL glucose (impaired fasting glucose, IFG), or (c) a 2 h plasma glucose of 140 \200\223199 mg/dL (impaired glucose tolerance, IGT). There is g rowing evidence that treatment of prediabetes with lifestyle modification and/or pharmacolo gic therapy may delay or prevent the progression of disease and end-organ damage. Testing i n asymptomatic patients Should be considered in all over- weight adults (body mass index [B MI] >25 kg/m 2 ) and who have one or more additional risk factors for diabetes (metabolic s yndrome, above). Without risk factors, screen adults >45 yrs. 288