tient is rolled directly into bed for observation. Relative Hypertension (>160/95), hypotension, perinephric abscess, pyelonephritis, hydronep hrosis, severe anemia, large renal tumors, and renal cysts are all relative contraindicatio ns to renal biopsy. Where possible they should be corrected before undertaking the biopsy. The presence of a solitary functioning kidney is considered to be a relative contraindicati on to percutaneous biopsy. It has been argued that performing the biopsy with direct visual ization is required in this circumstance. However, the postbiopsy nephrectomy rate of 1:200 0 to 1:5000 is similar Since no single \201 xative allows good quality immuno \202 uores- cence, light or elect ron microscopy to be performed on the same sample, the biopsy cores are divided into three and placed in: \200 Formalin for conventional light microscopy. \200 Normal saline for subsequent snap-freezing in liquid nitrogen for immuno \202 uorescence microscopy. Glutaraldehyde for electron microscopy. P. TOPHAM 34 There are a number of variations of the percutaneous renal biopsy technique. For example, s ome operators use ultrasound to localize the kidney and to determine its depth and the angl e of approach of the needle. The biopsy is then performed without further ultrasound guidan ce. The success and complication rates of this technique appear to be no different from tha t seen with continuous ultrasound guidance. Computed tomography guidance has been advocated for patients in whom the biopsy can be technically challenging. Alternatives to the percutaneous approach When a percutaneous approach is contraindicated, alter- native approaches to renal biopsy have been described. The choice of technique in an y situation depends on the safety, morbidity, recovery period, and adequacy of the techniqu e, but above all on the local expertise that is available. Transvenous (transjugular or transfemoral) renal biopsy Transvenous sampling of the kidney is theoretically safer than the percutaneous approach because: \200 the needle passes fro m the venous system into the renal parenchyma and is directed away from large blood vessels ; Renal transplant biopsy The general technique for renal transplant biopsy is similar to tha t of the native kidney. The proximity of the allograft to the anterior abdominal wall and t he lack of movement on respiration facilitate its biopsy. If the biopsy is being performed to identify the cause of acute allograft dysfunction a formalin- \201 xed sample for con- ventional light microscopy is usually suf \201 cient. A snap-fro- zen sample for C4d immun ostaining should be obtained if antibody-mediated rejection is suspected. If recurrent or d e-novo glomerulonephritis is suspected, additional sam- ples for electron microscopy and im muno \202 uorescence microscopy should be collected. it is suggested that any bleeding that occurs should be directed back into the venous system; if capsular perforation occurs, signi \201 cant bleeding points can be immediately identi \201 ed and controlled by coil embolization. The transjugular renal biopsy cannot be regarded as rou- tine because it requires specialis t skill, and involves addi- tional time and expense. Indications for this approach are: \200 an uncontrollable bleeding diathesis; \200 the need to obtain tissue from more than one organ Post-biopsy monitoring Following the biopsy the patient is placed supine and is put on stri ct bed rest for 6 \200\2238 h. The blood pressure is monitored frequently, the urine is exa mined for macroscopic hematuria, and the skin punc- ture site is examined for excessive ble eding. If after 6 \200\2238 h there is no evidence of bleeding the patient is sat up in bed and subsequently allowed to mobilize. If macroscopic hematuria develops, bed rest is conti nued until the bleeding settles. Historically patients were observed in hospital overnight following the renal biopsy. including the kidney, liver, or heart; large volume ascites (precludes the prone position); \200 uncontrolled hypertension; \200 morbid obesity; \200 severe respiratory insuf \201 ciency; \200 solitary right k idney; \200 failed percutaneous approach; \200 coma. Studies report diagnostic yields f or transjugular biopsy of between 73 and 98%. Despite these being high risk patients, the c omplication rate appears to be similar to that seen in percutaneous renal biopsy Day case renal biopsy Day case renal biopsy with same-day discharge after 6 \200\2238 h of observation has become increasingly popular. This has been largely driven by the \201 nan cial and resource implications of overnight hospital admission and has been justi \201 ed by the perception that any signi \201 cant complica- tions of renal biopsy will develop wi thin 6 \200\2238 h post-biopsy. However, a recent study has suggested that only 67% of the major complications observed after renal biopsy in 750 patients became apparent within 8 h after biopsy. Up to half of our renal biopsies are performed as day cases. Patients with th e highest risk of complications \200\223 signi \201 - cantly impaired renal function (ser um creatinine >250 mol/L); small kidneys; and uncontrolled hyperten- sion \200\223 shoul d not be considered for a day case renal biopsy. In properly selected cases up to 5% of pat ients can develop a self-limiting postbiopsy complication within 8 h that requires a short hospital admission for observation, and 0.75% of patients return 1 \200\2234 days after sam e-day discharge with either macroscopic hematuria or loin pain due to perirenal hematoma. T ypically such complications settle with conservative management. Therefore, day case biopsy is acceptably safe when a low- risk patient population is selected. Open renal biopsy This is a safe alternative to percutaneous biopsy when uncor- rectable co ntraindications exist. Published studies report tis- sue adequacy of 100% with no major com plications. However, the risk of general anesthesia and the delayed recovery time have prev ented its widespread adoption. It is most useful when a renal biopsy is required in patient s who are undergoing an abdominal procedure for other reasons. Laparoscopic renal biopsy This procedure requires general anesthesia and two lapar- oscopic ports in the posterior and anterior axillary lines to gain access to the retroperitoneal s pace. Laparoscopic biopsy forceps are used to obtain cortical samples, and the biopsy sites are coagulated with laser and packed to pre- vent hemorrhage. The largest published study reported that adequate tissue was obtained in 96% of 74 patients. Signi \201 cant bleeding occurred in three patients, the colon was injured in one, and a biopsy was performed inadv ertently on the spleen and liver in two others. Complications of renal biopsy The complication rates compiled from large series of renal bi opsies are shown in Table 1.7.4. Hemorrhagic CHAPTER 1.7 Renal biopsy 35 complications still occur but other serious complications are now rare. Since most are clinically silent and >95% resolve spontane- ously within two years, routine screening is not recom- mended. Unusually arteriovenous \201 stulae can lead to macrosco pic hematuria, hypertension, and renal impairment, in which case embolization is appropriat e. Table 1.7.4 Complications of renal biopsy (1990 to present) No. of biopsies 3884 Other complications Other rare complications have been reported, including: \200 biopsy o f other organs (liver, spleen, pancreas, bowel, Hematoma 3% Macroscopic hematuria 3% and gallbladder); \200 pneumothorax; \200 hemothorax; \200 calyceal \200\223peritonea l \201 stula; \200 dispersion of carcinoma; \200 Page kidney (compression of the kidn ey by a perirenal hematoma leading to renin-mediated hypertension). Arteriovenous \201 stula formation 0.2% Surgery 1 case Death 1 case Pain A dull ache around the needle entry site is almost invaria- ble when the local anesthe tic wears off. Patients should be warned about this in advance. This can be managed with si mple analgesia such as para- cetamol or paracetamol/codeine combinations. More signi \201 cant pain may indicate signi \201 cant perirenal hemorrhage. Opiate analgesia may be neces sary and appropriate investigations should be undertaken to clarify the severity of the ble ed. Macroscopic hematuria may be associated with ureteral colic (clot colic). Death Death resulting directly from the renal biopsy has become much less common according to recent biopsy series when compared with earlier reports. The vast majority of deaths are the result of uncontrolled hemorrhage in high risk patients, particularly those with acute kidney injury. Further reading Appel GB. Renal biopsy: how effective, what technique, and how safe. J Nephrol 1993; 6: 4. Hergesell O, Felten H, Andrassy K, et al. Safety of ultrasound-guided percutaneous renal bi opsy-retrospective analysis of 1090 con- secutive cases. Nephrol Dial Transplant 1998; 13: 975. Hemorrhage Some perirenal bleeding postbiopsy is inevitable. On aver- age hemoglobin may fa ll by 1 g/dL post biopsy. Signi \201 cant perirenal hematomas are almost invariably asso- ciated with severe loin pain. Both macroscopic hematuria and painful hematoma are seen in 3 % of patients after biopsy. The initial management involves strict bed rest and mainte- nan ce of normal coagulation indices. If the bleeding is either associated with hypotension or prolonged and fails to settle with bed rest, renal arteriog- raphy should be performed to i dentify the source of bleed- ing. Coil embolization can be performed during the procedure a nd this has largely eliminated the need for open surgical intervention and nephrectomy. Madaio MP. Renal biopsy. Kidney Int 1990; 38: 529. Manno C, Strippoli GF, Arnesano L, et al . Predictors of bleeding complications in percutaneous ultrasound-guided renal biopsy. Kidn ey Int 2004; 66: 1570. Sam R, Ing TS. Transjugular renal biopsy: when to do it and when not to? Int J Artif Organs 2001; 24: 595. Schwarz A, Gwinner W, Hiss M, et al. Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 2005; 5: 992. Stiles KP, Yuan CM, Chung EM, et al. Renal biopsy in high-risk patients with medical diseas es of the kidney. Am J Kidney Dis 2000; 36: 419. Internet resources National Kidney Federation biopsy information: http://www.kidney.org.uk/Medical-Info/kidney- disease/biopsy.html Renal biopsy information for patients: Arteriovenous \201 stula When specifically sought by duplex USS or contrast- enhanced CT they can be found in as many as 18% of patients. http://patients.uptodate.com/topic.asp?file= kidn_dis/6752 J. FEEHALLY 36 Immunological investigation of renal disease Immunological tests on blood and urine are never diagnos- tic of kidney disease. Results mu st always be interpreted in the light of clinical evaluation. Commonly useful tests include : \200 serum immunoglobulins (Igs); \200 serum and urine protein electropheresis; \200 complement: C3, C4, CH50; \200 antineutrophil cytoplasm antibodies (ANCA); \200 anti- GBM (glomerular basement membrane) antibodies; \200 anti-DNA antibodies; \200 anti-ENA antibodies; \200 anti-C1q antibodies; \200 antiphospholipid (APL) antibodies. Urine protein electrophoresis (UPEP) This detects urine free immunoglobulin light chains. I t has replaced Bence \200\223Jones proteinuria as the routine test for light chains. The pr esence of free light chains in the urine strongly sug- gests myeloma kidney, amyloid, or MI DD. Cryoglobulins Cryoglobulins are measured as g/L or as a \200\230cryocrit \200\231 \200 \223 the percent precipitate as a function of the total serum volume tested. They must be m easured in serum kept at 37 C from the time of venesection until the serum has been separa ted. Cryoglobulins may be monoclonal or polyclonal. Clinical features of cryoglobulin-relat ed disease include livedo reticularis, liver dysfunction, neuropathy suspicion of lympho proliferative disease. If there is a clinical suspicion of cryoglobulinemia but the cryoglo bulin test is negative, repeat twice since specimen collection requirements can make testin g unreliable. Clinical context Immunological testing is useful in the following contexts: \200 urgent e valuation of unexplained renal failure \200\223 usually as an inpatient; evaluation before renal biopsy; \200 to obtain additional diagnostic information in the l ight of renal biopsy \201 ndings; Complement C3 and C4 components are reported in g/L or mg/dL. C3 and C4 measure the circula ting amount, but do not assess complement activation, which requires measure- ment of CH50 (50% hemolyzing dose of complement); or C3d (or other breakdown products of C3). A low C3 u sually implies tissue injury with activation of complement (classical or alternative pathwa y). A low C4 implies activation of classical pathway or the presence of a hereditary null a llele. In most clinical situations C3 and C4 are sufficient when interpreted with clinical and other laboratory information. follow-up when the diagnosis is known to assess progress, including the response to treatment. Tables 1.8.1 \200\2231.8.3 show the use of tests in these contexts Serum immunoglobulins Reduced serum immunoglobulins Serum IgG, IgA, IgM are reported in g/L . Serum IgG and IgA are typically low in nephrotic syndrome because of urinary loss; serum IgM is not reduced, since the larger pentameric IgM is not lost in urine. A monoclonal incr ease in Ig in myeloma may be accompa- nied by reductions in other serum Igs (immune paresis ). Raised serum immunoglobulins Serum IgA is raised in about one-third of people with IgA neph ropathy. Raised levels of serum Igs must be interpreted in the con- text of the results fro m serum and urine protein electro- phoresis (SPEP and UPEP respectively): \200 polyclonal increases in Igs accompany a number of in \202 ammatory states, including systemic lupus erythema- tosis and vasculitis; Nephritic factor C3 nephritic factor (C3Nef) is a circulating IgG auto-anti- body against C 3 convertase; it stabilizes C3 convertase producing gain-of-function and C3 consumption. C3 Nef is associated with mesangiocapillary GN type II (dense deposit disease). C3Nef should b e measured in glomerulonephritis if the serum C3 is persistently reduced. C4 Nef and Nef ag ainst the alternative pathway convertase occur rarely. a monoclonal increase in Ig is characteristic of myeloma. Serum and urine protein electrophoresis Serum protein electrophoresis (SPEP) SPEP showing a monoclonal Ig band with reduction in other Igs (immune paresis) strongly suggests myeloma. However, this does not prove that the renal disease is myeloma cast nephropathy. Amyloid a nd monoclonal immunoglobulin deposition disease (MIDD) cannot be excluded. SPEP showing a m onoclonal band without immune paresis often means MGUS (monoclonal gammopathy of uncer- tai n signi \201 cance), but this does not exclude a diagnosis of amyloid or MIDD. Factor H Genetic de \201 ciency in factor H, an alternative pathway reg- ulatory protein, is associated with familial hemolytic \200\223ure- mic syndrome, and predisposes to mesangi ocapillary GN type II. The variations in complement associated with renal dis- ease are sho wn in Table 1.8.4. CHAPTER 1.8 Immunological investigation of renal disease 37 Table 1.8.1 Immunological testing for urgent evaluation of renal disease Table 1.8.3 Immunological testing during follow-up of renal disease Clinical setting Tests Diagnosis Test Comments Rapidly progressive renal failure with active urine sediment ANCA Anti-GBM Anti-DNA C3, C4 ANCA-associated vasculitis ANCA Rising titer usually precedes relapse Occasionally persistently positive in remission If also suspicion of lymphoproliferative disease or cryoglobulinemia SPEP UPEP Cryoglobulins Anti-GBM disease Anti-GBM Early testing to follow disappearance of antibody with or without treatment Once antibody negative, test only if clinical suspicion of relapse Serum Igs Anti-DNA C3, C4 Nephrotic syndrome, especially in women with clinical evidence of multisystem extrarenal di sease Lupus nephritis Anti-DNA C3, C4 Anti-C1q Anti-PL, anti-ENA for speci \201 c clinical indications Nephrotic syndrome age >40 years Serum Igs Anti-DNA C3, C4 SPEP UPEP Immunological testing should not be unnecessarily frequent; it is rarely required more ofte n than monthly unless there are rapid changes in the clinical state. Serum Igs SPEP UPEP Unexplained renal failure age >40 years with clinical suspicion of myeloma (anemia, hyperca lcemia, bone pain) Unexplained renal failure age >70 years with bland urine Serum Igs SPEP UPEP Thrombotic microangiopathy without infective prodrome Anti-ADAMTS13 Table 1.8.2 Immunological testing before nonurgent renal biopsy Clinical setting Extra-renal disease Tests Comment Microscopic hematuria None (Anti-GBM) Rare presentation of anti-GBM disease Proteinuria Proteinuria and hematuria Nephrotic None Serum Igs Anti-DNA C3, C4 Age >50 years, add SPEP UPEP syndrome Serum Igs Anti-DNA C3, C4 ANCA Nephrotic syndrome Including those with multisystem extra-renal disease Serum Igs Anti-DNA C3, C4 ANCA SPEP UPEP Nephrotic syndrome age >40 years J. FEEHALLY 38 Table 1.8.4 Altered complement levels in renal disease Pathway affected Complement changes C3 d, C4 d, CH50 d Glomerular diseases Nonglomerular diseases Lupus nephritis (especially class IV) Mixed essential cryoglobulinemia Mesangiocapillary GN type I Classical pathway activation C3 d, C4 d, CH50 d [ C4 nephritic factor] C3 d, C4 normal, CH50 d Post-streptococcal GN GN associated with other infection: \200 endocarditis \200 shunt nephritis \200 hepatitis B Hemolytic uremic syndrome Mesangiocapillary GN type II (dense deposit disease) Alternative pathway activation Atheroembolic renal disease C3 d, C4 normal, CH50 d + C3 nephritic factor Factor H de \201 ciency Hepatic disease Malnutrition Acquired Reduced complement synthesis Systemic lupus erythematosis Familial hemolytic uremic syndrome Hereditary C4 null allele Hereditary C2 de \201 ciency Factor H de \201 ciency In GN associated with visceral abscesses, complement usually normal or raised (elevations b ecause complement components are acute phase reactants). Table 1.8.5 Autoantibodies in systemic lupus and allied conditions Class III and IV lupus nephritis Comments Sensitivity Speci \201 city ANA >98% Low: 30% healthy women positive Also positive in CREST syndrome, scleroderma Sj gren \200\231s syndrome, Mixed connective tissue disease (MCTD) Anti-dsDNA 95% 95% Sm (a small nuclear riboprotein) 20 \200\22330% 90% Associated with lupus AND with nephritis Anti-C1q antibodies 95% 35% in inactive nephritis 25% in lupus without nephritis Anti-Ro (SSA) and anti-La (SSB) Very low Very low MCTD: 90% positive Sj gren \200\231s syndrome: 70 \200\22380% positive Increased congenita l heart block Antiphospholipid (IgG or IgM) antibodies \200\223 \200\223 Anti-PL syndrome: 95% positive Prolong APTT and KCT in vitro, but associated with thrombosi s in vivo Anti-Scl 70 (topoisomerase 1) \200\223 \200\223 Scleroderma: 60% positive; associated with lung involvement and extent of cutaneous change Anticentromere Ab \200\223 \200\223 CREST syndrome: 95% positive CREST: Calcinosis, Raynaud \200\231s syndrome, Esophageal dysmotility, Sclerodactyly, Telan giectasia. CHAPTER 1.8 Immunological investigation of renal disease 39 Antineutrophil cytoplasmic antibodies (ANCAs) IgG ANCAs may be detected by a \202 uoresce nce bind- ing test. ANCA are categorized according to the neutrophil antigen speci \201 ci ty of the antibodies (either PR3 (proteinase 3) or MPO (myeloperoxidase)) and reported in a rbitrary units (AU). ANCAs are strongly associated with small vessel vasculitis with renal involvement, although 10% are ANCA negative at presentation. PR3 antibodies are most commo nly seen in Wegener \200\231s granulomatosis; MPO antibodies are most commonly seen in micr oscopic polyangiitis. However, these associations are not absolute. ANCAs with other antige n speci \201 cities occur, but not usu- ally in association with renal disease. ANCA titer s fall in response to treatment, and in many become negative. There can be persistent ANCA positivity during remission. Antiphospholipid antibodies These can be found with or without systemic lupus and are assoc iated with recurrent venous thrombosis (antiphospholipid syndrome), and intrarenal small ve ssel thrombosis. Anti-C1q antibodies Anti-C1q antibodies are highly speci \201 c for active lupus nephritis (ISN/RPS II, III, IV). Autoantibodies against ADAMTS13 ADAMTS13 is a metalloprotease which normally prevents accum ulation in the circulation of large multimers of von Willebrand factor. Low ADAMTS13 activi ty, either due to genetic deficiency, or to an acquired autoantibody to ADAMTS13, is associ ated with atypical, often recurrent, thrombotic microangiopathy. Other autoantibodies A number of other autoantibodies are associated with lupus and associa ted immune disorders, but because of low speci \201 city they have a limited role in inves tigation of renal disease (Table 1.8.5). Anti-glomerular basement antibodies These are reported in AU of antibody against puri \201 ed GBM. They are strongly associated with anti-GBM disease. They are diagnostic in the con text of pulmonary hemor- rhage and rapidly progressive GN, and therefore renal biopsy may n ot be necessary. The anti-GBM titer follows disease activity. The titer is useful in follow ing treatment response (falls with plasma exchange and immunosuppression). Antibodies are a bsent in remission, and reappear with relapse. Further reading Berden JHM, Wetzels JFM. Immunological investigation of the patient with re nal disease. In: Davison AM et al. (eds), Oxford Textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press; 2004. pp.183 \200\223193. See also Mesangiocapillary glomerulonephritis, p. 112 Mixed cryoglobulinemia and hepatitis C infection, p. 176 Systemic lupus erythematosus, p. 180 Infection related glomerulonephrit is, p. 128 Antiglomerular basement membrane disease, p. 124 Crescentic glomerulonephritis, p. 120 Systemic vasculitis, p. 168 Amyloid or immunotactoid glomerulopathy, p. 150 Rheumato id arthritis, connective tissue diseases and Sj grens syndrome, p. 188 Scleroderma \200 \223 systemic sclerosis, p. 186 Hemolytic uremic syndrome and thrombotic thrombocyt- penic purpura, p. 348 Anti-DNA antibodies Anti-ds (double-stranded) DNA antibodies are character- istic of system ic lupus (Table 1.8.5). Active lupus nephritis (ISN/RPS Class III/IV) is almost always asso ciated with high titer anti-DNA antibodies. Less active lupus nephritis (ISN/RPS Class I, I I, V) is typically associated with low titer anti-dsDNA antibodies. The antibody titer para llels renal disease activity in some patients only. Always interpret the antibody titer in the context of com- plement levels (C3, C4 low in active nephritis) and the clinical featur es. This page intentionally left blank 41 Chapter 2 Fluid and electrolyte disorders Chapter contents Hypo-/hypernatremia: disorders of water balance 42 Hypo-/hyperkalemia 46 Hypo-/hypercalcemi a 52 Hypo-/hyperphosphatemia 56 Hypo-/hypermagnesemia 60 Clinical acid \200\223base disorde rs 64 M. ARICI 42 Hypo-/hypernatremia: disorders of water balance Sodium (Na+) is the major cation in the extracellular \202 uid (ECF). It is also the majo r determinant of serum osmolality. The serum sodium concentration ([Na+]) re \202 ects the rela- tive amount of sodium to water. Serum [Na+] disorders therefore result from changes in water balance. Water balance is controlled by osmoreceptors in the hypothalamus that reg ulate water intake (thirst mechanism) and renal water excretion (antidiuretic hormone (ADH) or vasopressin). ADH decreases renal free water excretion through engagement of V2 recepto rs in the collecting duct. Serum [Na+] disorders usually occur as a result of altered thirs t (excess or inadequate water intake) and aberrant ADH action. Serum [Na+] disorders usuall y result in alterations in serum osmolality. Changes in serum osmolality cause signi \201 cant free water shifts in and out of the intracellular compart- ment to maintain osmotic eq uilibrium. The rapid transcellular shift of water can lead to cellular damage, particularly in the central nervous system (CNS). Most cases are mild, but in acute or inappropriately man- aged cases of hypo- or hypernatremia, substantial morbid- ity and mortality may develo p due to CNS damage. Mannitol, glycine and radiocontrast infusions may also cause translocational hyponatremia Hyponatremia with iso-osmolality (pseudohyponatremia) This is the result of a laboratory ar tifact caused by hyperli- pidemia and hyperproteinemia when the [Na+] is meas- ured by \202 ame photometry. This is not a problem when direct ion-selective electrode measurement is utilized, which is currently the standard method for measuring [Na+]. Pseudohyponatremia is therefore currently rarely a clinical issue. Hyponatremia with hypo-osmolality (true hyponatremia) This is due to a relative excess of w ater and can occur with hypo-, eu- or hypervolemia Clinical evaluation of the underlying ca uses of hypo-osmo- lar hyponatremia is facilitated by clinical assessment of the ECF volume status (Fig. 2.1.1). Decreased ECF volume indicates renal and extra-renal salt and water l osses. Loss of Na+ exceeds loss of water. Thiazide diuretic use is a common cause. Water ex cretion is prevented by baroreceptor-mediated ADH secretion. The most common cause of euvol emic hyponatremia is SIADH. SIADH is also the most common cause of hyponatremia among hospi talized patients. The causes of SIADH are malignant disease, pulmonary disease, disor- ders of the CNS, and drugs. The presence of edema indicates an increase in total body Na+. Hypo natremia occurs as the increase in total body water exceeds that of Na+. Congestive heart f ailure, cir- rhosis, nephrotic syndrome and renal failure are common causes. Water excretio n is prevented by baroreceptor- mediated ADH secretion. Hyponatremia Serum [Na+] <135 mmol/L. Epidemiology Hyponatremia is the most frequent electr olyte abnormal- ity with an incidence of 1% and a prevalence of 15 \200\22322% in hospitali zed patients. Its prevalence is 7% in ambulatory patients. It is more frequent in the elde rly, with reported incidences as high as 30 \200\22350%. Hyponatremic encephalopathy risk i s highest in children, menstruating females, hypoxic patients and patients with brain injur y. Signs and symptoms A low [Na+] concentration is usually associated with hypo-osmolality. Lo w serum osmolality results in water movement into cells, and thus causes cellular swelling, which is clinically most important in brain cells. This osmo- lar shift of water is primar ily responsible for the neurologic symptoms and potentially life-threatening complications. Brain cells compensate for hypo-osmolality by excreting electrolytes and osmolytes, but th is process can take up to 48 h. Symptoms depend on the absolute level of serum [Na+] and th e rapidity of onset of hypo-osmolality. At any [Na+] level, patients with \200\230acute \200\231 hyponatremia (duration <48 h) will have more severe symptoms. In chronic cases, sy mptoms are fewer, milder and less speci \201 c. Most patients with a serum [Na+] >125 mmol /L are asymp- tomatic. Patients with a serum [Na+] \211 125 mmol/L may have anorexia, mala ise, nausea and vomiting. Headache, lethargy, disorientation, confusion and depressed re \202 exes may occur with serum [Na+] <120 mmol/L. With severe (serum [Na+] usually <110 mmo l/L) and rapidly evolving hyponatremia, seizures, coma, brain stem herniation, respi- rator y arrest and death may occur. Pathophysiology Hypo-osmolal hyponatremia occurs when the ingestion of water exceeds excret ion. The most common pathophysiological mechanism is the persistent secretion of antidiuret ic hormone (ADH, vaso- pressin) that prevents maximal urinary dilution. Persistent ADH rele ase is most commonly due to: decreased effective circulating volume, cortisol de \201 cien cy or hypothyroidism, and the syndrome of inappropriate ADH secretion (SIADH). Etiology Hyponatremia can be associated with low, normal or high osmolality: Hyponatremia with hyperosmolality (translocational hyponatremia) This results from the shif t of water out of cells in response to the presence of a nonsodium solute in plasma. The mo st common cause is hyperglycemia. Each 5.6 mmol/ L increase in the serum glucose concentrat ion decreases the serum [Na+] by 1.6 mmol/L. Diagnosis Hyponatremia is rarely suspected from the clinical pres- entation; the diagnosis is made by measurement of the serum [Na+]. CHAPTER 2.1 Hypo-/hypernatremia 43 True hyponatremia Serum [Na+] <135 mmol/l & serum osm <275 mosm/kg Measure serum [Na+] And urine osmolality Assess clinical volume state Hypovolemia Euvolemia Hypervolemia Total body Na+ \206\223 \206\223 Total body water \206\223 Total body Na+ \206\221 Total body water \206\221 \206\221 Total body Na+ normal Total body water \206\221 Pathophysiological condition Urine [Na+] >20 mmol/L Urine [Na+] <20 mmol/L Urine [Na+] >20 mmol/L Urine [Na+] <20 mmol/L Urine [Na+] >20 mmol/L Urine [Na+] <20 mmol/L Measure urine [Na+] Renal loss Diuretics Adrenal insufficiency Salt-losing nephropathy Cerebral salt wasting Extra-renal loss GI loss Skin loss Third-space loss Hypothyroidism Adrenal insufficiency Drugs SIADH Water intoxication Psychogenic polydipsia Renal failure Heart failure Cirrhosis Nephrotic syndrome Underlying Disease process Treatment Water restriction Water restriction Diuretics Isotonic saline Fig. 2.1.1 Take a careful history (for water intake and loss, medications, underlying disease). Clinic ally assess the ECF volume status and perform a neu- rologic evaluation including fundoscop y. Acute and symptomatic hyponatremia The [Na+] is usually <120 mmol/L and needs to be promptl y treated. Failure to treat promptly risks further brain edema, tentorial herniation and de ath. Administer hypertonic saline (3% NaCl, 1 \200\2232 ml/kg/h) with IV furosemide (20 \200\22340 mg) with a maximal rate of correc- tion of serum [Na+] in the range of 1 \200 \2232 mmol/L/h until symptoms resolve. The total magnitude of correction should not exceed 8 \200\22310 mmol/day. The target is to raise the serum [Na+] to safe levels (120 \200\2231 25 mmol/L). During treatment close monitoring of the patient, serum [Na+], \202 uid intak e, urine output and neurologic symptoms are necessary and should preferably be undertaken i n an intensive care setting. Several formulas can be used to calculate the Na+ require- men t (Formula 1), water excess (Formula 2) or to estimate the effect on serum [Na+] concentrat ion of any infused solution (Formula 3) (Table 2.1.1). These formulas can be used to determ ine the initial rate of hypertonic saline infu- sion, but the rate of infusion should be ad justed according to the [Na+] that is measured every 2 \200\2233 h. Chronic, symptomatic hy ponatremia Patients with hyponatremia of over 48 h duration with mild to moderate symptoms need to be treated with caution as overaggressive correction risks CPM. The maximal rate of correction of serum [Na+] should not exceed 0.5 \200\2231.0 mmol/L/h. Laboratory studies: \200 Serum electrolytes and osmolality. \200 Glucose, urea, creatin ine, uric acid, triglycerides and albumin. Urine [Na+] concentration and osmolality. \200 Adrenal and thyroid function tests (in sel ected cases). SIADH is a diagnosis of exclusion. Essential diagnostic fea- tures are: \200 Low plasma osmolality (<275 mOsmol/kg H2O). \200 Elevated urine osmolality (>100 mOsmol /kg H2O in the face of a low plasma osmolality). Presence of clinical euvolemia. \200 Urine [Na+] >40 mmol/L with normal dietary salt inta ke. \200 Normal thyroid, adrenal, and kidney function. \200 No recent diuretic use. \200 Hypouricemia (<238 mol/L) and low [urea] (<3.5 mmol/L) are supplementary features o f SIADH. A diagnostic algorithm for hypo-osmolal hyponatremia is shown in Fig. 2.1.1. In a euvolemic patient with hyponatremia, a urine osmolal- ity <100 mosm/L indicates the presenc e of primary poly- dipsia, reset osmostat or beer potomania. Treatment Treating the underlying cause and restricting \202 uid intake is suf \201 cien t in most cases. Morbidity and mortality are related to neurologic com- plications of eithe r acute cerebral edema in severe, acute cases or central pontine myelinolysis (CPM) due to improper management (too rapid correction or overcorrection). Treatment choices are depende nt on the rapidity of onset of hyponatremia, the severity of symptoms and the ECF volume st ate. Asymptomatic hyponatremia Treatment should focus on underlying causes. \200 In the hypovo lemic patient, prevent further \202 uid loss and replace the ECF volume de \201 cit with normal saline. Once euvolemia is established, ADH production will be sup- pressed and exce ss water will be excreted. For hypervolemic patients, treat the underlying disorder. Restrict salt and water intake an d administer diuretics if necessary. Ultra \201 ltration and dialysis may be required in t hose with resistant heart failure or renal failure. M. ARICI 44 In euvolemic patients, \202 uid restriction (<800 \200\2231000 mL/ day) is the treatment of choice. Some patients may need pharmacologic antagonism of ADH with demeclocycline or li thium. Supplementation of the diet with additional sol- ute in the form of protein, salt or urea may also be helpful. Hypervolemic hypernatremia indicates net sodium gain. Most cases are iatrogenic. Signs and symptoms High serum osmolality results in water movement out of cells, leading to cellular dehydration and cell shrinkage, particularly in brain cells. This osmolar shift o f water is pri- marily responsible for the neurologic symptoms and potentially life-threate ning complications. Brain cells compensate for hyperosmolality by increasing intracellular electrolyte and osmolyte concentrations over a 24 \200\22348 h period. Symptoms of hypernat remia depend on the absolute level of serum [Na+] and the rapidity of onset of hyperosmolal ity. In severe, acute hypernatremia (duration <48 h) brain shrinkage may be substantial, re sulting in cerebral and sub- arachnoid hemorrhage. In less severe chronic hypernatremia, ma nifestations are nonspeci \201 c (nausea, muscle weakness, and alterations in mental statu s ranging from lethargy to coma). Elderly patients have generally few symptoms unless serum [Na+] is >160 mmol/L. Diagnosis Hypernatremia is rarely suspected from the clinical pres- entation; the diagnosis is made by measurement of the serum [Na+]. Take a careful history ( for water intake and loss, polyuria, medications, underlying diseases). Clinically assess t he ECF volume status and perform a neu- rologic evaluation. Laboratory studies: \200 seru m electrolytes and osmolality; \200 glucose, urea, creatinine, calcium; \200 urine sodi um concentration and osmolality. Most patients have signs and symptoms of hypovolemia. Euvo lemic patients are usually mildly hypernatremic, but complain of polyuria. Polyuria is de \201 ned as a urine output of >3 L/day. The water deprivation test followed by administrati on of ADH helps to differentiate central from nephrogenic DI (Chapter 5.5 for details). A d iagnostic algorithm for hypernatremia is shown in Fig. 2.1.2. In a hypo- or euvolemic patie nt with hypernatremia, a urine osmolality >700 mOsm/L indicates the presence of an extraren al source for water loss. A new class of drugs known as vasopressin receptor antag- onists induces free water diuresi s without natriuresis or kaliuresis (aquaretics) by antagonizing V2 receptors in the collec ting duct. Conivaptan (V1a and V2 antagonist) has been approved by the Food and Drug Admini stration for IV treatment of euvolemic and hypervolemic hyponatremia. Several orally active drugs that are speci \201 c to V2 receptors are still being investigated. Prevention Avoid hypotonic \202 uid use in high risk hospitalized patients, especially in the postoperative period. Be cautious with thiazide use in the elderly. Hypernatremia Serum [Na+] >145 mmol/L. Epidemiology In hospitalized patients the prevalence of hypernatremia is 0.5 \200\2233.5%. The highest risk is in patients with altered mental status, the elderly, intubated patients and infants. Pathophysiology Hypernatremia is generated by net water loss or hyper- tonic Na+ gain, but maintained by a failure to sense thirst and/or an inability to access water. Normally the d evelop- ment of thirst prevents the maintenance of hypernatremia. A defect in urine concent ration with an inadequate water intake will cause hypernatremia. A decrease in the level or activity of ADH prevents maximal urinary concentration. Hypernatremia is most often due to net water loss in excess of sodium. This may be due to renal or extrarenal water loss. Etiology Hypernatremia is always associated with hyperosmolality. Hypernatremic conditions are classi \201 ed according to the ECF volume status (Fig. 2.1.2) Hypernatremia with decr eased ECF volume indicates renal or extrarenal salt and water losses in which the loss of w ater exceeds that of sodium. Euvolemic hypernatremia is usually caused by diabetes insipidu s (DI). In DI, there is either an abnormality in ADH secretion (central DI) or resistance t o ADH action in the kidney (nephrogenic DI). Table 2.1.1 Formulas used in calculating initial therapeutic targets of hypo- and hypernatr emia Formula 1: Sodium requirement = TBW \227 (Desired serum [Na+] \200\223 Actual serum [Na+] ) Formula 2: Water excess (in L) = TBW \227 {1 \200\223 (Actual serum [Na+]/Desired serum [Na+])} Formula 3: Serum [Na+] change (after 1 L of IV \202 uid) = ([Na+] concentration in IV \202 uid \200\223 Actual serum [Na+])/(TBW + 1) Formula 4: Water de \201 cit (in L) = TBW \227 {(Actual serum [Na+]/Desired serum [Na+]) \200\223 1} TBW: total body water (in L) is estimated as body weight \227 0.6 in men and \227 0.5 in women. CHAPTER 2.1 Hypo-/hypernatremia 45 Prevention Administering adequate \202 uid avoids hypernatremia in high risk settings. Be cautious with hypertonic solution (such as sodium bicarbonate) administration. Treatment Treating the underlying cause and giving water is suf \201 cient in most cases. Acute symptomatic hypernatremia In this situation rapid correction of the water de \201 ci t is required. Water should be administered (usually as IV 5% dextrose solution) at a rate that reduces the serum [Na+] by 1 mmol/L/h until symptoms have resolved. The total magnitud e of correction should not exceed 8 \200\22310 mmol/ day. During treatment close monitoring of the patient, the serum [Na+], \202 uid intake, urine output and neurologic symptoms a re necessary and should preferably be done in an intensive care unit. Several formulas can be used to calculate the water de \201 cit (Formula 4) or to estimate the effect on serum [Na+] con- centration of any infused solution (Formula 3) (Table 2.1.1). Further reading Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000; 342: 1493 \200\2231499. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342: 1581 \200\2231589.