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Azotemia and Urinary Abnormalities

Azotemia
Assessment of GFR
Direct measurement:
o admin of radioactive isotope (inulin or iothalamate); measured in mL/min
serum creatinine as surrogate to estimate GFR
urea and crea are both problematic:
o urea is reabsorbed in the tubule
o crea is derived from muscle metabolism
CrCl= (Uvol x Ucr)/ (Pcr x Tmin)
If only serum crea available:
o Cockcroft-Gault:
CrCl= (140-age) x weight (kg) x (0.85(if F))/(72 x sCr (mg/dL)
o MDRD (four variables) just check whats on the book haha
o Also take note of the new CKD-EPI eGFR formula
Comments on serum crea reliant formulae:
o Assumpes that patient is in steady state
o MDRD has poorer accuracy when GFR>60mL/min/1.73m2
o Loss of muscle can mask GFR changes
Cystatin C:
o Member of cystatin superfamily of cysteine protease inhibitors
o Constant rate of prdxn from nucleated cells
o More sensitive marker of early GFR decline
o Still influenced by age, race and sex
Approach to patient with azotemia (check Fig 44-1, really helpful)
Oliguria: 24h urine output < 400mL
Carries a more serious prognosis for renal recovery except prerenal azotemia
Anuria: complete absence or <100mL
Nonoliguria: urine output > 400mL/day in patients with azotemia
Disturbances of K and H balance are less severe and recovery to normal renal fxn is usu more rapid

Abnormalities of urine
Proteinuria (check Fig 44-3)
Dipstick measurement:
o Only albumin
o False positive when pH>7.0; very conc urine; contaminated with blood
o False negative with very dilute urine
Albumin-creatine ratio helps approximate 24-h albumin excretion rate
o ACR(mg/g)AER (mg/24h)
Tests to measure total urine protein conc accurate reiles on precipitation with sulfosalicylic or trichloracetic acid
If charge and size selectivity is disrupted at glomerular wall--- plasma proteins leak into urine (glomerular proteinuria)
Smaller proteins (<20kDa) are freely filtered --- but readily reabsorbed by proximal tubule
Healthy individuals excrete <150mg/day of total protein; <30 mg/day of albumin
Remainder of protein excreted by tubules
May also occur with excessive prdxn of abnormal protein
o Plasma cell dyscrasias and assoc with monoclonal prdxn of Ig light chains
Glomerular basement membrane traps most large proteins (>100kDa)
Selective proteinuria: usu with MCD--- fusion of GBM with foot processes
Nonselective: combo of inc pressure and larger pores
If total daily excretion >3.5g: hypoalbuminemia, hyperlipidemia and edema are often present
Light chains from plasma cell dyscrasias:
o Not detected by dipstick
o Filtered by glomerulus and overwhelm the reabsorptive capacity of proximal tubule
! Hypercoagulability arises from urinary losses of antithrombin III, reduced proteins S and C, hyperfibrinogenemia and enhance
PLT aggregation
Hypercholesterolemia: results from inc hepatic lipoprotein synthesis
Loss of Iginc risk of infxn
Hematuria, pyuria and casts (check Figs 44-2)
Hematuria: 2-5RBCs/HPF
o Dipstick:
False positive: occurs with myoglobinuria (rhabdomyolysis)
o Isolated hematuria:
Stones; neoplasms; TB; trauma and prostatitis
o Gross hematuria:
Usually not intrinsic renal process (usu postrenal source)
o Persistent or significant hematuria (>3RBC/HPF on 3 urinalysis; or single urinalysis with >100 RBC or gross
hematuria)
Significant renal or urologic lesions (9.1% of cases)
o Hypercalcuria and hyperuricosuria are also risk factors for unexplained isolated hematuria
Isolated microscopic hematuria
o Manifestation of glomerular diseases
o If glomerular origin: RBCs are dysmorphic by phase-contrast microscopy
o Irregular RBC shapes may also be from pH and osmolarity changes in distal nephron
o Most common etiologies:
IgA nephropathy
Hereditary nephritis
Thin basement membrane disease
Hematuria with dysmorphic RBCs, RBC casts and protein >500mg/d--- virtually diagnostic of GN
Isolated pyuria:
o Unusual since inflammatory rxns of kidney almost always involve hematuria too
o With bacteria: infxn; with bacteria and WBC casts: pyelonephritis
o WBC/WBC casts: seen in acute GN as well as in tubulointerstitial processes (interstitial nephritis and transplant
rejection)
o Waxy casts: seen in chronic renal diseases; are degenerated cellular casts
o Broad casts: arise in dilated tubules of enlarged nephrons that undergo compensatory hypertrophy in response to
reduced renal mass
o Broad casts + cellular casts + RBCs --- chronic glomerulonephritis or other smoldering processes

Abnormalities of Urine Volume
Polyuria (Fig 44-4)
True polyuria (>3L/d)
2 mechanisms:
o Excretion of nonabsorbable solutes
o Excretion of water
o Urine osmolality measured to determine between solute diuresis and water diuresis
Avg person excretes bet 600-800 mosmol of solutes per day (urea and electrolytes)
If UO >3L/d + urine is dilute (<250mosmol/L)--- total mosmol excretion is normal and water diuresis is present
o Arises from polydipsia; central diabetes insipidus; failure of renal tubular response to vasopressin (nephrogenic
diabetes insipidus)
UO> 3L/d + osmolality>300mosm/L--- solute diuresis
o Poorly controlled DM: most common cause of solute diuresis
Plasma vasopressin level: best method for distinguishing between central and nephrogenic diabetes insipidus
Water deprivation test + exogenous vasopressin: distinguishes primary polydipsia from central and nephrogenic diabetes
insipidus

Hypokalemia
Plasma K conc <3.6mM
Causes (check Table 45-4)
Redistribution and hypokalemia
Na, K, ATPase mediated cellular uptake of K
o Promoted by insulin, beta2-adrenergic activity and thyroid hormone
Inhibition of passive efflux of K
o Occurs in setting of systemic inhibition of K channels by toxic barium ions
Iatrogenic hypokalemia
o Exogenous insulin administration
Stimulation of endogenous insulin in malnourished pxs given carbo load
Alterations in activity of endogenous SNS
o Alcohol withdrawal
o Hyperthyroidism
o Acute MI
o Severe head injury
Beta 2 agonists
o Powerful activators of cellular K uptake
Xanthine dependent activation of cyclic AMP-dependent signaling downstream of beta 2 receptor
Hyperthyroidism
Familial hypokalemic periodic paralysis
o Missense mutations of voltage sensor domains in alpha1 unit of L-type calcium channels or skeletal Na channel
Nonrenal loss of potassium
Loss of K in sweat
Direct gastric losses
o Hypochloremic alkalosis--- persistent kaliuresis
Intestinal loss of K due to diarrhea
Colonic pseudo-obstruction (Oglivies syndrome)
o Marked activation of colonic K secretion--- diarrhea with abnormally high potassium content
Renal loss of potassium
Diuretics
o Thiazide
Secondary to thiazide associated hypocalcuria--- dec downstream luminal calcium--- no inhibition of
EnaC in principal cells--- no reduction in lumen negative potential difference--- distal K excretion not
attenuated
Penicillin-related antibiotics
o Obligatory K excretion by acting as nonreabsorbable anions in distal nephron
Primary and secondary hyperaldosteronism
Systemic inc in glucocorticoids
o Cushings syndrome
Magnesium deficiency and hypokalemia
Inhibitory effects on muscle Na K ATPase activity--- reduced influx into muscle cells--- causes secondary kaliuresis
Exaggerated K secretion by distal nephron
o Reduction in Mg dependent intracellular block of K efflux through secretory K channel of principal cells
Clinical features
Major risk factor for ventricular and atrial arrhythmias
Predisposition to digoxin toxicity
o Reduced competition bet K and digoxin for shared binding sites on Na K ATPase
ECG changes (marked when serum K is <2.7mmol/L
o Broad flat T waves
o ST depression
o QT prolongation
Hyperpolarization of skeletal muscle--- impairment in depolarization and contraction--- weakness and paralysis
Skeletal myopathy and rhabdomyolysis predisposition
Intestinal ileus
Renal effects
o Na-Cl and HCO3 retention
Generation of metabolic alkalosis
o Polyuria
Due to combo of polydipsia and AVP resistant renal conc defect
o Phosphaturia
o Hypocitraturia
o Activation of renal ammoniagenesis
o Structural changes:
Vacuolizing injury to proximal tubular cells
Interstitial nephritis
Renal cysts
o Predisposition to acute kidney injury--- end stage renal disease (long-standing hypokalemia due to eating disorders
and/or laxative abuse
Diagnostic approach (see Fig 45-7)
PE
o Focus on BP, volume status and signs suggestive of specific hypokalemic disorders
Laboratory exams
o Initial: electrolytes, BUN, creatinine, serum osmolality, Mg, Ca, CBC, urinary pH
o Non-anion gap
Suggests distal hypokalemic renal tubular acidosis or diarrhea
Calc of urinary anion gap helps differentiate
o Renal K excretion in 24h
<15mM: indicative of extrarenal cause of hypokalemia
o Serum and urine osmolality: calc transtubular K gradient
<3-4 in presence of hypokalemia
o Urine Cl
Usu dec in patients with hypokalemia
o Plasma aldosterone:PRA ratio >50
Hyperaldosteronism
Primary:
o Tested for chimeric FH-I/GRA gene
Treatment
Urgent but cautious K replacement with severe redistributive hypokalemia <2.5mM
o Risk for rebound hyperkalemia
If excessive SNS activity
o High-dose propranolol 3mg/kg
Corrects hypokalemia without risk of rebound
Oral replacement with KCl (mainstay)
Potassium phosphate (PO/IV)
o Appropriate in pxs with combined hypokalemia and hypophosphatemia
Potassium bicarbonate or potassium citrate
o For pxs with concomitant metabolic acidosis
Hypomagnesemic pxs
o Refractory to K replacement alone
o Oral or IV Mg repletion
IV administration should be limited to pxs unable to utilize enteral route
IV KCl
o Always administer in saline solution rather than dextrose
Dextrose-induced inc in insulin--- exacerbates hypokalemia
o Peripheral IV dose is usu 20-40mmol of KCl per liter
o Higher conc
Localized pain from chemical phlebitis, irritation and sclerosis
o If severe hypokalemia <2.5mmol/L and critically symptomatic
Admin through central vein with cardiac monitoring in intesntve care setting at rates of 10-20 mmol/h
o Absolute amount of K should be restriced to 20mmol in 100 mL of saline
o Femoral veins are preferable
Internal jugular or subclavian central lines can acutely inc local conc of K--- affects cardiac conduction
Minimizing K losses
o Minimizing dose of non-K sparing diuretics
o Restricting Na intake
o Using clinically approp combo of non K sparing and K sparing medications (loop diuretics with ACE inhibitors)

























Bladder and Renal Cell Carcinomas

Bladder Cancer
90% at bladder, 8% at urethra
5:1 incidence to mortality ratio
3x higher in male than female
Twofold higher in whites than blacks
Median age of dx= 65
!Once diagnosed: urothelial tumors exhibit polychronotropism- they tend to recur over time and in new locations in urothelial
tract
Epidemiology
o Cigarette smoking
50% of male CA; 40% of female CA
2-4 fold increase in male smokers
Risk continues 10 years or longer after cessation
o Aniline dyes
o Phenacetin and chlornaphazine
o External beam radiation
o Chronic cyclophosphamide
o Vitamin A supplements appear to be protective
o Schistosoma haematobium increases both squamous and transitional cell carcinomas of the bladder
Pathology
o 75% superficial, 20% invade muscle, 5% metastatic at presentation
o 95% transitional cell in origin
o 3% pure squamous with keratinization, 2% adenocarcinomas, <1% small cell tumors
o Adenocarcinomas
Primarily in urachal remnant in dome of bladder
o Lymphomas and melanomas are rare
o Transitional cell tumors
o Low-grade papillary lesions that grow on central stalk are most common
Tumors are very friable and have tendency to bleed
High risk for recurrence
o CISL high-grade tumor and precurosor of lethal muscle-invasive disease
Pathogenesis
o Low-grade papillary tumors that dont tend to invade or metastasize
Receptor-tyrosine kinase-Ras signal transduction pathway
High freq of fibroblast growth factor receptor 3 FGFR3
o CIS and invasive tumors
TP53 and RB gene alterations
Tis, T1 and T2, p53, p21 and or RB tumors
Higher probability of recurrence, metastasis and death
Clinical presentation, dx and staging
o Hematuria: 80-90% of pxs
Often reflects exophytic tumors
Bladder is most common source of gross hematuria
Microscopic hematuria usu of prostate origin
Once documented
Urinary cytology, CT or IV pyelogram and or cystoscopy recommended if no other etiology is
found
TTT
o Superficial disease
At minimum
Complete endoscopic resection with or without intravesical therapy
Intravesical therapy depends on histologic subtype, number of lesions, depth of invasion, presence or
absence of CIS and antecendent history
50% recurrence--- 5-20% progresses to advanced
Solitary papillary lesions
Transurethral surgery alone
CIS and recurrent dse
Transurethral sx ffd by intravesical therapy
Intravesical therapy
2 general contexts
o Adjuvantto complete resection for recurrence prevention
o Eliminate disease that cannot be controlled by resection alone
Advised for:
o Recurrent dse
o >40% involvement of bladder surface by tumor, diffuse CIS or T1 dse
BCG in six weekly instillations--- monthly maintenance admin for more than a year
Mitomyscin-C , Interferon and gemcitabine also used
Side effects
o Dysuria, urinary frequency, myelosuppression or contact dermatitis
Ffg endoscopic resection--- monitor for 3 month intervals during first yr for recurrence
If with persistent dse in bladder--- 2
nd
course of BCG or intravesical chemo
If ureter or renal pelvis tumors--- typically resection or instillation in renal pelvis
o Invasive disease
Radical cystectomy is the standard
Aborted if metastasis is detected
In males
o Removal of prostate, seminal vesicles and proximal urehra too
Impotence is universal unless nerves for erectile function are preserved
In females
o Bladder, urethra, uterus, fallopian tubes, ovaries, anterior vaginal wall and
surrounding fascia
Bladder-sparing approach sometimes
Complete endoscopic resection
Partial cystectomy
Or resection systemic chemo and external beam radiation therapy
Neobladder
Drained more naturally compared to cutaneous reservoirs (intermittent cath)
Contraindications
o Renal insufficiency
o Inability to self-catheterize
o Exophytic tumor
o CIS in urethra
Partial cystectomy
If limited to bladder dome
Margin of 2 cm achievable
No CIS in other sites
Adequate bladder capacity after tumor removal
Cancers in ureter or renal pelvis
Ttd with nephroureterectomy with bladder cuff to remove tumor
Chemotherapy
Inadequate if done alone
o Metastatic disease
Goal is to achieve complete remission with chemo alone or combined-modality
Combined modality
Routine for ttt of germ cell tumors
o Chemotherapy
Drugs with activity as single agents
Cisplatin
Paclitaxel
Gemcitabinemost active
Standard Rx: 2,3,4 drug combinations
>50% response rates
o Methotrexate, vinblastine, doxorubicin and cisplatin
Standard
Neutropenia, fever, mucositis, diim renal and auditory function,
neuropathy
o Cisplatin and paclitaxel
o Gemcitabine and cisplatin
More common
Anemia and thrombocytopenia
o Gemcitabine paclitaxel and cisplatin
Not more effective than GC

Carcinoma of Renal Pelvis and Ureter
Nearly all are transitional cell CA
Assoc with chronic phenacetin abuse and Balkan nephropathy
Most common s/s: painless gross hematuria
Detected on IV pyelogram
Similar pattern of spread with bladder CA
Low-grade ds limited to renal pelvis and ureter--- nephroureterectomy with excision of distal ureter with portion of bladder
Metastatic tumors--- chemo similar to bladder CA

Renal Cell Carcinoma
Notable features
o Resistance to cytotoxic agents
o Infrequent response to biologic response modifiers (IL2 etc)
o Robust activity to antiangiogenesis targeted agents
o Variable clinical course for pxs with metastatic dse
Reports of spontaneous regression
o Epidemiology
Male:female= 2:1
Peak 50-70 yrs
Strongest assoc with cigarette smoking
Acquired cystic dse of kidney assoc with ESRD
Familial forms
Von HIppel Lindau syndrome
o Autosomal dominant
o 35% of individuals with VHL have renal CA
o Pathology and genetics (check table 94-3)
Papillary tumors: usu bilateral and multifocal
Chromophobic: more indolent clinical course
Oncocytomas: considered benign neoplasms
Bellini duct carcinomas: very rare but bery aggressive
Clear cell tumors
Predominant histology (>80% of those with metastases)
Arise from epithelial cells of proximal tubules
3p deletions seen
o 3p21-26 (site of VHL gene maps)
VHL encodes protein responsible for regulation of VEGF, PDGF and
other hypoxia-inducible proteins
Inactivation--- tumor angiogenesis and growth
o Clinical presentation
Presenting triad: hematuria, abdominal pain, flank or abdominal mass
Others: fever, weight loss, anemia and varicocele
Commonly detected as incidental finding on radiograph
Paraneoplastic syndromes assoc with renal cell:
Erythrocytosis
Hypercalcemia
non-metastatic hepatic dysfxn (Stauffer syndrome)
acquired dysfibrinogenemia
Standard eval of pxs with suspected tumors
CT scan of abdomen and pelvis
CXR
UA and urine cytology
CT scan of chest if risk for metastasis
o Staging and prognosis (check Fig 94-2)
Stage I <7 cm and confined to kidney
Stage II >=7cm and confined to kidney
Stage III
Extend through renal capsule
IIIa confined to Gerotas fascia
Involve single hilar lymph node N1
Stage IV disease
Tumors that involve multiple lymph nodes
Distant metastases
o TTT
Localized tumors
Standard for I or II and selected III--- Radical nephrectomy
o En bloc removal of Gerotas fascia and contents (kidney, ipsilateral adrenal gland,
adjacent hilar lymph nodes)
Regional lymphadenectomy
Nephron sparing approaches
o Open or lap sx
o Approp for pxs who have only one kidney
o Also for pxs with bilateral tumors accom by radical nephrectomy
Advanced dse
Sx role is limited
o For metastases at initial presentation
For pain alleviation or hemorrhage of primary tumor
o Cystoreductive nephrectomy before systemic ttt--- im-roves survival for selected
Stage IV tumor pxs
Highly refractory to chemotherapy
o Cytokine Rx with IL-2 or IFN-alpha--- regression in 10-20%
o Cytokine is considered unsatisfactory for most pxs
o Sunitinib
Given PO at dose of 50mg/day for 4 wks out of 6
Diarrhea: main toxicity
o Sorafenib
Usu 400 mg bid
Toxicities:
Diarrhea
Rash
Fatigue
Hand-foot syndrome
o Temsirolimsus, everolimus
Inhibitor of mammalian target of rapamycin (mTOR)
Pxs with unttd poor-prognosis tumors and sunitinib/sorafenib
refractory tumors
Variable prognosis


Benign and Malignant Dses of Prostate

Prostate Cancer
Epidemiology
o African American
o High consumption of dietary fats
o Polycyclic aromatic hydrocarbons
o Development of prostate CA is a multistep process
Hypermethylation of GSTP1 gene promoter (early changes)--- loss of fxn of gene tat detoxifies
carcinogens
No cancer diagnosis
o Prevention
5alpha reductase inhibitors
Predom therapy to reduce future risk of prostate CA dx
o PE
Need to pursue dx of prostate CA based on s/s, abn DRE or change in or elevated PSA
Urologic hx
Focus on s/s of outlet obstruction, continence, potency or change in ejac pattern
DRE
Focus on prostate size, consistency and abnormalities within or beyond the gland
Many occur in periph zone
Characteristically hard, nodular and irregular
Induration may also be due to BPH or calculi
o PSA (check Fig 95-2)
Kallikrein-related serine protease--- liquefaction of seminal coagulum
Serum lvls are not affected by DRE
Prostate bx--- inc PSA 10 fold for 8-10 wks
PSA in blood is inactive
Free PSA rapidly eliminated from blood by glom filtration--- half life of 12-18 hrs
PSA bound to alpha1-antichymotrypsin- slow (r/t size--- too big)
Undetectable 6 wks after prostate removal
PSA plus DRE annually for men older than 50
African americans and people with hx
Assess PSA plus DRE since 45
o Prostate bx
Dx est by TRUS- guided needle bx
Min of 6 cores, three right and three left is advised
Men with prostatitis
Should have course of antibiotics before bx
Men with abn PSA and negative biopsy
o Pathology
Gleason grading system is used
o Prostate CA staging
T1c- purely based on abn PSA
T2- palpable but clnically confined
T3,4- extended outside of gland
TRUS
Most frequently used to assess primary tumor
Chief use is in directing prostate biopsies, not staging
CT lacks sensitivity and specificity for extraprostatic extension, MRI in visualization of lymph nodes
MRI with endorectal coil
Superior to CT
T1- high signal in periprostatic fat, periprostatic venous plexus, perivesicular tissues, lymph
nodes and bone marrow
T2- demonstrates internal architecture of prostate and seminal vesicles
Most CA with low signal while normal peripheral zone has high signal
o Treatment
Clinically localized disease
Nonmetastatic after staging studies
Managed by radical prostatectomy, radiation therapy or active surveillance
Choice depends on :
o Presence of symptoms
o Probability of untttd tumor affecting quality of survival
o Probability that tumor can be cured by single therapy
If PSA detectable >4wks after removal by sx
o Persistent disease
After radiation, PSA remains detectable
Radical prostatectomy
o Goal:
Excise cancer completely with clear margin
Preserve potency
o Advised for patients with life expectancy of 10 yrs or more
Radiation therapy
o External beam radiation
Requires three-dimensional confomal treatment plans intensity-
modulated radiation therapy
Cancer control after radiation therapy
Decline in PSA to 0.5 or 1ng/mL
Nonrising PSA values
Negative biopsy of prostate 2 years after completion
o Brachytherapy
Current standard technique achieves more homogenous dose
distribution by placing seeds accdg to a customized template based on
CT and utz assessment of tumor
Fwer complications
Well tolerated
SE:
Urinary frequency and urgency for several months
Incontinence (2-4%)
Higher complication rates with pxs undergone TURP
Active surveillance
o Policy of monitoring the illness at fixed intervals with DRE, PSA and ill-prostate
biopsies
Rising PSA
Pxs whom sole manifestation of dse is rising PSA after surgery and/or radiation therapy
Dse in primary site may still be curable by additional local ttt:
o External beam radiation for those who underwent sx
o Prostatectomy for pxs who underwent radiation Rx
Rise in PSA after sx or radiation indicates subclinical or micrometastsatic disease
Most physicians advise ttt when PSA doubling times are 12 months or less
Metastatic disease: Noncastrate
Men with metastases and noncastrate levels of testosterone (>150ng/dL)
Symptoms of metastatic disease
o Pain from osseous spread
o Many are asymptomatic
o Anything r/t coagulopathy or spinal cord compression
Standard treatment
o Deplete/lower androgens by medical or surgical means
o Block androgen binding o AR in testes
o Surgical orchiectomy is gold standard, but least acceptable to pxs
Testosterone-lowering agents
o GnRH agonists/antagonishsts, 17,20-lyase inhibitors, estrogens, progestational
agents
o Estrogens fallen out of favor due to risk of vascular complications (fluid retention,
phlebitis, emboli and stroke)
o GnRH analogues init rise in leutinizing hormone and FSH with downregulation of
receptors in pituitary gland
Contraindicated in men with significant obstructive symptoms, cancer-
related pain or spinal cord compromise
o GnRH antagonists: castrate levels of testosterone within 48 hours without init rise
in serum testosterone seen in GnRH analogues
o Androgen depletion syndrome seen wih such agents:
Hot flushes
Weakness
Fatigue
Impotence
Sarcopenia
Anemia
Change in personality
Depression
Changes in lipids, obesity, insulin resistance, with inc risk of DM and
CVD
Decrease in bone density
Antiandrogens
o Nonsteroidal antiandrogens (flutamide, bicalutamide and nilutamide)
Blocks ligand binding to AR
Gynecomastia remains significant problem
Intermittent Androgen Deprivation Therapy
o Proposed as a way to prevent selection of cells that are resistant to androgen
depletion
o Allowing endogenous testosterone levels to rise--- cells that survive induce a new
differentiation pathway
o Here, androgen depletion carried on for 2-6 mos beyond point of maximal
response
Outcomes of Androgen Depletion
o Antiprostate cancer effects of diff agents are similar:
Initial response--- period of stability (dormant and nonproliferative
tumor cells)--- variable period of time of rise in PSA and regrowth
visible in a scan as castration-resistant lesion
o Not curative because cells that survive castration are present when disease is first
diagnosed
Metastatic Disease: Castrate
Castration-resistant prostate cancer progresses despite androgen suppression by medical or
surgical Rxs
Testosterone levels are 50ng/mL or lower, continues to express AR and is dependent on
signaling through receptor for growth
Manifestation
o Rise in PSA with no change in radiographs and no new symptoms
o Rising PSA and progression in bone with or without s/s
o Soft tissue disease with or without osseous metastases
o Visceral spread in others
Management of pain secondary due to osseous metastatic disease is critical esp for
neurologic symptoms
Mitoxantrone: first cytotoxic agent that provides pain palliation for castrate metastatic
disease
Docetaxel: a q3w therapy was superior to weekly therapyto mitoxantrone
Two bone-seeking radioisotopes, 89Sr (Metastron) and 153 Sm0EDTMP (Quadramet) are
approved for palliation despite having no effect on PSA
Biphosphonates inhibit osteoclasts--- protect against bone loss assoc with androgen depletion
and prevent skeletal eents

Benign Disease
Symptoms
o Hesitancy, intermittent voiding, diminished stream, incomplete emptying, postvoid leakage
o AUA index (Table 95-2)
o Resistance to urine flow--- reduced bladder compliance--- nocturia--- urgency and urinary retention
o Typically remain stable over time and obstruction does not occur
Diagnostic procedures and ttt
o Asymptomatic patients do not require treatment regardless of size of gland
o Those with inability to urinate, gross hematuria, recurrent infxn, or bladder stones may require surgery
o Uroflowmetry can identify those with normal flow rates and those with high postvoid residuals
o Pressure flow studies: detects primary bladder dysfxn
o Cystoscopy: if hematuria is documented
o Medical therapiesL
5alpha reducatase inhibitors and alpha-adrenergic blockers
Adrenergic blockers relax the smooth muscle of bladder neck--- inc peak urinary flow rates
o Surgical approaches
TURP, transurethral incision, or removal of gland via retropublic, suprapubic, or perineal approach
TULIP (transurethral ultrasound guided laser-induced prostatectomy), stents and hyperthermia



Nephrolithiasis
Types of stones
Calcium oxalate and calcium phosphate stones (75-85%)
o CaPO4 usually hydroxyapatite or less commonly brushite
Calcium stones
o More common in men
o Avg age of onset is 3
rd
or 4
th
decade
o Avg rate for recurrent stone formers: 1 stone every 3 years
Uric acid stones (5-10%)
o More common in men
Struvite (5%); cysteine (1%)
Manifestations of stones
Stone passage
o As it traverses ureter (may be asymptomatic) but usually produces pain and bleeding
Begins gradually in flankinc over next 20-60 min
Pain may remain in flank or spread downward and anteriorly toward ipsilateral loin, testis, or vulva
o Stone in portion of ureter within bladder wall
Causes frequency, urgency and dysuria--- confused as UTI
o Vast majority of ureteral stones (<0.5cm) pass spontaneously
o Helical computed tomography s radiocontrast enhancement: standard radiologic procedure
o XR may be used to monitor patients for formation and growth of kidney stones as they are less expensive and with
less radiation exposure
Ca, cysteine, and struvite: radiopaque; uric acid stones: translucent
Other syndromes
o Staghorn calculi
Fills renal pelvis and extends outward through infundibula to calyces themselves
Very few symptoms; may lead to eventual loss of kidney fxn
o Nephrocalcinosis
Ca stones grow on papillae
Most break loose--- cause colic
Others remain in place--- multiple papillary calcifications found by x-ray nephrocalcinosis
Common in hereditary renal tubular acidosis (RTA)
Medullary sponge kidney dse--- calcification occurs in dilated distal collecting ducts
Infection
Activity of stone dse
o Sequential radiographs are needed to document the growth or appearance of new stones and ensure that passed
stones are actually newly formed, not preexistent
Pathogenesis of stones
Protective mechanisms from stone formation:
o Pyrophosphate, citrate and glycoproteins
Supersaturation
o Calcium, oxalate and phosphate form many soluble complexes among themselves and with other substances in
urine such as citrate--- free ion activities are below chemical conc--- reduction in ligands such as citrate--- increases
ion activity--- supersaturation
o Increased by:
Dehydration
Overexcretion of calcium, oxalate, phosphate, cysteine or uric acid
Urine pH is impt too
Phosphate and uric acids dissoc readily over physiologic range of urine
Alkaline urine has more dibasic phosphates--- brushite and apatite deposits
pH 5.5
o uric acid crystals predominate, phosphate crystals are rare
! solubility of calcium oxalate is not influenced by pH changes
Crystallization
o Excessive supersat--- nucleation of crystals---- grows in size if urine is supersaturated with respect to crystal phase---
multiple crystals aggregate--- kidney stone
o Common calcium oxalate form as overgrowths on apatite plaques in renal papillae (Randalls plaques)
Plaques are excellent surface for heterogenous nucleation of calcium oxalate salts
Begin in the deep medulla in basement membraneof papillary urothelium
Urothelium damage--- plaque exposed to urine--- ca oxalate crystals form--- growth into
stones
o Calcium phosphate stone formers dont follow Ca oxalate pattern
Relies on brushite
Inner medullary collecting ducts are plugged with apatite crystals--- stones form as extension of those
plaques
Renal papillae are often fibrotic and deformed
Evaluation and TTT of patients with nephrolithiasis
Practical outpatient evaluation
o 2 24-h urine collections
o Blood sample
o Measurements of serum and urine calcium, uric acid, electrolytes and creatinine, along with urine pH, volume,
oxalate and citrate
o At least one urine collection should be made on weekend and another on a workday
o Every px should be counseled to avoid dehydration and drink copious amounts of water
o Inc of urine volume to 2.5L per day--- 50% reduction of stone recurrence compared with control
o Treatment: nephrolithiasis
Oral alpha1 adrenergic blockers--- relax ureteral muscle--- reduce time to stone passage
Extracorporeal lithotripsy: in situ fragmentation of stones in kidney, renal pelvis or ureter
Percutaneous nephrolithotomy: requires passage of nephroscope into renal pelvis through small incision
in flank--- stones disrupted by small utz transducer or holmium laser
Ureteroscopy with stone disruption with holmium laser
Calcium stones
o Idiopathic hypercalciuria
Most common metabolic abnormality found in pxs with nephtolithiasis
Familial and polygenic trait
Diagnosed by hypercalciuria without hyperaclecima and absence of other systemic d/o
Vit D overactivity
Treatment:
Low-sodium and low-protein diet
Thiazide diuretics may be used if diet therapy is insufficient
o Hyperuricosuria
20% of Ca oxalate stone formers
Excessive intake of purine from meat and fish
Salting out calcium oxalate by urate
Low-purine diet is therapeutic but difficult
Allopurinol as alternative
o Primary hyperparathyroidism
Est by documenting hypercalcemia that is unexplained and is accompanied by inappropriate elevated
serum conc of PTH
Hypercalciuria is usu present
Ca oxalate from on interstitial apatite plaque
Ca phosphate form on apatite crystals--- obstructing collecting ducts
Parathyroidectomy should be carried out before recurrent stones or renal damage occurs
o Distal renal tubular acidosis
Defect resides in distal nephron--- unable to establish normal pH gradient bet urine and blood---
hyperchloremic acidosis
Dx suggested by minimum urine pH>5.5 in presence of systemic acidosis
CaPO4 stones form--- nephrocalcinosis common
Osteomalacia or rickets may occur
Apatite deposits--- extensive medullary tubular interstitial nephropathy--- reduced kidney function
Topiramate: commonly for seizures and migraines
Inhibits carbonic anhydrase--- causes calcium nephrolithiasis
TTT
Supplemental alkali--- limits prdxn of new stones and reduces hypercalciuria
o Potassium citrate is preferred 0.5mEq/kg body wt (2-3 divided doses per day)
Thiazide ttt: with incomplete RTA that develop because of idiopathic hypercalciuria
Monitor changes in urine citrate and pH
If urine pH inc without citrate inc--- stone disease may worsen
o Hyperoxaluria
Urine oxalate comes from diet and endogenous metabolic production 40-50% from dietary sources
Upper limit of normal oxalate excretion 40-50mg/day
Mild hyperoxaluria (50-80mg/day) sually excessive intake of high-oxalate food (spinach, nuts and
chocolate)
Low-calcium diets promote hyperoxaluria
Oxalate excretion is often >100mg/day
Enteric hyperoxaluria may be due to
Jejunoileal bypass for obesity
Pancreatic insufficiency
Extensive small-intestine involvement from Crohns dse
Fat malabsorption--- Ca binds with FA instead of oxalate
Unabsorbed FA and bile salts--- injures colon--- inc oxalate absorption
Primary hyperoxaluria
Rare autosomal recessive
Recurrent calcium oxalate stones in childhood
Type I
o Deficiency in peroxisomal enzyme alanine: glyoxylate aminotransferase
Type II
o Deficiency in D-glyceric dehydrogenase
TTT
Diet low in oxalate and normal intake of Ca and Mg
Enteric hyperoxaluria
o Low-fat, low-oxalate diet and Ca supplements
o Oxalate-binding resin cholestyramine
Primary hyperoxaluria
o High fluid intake, neutral phosphate, potassium citrate and pyridoxine (25-
200mg/d)
Liver transplantation: successful for patients with primary hyperoxaluria
o Hypocitraturia
20-40% of stone formers either as single d/o or in combo with other metabolic abnormalities
Can be secondary to systemic d/o (RTA, chronic diarrheal illness and hypokalemia)
Idiopathic hypoctiraturia is primary
TTT
Alkali--- inc urine citrate excretion
o Bicarb or citrate salts
o Potassium salts preferred as sodium loading inc urinary excetion of Ca--- reducing
effectiveness of TTT
Lemonade and other citrate-rich beverages have been used but not as great a change in urine
citrate as seen with pharma dosing of citrate salts
o Idiopathic calcium lithiasis
Best ttt
High fluid intake so that urine sg remains <=1.005
Thiazide diuretics and citrate therapy helps reduce crystallization of Ca salts
Oral phosphate at 2g daily--- lowers urine calcium, inc urine pyrophosphate
Orthophosphate: mild nausea and diarrhea but tolerance may improve with continued intake
Uric acid stones
o Persistently acidic urine is major risk factor
o Urine pH is low--- protonated form of uric acid predominates--- soluble in urine at conc of 100 mg/L
Supersaturation at above this conc
o Common causes of acidic urine and uric acid stones
Metabolic syndrome
Chronic diarrheal stats
Gout
Idiopathic uric acid lithiasis
o Myeloproliferative syndromes, chemo for malignan tumors, Lesch-Nyhan syndrome--- massive production of uric
acid
o Obstruction of renal tubules--- can cause acute renal failure
o TTT
Raise urine pH and lower excessive urine uric acid excretion to <1g/d
Supplemental alkali: 1-3mEq/kg BW/day, 3-4 divided doses, 1 dose at bedtime
Goal: urine pH bet 6-6.5 in 24 h urine collection
Going over 6.5 has no additional benefit but inc risk for Ca PO4 stone formation
Potassium citrate may reduce risk of Ca salts crystalizing
Sodium salts increase risk of Ca salts
Low-purine diet should be instituted
If pxs continue to form uric acid despite ttt with fluids, alkali and low-purine diet--- allopurinol added to
their regimen
Cystinuria and cysteine stones
o Inherited d/o
o Proximal tubular and jejunal transport of dibasic amino acids, cysteine, lysine, arginine and ornithine is defective---
excessive amts lost in urine
o Cysteine crystals plug terminal collecting ducts--- stones may grow--- damage to papillae and medulla from crystal
obstruction--- kidney fxn reduced
o Pathogenesis
Defective transpo by brush borders of renal tubule and intestinal epith cells
Mutations In heavy and light chains of heteromeric amino acid transporter in proximal tubule
Two main types of cystinuria
Type I
o Heterozygotes have normal urine cysteine excretion
o Autosomal recessive
Non-type I
o Heterozygotes have mod elevated urine cysteine excretions with homozygotes
having much higher urine cysteine
o Dominant trait with incomplete penetrance
o Diagnosis
Only by pxs with cystinuria
10% of stones of cystinuric pxs do not have cysteine--- screen every stone former
Sediment from first morning urine specimen with homozygous cystinuria--- typical hexagonal, platelike
cysteine crystals
Also detected by urine sodium nitroprusside test
Sensitive: positive in many asymptomatic heterozygotes
Cysteine stones seldom form in adults unless adult urine excretion is at least 300 mg/d
o TTT
High fluid intake even at night (should exceed 3L)
Raising urine pH with alkali is helpful provided that it exceeds 7.5
Low-salt diet can reduce cysteine excretion
Drugs such as penicillamine and tiopronin
Forms mixed soluble disulfide cysteine-drug complexes
Only when fluid loading, salt reduction and alkali therapy are ineffective
Low-methionine diets: not proven practical for clinical use, but pxs should avoid protein gluttony
Struvite stones
o Result of urinary infxn usu Proteus species
o Urease--- degrades urea to NH3 and CO2--- NH3 hydrolyzes to NH4 and raises urinary pH to 8 or 9--- NH4
precipitates PO4 and Mg--- MgNH4PO4 formation
o Presence of struvite crystals in urine: rectangular prisms that resemble coffin lids, indicates infxn with urease-
producing organisms
o TTT
Complete removal of stone with subsequent sterilization
Percutaneous nephrolithotomy is preferred approach
Extracorporeal lithotripsy plus percutaneous approach could be done
Open sx is rarely required
Hemiacidrin: dissolves struvite--- reduces recurrence after sx via irrigation of pelvis and calyces
Antimicrobial ttt after sx and in dealing with acute infxn
Urine cultures and culture of stone fragments should be done as guide for antibiotic choice
Acetohydroxamic acid: for pxs who are not candidates for sx
Urease inhibitor
SE: headache, tremor, thrombophlebitis
Urinary Tract Obstruction
Etiology
Intrinsic or extrinsic mechanical blockade and functional defects
Common sites of obstruction:
o Ureteropelvic and ureterovesical junctions
o Bladder neck
o Urethral meatus
Lesions below the bladder: bilateral involvement; lesions above the bladder: unilateral involvement
Children:
o Usu congenital malformations
Most common: abnormal insertion of ureter into the bladder
o Reinsertion of ureter into bladder is done if reflux is severe and unlikely to improve spontaneously
Or if renal fxn deteriorates or UTI recur despite chronic antimicrobial therapy
o Vesicoureteral reflux may cause prenatal hydronephrosis, and if severe can lead to recurrent urinary infections and
renal scarring in childhood
o Most common cause of bilateral hydronephrosis in boys: posterior urethral valves
In adults urinary tract obstruction is mainly due to: acquired defects
o Pelvic tumors, calculi and urethral strictures predominate
Ligation of or injury to ureter during pelvic or colonic surgery--- hydronephrosis--- unilateral--- remains undetected
Functional impairment of urine flow
o Disorders of both ureter and bladder usually
o Causes include neurogenic bladder, often with adynamic ureter and vesicourethral reflux
o May be the result of alpha-adrenergic and anticholinergic agents as well as opiates
Hydronephrosis in pregnancy: relaxation effects of progesterone on smooth muscle of renal pelvis as well as ureteral
compression by enlarged uterus
Clinical features and pathophysiology (Table 289-2)
Pain:
o Most common symptom that earns medical attention
o Related to distention of collecting system or renal capsule
o Influenced more by rate at which distention develops than by degree of distention
o Acute supravesical obstruction--- renal colic
Radiates to lower abdomen, testes or labia
o Chronic narrowing of ureteropelvic junction--- little pain or no pain but result in total destruction of affected kidney
o Flank pain that only occurs with micturition
Pathognomonic of vesicoureteral reflux
o Obstruction below bladder, presents with:
Hesitancy and straining; post void dribbling; urinary frequency; incontinence
o Obstruction of urine flow--- inc in hydrostatic pressures proximal to obstruction site--- buildup of pressure--- pain+
elevated intratubular pressures--- initiates tubular dysfunction--- inc hydrostatic pressure in glomerular space---
further filtration decreases or ceases
Azotemia:
o Develops when overall excretory function is impaired
o If acute renal failure + anuria--- complete bilateral obstruction
o Assess for UTO if
Renal failure otherwise unexplained
History of nephrolithiasis, hematuria, DM, prostatic enlargement, pelvic sx, trauma, or tumor
o Acute setting: partial bilateral obstruction may mimic prerenal azotemia with conc urine and sodium retention
o More prolonged obstruction--- polyuria and nocturia commonly accompany partial UTO; results from diminished
renal conc ability
o Downregulation of transport proteins (Na, K, ATPase transporter, NaKCL cotransporter in thick ascending limb and
epith Na channel in collecting duct cells--- impairment of transcellular salt reabsorption in proximal tubule,
medullary thick ascending limb of Henle and collecting duct cells--- failure to produce urine freel of salt (natriuresis)
+ loss of medullary hypertonicity--- urinary conc defect
o Indirect effects that decrease salt reabsorption across nephron:
Inc PGE2 (r/t induction of COX-2)
Angiotensin II (r/t Na transporter downregulation)
ANP (volume expansion in azotemic patient)
o Dysregulation of aquaporin-2 in collecting duct--- polyuria contribution (does not improve with admin of
vasopressin) a form of nephrogenic diabetes insipidus
o Wide fluctuations in urine output with azotemia--- possibility of intermittent or partial UTO
o Inadequate fluid intake--- severe dehydration and hypernatremia
Acquired distal renal tubular acidosis, hyperkalemia, renal salt wasting
o r/t partial bilateral UTO
o trafficking of intracellular H pumps from cytoplasm of cell membrane: disrupted in UTO
o dec fxn of ENaC in apical membrane of collecting duct principa cells--- dec Na reabsorption, dec electronegativity of
tubule lumen--- dec K secretion via K channels--- hyperkalemia
o --- dec H secretion via H-ATPases--- distal renal tubular acidosis
o Proximal tubule ammoniagenesis impaired--- accompanied by renal tubulointerstitial damage
o Azotemia with hyperkalemia and metabolic acidosis should prompt consideration of UTO
Early in UTO: renal interstitium becomes edematous and infiltrated with mononuclear inflammatory cells
Later: interstitial fibrosis + atrophy of papillae and medulla
Angiotensin II inc--- inflammatory response and fibroblast accumulation--- eventually chronic kidney dse
! consider UTO always in pxs with UTI or urolithiasis
HPN: frequent in acute and subacute unilateral obstruction; usu consequence of inc renin release
o CKD dse from bilateral UTO often with extracellular volume expansion--- significant HPN
Erythrocytosis: infrequenc complication of obstructive uropathy
o Secondary to inc erythropoietin prdxn
Diagnosis
Hx of difficult voiding, pain, infxn or change in urinary volume
Urinalysis: hematuria, pyuria, and bacteriuria
o Urine sediment often normal, even with marked azotemia and extensive structural damage
! If UTO is suspected: insert bladder catheter
Abdominal UTZ: performed to eval renal and bladder size and pyelocalycea contour
o 90% specific and sensitive for hydronephrosis detection
o False positive: diuresis, renal cysts, presence of extrarenal pelvis
o Congenital ureteropelvic jxn--- mistaken for renal cystic dse
o Absent hydronephrosis on UTZ if:
If less than 48 hours in duration
Associated with volume contraction
staghorn calculi
retroperitoneal fibrosis
infiltrative renal dse
o Duplex Doppler UTZ: detects inc resistive index in urinary obstruction
High-resolution multidetector row CT scan:
o Advantages of visualizing retroperitoneum plus identifying both intrinsic and extrinsic sites of obstruction
Noncontrast CT scans: improve visualization of urinary tract with renal impairment
o Safer for pxs at risk for contrast nephropathy
MR urography
o Risk of certain gadolinium agents in pxs with renal insufficiency
IV urogram
o Defines site of obstruction and demonstrates dilation of various structures above obstruction
Radionuclide scans
o Differential renal fxn but less anatomic detail
Retrograde or antegrade urography
o No risk of contrast-induced ARF
o Retrograde: catheterization of involved ureter under cystoscopic control
o Antegrade: provides immediate decompression of unilateral obstructing lesion
Retrograde done first unless catheterization is unsuccessful
Voiding cystourethrography
o Dx of vesicoureteral reflux and bladder neck and urethral obstructions
o Postvoiding films: residual urine
Endoscopic visualization: precise identification of lesions involving urethra, prostate, bladder and ureteral orifices
TTT
UTO complicated by infxn: needs immediate relief of obstruction--- prevent devt of generalized sepsis and progressive RF
Drainage possible via:
o Nephrostomy, ureterostomy, or ureteral, urethral or suprapubic catheterization
Prolonged antibiotic ttt may be necessary
Nephrectomy indicated if:
o Chronic or recurrent infxns in poorly fxning obstructed kidney
Infxn not present:
o Sx delayed until acid-base, fluid and electrolyte status is restored
Fxnal obstruction secondary to neurogenic bladder
o May be decreased with combo of frequent voiding and cholinergic drugs
Prognosis:
Complete obstruction with infxn--- total destruction of kidney within days
Partial return of GFR follows relief of complete obstruction of 1 and 2 weeks duration
o After 8 weeks of obstruction: recovery unlikely
In absence of definitive evidence of irreversibility--- every effort should be made to decompress obstruction
Renal radionuclide scan
o Performed after prolonged period of decompression
o Used to predict reversibility of renal dysfxn
Postobstructive diuresis:
Only with relief of bilateral complete obstruction
Polyuria after which may be massive
Hypotonic urine with large amounts of NaCL, K, PO4, Mg
Natriuresis:
o Due in part to excretion of retained urea (osmotic diuresis)
o Natriuretic factors accumulated during uremia
o Depressed salt and water reabsorption
Results usually in appropriate excretion of excesses of retained salt and water
Abates spontaneously when ECF volume and composition return to normal
Iatrogenic expansion of ECF volumeresponsible for or sustains postobstructive diuresis
o IV replacement in amts less than urinary losses prevents this
Loss of electrolyte-free water with urea--- hypernatremia
Na and urine sodium and osmolal conc--- guide approp use of IV replacement
o Replacement with 0.45% saline
Dec tubule reabsorptive capacity--- probably responsible for marked diuresis
TTT
o IV administration of salt-containing solutions to replace Na and volume deficits

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