Oxygen should be used with care in patients with severe COPD who are breathing spontaneousl y. In this situation, aggressive use of oxygen may worsen respiratory acidosis (through los s of hypoxic respiratory drive). Furthermore, rapid correction of hypercapnia may pro- voke complications such as cardiac arrhythmias and reduced cerebral perfusion which may lead to seizures. In chronic respiratory acidosis, general measures such as cessation of cigarette smoking, use of oxygen, bronchodila- tors, corticosteroids and diuretics should be careful ly considered. Respiratory alkalosis Respiratory alkalosis is characterized by: \200 high arterial blood pH (alkalemia); \200 reduced PCO2; \200 normal or reduced serum HCO3 \200\223 concentration (due to renal compensation). Respiratory alkalosis and decreased PCO2 (hypocapnia) is due to increased alveolar ventilat ion which increases the HCO3 Thus hypocapnia develops when ventilation is increased and the elimination of PCO2 from the lungs is increased relative to its production in the tissues. The most commonly observed acid \200\223base disturbance in critically ill patients is res piratory alkalosis and when severe it is associated with a poor prognosis. It may be associ ated with mechanical ventilation and many cardiopulmonary disorders. Increased bicarbonate excretion occurs in acute respira- tory alkalosis and within hours is followed by reduced n et acid excretion. In chronic hypocapnia, the serum bicarbonate concentra- tion is reduced but rarely falls to <12 mmol/L in uncompli- cated respiratory alkalosis. \200\223/PCO2 ratio as well as the blood pH. Etiology of respiratory alkalosis Central nervous system disease (with a direct effect on t he respiratory center) \200 Head injury. \200 Pain. \200 Anxiety, psychogenic. \200 Fever. \200 Meningitis/encephalitis. \200 Cerebovascular accident. \200 Tumor. \200 Trauma. \200 Various endogenous toxins, e.g. toxins in patients with chronic liver dise ase, progesterone in pregnancy, cytokines during sepsis. Investigation of respiratory alkalosis The diagnosis and evaluation of respiratory alkalosi s requires measurement of arterial pH and PCO2 as well as a detailed clinical history and p hysical examination. Drugs \200 Salicylates. \200 Analeptics (respiratory stimulants). \200 Methylxanthine s. \200 Nicotine. Hypoxemia \200 High altitude. \200 Severe anemia. \200 Pneumonia. \200 Pulmonary edema Investigations include Arterial blood gas analysis: \200 con \201 rm the presence of alkalemia; \200\223. \200 exclude metabolic acidosis as cause of low HCO3 Serum/plasma urea, creatinine, electr olytes, bicarbonate and chloride. Drug screen as appropriate. Chest X-ray. P. GUPTA AND W. MADIRA 74 In the evaluation of a patient suspected of hyperventilation syndrome, the organic and meta bolic disorders such as pulmonary embolism, cardiac ischemia and hyperthy- roidism should b e considered and excluded. Kraut JA, Krutz I. Metabolic acidosis of CKD: diagnosis, clinical char- acteristics and treatment. Am J Kidney Dis 2005; 45: 978 \200\223993 Kraut JA, Krutz I. Use of base in the treatment of severe acidaemic states. Am J Kidney Dis 2001; 38: 703 \200\223727. Morgan TJ. What exactly is the strong ion gap and does anybody Treatment of respiratory alkalosis As respiratory alkalosis is rarely life-threatening, tre atment should focus on identifying and alleviating the underlying cause. Rebreathing from a paper bag during symptomatic attacks, reassurance, and awareness of the underlying psychol ogi- cal stress are useful in the management of patients with the hyperventilation syndrome . care? Crit Care Resusc 2004; 6: 155 \200\223159. Penney MD, Oleesky DA. Renal tubular acidosis. Ann Clin Biochem 1999; 36: 408 \200\223422. Schwartz GJ. Plasticity of intercalated cell polarity: effect of meta- bolic acidosis. Nephron 2001; 87: 304 \200\223313. Wagner CA, et al. Renal acid \200\223base transportation: old and new players. Nephron Physiol 2006; 103: 1 \200\2236. Internet resources The Renal Association (2007) Clinical Practice Guidelines: Further reading Chairat SA, Seth LA. Inherited renal tubular acidosis. Curr Opin http://www.renal.org/guidelines/index.html Review of the management of metabolic acidosis: Nephrol Hypertens 2000; 9: 541 \200\223546. Dubin A, et al. Comparison of three different methods of evaluation of metabolic acid \200 \223base disorders. Crit Care Med 2007; 35: 1264 \200\2231270. http://www.intox.org/databank/documents/treat/ treate/trt34_e.htm Review of the management of metabolic alkalosis: Dubose Jr, TD. Acid \200\223base disorders. In: Brenner BM (ed.), Brenner and Rector \200 \231s \200\234The Kidney \200\235. Philadelphia: WB Saunders; 2004. pp. 921 \200\223996. http://www.intox.org/databank/documents/treat/ treate/trt35_e.htm Review of renal physiolog y: English P, Williams G. Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J 2004; 80: 253 \200\223261 Fall PJ, Szerlip HM. Lactic acidosis: from sour milk to septic shock. http://www.brucegilbertmd.com/publications/ chapters/BRGcambells.htmL Review of acid \200 \223base disorders: J Intens Care Med 2005; 20: 255 \200\223271. Figge J, et al. Anion gap and hypoalbuminaemia. Crit Care Med 1998; 26: 1807 \200\2231810. Gluck SL. Acid \200\223base. Lancet 1998; 352: 9126. Heusel JW, Siggaard-Andersen O, Scott MG. Physiology and disor- ders of water, electrolyte, and acid \200\223base metabolism. In: Burtis CA, Ashwood ER (eds), Tietz Textbook of Clinical Chemistry. Philadelphia: Saunders; 1999. pp. 1095 \200\223124. http://www.kidneyatlas.org/book1/adk1_06.pdf Overview of acid \200\223base physiology: http://www.anaesthesiamcq.com/AcidBaseBook/ ABindex.php Hood VL, Tannen RL. Mechanisms of disease: protection of acid \200\223base balance by pH re gulation of acid production. N Engl J Med 1998; 339: 819 \200\223826. See also Hypo-/hyperkalemia, p. 46 Renal tubular acidosis, p. 208 Hypokalemic tubular disorders, p. 214 Dialysis and hemoperfusion treatment of acute poisoning, p. 336 Kellum JA, et al. The \201 rst international consensus conference on continuous renal rep lacement therapy. Kidney Int 2002; 62: 1855 \200\2231863. Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic meta- bolic acidosis in patients with chronic kidney disease. Kidney Int 2005; 67: S21 \200\223S27. 75 Chapter 3 Glomerular disease Chapter contents Proteinuria and/or hematuria 76 Nephrotic syndrome 80 Minimal change disease 86 Focal segme ntal glomerulosclerosis 92 Immunoglobulin A nephropathy and Henoch \200\223Sch nlein purpu ra 100 Membranous nephropathy 106 Mesangiocapillary glomerulonephritis 112 Acute endocapill ary glomerulonephritis 116 Crescentic glomerulonephritis 120 Antiglomerular basement membra ne (Goodpasture \200\231s) disease 124 Infection-related glomerulonephritis 128 Malignancy- associated glomerular disease 134 Glomerular disease in the tropics 138 J. FEEHALLY 76 Proteinuria and/or hematuria random (preferably early morning) urine specimen. In glomerular disease albumin is the majo r protein excreted in the urine. 24 h urine collections are tedious for patients and there- fore inaccurate. Urine ACR or PCR on a random sample is suf \201 cient in routine clinica l practice. Measure the excretory renal function: serum creatinine and calculation of estim ated GFR. Immediate microscopy of the urine may be helpful (only if a skilled observer is a vailable \200\223 see below). Renal imaging: ultrasound and plain abdominal radiograph (ra diograph is more sensitive for ureteric stones). If there is persistent proteinuria and/or hematuria with normal renal imaging: \200 \200 General principles Proteinuria and hematuria are two cardinal features of kidney disease. U rine dipstick testing to detect them is simple and widely available. Persistent proteinuria or hematuria is much more likely to indicate signi \201 cant renal disease. The combinati on of proteinuria and hematuria is more likely to indicate signi \201 cant and potentially progressive kid- ney disease than either alone. Urine testing is mostly opportunist. Sympt omless individuals often have a urine test if they require medical approval for some key li fe event, e.g. life insurance, employment, entry into armed forces. Screening is only for h igh risk populations, e.g. those patients with diabetes, hypertension, cardiovascular dis- ease, family history of renal disease. Not all people with kidney disease have proteinuria or hematuria. Proteinuria is most characteristic of glomerular disease. In tubulointerstiti al and vascular renal parenchymal disease, proteinuria often develops later or not at all. Not all people with proteinuria or hematuria have kidney disease. Hematuria has many other possible causes in the renal tract. immunological tests (see Chapter 1.8); consider renal biopsy (see below for speci \201 c c riteria and Chapter 1.7). Tests of coagulation are only indicated for hematuria if there is clinical suspicion of a b leeding disorder or as prep- aration for a renal biopsy. Interpreting proteinuria values Normal Urine protein:creatinine ratio (uPCR) <15 mg protein / mmmol creatinine (approximately equivalent to <150 mg/24 h). Nephrotic-range proteinuria uPCR >350 mg/mmol. Absolutely characteristic of glomerular dise ase. Initial evaluation Repeat the urine dipstick 2 \200\2233 times to con \201 rm it is per- s istent. Ignore trace hematuria or proteinuria (the sticks are very sensitive). Urine cultur e. If the dipstick is persistently positive in the absence of infection: Non-nephrotic proteinuria uPCR 15 \200\223350 mg/mmol. This is much less speci \201 c. It occurs with a wide range of nonglomerular parenchymal renal diseases as well as with urinar y tract conditions beyond the kidney. Microalbuminuria 30 \200\223300 mg albumin/day (it is usually measured as urine ACR: microa lbuminuric range is 2.5 \200\22330 mg/mmol in men, and 3.5 \200\22330 mg/mmol in women). Th is is below the sensitivity of the urine dipstick. It is used to identify early diabetic ne phropathy. It may also be used to assess cardiovascular risk, for exam- ple in patients wit h hypertension (controversial). History Enquire about: \200 \200 \200 \200 \200 lower urinary tract symptoms; visible hematuria; frothy urine; swelling; symptoms suggestiv e of multisystem immune disease (skin, eyes, joints, etc.); history of hypertension; histor y of deafness; Family history of kidney disease or hypertension. \200 \200 Interpreting evidence of hematuria Hematuria is usually detected by dipstick testing. The d ipstick is very sensitive, therefore ignore \200\230trace \200\231 readings. The dipstick does not differentiate between hematuria and hemoglobinuria so should be interpreted in the clinical context. Microscopic hematuria has a quantitative de \201 nition based on the nu mber of red cells seen on urine microscopy. This is not helpful in clinical practice; there is no value in con \201 rming the presence of red cells by routine microscopy in the labo ratory (they are often absent because of cell lysis in hypotonic urine before it reaches th e laboratory). Examination Look for: \200 edema; \200 hypertension; \200 renal masses; \200 abnorm alities on urine microscopy (if a skilled observer is available). Investigations Quantify proteinuria: either urine albumin:creatinine ratio (ACR) or protein :creatinine ratio (PCR) on a CHAPTER 3.1 Proteinuria and/or hematuria 77 Proteinuria appears later in the day (uPCR usually <100) and is isolated proteinuria (i.e. no hematuria, normal BP, normal GFR). The prognosis is uniformly good and renal biopsy is t herefore not indicated. Glomerular disease is no less likely if the dipstick is positive and routine urine microsco py is negative. Immediate microscopy of urine by a skilled observer is use- ful (but often unavailable): \200 \200 Persistent non-nephrotic proteinuria Persistent non-nephrotic proteinuria is usually caused by glomerular disease. If the GFR is preserved and the uPCR <100, renal biopsy is not requ ired. Prolonged follow-up is necessary while proteinuria persists, since there is a small r isk of progressive renal disease. casts indicate parenchymal renal disease; dysmorphic red cells under phase contrast microsc opy indicate glomerular hematuria. Asymptomatic proteinuria (Fig. 3.1.1) \200\230Functional \200\231 proteinuria This is tran sient non-nephrotic proteinuria that can occur with fever, exercise, or heart failure. It i s benign and assumed to have a hemodynamic cause. Role of renal biopsy Although controversial, many nephrologists will perform a renal biopsy in patients with a normal GFR and no hematuria if there is persistent non-nephrotic protei nuria (PCR >100), especially if it persists following ACEI or ARB treatment. Tubulointersti tial disease can also cause low-grade proteinu- ria (usually uPCR <200) and typically indic ates a poor long- term renal prognosis. Over \202 ow proteinuria This is caused by increased \201 ltration of proteins through a normal glomerular barrier. It is typical of urinary light chain excretion in myeloma. Susp ect if the urine dipstick is negative for albumin despite large amounts of proteinuria by o ther tests. Tubular proteinuria In addition to the loss of tubular proteins (such as 1- or B2-microgl obulin), tubular injury will also lead to some albuminuria owing to impaired tubular reabso rption of \201 ltered albumin. Tubular proteinuria accompanying glomer- ular (nonselectiv e) proteinuria is an adverse prognostic sign in various glomerular diseases as it usually i ndicates advanced tubulointerstitial damage. Asymptomatic proteinuria with hematuria The risk of signi \201 cant glomerular injury, hyp ertension, and progressive renal dysfunction is much higher compared with proteinuria or he maturia alone. In general the prognosis is worse, whatever histological pattern is identi \201 ed by renal biopsy. Renal biopsy is indicated if hematuria is accompanied by uPCR >50. Orthostatic proteinuria In this benign condition, proteinuria does not occur in the recumbe nt position, so there is no protein in the early morning urine. Proteinuria with hematuria and with multisystem disease Thresholds for renal biopsy are low er when proteinuria and/or hematuria accompany clinical and laboratory Asymptomatic proteinuria Quantify proteinuria: uPCR Measure renal function: eGFR Non-nephrotic: uPCR <350 Normal GFR Recumbent overnight Test morning urine uPCR >100 Reduced eGFR Dipstick negative Orthostatic proteinuria No further action Dipstick positive Persistent proteinuria Serological tests Renal imaging Reassess 6 \200\22312 monthly Urine dipstick uPCR eGFR BP IF uPCR >100 and rising Hematuria BP rises eGFR falls RENAL BIOPSY Reassess annually if: Normal BP Normal eGFR uPCR stable Fig. 3.1.1 Evaluation of asymptomatic isolated proteinuria without hematuria. J. FEEHALLY 78 evidence of multisystem immune disease, most commonly systemic lupus erythematosus or syste mic vasculitis; active glomerular disease requiring therapeutic intervention is more likely . Urological evaluation Persistent isolated microscopic hematuria in patients aged >40 years (without evidence of a glomerular cause): cystoscopy is mandatory to exclude uroepithelial malignancy. Persistent isolated microscopic hematuria in patients aged <40 years: uroepithe lial malignancy is so rare that cystos- copy is not recommended. If age is >40 years and th ere is hematuria with proteinuria, the possibility of two coincidental diagnoses should not be forgotten. If in doubt and particularly if risk factors for urothelial malignancy are p resent, undertake cystoscopy to exclude malignancy. Isolated microscopic (nonvisible) hematuria (Fig. 3.1.2) Microscopic hematuria (without pro teinuria) is common in many glomerular diseases, especially IgA nephropathy (IgAN), thin ba sement membrane nephropathy (typically an autosomal dominant condition), and Alport syndrom e (usually X-linked and occurs with deafness). There are, however, many other causes of hem aturia in the genitourinary tract beyond the kidneys. The prevalence of isolated microscopi c hematuria is high, increases with age, and is more common in women than men. A single pos itive test for blood is found in up to 20% of older women. Persistent microsopic hematuria requires further evaluation. Any detectable proteinuria coinciding with microscopic hematur ia virtually excludes \200\230urological \200\231 bleeding and strongly suggests a glomeru lar origin. If urine microscopy is available, suspect glomerular hema- turia if: \200 \200 Role of renal biopsy If all these evaluations are negative, consider a glomerular cause for isolated microscopic hematuria. Renal biopsy is usually not indicated since the prognosis is excellent if there is normal renal function, normal blood pressure, and low grade protei nuria (uPCR <50). Renal biopsy will identify the cause of familial hematuria (where no affe cted family member has previously had a biopsy) and therefore may avoid other family member s undergoing extensive evaluation. Renal biopsy may be needed to facilitate medical certi \201 ca- tion, e.g. for immigration requirements, for life or health insurance, or for recr uitment to public or military service. Whether or not the cause of hematuria is de \201 ne d by renal biopsy, repeated clinical evaluation (urinalysis, eGFR, blood pressure) is manda tory while hematuria persists, since a good long-term renal prognosis cannot be absolutely guaranteed. >5% of the red cells are \200\230acanthocytes \200\231; red cell casts are present (usuall y only seen with pro- teinuria). Urine cytology (looking for malignant cells) is not useful. Renal imaging will identify mac roscopic structural kidney disease (e.g. polycystic kidneys), stones, tumors, or (rarely) a rteriovenous malformations. Asymptomatic persistent microscopic haematuria Quantify proteinuria: uPCR Measure renal function: eGFR Renal imaging Age <40 years Renal imaging normal uPCR <50 Normal BP Normal eGFR Renal imaging - stone or suspected tumor Age > 40 years Renal imaging normal Urological evaluation including cystocopy Urological management Reassess annually Undiagnosed familial renal disease Professional/social reasons for early diagnosis IF uPCR >50 and rising BP rises eGFR falls RENAL BIOPSY Fig. 3.1.2 Evaluation of asymptomatic microscopic hematuria without proteinuria. CHAPTER 3.1 Proteinuria and/or hematuria 79 Macroscopic hematuria requires urological evaluation including renal imaging and cystoscopy at any age unless it occurs in a young person and the history is characteristic of glomeru lar hematuria. Macroscopic (visible) hematuria Macroscopic hematuria associated with glomerular disease is usually episodic and is brown or \200\230smoky \200\231 rather than red, and clots are un usual. It is usually painless although the kid- neys may ache. It must be distinguished fro m other causes of red or brown urine: \200 \200 \200 \200 \200 Further reading Cameron JS. The patient with proteinuria and/or haematuria. In: Davison AM, et al. (eds), Oxford Textbook of Clinical Nephrology, 3rd edn. Oxford: Oxford University P ress; 2004. pp. 389 \200\223414. Floege J, Feehally J. Introduction to glomerular disease: clinical pres- entations. In: Feehally J, Floege J, Johnson R (eds), Comprehensive Clinical Nephrology. St Louis, MO: Mosby; 2007. pp. 193 \200\223207. hemoglobinuria; myoglobinuria; porphyrias; consumption of food dyes, particularly beetroot; drugs, particularly rifampicin. See also Urinalysis and microscopy, p. 8 Imaging in renal disease, p. 20 Renal biopsy, p. 3 2 Immunological investigation of the patient with renal dis- ease, p. 36 Nephrotic syndrome , p. 80 IgA nephropathy, p. 100 Macroscopic hematuria caused by glomerular disease is usually seen in children and young ad ults and becomes rare beyond the age of 40 years. The commonest cause is IgAN, but it may o ccur with other glomerular diseases. In IgAN, the frank hematuria is usually episodic, occu rring within a day of an upper respiratory infection. This is a clear distinction from the 2 \200\2233 week latency between an upper respiratory tract infection and hematuria that is highly suggestive of postinfectious (usually post-streptococcal) GN, when there may also b e other features of nephritic syndrome. P. TOPHAM 80 Nephrotic syndrome Nephrotic syndrome is the term given to the constella- tion of: \200 The GCW is a trilaminar structure comprised of fenes- trated glomerular endothelial cells, the glomerular base- ment membrane (GBM), and podocytes. It is richly decorated throughout with an anionic glycocalyx which electrostatically repels negatively charged proteins. In a ddition, the structure of the GBM and the podocyte intercellular junctions (slit-diaphragms ) restricts the pas- sage of proteins according to molecular size. Proteinuric disease is a lmost invariably associated with structural or functional changes in the GCW. In particular , it is now recognized that most nephrotic diseases are asso- ciated with podocyte injury a nd dysfunction (manifest on electron microscopy as foot process effacement), and the loss o f anionic charge in the GCW. Thus proteinuria usually results from a loss of both charge an d size selectivity in the GCW. The precise mechanism underlying these changes is unknown fo r most diseases, but in in \202 ammatory conditions, a variety of cytokines, eicosanoids, and complement components (e.g. C5b-9, TNF- , interleukin-1 ) may be implicated. Hemodyna mic changes in the glomeruli may also promote proteinuria. Experimentally, an increase in i ntraglomerular pressure results in proteinuria, and the corollary of this is that currently available therapies which reduce intra- glomerular pressure are antiproteinuric. heavy proteinuria (>40 mg/m2/h or >50 mg/kg/day (i.e. >3.5 g/day in a 70 kg adult)); hypoal buminemia (<25 g/L); edema; hyperlipidemia; lipiduria. \200 \200 \200 It is associated with a variety of other complications including, hypercoagulability, negat ive nitrogen balance, and infection. Etiology Common causes of nephrotic syndrome are listed in Table 3.2.1. Substantial protein uria may also be seen in the absence of edema or the other complications of the nephrotic s yndrome. This usually results from glomerular disease with the same etiologies as the nephr otic syndrome, but is not associated with the same clinical and management complications. H eavy proteinuria in this setting is often due to secondary FSGS. Clinical features, complications, and pathogenesis Presenting features Patients with the ne phrotic syndrome characteristically present with edema. This is often \201 rst noticed in a periorbital distribution \201 rst thing in the morning. This is characteristic of neph rotic syndrome: facial edema is rare in heart failure or cirrhosis because in those conditi ons patients are unable to lie \202 at due to the devel- opment of pulmonary edema or pre ssure on the dia- phragm from massive ascites in heart failure and cirrhosis respectively. As the degree of edema increases, \202 uid will accumulate around the ankles, sacrum and elbows in a gravity-dependent manner, and then become more generalized. Genital edema may e nsue and cause signi \201 cant distress. Severe edema may be associated with striae, even in the absence of steroid therapy. Pleural effusions and ascites may develop. In children, the edema is less gravity dependent and ankle edema may be absent even in the presence of a scites and pleural effusions. Hypoalbuminemia is also associated with loss of normal pink c oloration of the nail. This results in white nails or, if the nephrotic syndrome is transie nt, white bands (Muerhrcke \200\231s bands). Xanthelasma may also develop as a result of th e associated hyperlipidemia. Hypoalbuminemia This largely results from urinary losses of protein. A contribution from pr otein catabolism by tubular epithe- lial cells may also be relevant. In response, hepatic a lbumin synthesis is increased but this is insuf \201 cient to prevent a fall in serum albu min con- centration. Hepatic synthesis of other proteins is also enhanced and if these prot eins are too large to be lost in the urine, their plasma concentration may actually increas e. This under- lies some of the other complications of the nephrotic syn- drome, e.g. hyper coagulability and hyper lipidemia. Edema Edema is thought to result from two distinct mechanisms: Under \201 ll model This is thought to be more common in children. The reduced plasma onco tic pressure promotes the trans- location of \202 uid from the vascular compartment into the extracellular \202 uid compartment. The reduction in plasma volume stimulates both ac tivation of the renin \200\223angiotensin \200\223aldosterone system, and release of vasopr essin, which results in sodium and water reab- sorption in the distal nephron. Capillary hy drostatic pressure is increased and this promotes further \202 uid movement into the extr avascular compartment. Proteinuria Nephrotic range proteinuria is almost always due to glomerular disease. Under n ormal circumstances the passage of most plasma proteins (particularly albumin) into the uri ne is prevented by the glomerular capillary wall (GCW). Over \201 ll model This results primarily from a defect of sodium excretion in the distal nephron. The cause of the natriuretic defect is unclear but may relate to tubulointerstitia l in \202 ammation that often accompanies proteinuria. CHAPTER 3.2 Nephrotic syndrome 81 Thrombotic episodes are typically venous, but arterial involvement can rarely occur. The ri sk of thrombosis is inversely proportional to the serum albumin concentration, and is incre ased markedly at levels <20 g/L. Membranous nephropathy is more frequently complicated by t hrombotic events than other causes of nephrotic syn- drome. The reason for this is unknown. The pathogenesis of the increased thrombotic risk is multi- factorial (Table 3.2.2). Table 3.2.1. Common causes of nephrotic syndrome Prevalence (%) Children Young adults Middle and old age Minimal change disease 77 23 18 Focal segmental glomerulosclerosis 8 18 15 Mesangiocapillary glomerulonephritis 7 13 5 Table 3.2.2. Coagulation abnormalities that promote thromboembolism in patients with the ne phrotic syndrome Membranous nephropathy 2 10 34 Other proliferative glomerulonephritis 6 30 15 Immobility Hemoconcentration Increased viscosity (increased \201 brinogen levels) Physical factors Amyloid 0 2 16 Increased concentration (increased hepatic synthesis) Fibrinogen Factors V and VII Von Will ebrand factor Protein C 1-Macroglobulin Unchanged/reduced concentration (increased hepati c synthesis offset by increased urinary loss) Factors IX, X, XI, XII Antithrombin III Clotting factor abnormalities Sodium retention results in an increased blood volume associated with suppressed vasopressi n and angiotensin/ aldosterone levels. The increased intracapillary hydrostatic pressure an d the low oncotic pressure favors movement of \202 uid into the extravascular compartment . Hyperlipidemia This is very common in nephrotic patients (>90% of patients with >3 g protei nuria per day will have serum cholesterol >5.2 mmol/L). Therefore hyperlipidemia is usu- al ly included in the de \201 nition of nephrotic syndrome. Serum cholesterol concentrations may be extremely elevated, as much as >10 mmol/L in 25% of patients. Triglyceride concentra tions are more variable. The degree of hyperlipidemia correlates inversely with the serum a lbumin concentration. The enhanced hepatic lipo- protein synthesis is stimulated primarily by reduced plasma oncotic pressure. The nephrotic lipid pro \201 le is regarded as atherog enic (increased LDL (particularly the more atherogenic LDL III), IDL and VLDL; increased li poprotein (a); reduced HDL-2 and -3) and nephrotic patients (with the exception of those wi th minimal change disease) have \201 ve-fold increased risk of cardiac death. Hyperlipide mia may also independently promote progres- sive renal dysfunction. Hyperlipidemia results from: \200 Altered prostaglandin metabolism Altered membrane lipids Increased von Willebrand factor Enhanced platelet function Possibly resulting from lipid abnormalities Abnormal endothelial function Infection Historically infection was a common cause of death in childhood nephrotic syndrom e. With the advent of effec- tive treatment with steroids, infection is now less of a probl em but remains a signi \201 cant concern in developing countries. The characteristic infec tions are primary peritonitis (usually pneumococcal) and cellulitis ( -hemolytic streptoco cci). The pathogenesis of the increased infection risk is multi- factorial: \200 Increased hepatic synthesis of very low density lipopro- tein (VLDL). This leads to a downs tream increase in both intermediate density lipoprotein (IDL), and low density lipoprotein (LDL). Reduced catabolism of lipoproteins due to inhibition of endothelial lipoprotein lipa se activity. This further increases VLDL levels. Urinary loss of high density lipoprotein ( HDL)-3 and reduced activity of lecithin cholesterol acyltransferase (LCAT) leads to reduced levels of the cardioprotective HDL-2. Edema results in fragile skin that can break down easily, and dilution of local humoral def enses. In addition it pro- vides \202 uid collections in which bacteria can grow easily. Urinary loss of IgG and complement components (par- ticularly factor B). Urinary loss of zi nc and transferrin (required for lym- phocyte function). Neutrophil and T-lymphocyte dysfun ction. Metabolic abnormalities A variety of metabolic complications can arise: Urinary loss of vit amin-D-binding protein. Plasma 25-(OH) vitamin D levels are reduced but free vitamin D leve ls are usually normal. Osteomalacia and hyperparathyroidism are therefore rare. Hypercoagulability and thrombosis 10% of nephrotic adults and 2 \200\2233% of children will have a clinically apparent thrombotic complication. Subclinical thrombosis can be identi \201 ed in up to 50% of adults and 28% of children when sought. P. TOPHAM 82 Tubular dysfunction Fanconi syndrome has been described rarely in patients with nephrotic s yndrome. This may result from proteinuria-induced tubular injury, or from tubular injury me diated by the underlying disease process. In children, evidence of tubular dysfunction favo rs a diag- nosis of FSGS rather than minimal change disease. Urinary loss of thyroid-binding globulin. Total thyroxine is usually low but free T4 and th yroid-stimulating hormone levels are usually normal. Rarely copper, zinc, and iron de \201 ciency can result from uri- nary loss of binding proteins. Hypoalbuminemia affects the fre e drug levels of drugs that are protein-bound. This usually does not require dose alter- at ion but warfarin activity may be enhanced, and it may have an impact on the response to fur osemide (see later). Management The \201 rst stage of management is to determine the underly- ing cause of nep hrotic syndrome using serological investi- gations and renal biopsy in order to determine w hether speci \201 c therapy is indicated. Treatment of the speci \201 c causes of nephrot ic syndrome is dealed with in their respective chapters. However, in addition, the clinical consequences of neph- rotic syndrome need to be addressed for as long as neph- rosis persi sts. Protein wasting/negative nitrogen balance Many nephrotic patients become seriously wasted d uring the course of their illness. Loss of 10 \200\22320% of lean body mass is not uncommon . This is often masked by the edema. It results from a combination of urinary protein loss and enhanced tubular catabolism of protein. Increasing protein intake (>1.5 g protein/kg/da y) can be counterproductive since it increases intraglomerular hydrostatic pressure and inc reases proteinuria, without any effect on serum albumin. Protein restriction ( \211 0.8 g/k g/day), may reduce proteinuria, but tends to worsen the negative nitrogen balance. Edema Nephrotic edema is managed using a combination of sodium restriction (50 \200\22380 m mol/day (this also potentiates the anti- proteinuric effect of RAS inhibition)), and loop d iuretics. Nephrotic patients are relatively diuretic resistant because: \200 Diuretics ar e protein-bound. Hypoalbuminemia increases the proportion of unbound drug which increases i ts vol- ume of distribution. Plasma concentrations are therefore reduced. Diuretic that ent ers into the renal tubules becomes bound to the urinary proteins, limiting its effectivenes s. The loop of Henle is relatively resistant to loop diuretics. Absorption of oral diuretic may be delayed in severely nephrotic patients due to intestinal edema. Renal dysfunction Acute kidney injury Patients with nephrotic syndrome are at risk of devel oping acute renal insuf \201 ciency. This is most common in adults with minimal change/FSG S. It is usually present at the time of the initial presentation with the nephrotic syndrom e and only unusually develops after diagnosis. The potential causes of this are listed in T able 3.2.3. Table 3.2.3. Causes of acute kidney injury in nephrotic syndrome Diuretics should be administered in a stepwise fashion until an appropriate response is ach ieved (e.g. Fig. 3.2.1). If high-dose loop diuretic fails to induce a diuresis, the additio n of a thiazide may be effective. Spironolactone is rarely effective in this setting and sh ould not be used. If there is concern about drug absorption, IV administra- tion (either as bolus or infusion) should be considered. Infusion of salt-poor albumin prior to IV loop di uretic can induce a diuresis in some resistant cases. Caution needs to be exhibited since p ulmonary edema can be precipitated if a diuresis is not induced. Finally, patients resistan t to these measures may require mechanical ultra \201 ltration although this may precipita te acute kidney injury as a result of intravascular volume depletion. In any patient and wi th any treatment the rate of \202 uid loss should be limited to <2 kg per day, to avoid s evere volume depletion and the risk of precipitating acute kidney injury. Close monitoring of electrolytes is required. If hypokale- mia develops, potassium supplements or a potassiu m- sparing diuretic should be added. Pre-renal failure due to volume depletion/sepsis (potentially compounded by the use of ACEIs, ARBs, and NSAIDs). \200 Acute tubular necrosis due to vol ume depletion/sepsis. \200 Acute interstitial nephritis. Usually due to drugs including diuretics. Intrarenal edema causing tubular (and vascular) compression. Transformation of underlying glomerulopathy, e.g. crescentic glomerulonephritis in patient with membranous nephropathy. Renal vein thrombosis. Chronic kidney disease (CKD) With the exception of minimal change disease, nephrotic range proteinuria is associated with an increased risk of progressive renal dysfunction and CKD. The risk is proportional to the degree of proteinuria and is largely independent of the und erlying cause. While the link between proteinuria and progressive renal disease may be due to the severity of the underlying glomer- ular disorder, there is increasing evidence that proteinuria is a mediator of tubulointerstitial in \202 ammation and \201 brosis. In sup port of this, strategies that reduce proteinuria also limit the development of tubulointers titial \201 brosis and renal impairment. Proteinuria Given the evidence that persistent heavy proteinuria pre- dicts progressive ren al dysfunction, reduction of proteinu- ria is an important therapeutic goal. In the absence of disease-speci \201 c therapy, a number of approaches are available. CHAPTER 3.2 Nephrotic syndrome 83 Low protein diet Dietary protein restriction reduces intraglomerular pres- sure (via constr iction of afferent arterioles). However, in nephrotic patients dietary protein restriction risks making the negative nitrogen balance worse. It is therefore recommended that dietary protein intake should be 0.8 g/kg/day plus 1 g of protein per gram of proteinuria. Antiproteinuria therapy works mainly by altering glomeru- lar hemodynamics to reduce intrag lomerular hydrostatic pressure. RAS inhibition The most commonly used drugs are inhibitors of the renin \200\223angiotensin system. These result in efferent arteri- olar dilatation. There is accumulating evidence t hat a combination of ACEIs and ARBs provides an additional antiproteinuric effect, and furt her slows renal function decline when com- pared with either agent alone. Therefore both an ACEI and an ARB at the maximum dose tolerated may be used in nephrotic patients. The serum potassium concentration needs to be carefully monitored. Hyperkalemia can usually be manag ed with dietary measures. Excessive sodium intake can eliminate the bene \201 t of RAS blo ckade. Therefore, the dietary sodium intake should be limited to 50 \200\22370 mmol/day. Other pharmacological approaches NSAIDs and ciclosporin both cause afferent arteriolar cons triction, and dipyridamole causes efferent arteriolar dilatation. They have all been used i n nephrotic patients but the clear bene \201 t (and safety) of RAS inhibition has led to o ther agents being used less commonly. In morbidly nephrotic patients with an inadequate res ponse to RAS inhibition, NSAIDs can be very effective. They may, however, precipitate AKI, particularly in volume- depleted patients, and therefore need to be used very cautiously. Nephrectomy Rarely, the nephrotic syndrome can be very severe and resistant to treatment. I n such patients the complications of nephrotic syndrome can become potentially life-threat- ening; nephrectomy, dialysis and intensive nutrition may be the preferred treatment. Nephr ectomy can be achieved surgically, radiologically by renal artery embolization, or medicall y using high dose diu- retics, RAS inhibitors, and NSAIDs. Oral loop diuretic eg furosemide 40mg bd or bumetanide 1mg bd No response Sequentially double the dose until diuresis is induced Maximum dose furosemide 250mg bd bum etanide 5mg bd Hyperlipidemia The severity of hyperlipidemia is proportional to the degree of proteinuria. Therefore successful disease-speci \201 c treatment or antiproteinuria treatment usually leads to an improvement in the lipid pro \201 le. Dietary fat restriction has only a modes t effect on hyperli- pidemia in nephrotic patients. Statins (HMG CoA reductase inhibitors) are the most commonly used agents for the treatment for nephrotic hyperlipidemia. LDL chole sterol can be reduced by 35 \200\22340% and triglycer- ides by 15 \200\22330%. Lipoprotein (a) concentrations are not affected. Statins are generally safe and indeed there is some ev i- dence to suggest that statins may reduce proteinuria and slow renal function decline. Re versible myopathy can complicate statin use. Rarely this can lead to rhabdomyolysis and AKI . Serum creatine kinase levels should be monitored after initiation of a statin. Fibrates h ave a less potent effect on LDL-cholesterol than statins, and since lowering LDL is the mai n aim in nephrotic patients, \201 brates are uncommonly used. Fibrate-induced muscle inju ry is also more common in patients with renal impairment. No response Add oral thiazide diuretic eg hydrochlorthiazide 25 - 50mg bd or metolazone 2.5 - 5mg od No response Administer loop diuretic intravenously either as bolus injection twice daily or as infusion