e n i c i d e m l a n e R 253 Figure 8.1 Urine microscopy 254 Principle source: M. Longmore An Atlas of Microscopy rcgp . When you find red cells, consider their morphology to understand where in the GU tract they come from. If >80% of RBCs are dysmorphic G1 cells, suspect glomerular bleeding and look h ard for red cell casts. Acanthocytes are RBCs with donut shapes, target configurations, and membrane protrusions or blebs. Acanthocyturia of >5% is considered indicative of glomerula r hematuria. www.uninet.edu/cin2003/conf/nguyen/nguyen.html Urinary tract imaging Kidney, ureters, bladder (KUB) x-ray Look at kidneys, path of the ure ters, and bladder. Abnormal calcification may be related to calculi (only 80% of stones are visible on plain films: See CT below), dystrophic calcifica- tion; e.g., in carcinomas or TB (uncommon) and nephrocalcinosis. Note: Plain abdominal movie focuses more on bowel, not urinary system, and may miss stones. Ultrasound is the usual initial image in renal medicin e. May be performed with Doppler. Abnormal parenchyma if echogenicity is greater than that of the liver. It shows: \212Renal size . S mall (<9 cm) implies CKD; large in renal masses , benign cysts 1 ; hypertrophy if other kidney missing, polycystic kidney disease, amyloido sis, diabetes, and lymphomatous infiltration 1 Cysts may be inherited, developmental, or acquired; e.g., polycystic kidney disease, medu llary sponge kidney, multicystic dysplastic kidney, medullary cystic disease, tuberous scle rosis, renal sinus cysts, von Hippel \200\223Lindau \200\231s disease. \212Hydronephrosis , which indicate renal obstruction or reflux \212Perinephric collectio ns (trauma, postrenal biopsy) \212Transplanted kidneys (collections, obstruction; color Do ppler indicates e n i c i d e m perfusion) \212Bladder residual volume \212Power Doppler ultrasound evaluates for renal artery steno sis. Advantages: Fast, cheap, independent of renal function, no IV contrast or radiation ri sk. Disadvantages : Intraluminal masses, such as transitional cell carcinomas (TCC) in the upper tracts, may not be seen; not a functional study; only suggests obstruction when there is dilatation of the collecting system ( 1 \200\2232% of obstructed kidneys have nondilate d systems). Disadvantages : May miss obstruction and hydroureter early on in the disease. H elical noncontrast/CT is gold standard for diagnosis of renal colic. Noncontrast scans are 97% sensitive for calculi and show other patholo- gies. CT allows detailed characterization of masses (solid or cystic, contrast enhancement, calcification, local/distant extension, renal vein involvement); renal trauma (hemorrhage, devascularization, laceration, urine lea k); retro- peritoneal lesions. CT urogram for hematuria uses IV contrast to visualize colle cting system if noncontrast CT is negative. Intravenous urogram/pyelogram (IVU/IVP) A study for defining anat- omy (especially pelvi-calyceal) and for detecting pathology distorting the collecting system. It yields limited functional information. Abdominal films are taken before and after IV contrast, which is filtered by the kidney, reach- ing the renal tubules at 1 min (nephrogram phase). Later images show contrast in the system (pyelogram), ureter s, and bladder. Detects papillary necrosis, medullary sponge kidney. Side effects (SE) : Fl ushing, nausea, rash, contrast nephropathy (Caution: Risks include preexisting CKD, DM). Re trograde pyelography is good at showing anatomy of the pelvi-calyceal systems and ureters a nd for detecting pathology, such as transitional cell carcinoma (TCC). Contrast is injected via a ureteric catheter. Percutaneous nephrostomy The renal pelvis is punctured with imagi ng guidance. Diagnostic images are obtained following contrast injection. A nephrostomy tub e may then be placed to allow drainage of an obstruction above the bladder. Renal arteriogr aphy Still the gold standard for renal artery stenosis. Can perform pressure monitoring acr oss stenosis for significant pressure change for borderline lesions. Therapeutic indication s include angioplasty, stenting, and selective embolization (bleeding tumor, trauma, or art eriovenous [AV] malformations). Magnetic resonance imaging (MRI) offers improved soft tissu e resolu- tion; it may be used to clarify equivocal noncontrast CT findings. Magnetic reson ance angiography ( MRA ) is useful in imaging renal artery stenosis. Avoid gadolinium in se vere CKD. Radionuclide imaging scans quantify each kidney \200\231s contribution to renal f unction and can detect renal scarring ( 99 TC m DTPA, diethylenetriamine penta-acetic acid) . Radiolabeled metal chelators such as 51 Cr-EDTA (ethyl- enediaminetetraacetic acid), 125 I iothalamate, or 99 Tc m DTPA, can also mea- sure GFR. l a n e R 255 Renal biopsy See Table 8.1. Table 8.1 Renal biopsy Most acute kidney injury is due to prerenal causes or ATN, and recov- ery of renal function typically occurs over the course of a few weeks. Renal biopsy should be performed if knowi ng histology will influence management. Once CKD is long-standing with small kidneys, risks of bleeding from biopsy may be increased and therapy may be limited. Indications for renal biopsy: \212 \212 What is the cause of this acute kidney injury (p. 268)? Investigating func- isolated hematu ria with normal tion and minimal proteinuria to rule out glomerulonephritis is nephrologist -dependent. Is persistent hematuria in this scenario from IgA nephropathy, thin basement me mbrane disease, or hereditary nephropathy? What is the cause of this heavy proteinuria (e.g ., >2 \200\2233 g/d) when diabetic nephropathy is unlikely? Renal dysfunction post-transpla ntation: Is the cause rejection, drug toxicity, or recurrence of renal disease? renal \212 \212 Preprocedure: Check cbc, coagulation profile. Obtain written informed consent. Ultrasound. Hold aspirin, NSAIDs, and anticoagulation at least 7 d prior to procedure if possible. Rela tive contraindications (CI) : 1 One kidney or horseshoe kidney 2 Morbidly obese 3 Uncontrol led HTN (systolic >160 mm Hg) In these instances, consider open procedure or CT-guided biop sy. Procedure: Biopsy may be performed with real-time ultrasound using needle guides, with the patient lying in the prone position and the breath held. May also be performed by radio logy via transjugular approach or surgically via laparoscopic or open techniques for those who are obese or who are at increased risk for bleeding. Samples should be sent to patholog y for routine stains, immunofluorescence, and electron microscopy. A clear indication on th e request form of why the test has been done(e.g., exclude amyloidosis) will help in the se lection of special stains, immunofluorescence, and use of electron microscopy. Postprocedur e: Bed rest for 6 \200\22324 h. Monitor pulse, BP, symptoms, and urine color. Bleeding is t he main complication with nephrectomy and death ( 1/1,000 cases). 256 Urinary tract infection Definitions Bacteriuria: Bacteria in the urine may be asymptomatic or symptomatic. UTI: The presence of a pure growth of 10 3 colony forming units (CFU)/mL or >10 3 of uropathogen with pyuria and symptoms. UTI sites : Bladder ( cystitis ), prostate ( prostatitis ), or kidney ( pyelonephritis ). Up to one-third of women with symptoms do no t have bacteriuria; a con- dition known as urethral syndrome . Classification : UTIs may be classified as uncomplicated (normal renal tract and function) or complicated (most male pa tients, abnormal renal tract, impaired renal function, impaired host defenses, virulent org anism). A recurrent UTI is a further infection with a new organism. A relapse is a further infection with the same organism. Risk factors Female sex, sexual intercourse, diaphragm or spermicide con- traceptive, DM, immunosuppression, pregnancy, menopause, urinary tract obs truction (p. 260), nephrolithiasis, instrumentation, or malformation. Organisms E. coli is the most common ( 80% in the community but <41% in hospital). Others include Staphylococcus saprophyticus, Enterococcus faecalis, Proteus mirabilis, Klebsiella spp., Enterobacter spp ., Acinetobacter spp., Pseudomonas aeruginosa , and Serratia marcescens . In men <35, shoul d consider sexually transmitted infections (STIs; e.g., N. gonorrhea or C. tra- chomatis ) as cause of prostatitis. See Table 8.2. Symptoms Cystitis: Frequency, dysuria, urgency, hem aturia, suprapubic pain. Acute pyelonephritis: Fever, rigors, vomiting, loin pain and tende rness. Prostatitis: Flu-like symptoms, low backache, few urinary symptoms, swol- len, boggy , tender prostate. Signs Fever, abdominal or flank tenderness, renal mass, distended bladde r, enlarged prostate. Tests Microscopic exam for leukocytes or dipstick test for leukocyte esterase or nitrites. May treat uncomplicated empirically if symptoms con- sistent with acu te uncomplicated UTI. If complicated, UTI, pyelonephritis, uncertainty of diagnosis, child, pregnancy, ill-appearing, or if recent recur- rence after therapy, send a fresh clean-catc h specimen to the lab for culture and sensitivity. Should avoid first morning void for samp le. A pure growth of >10 5 cfu/ml is diagnostic for complicated UTIs or if bacteria is not always pathogenic. Two consecutive cultures with same bacteria are required for asymptomati c patients in complicated UTIs. If <10 3 cfu/ml and pyuria, the result is significant. Cult ured organisms are tested for sensitivity to a range of antibiotics. Blood tests: CBC, BUN, creatinine, blood cultures, if systemically ill-appearing. Ultrasound, IVP, CT pyelogram/c ystoscopy: Consider for UTI in infants, chil- dren, or men; recurrent UTI; pyelonephritis; unusual organism; persistent fever; persistent or gross hematuria. Ultrasound or IVP? Ultra sound may miss stones, papillary necrosis, and clubbed calyces. Can do ultrasound first bec ause it avoids contrast agents and radiation. Treatment Advice: Drink plenty of fluids, uri nate often, double void (going again after 5 min), postintercourse voiding, wipe front to b ack after micturi- tion. Antibiotics: Know your local pattern of resistance: Increasingly, options are narrowing. Cystitis: Trimethoprim/sulfamethoxazole (tmp/smx)160/800 mg bid po \227 3 d). Alternative: Quinolone antibiotics (norfloxacin 400 g po bid or ciprofloxacin 25 0 mg po bid). Longer courses (10 \200\22314 d) may be needed in complicated UTI (see above) if fever present. Sensitivity profile determines treatment, although quinolones may be use d empirically for severe symptoms. e n i c i d e m l a n e R 257 Acute pyelonephritis : Tmp/smx or quinolones orally unless severe gi symptoms, hemodynamic instability, significant systemic symptoms, noncompliance. Prostatitis: Acute : \211 35, Ciprofloxacin 500 mg/d PO for 10 \200\22314 d. If <35 (or suspected STI), Ceftriaxone 250 m g IM \227 1, then doxycycline 100 mg bid \227 10 d. Chronic : Ciprofloxacin 500 mg PO/12 h x 4 weeks. Pregnancy: Ask OB. Prevention: Antibiotic prophylaxis, either continuous or po stcoital. Self-treatment with 1 \200\2233 d course as symptoms start is an option. Cranberr y juice may inhibit adherence of E. coli to bladder cells, but needs further assessment. Fo r patients with renal transplant, end-stage renal disease (ESRD), and indwelling urologic d evices, medication choices may need to be adjusted based on clinical scenario and culture d ata. Table 8.2 Causes of sterile pyuria Renal TB (do three early morning urines). Inadequately treated UTI Papillary necrosis from DM, analgesic excess, sickle cell Appendicitis Calculi, prostatitis Bladder tumor UTI with fastidious culture requirement Interstitial nephritis, polycystic kidney Chemical cystitis Renal calculi (nephrolithiasis) Renal stones (calculi) consist mainly of crystal aggregates . Stones form in the collecting ducts and may be deposited anywhere from renal pelvis to ur ethra. See Table 8.3. Epidemiology Prevalence: 0.2%. Lifetime incidence: Up to 12%. Peak ag e: 20 \200\22350 yrs. \231\202 : \231\200 >4:1. Risk factors: Dehydration, UTI with ureas e produc- ing organisms, hypercalcemia, hypercalciuria, hyperoxaluria, hypocitratu- ria, hy peruricosuria, small intestinal disease or resection, chronic diarrhea, cystinuria, distal renal tubular acidosis, gout, drugs (triamterene, indinavir), family history, anatomic abno rmality (medullary sponge kidney). Types of stone Calcium (usually oxalate 75% with pure c alcium phos- phate rare [5%]), struvite (ammonium magnesium phosphate calcium phosphate 15 \200\22320%), uric acid ( 10%), cystine ( 1%), drug (acyclovir, indi- navir, sulfadiazi ne). Clinical features Vary widely from asymptomatic to multiple symptoms. Pain: Stones in the kidney cause flank pain. Stones in the ureter cause ure- teric colic. This classically radiates from the flank to the groin and is associ- ated with nausea and vomiting. Bladder or urethral stones may cause pain on micturition or interruption of urine flow. Infection m ay be acute, chronic, or recurrent. It may present with cystitis (frequency, dysuria), pyel onephri- tis (fever, rigors, flank pain, nausea, vomiting), or pyonephrosis (infected hydro nephrosis). Other: Hematuria, sterile pyuria, anuria from obstructing bladder calculi or ur eteral calculi with solitary functioning kidney. 258 Tests Blood : BUN, creatinine, electrolytes, Ca 2+ , PO 4 3 \200\223 , intact parathyroid hormone (PTH) if hypercalcemic, uric acid. Urinalysis: Urine ph (normal range 4.5 \200\2238 ). Acidic urine \206\221 uric acid stone formation and alkaline urine \206\221 phosphate stone formation). 24 h urine : Best done in the outpatient setting with patient consuming u sual diet ; Ca 2+ , sodium, sulfate/urea nitrogen reflects animal protein/protein intake, p hosphate, uric acid, citrate, pH, oxalate, volume, creatinine for accuracy of collection. I maging: Noncontrast helical CT is the imaging modality of choice for stones. Renal ultrasou nd excludes hydronephrosis or hydroureter. Abdominal KUB movie (kidneys + ureters + bladder ). Management Stones not causing obstruction between attacks of renal colic may be managed conservatively. Advise patient to increase fluid intake and strain urine to retrieve stone for biochemical analysis. Note that stones often take \211 30 d to pass. Ureteric stones <5 mm in diameter usually pass spontaneously. They may need to be fragmented or removed end oscopi- cally from below. If >5 mm, <50% pass spontaneously. Pelvicaliceal stones <5 mm do not need treatment unless causing obstruction or infection. Stones <2 cm in diameter are su itable for lithotripsy. Stones >2 cm are usu- ally removed by percutaneous or cystoscopic m ethods. Renal colic: Give IV fluids if unable to tolerate oral fluids; analgesia and antibi otics if evidence of infection. Seek urological help urgently if evidence of obstruction . Procedures include retrograde stent insertion, nephrostomy, and antegrade pyelogra- phy (p. 255). These may be combined with lithotripsy. Open surgery is rarely needed. Prevention Dr ink plenty of fluid to keep urine output >2 \200\2233 L/24 h. It may be necessary to drink at night to cause voiding at night. Calcium oxalate stones: Hypercalciuria: Low-salt diet(2 g/d); watch animal protein intake; thiazide diuretic. Hyperoxaluria: Calcium intake (dairy products) with meals; \206\223 oxalate intake (less tea, chocolate, nuts, strawberries, r hubarb, spinach, nuts); calcium supplements with meals if enteric hyperoxaluria due to smal l bowel disease with increased absorption of oxalate. Hyperuricosuria: Restrict dietary pur ine intake, allopurinol. e n i c i d e m l a n e R 259 Hypocitraturia: Potassium citrate, orange juice or lemonade. Uric acid: Alkalinize urine if acidic urine PH with goal urine pH >6. Hyperuricosuria; dietary purine restriction or allo purinol. Struvite : Antibiotics; urologic removal of stones. Uric acid stones : Urinary alk alinization (to maintain PH >6); allopurinol (100 \200\223300 mg/d). Cystine stones: Vigoro us hydration to keep cystine concentration <250 \200\223300 mg/L of urine, D-penicillamine, tiopronin, captopril; urinary alkalinization to achieve urine pH >7 \200\2237.5. Table 8.3 Questions for patients with stones What is its composition? In order of frequency, the likely answer is: \200\224 Calcium oxalate stones: These are spiculated \200\224 Calcium phosphate stones a re smooth and may be (radiopaque) (radiopaque) large \200\224 Struvite staghorn stone: Large; spiculated \200\224 Uric acid: (smooth, brown, a nd soft) \200\224 Cystine stones: Yellow and crystalline Risk factors? \200\224 Diet: Exc ess salt and animal protein intake for hypercalciuria, calcium restriction with meals; incr eased oxalate intake (chocolate, tea, nuts, spinach) for hyperoxaluria; increased purine in take for calcium and uric acid stones \200\224 Hypercalciuria/hypercalcemia (e.g., hyperpa rathyroidism, sarcoidosis, (radiopaque) (radiolucent) (semiopaque) neoplasia, hyperthyroidism, Li + , vitamin D excess) \200\224 Dehydration: All stones. Acidic urine can lead to uric acid stones \200\224 Medu llary sponge kidney \200\224 Primary or secondary hyperoxaluria (excess oxalate gut reabso rption because of small bowel malabsorption) \200\224 Gout and \206\221 urine uric acid: Increases both calcium oxalate and uric acid stone risk \200\224 UTI (predisposes to struvite stones with urease splitting organisms and from staghorn calculi) \200\224 Distal renal tubular acidosis: Acidosis leads to low urine citrate, and alkaline urine leads to increased precipitation of calcium phosphate stones. (Sj gren \200\231s i s secondary distal RTA) \200\224 Cystinuria \200\224 Family history? X-linked nephrolithiasis or Dent \200\231s d isease: Low- molecular-weight proteinuria, hypercalciuria, nephrocalcinosis? 260 Is there infection above the stone? Fever? Flank tender? Pyuria? Urinary tract obstruction Urinary tract obstruction is common, often reversible, and should be con- sidered in any patient with impaired renal function due to bilateral or uni- later al in solitary functioning kidney. It may occur from the renal calyces to the urethral meat us. It may be partial or complete , unilateral , or bilat- eral . Obstructing lesions are l uminal (stones, blood clot, sloughed papilla, tumor), mural (e.g., congenital or acquired s tricture, neuromuscular dys- function, schistosomiasis), or extramural (abdominal or pelvic mass/tumor, retroperitoneal fibrosis). Unilateral, partial, or slowly developing obstruc- tion may be asymptomatic (i.e., normal urine output). Bilateral obstruction or obstruction + infection requires urgent treatment. Note that a patient still producing urine does not r ule out obstruction. Clinical features Acute upper tract obstruction : Flank pain radiat ion to groin. There may be superimposed infection. Chronic upper tract obstruction: Flank p ain, renal failure, superimposed infec- tion. Polyuria may occur due to impaired urinary co ncentration. Acute lower tract obstruction: May be urinary retention; usually presents with severe suprapubic pain, often preceded by symptoms of bladder outflow obstruction. Exam : Distended, palpable bladder. Chronic lower tract obstruction: Symptoms: Urinary frequency, hesitancy, decreased stream, dribbling, overflow incontinence, nocturia, suprapubic fullness. Signs: Distended, palpable bladder; enlarged prostate. Complications : UTI, urinary retention. Tests Blood : Electrol ytes, BUN, creatinine. Urine: Dipstick and microscopic exam. Urine pH (may be elevated from acidification defect, distal nephron damage). Ultrasound (p. 255) is the imaging test of c hoice. If obstruction is above the bladder, antegrade or retrograde pyelography/nephrostomy : Offers therapeutic option of drainage. Radionuclide imaging enables functional assessmen t of collecting system dila- tion which may be from vesicoureteral reflux, chronic pyelonep hritis, preg- nancy (R > L), increased urine flow states, instead of true obstruction. CT a nd MRI may help identify location and etiology of obstruction. Treatment Drainage is urgent if there is infection above an obstruction . Upper tract obstruction: Acute, nephrostomy. Chronic, ureteral stent or pyeloplasty. Lower tract obstruction: Urethral or suprapubic cat heter. Treat the underlying cause if possible. Beware of large diuresis after relief of obs truction; a temporary salt-losing nephropathy may occur with the loss of several liters of fluid a day. Monitor vital signs for hypotension, weight, fluid balance, and electrolytes i n case IV fluids (e.g., 0.45% ns) required. e n i c i d e m l a n e R Retroperitoneal fibrosis A disorder that is part of chronic periaortitis, which includes in flammatory abdominal aortic aneurysms and perianeurysmal retroperitoneal fibrosis. In this rare autoimmune condition, there is vasculitis of adventitial aortic vas vasorum and periao rtic small vessels with fibrous tissue embedding the ure- ters, resulting in progressive ob struction. Primary and secondary causes. Associations: Drugs (e.g., \222 -blockers, bromoc riptine, methysergide, ergot- amines), malignancy (carcinoid, lymphoma, sarcomas, carcinoma of colon, prostate, breast, stomach), infections (TB, histoplasmosis), radiation ther- apy , surgery (colectomy, hysterectomy), others (trauma, thyroiditis). Typical patient: Middle- aged men with dull, noncolicky backache with con- stitutional symptoms of weight loss, fati gue, anorexia, \206\221 BP, edema. Tests: Blood: Anemia, uremia, \206\221 ESR, \206 \221 CRP, ANA and few antineutrophil cytoplasmic antibody (anca) +ve. Imaging: Ultrasound/I VP : Dilated ureters (hydronephrosis) + medial devia- tion of ureters with extrinsic compre ssion, peri-aortic mass. Rarely, ultra- sound may be negative. CT/MRI: Periaortic mass that entraps ureters (this allows biopsy, which confirms the diagnosis). Treatment: Retrograde stent placement to relieve obstruction + steroids or other immunosuppressive medications (m ycophenolate mofetil, metho- trexate) or tamoxifen surgery (open/laparoscopic ureterolys is). 261 Glomerulonephritis Abbreviations : ANA, antinuclear antibody; ASO, antistreptolysin O titer ; BM, basement membrane (glomerular); EM, electron microscopy; ESRD , end-stage renal di s ease; HCV, hepatitis C virus; IF, immunofluorescence. Introduction The presentation of GN v aries widely, from asymptomatic to microscopic or macroscopic hematuria, proteinuria, the n ephrotic syn- drome, renal failure, or HTN. Diagnosis is usually made on renal histology, i nterpreted in the light of clinical, biochemical, and immunologic features. Pathophysiology The nephritic syndromes can perhaps be easiest remembered on the basis of the mechanisms b y which injury occurs. These include: Antibodies directed against the glomerular basement membrane; immune complex \200\223mediated disease; pauci-immune mediated endothelial injury (ANCA-associated and no n-ANCA associated); and inherited disorders. (See Figure 8.1) Tests In general, testing sho uld be directed towards the suspected clinical syndrome. However, the clinical history can often be ambiguous, and sero- logic testing can help differentiate the diagnoses. Blood: Co mplement (C3, C4); CBC; electrolytes, BUN, creatinine; liv- er-function tests (LFT); ESR. A utoantibodies : ANA, ANCA, anti-dsDNA ( double stranded DNA ), anti-GBM ( glomerular baseme nt membrane ); blood culture; ASO; HBsAg; anti-HCV, cryoglobulins, serum electrophoresis (s ee Figure 8.2). Urinalysis: To diagnose glomerular bleeding, look for RBC casts, dysmorphic RBCs, and acanthocyturia (5% of RBCs [p. 252]). Urinalysis dipstick and microscopic exam. 24 h urine for protein and creatinine excre- tion/creatinine clearance. Spot urine protein to creatinine ratio for approxi- mation. Chest x-ray (CXR); renal ultrasound; renal biopsy. Management Prompt consultation or referral to a nephrologist is vital to assist with diagn osis and treatment. Antiglomerular basement membrane Rare disorder, seen more frequently in Caucasians and with a bimodal age distribution (second and third decades, and sixth and se venth decades). Autoantibodies generated against type IV collagen lead to injury. Figure 8.2 Nephritic Syndrome 262 Anti-GBM Ab Immune Complex Pauci - immune Inherited ANCA Non-ANCA MPGN* SLE* Post-Infectious GN* Cryoglobulinemia* IgA Nephropathy HSP Alport Thin Basement Membrane HTN crisis Scleroderma Pre-/Eclampsia HUS-TTP APLA Microscopic Polyangiitis Churg \200\223Strauss GPA Associated with low complement \200 - Granulomatosis with polyangiitis (formerly Wegene r \200\231s granulomatosis) Clinical features Over half of patients have rapidly progressive GN with pulmonary involvem ent (Goodpasture \200\231s syndrome) and approximately one-third have isolated GN. Serologi c testing for anti-GBM antibodies. Can also find ANCA positivity in 30 \200\22340% of patie nts. Diagnosis : Renal biopsy: Crescent formation; IF reveals intense linear stain- ing for IgG. Treatment : Plasmapheresis for pulmonary hemorrhage and consider for renal involvemen t (if not extensive fibrosis on biopsy and not dialysis dependent in <72 h from presentatio n), high-dose glucocorticoids, and cyclophosphamide. Prognosis : Without treatment, progres ses quickly to ESRD. Milder forms that do not require dialysis tend to respond to treatment . Immune complex diseases IgA nephropathy (Berger \200\231s disease) Most common cause of G N Clinical features Children, young adults, males (2:1). Presentations Episodic macroscopic gross hematuria 1 \200\2232 d after precipitat- ing URI (40 \200\22350%). This is sometime s known as synpharyngitic hematuria. Diagnosis Renal biopsy: Mesangial proliferation with + ve immunofluores- cence (IF) for IgA and C3. Prognosis 4 \200\22338% of adults develop ESRD over 10 yrs. Risk factors for progression include \206\221 creatinine, \206\221 BP, and >1 g/d pro- teinuria. Treatment: Angiotensin-converting enzyme (ACE)-inhibitors and/ or an giotensin receptor blocker (ARB) for HTN or proteinuria. Consider fish oil supplementation. Immunosuppression if active crescents seen on biopsy or proteinuria >2 \200\2233 g/d despi te ACE inhibitors. Henoch \200\223Sch nlein purpura (HSP) can be regarded as a systemic vari- ant of IgA nephropathy. Clinical features: Polyarthritis of the large joints, purpuri c rash on the exten- sor surfaces, abdominal symptoms, GN. Diagnosis: Usually clinical. May be confirmed by finding positive IF for IgA and C3 in skin lesions or renal biopsy (identi cal to IgA nephropathy). Prognosis: 50% remission; 15 \200\22320% impaired renal function; 3 \200\2235% renal failure. Treatment: For severe proteinuria and renal failure, consider i mmunosup- pression with steroids. Lupus nephritis (LN) 50% of patients with SLE will have renal involve- ment. There are six classifications of lupus nephritis (Table 8.1). The clin ical presentation is widely varied, from microscopic hematuria or mild protei- nuria to mac roscopic hematuria, nephrotic syndrome, and rapidly progres- sive renal failure. Diagnosis: Suggestive lab findings include low C3 and C4 and positive ANA/anti-DNA Ab. Specific diagn osis is confirmed by biopsy. See Table 8.4 for classes of lupus nephritis. In general, it i s a proliferative GN, with mesan- gial and endocapillary involvement, except for membranous type, which should not have endocapillary involvement. A finding of a mixed picture, such as class III/V or class IV/V is not uncommon. Immunofluorescence shows positivity for the f ive antibodies commonly used (against IgG, IgM, IgA, C3, and C1q) to give a \200\234 full house \200\235 staining pattern. See Table 8.4. Additional biopsy findings can include thr ombotic microangiopathy, IC vas- culopathy, vasculitis, and interstitial nephritis. e n i c i d e m l a n e R 263 Table 8.4 Classification of lupus nephritis Class I Class II Class III Class IV Class V Class VI Minimal mesangial LN Mesangial proliferative LN Focal proliferative LN (<50% glomeruli invo lved) Diffuse proliferative LN (>50% glomeruli involved) Membranous LN Advanced sclerosing LN ( > 90% glomeruli globaly sclerosed) Treatment : Target is to quickly decrease immune activity followed by a more prolonged cour se of immunosuppression (induction and mainte- nance therapy). Depending on severity, induc tion utilizes high-dose gluco- corticoids + cyclophosphamide or mycophenolate mofetil. This is followed with maintenance dose glucocorticoids plus additional immunomodulating therapi es such as mycophenolate mofetil, azathioprine, calcineurin inhibi- tors (cyclosporine or t acrolimus). Coordination of care between patient \200\231s primary care, nephrologist, and rheumatologist is key. Prognosis : Worse prognosis is associated with \206\221 serum creat inine, HTN, nephrotic-range proteinuria; chronic tubulointerstitial disease, extensive cres cents on biopsy; delayed initiation of immunosuppression, incomplete remission, or relapse. Despite treatment, 10 \200\22330% of patients with prolifera- tive GN will progress to ESR D. Monitoring for renal disease in the patient with sle Given that early detection is importan t in delaying progression of lupus nephritis, close monitoring of SLE patients without acti ve urine sediment is important. Screening of UA for proteinuria or hematuria and monitor- i ng serum creatinine should be performed every 3 \200\2236 months for the first several year s and then every 6 months to 1 yr thereafter. 264 Membranoproliferative GN Accounts 8% of children and 14% of adults with nephrotic syndrome. Variable presentation: Hematuria, non-nephrotic proteinuria, slowly progressive glomerular disease, nephrotic syndrome. Diagnosis: Biopsy shows glomeruli with mesangial proliferatio n and \200\234double contoured \200\235 BM. Three histological types: Type I (subendotheli al and mesan- gial deposits). Type II (intramembranous and mesangial deposits). Type III (s ubendothelial, mesangial, subepithelial deposits). Reduced serum C3 and C3 nephritic factor s are found in most patients (type II more than type I). Associations: Hep C, SLE, chronic bacterial infections (endocarditis, vis- ceral abscess, shunt nephritis, syphilis), HBV, sc histosomiasis, mixed cryo- globulinemia, monoclonal gammopathy, 1 -antitrypsin deficienc y, chronic leukoblastic leukemia (CLL), partial lipodystrophy, complement dysregula- tion r esulting in complement activation. New classification scheme pro- posed is based on renal b iopsy immunofluorescence findings predominantly positive for IgGs (infection, neoplastic or autoimmune etiologies), com- plement (genetic complement dysregulation), or neither (chron ic throm- botic microangiopathy). Treatment: In adults, long-term benefit of ASA + Pyridamo le, steroids, or other immunosuppressive meds is unclear. Hep C-related treatment (p. 565). Prognosis: Risk factors for worse prognosis include nephrotic proteinuria, \206\221 SCR a t presentation, HTN, interstitial fibrosis on biopsy. 50% develop ESRD if untreated. Acute postinfectious GN Classically occurs 1 \200\2233 wks following phar- yngitis, or 3 \200\2236 wks following skin infection. Although the chief cause is Streptococcus, it can b e seen in a variety of bacterial, fungal, parasitic, and viral infections. Clinical feature s: Hematuria, proteinuria, nephritic syndrome, nephrotic syndrome, renal failure (rare). Re nal biopsy: Hypercellularity, mesangial and endocapillary proliferation, inflammatory cell infiltrate, and cellular crescents in severe cases; IF positive for granular IgG and C3; an d subepithelial deposits on EM. Serology: \206\221 ASO; \206\223 C3. Treatment: Antibioti cs, diuretics, and antihypertensives as necessary. Dialysis is rarely required. Prognosis: Generally good, especially in children. Poorer prognosis in patients >65 and DM with diabet ic glomerulosclerosis. Pauci-immune GN, ANCA-associated granulomatosis with poly- angiitis (GPA)/microscopic polyangiitis (MPA) Occurs more in older adults, more commonly in Caucasia ns. Many have prodrome of a flu-like illness: Fevers, malaise, arthralgias. Renal disease p resents with ARF, hema- turia, and proteinuria. Upper respiratory involvement more common i n GPA, both can have pulmonary involvement. Other organ involvement can include skin (purpu ra), nervous system (mononeuritis multiplex), heart (pericarditis and conduction abnormalit ies), and GI tract. Diagnosis : Serologic testing for ANCA. Although overlap between the sy ndromes exists, GPA is generally PR3 ANCA +, and mpa is generally mpo ANCA +. Histology sho ws focal and segmental fibrinoid necrosis and cellular crescents. MPA lacks granulomas. If shows a paucity of immune deposits. Treatment : High-dose corticosteroids and cyclophospham ide. Consider plasma exchange for pulmonary involvement and severe renal dysfunction (those requiring dialysis). Rituximab without cyclophosphamide can also be considered. Prognosis : Untreated mortality high ( 90% at 2 yrs) versus a 12% mortality at 7 \200\2238 yrs in pat ients treated with cyclophosphamide. Worse renal outcome associated with \206\221 Cr at pr esentation, age >65, lack of response to treat- ment, renal relapse, and \206\221 fibrosis on biopsy. Non-ANCA associated : Essentially due to endothelial damage from mechanical inj ury via thrombotic microangiopathy. See p. 279 for discus- sion on specific conditions. Inh erited disorders Thin basement membrane nephropathy (autosomal dominant). There is persiste nt microscopic hematuria minor proteinuria, with normal BP and renal function. Diagnosis : Positive family history. Renal biopsy: Decreased width of glomerular BM. Prognosis: Benig n. Alport syndrome Predominantly X-linked, although autosomal domi- nant and recessive form s do exist). Caused by a defect in type IV collagen, resulting in progressive glomeruloscle rosis of GBM. Patients have persistent microscopic hematuria proteinuria, bilateral sens orineural hearing loss, and ocular manifestations involving the lens (lenticonus), retina, or cornea. Diagnosis : Positive family history. Can pursue renal biopsy, skin biopsy, or ge netic testing. Renal biopsy : Findings vary depending on timing of biopsy; early disease ma y look normal on LM, with progressive disease showing glomerulosclerosis. If utilizes Ab di rected against subunits of type IV col- lagen and may be useful in diagnosis. On EM, GBM shows thickening and a \200\234basket-weave \200\235 appearance. Prognosis : ESRD typical ly occurs between ages 15 and 35 in patients with X-linked or autosomal recessive forms, la ter for autosomal dominant forms. Treatment : Control BP, supportive manage- ment of renal failure, dialysis, transplantation. e n i c i d e m l a n e R 265 Rapidly progressive GN (RPGN) ESRD develops over weeks or months if untreated. Causes : Ant i-GBM disease (Goodpasture \200\231s), SLE, cryoglobulinemia, Henoch-Sch nlein purpura/I gA nephropathy, postinfectious glomerulone- phritis, Pauci-immune GN. See above discussions regarding clinical features, biopsy findings, and treat- ment. Urgent consultation with a nephrologist is warranted if these entities are suspected. The nephrotic syndrome When there is edema, check a urinalysis for protein to avoid missing this diagnosis. Definition Nephrotic syndrome is the combination of edema, proteinu- ria ( >3 g/24 h), hypoalbuminemia (albumin <3.5 g/dl), and hyperlipidemia. In some cases, this is due to \206\221 urine protein loss resulting in \206\223 albumin, hence \206\223 plasma oncotic pressure (minimal change disease). However, most patients may have a normal or \206\221 plasma volume, suggesting primary salt retention. Causes Minimal change disease (c ommon in children and young adults), focal segmental glomerulosclerosis (common in African Americans), mem- branous nephropathy (common in middle-aged/elderly), DM (the most common c ause), amyloidosis, SLE, membranoproliferative GN. Minimal change glomerulonephritis (MCGN) Commonest cause of nephrotic syndrome in children (76%; 25% of nephrotic adults). Associat ions: Hodgkin \200\231s lymphoma; various drugs (NSAIDs). Clinical features: Nephrotic synd rome; BP \206\221 ; usually little renal impairment; however, acute kidney injury in elder ly from ATN or secondary to NSAIDs with interstitial nephritis. Diagnosis: Selective protei nuria (especially in children). Renal biopsy shows loss of podocyte foot processes on EM. T reatment: Corticosteroids induce remission in >90% of children and 80% of adults (slower re sponse). Indications for other immunosuppression: Cyclophosphamide, cyclosporine; frequent relapses; steroid resistance or dependence. Prognosis: 1% progress to ESRD. Focal segmental glomerulosclerosis can be similar to MCGN as only some glomeruli have segmental sclerosis. It may be primary (idiopathic) or secondary (reflux, sickle-cell disease, obesity, HIV, he roin use, renal scarring after glomerulonephritis). Clinical features: Nephrotic syndrome, proteinu- ria, microscopic hematuria, \206\223 renal function, BP \206\221 . Renal biopsy : Segmental areas of glomerular sclerosis, hyalinization of glomerular capillaries, and pos itive IF for IgM and C3. Treatment: 35 \200\22360% complete and partial remis- sion to ster oids, but prolonged course of high doses (1 mg/kg/d) for >3 \200\2234 months may be require d. Cyclophosphamide or cyclosporine may be used in steroid-resistant cases. Prognosis: 10 \200\22340% if subnephrotic, 45 \200\22370% if neph- rotic progress to ESRD in 10 yrs. Memb ranous nephropathy Accounts for 20 \200\22330% of nephrotic syndrome in adults, 2 \200\2235 % in children. Associations: Malignancy (adenocarcinoma of colon, lung, breast), drugs (gol d, penicillamine), autoimmune (SLE, rheu- matoid arthritis [RA]), infections (HBV, syphilis , leprosy). Signs: Nephrotic syndrome, proteinuria, hematuria, BP \206\221 , renal impairm ent. Hypercoagulable state; see below. Diagnosis: Renal biopsy shows thickened BM, IF +ve f or IgG and C3 and subepithelial deposits on EM. Prognosis: About one-third experience spont aneous remission, one-third have persistent proteinuria but not ESRD, one-third have ESRD o ver 5 \200\22310 yrs. 266