Professor Robert Unwin St Peter \200\231s Professor of Nephrology Center for Nephrology Roy al Free and University College Medical School London Dr Andy Salmon Clinical Lecturer in Nephrology The Richard Bright Renal Unit Southmead Hosp ital Bristol Professor Jean-Louis Vanherweghem Emeritus Professor of Nephrology Department of Nephrology H pital Erasme Universit Libre de Bruxelles (ULB) Brussels Belgium Mr Richard FJ Stanford Clinical Research Fellow Department of Cancer Studies & Molecular Me dicine University of Leicester CONTRIBUTORS xxii Dr William Van \200\231t Hoff Consultant Pediatric Nephrologist Department of Nephrology Gr eat Ormond Street Hospital London Dr Christopher Winearls Consultant Nephrologist Oxford Radcliffe Hospitals Oxford Dr Matthias TF Wolf Senior Research Fellow Department of Pediatrics University of Michigan Ann Arbor Michigan USA Dr Stephen Walsh Clinical Research Fellow Center for Nephrology, Royal Free and University College Medical School, London Dr Graham Warwick Consultant Nephrologist John Walls Renal Unit Leicester General Hospital Leicester Dr Graham Woodrow Consultant Renal Physician Department of Renal Medicine St James \200\231 s University Hospital Leeds Professor Alan Watson Professor of Pediatric Nephrology Children \200\231s Renal and Urolog y Unit Nottingham University Hospitals Nottingham Dr Rosnawati Yahya Consultant Nephrologist Department of Nephrology Hospital Kuala Lumpur J alan Pahang Kuala Lumpur Malaysia Dr Rachel Westacott Specialist Registrar in Nephrology John Walls Renal Unit Leicester Gene ral Hospital Leicester Dr Janak R de Zoysa Consultant Nephrologist Department of Renal Medicine Auckland City Hosp ital Auckland New Zealand Dr Stanley White Senior Lecturer Institute of Membrane and Systems Biology University of Le eds Leeds 1 Chapter 1 Assessment of renal disease Chapter contents History and clinical examination of patients with renal disease 2 Urinalysis and microscopy 8 Clinical assessment of renal function 12 Renal function in the newborn infant 16 The agi ng kidney 18 Imaging in renal disease 20 Renal biopsy 32 Immunological investigation of ren al disease 36 J. FLOEGE AND J. KANNMACHER 2 History and clinical examination of patients with renal disease Dysuria Pain or discomfort during micturition is usually a result of bladder, prostatic or urethral in \202 ammation. Cystitis also causes frequency and urgency of micturition. Peri neal or rectal pain in men indicates prostatitis. A patient with renal disease can present in different ways: \200 The patient complains of a symptom or shows physical signs typically associated with renal disease. The patient is asymptomatic and comes to attention through pathological results of clinical or laboratory examination. Disorders of urine volume Polyuria Urine output of >3 L per day is de \201 ned as polyuria . It is often dif \201 cult for patients to differentiate between polyuria and frequency. Thus the measurement of daily urine excre- tion is necessary to elucidate the symptom. In m any cases patients complain of thirst instead of increased urine volume. The possible cause s for polyuria are listed in Table 1.1.2. A systemic disease is diagnosed that can lead to renal involvement. The patient is examined because he has been exposed to nephrotoxic agents. The family history of the patient reveals inherited renal disorders. Investigation methods which often lead to the detection of asymptomatic renal patients are biochemical analysis, urine analysis and blood pressure measurement. Cardinal symptoms sugg esting underlying renal disease are disorders of micturition, disorders of urine volume, al tera- tion in urinary composition, edema, loin pain and hyper- tension. Furthermore there i s a large variety of symptoms or medical problems associated with advanced renal failure an d uremia respectively (Table 1.1.1). Oliguria A reduction in urine volume to <500 mL per day indicates AKI leading to a situatio n in which homeostasis cannot be maintained. Anuria The sudden development of urine output of <100 mL per day is most commonly due to ob struction of the urinary tract. Other possible causes are renal infarction or cortical necr osis. Disorders of micturition Frequency Frequent emptying of the bladder can be associated with normal or increased urine volume (polyuria). The former may be due to in \202 ammation, st one or tumor of the bladder or a reduced bladder capacity. Frequency is often accom- panied with nocturia. Table 1.1.2 Conditions which may cause polyuria Increased renal water loss Endocrinologic disorders Central (cranial) diabetes insipidus Poor urinary stream The most common cause is prostatic enlargement in men past middle age. Urethral obstruction leads to retention and back pressure. Addison \200\231s disease Hyporeninemic hypoaldosteronism Renal tubular disorders Nephrogenic diabetes insipidus Acquired tubular defects, e.g. salt-losing nephropathy Table 1.1.1 Typical symptoms and complications in patients with advanced renal failure Pyelonephritis - Analgesic nephropathy - Multiple myeloma - Obstructive uropathy - Sarcoido sis - Hypercalcaemia, chronic potassium Malaise, weakness, diminished appetite, sleep disorders, headache General nonspeci \201 c symptoms Water overload, dehydration, hyperkalemia, metabolic acidosis Water \200\223electrolyte, acid \200\223base imbalance depletion Anorexia, nausea and regurgitation, peptic ulcer, gastrointestinal bleeding, diverticulosis Gastroenterological problems Toxic agents (e.g. aminoglycosides, lithium, cisplatinum) Diuretic therapy Bartter \200\231 s syndrome Polyuric phase of acute or acute-on- chronic renal failure Hypertension, pulmonary edema, pleurisy, pericarditis, cardiomyopathy, cardiac arrhythmia Cardiovascular and pulmonary problems Secondary hyperparathyroidism, osteomalacia, infertility, disturbance of growth in children Endocrinological and metabolic problems Osmotic diuresis Glycosuria in diabetes mellitus Administration of mannitol Peripheral polyneuropathy, restless legs syndrome, cramps, seizures, tremor, coma Neuromuscular problems Administration of large volume of contrast agents Increased water intake Many different skin alterations, such as palor, hyperpigmentation, pruritus, scratch marks Dermatological disorders Psychogenic Medication Drugs causing xerostomia or thirst (e.g. anticholinergics or clonidine) Renal anemia, bleeding tendency, immunode \201 ciency Hematological and immunological disorders CHAPTER 1.1 History and clinical examination of patients with renal disease 3 Alteration in urinary composition Hematuria Hematuria may originate from any part of the re nal tract and there are many possible underlying conditions, such as glomerulonephritis, in fection, calculi, tumors, thrombocy- topenia or disordered coagulation. \200 The most com mon cause is urinary tract infection. \200 Recurrent macroscopic hematuria is often seen in IgA nephropathy, but may also be due to intermittent bleed- ing from a structural lesion . hepatic disease, or increased capillary permeability due to allergy, in \202 ammation or i schemia. As a consequence of long-term renal failure or nephrotic syndrome, up to 20 additi onal liters of \202 uid can accumulate in the body, leading to generalized swelling calle d anasarca. In advanced \202 uid overload, interstitial pulmonary edema is common. Admini stration of drugs such as calcium-channel antagonists and steroids or diuretic abuse may al so lead to edema. Pain If pain occurs as a symptom of renal disease, it mostly indi- cates inflammation or ob struction. Pain arising from pyelonephritis usually develops gradually and has a con- stant intensity, whereas an acute obstruction typically causes a sudden severe and colicky pain radiating to the scrotum or groin. Blood from the urethra only appears in the initial urinary stream. Blood from the bladder or prostate appears usually at the end of micturition. Intense exercise can cause transient hematuria. \200 Alteration in urine color does not a lways indicate the presence of blood (see Chapter 1.2). Clinical syndromes and other modes of presentation Nephrotic syndrome This is a consequence of severe proteinuria (usually de \201 ned as >3.5 g/24 h) and is characterized by hypoal buminemic edema and hyperlipoproteinemia. The underlying diseases are diverse, and include different types of glomerulone- phritis, diabetic nephropathy, myeloma or amyloidosis. Proteinuria A urinary protein loss of up to 150 mg/24 h is normal. Patients with higher con centrations sometimes report frothy urine, but mostly proteinuria is only deter- mined chem ically. Usually a dipstick test is used, but this method does not detect immunoglobulin lig ht chains or microalbuminuria. \200 Proteinuria arising from interstitial disease is gene rally Acute nephritic syndrome This is characterized by hematuria with red blood cell casts in th e urine, proteinuria, oliguria and hypertension. Common causes are post-streptococcal glome rulonephri- tis and the acute exacerbation of a chronic glomerular dis- order such as IgA n ephropathy. mild (up to 2 g/24 h). Proteinuria caused by glomerular disorders is variable (up to 10 g/24 h and more). Orthostatic proteinuria (proteinuria noted after being upright and absent in the \201 rst urine passed in the morn- ing after lying down) is usually harmless. Acute kidney injury (AKI) AKI is a rapid reduction of the glomerular \201 ltration rate, resulting in the retention of waste products such as urea, creatinine and other uremic toxi ns. It may cause metabolic disturbances and disorders of the \202 uid balance. AKI may be oliguric (urine volume reduced to <500 mL/day) or nono- liguric. The underlying conditions are varied and can be subdivided into pre-renal, renal and post-renal causes. The type of proteinuria can help in establishing a diagnosis (see page 9). Bacteriuria Bacteria in the urine do not always cause symptoms. Usually it is only consider ed signi \201 cant if there are >105 organisms per mL. Leukocyturia There are different conditions that lead to the presence of leukocytes in the urine such as nephrocalcinosis, analgesic nephropathy and papillary necrosis. In immunologi cally mediated tubulointerstitial nephritis, eosinophils may be present in the urine. Chronic kidney disease (CKD) CKD irrespective of etiology is classi \201 ed into \201 ve stages based on the GFR. Chronicity is de \201 ned as an abnormality for >3 months: 1 GFR normal or increased, but \201 ndings indicating kidney damage (e.g. proteinuria or hematuria) Pyuria Pyuria always indicates a signi \201 cant infection. Sterile pyuria may be due to c hlamydial infection or tuberculosis. 2 GFR of 89 \200\22360 mL/min/1.73 m2 (with abnormal urinalysis or structural renal lesion) 3 GFR of 59 \200\22330 mL/min/1.73 m2 4 GFR of 29 \200\22315 mL /min/1.73 m2 5 GFR of <15 mL/min/1.73 m2 or necessity for renal Pneumaturia This suggests a vesicocolonic \201 stula, which may arise as a consequence of Crohn \200\231s disease, diverticular disease or carcinoma of the colon. replacement therapy (dialysis or transplantation) The early forms of CKD are asymptomatic. Edema An increase of \202 uid in the interstitium in patients with renal disease may be c aused by hypoproteinemia. If this is the consequence of proteinuria (typically >3.5 g/24 h) it is part of the nephrotic syndrome. Initially this kind of edema is typically most visib le around the eyes in the morning and in the feet and ankles in the evening. Edema may also be caused by salt and water retention as a result of CKD, congestive cardiac failure and c hronic Macroscopic (visible) hematuria The underlying conditions of patients presenting with gross ly visible hematuria are diverse and vary with age. The most common causes are in \202 amm ation of the bladder or prostate, stones and, particularly in older patients, benign prosta tic hyperplasia and malignancy. In most young patients it is transient and of no consequenc e. Nevertheless a urologic evaluation is essential in all cases of macroscopic hematuria. J. FLOEGE AND J. KANNMACHER 4 Microscopic (nonvisible) hematuria Isolated microscopic hematuria is de \201 ned as the pr esence of >2 red blood cells per high-power \201 eld in a urine sedi- ment. It is very co mmon and mostly a chance \201 nding. At \201 rst benign causes should be excluded, e.g. menstruation, physical exercise or infection. If the hematuria persists and the etiology r emains unclear, or if the history points towards a speci \201 c cause, further investigati on is neces- sary (e.g. laboratory analysis, radiologic imaging, urologic evaluation). If m icroscopic hematuria is accompanied by proteinuria >1 g/day a \200\230urologic \200\231 ca use is unlikely and an intra-renal origin should be sought. Table 1.1.3 Conditions associated with renal disease Condition Associated renal disease Hypertension Hypertensive nephrosclerosis Secondary hypertension due to renal disease Diabetes mellitus Diabetic nephropathy Gout Urate calculi Recurrent cystitis and pyelitis Re \202 ux nephropathy Chronic headache Analgesic nephropathy due to analgesic abuse Asymptomatic proteinuria While proteinuria >1 \200\2232 g/day usually indicates glomerular disease, proteinuria <1 g/day usually should be closely fol- lowed but does not usually war rant invasive procedures such as renal biopsy, at least as long as it is not accompanied by a decreased GFR or an otherwise active urine sediment. Raynaud \200\231s syndrome Systemic sclerosis Systemic lupus erythematosus Cryoglobulinemia with renal involvement Recurrent sinusitis or ENT problems Wegener \200\231s granulomatosis Clinical history of the patient with renal disease History of the current complaint The chr onological order of the patient \200\231s presenting symp- toms should be established. This should include a full descrip- tion of the course of their intensity and quality. It is im portant to encourage the patient to describe his complaints in his own words, as otherwise essential information might be lost. Details of associated symptoms should be obtained. For example, upper respiratory tract symptoms at the time of visible hematuria may suggest a d iagnosis of IgA nephropathy. Hypertension is often related to renal disease and there- fore should always be investigated in detail. Patients suffering from pain should be asked abou t its local- ization and character, the mode of onset and aggravating or relieving factors. Any factors accompanying the presenting illness should be determined carefully. Pleurisy, pericarditis Rheumatoid arthritis Systemic lupus erythematosus Haemoptysis Wegener \200\231s granulomatosis Goodpasture \200\231s syndrome Recurrent thrombosis and fetal loss Antiphospholipid antibody syndrome Impaired hearing Alport syndrome Tonsillitis, scarlet fever Post-streptococcal glomerulonephritis Liver cirrhosis Hepatorenal syndrome Hepatitis B or C Membranous or membranoproliferative glomerulonephritis Diarrhea Hemolytic uremic syndrome Tuberculosis Urogenital tuberculosis Amyloidosis Sterile leukocyturia Past history Previous major illnesses and hospitalizations should be determined, including those in childhood and adolescence. Special attention must be paid to systemic diseases tha t are known to be associated with renal disease, e.g. systemic lupus erythematosus or Wegen er \200\231s granulomatosis. Some metabolic diseases are closely related to renal disease, such as diabetes mellitus, oxalosis or Fabry \200\231s disease. Examples of pre-existing co nditions that may be associated with renal disease are listed in Table 1.1.3. To complete t he past history, previous medical records should be obtained with particular emphasis on pr ior renal function tests. HIV infection HIV nephropathy Malignancy Membranous glomerulonephritis Drug history Complete details about recent drug intake should be obtained, including onset, duration and dosage of ingestion. The use of nonprescription drugs, especially nonsteroida l anti-in \202 ammatory drugs, should also be noted. Social and occupational history Social status may have considerable in \202 uence on the d evel- opment of renal disease. For example bacteriuria is more common in pregnant women of low socio-economic class, whereas calcium stones occur more often in men of higher social s tanding. During therapy poor compliance may be a serious problem, which is more frequent am ong patients of lower socio-economic status. It is important to ask patients about tobacco consumption. Smoking may contribute to the development and pro- gression of renal failure a nd is a risk factor for reno- vascular hypertension. Drug addiction is associated with seve ral renal complications, e.g. acute renal failure due to rhabdomyolysis, virus-related rena l disease, or infections. Gynecologic and obstetric history In females information about menstruation, contraception and pregnancy should be obtained. \200 Impaired renal function can be associated with del ayed menarche and amenorrhea. In women taking combined estrogen \200\223progesterone con- traceptives, renal disease sign i \201 cantly increases the risk of hypertension. Initiation or exacerbation of renal disease may be associ- ated with pregnancy. The increas e of pre-existing pro- teinuria during pregnancy can lead to the development of nephrotic s yndrome. Repeated fetal loss may suggest underlying systemic lupus erythematosus and antiphospholipi d antibody syndrome. CHAPTER 1.1 History and clinical examination of patients with renal disease 5 Development of renal disease may be associated with cer- tain occupational factors. \200 It has been shown that there is an increased incidence of patients originating from high prevalence regions such as India or Russia. Clinical examination Direct examination of the kidneys is usually not possible so a careful general examination is necessary to identify any abnormalities suggesting underlying renal disease. urothelial tumors in aniline dye workers. Miners, sewage workers and farm laborers are at higher risk of leptospirosis leading to AKI. Hantavirus infection originating from bank voles (Myodes glareolus) is more common in peopl e working outdoors or engaging in outdoor activities in endemic areas. Examination of the kidneys and the urinary tract Inspection In some patients an enlarged ki dney may be visible, e.g. in cases of advanced polycystic kidney disease. Rarely in patient s with bladder out \202 ow obstruction an extreme distension may be visible. Exposure to lead may cause CKD due to lead neph- ropathy. Family history Medical information on relatives may help in elucidating cases of inherited kidney diseases. Furthermore familial predispositions to systemic lupus erythematosus, IgA nephropathy or the development of diabetic nephropathy are known. The classi \201 cation o f inherited renal diseases is listed in Table 1.1.4. Palpation Palpation of the kidneys is possible but practicable only in thin patients. If th e patient lies with both arms beside the body, the kidneys are palpated by placing the left hand pos- teriorly in the loin and the right hand on the abdomen lat- eral to the umbilicu s. With the patient taking a deep breath the lower kidney pole may be palpable by pushing t he right hand inwards and upwards. The right kidney is more acces- sible to palpation than the left one, due to its lower abdomi- nal position. Size and shape of the kidneys should b e estimated. The surface normally feels smooth and relatively hard. Irregularities may sugg est cystic disease or malignancy. Ethnic and geographic factors The ethnic background of a patient is an important factor ass ociated with different incidences of kidney disease. \200 Renal failure associated with h ypertension or diabetes mellitus is more common in black patients. In the UK the incidence of end-stage renal disease in South Asians and African Caribbeans i s at least three times higher than in Caucasians. Percussion In patients suffering from pyelonephritis or acute glomeru- lonephritis slight p ercussion of the renal region may be suf \201 cient to cause severe pain, also referred to as cos- tovertebral tenderness. Pyelonephritis is rather accompa- nied by fever and dysuri a, whereas hematuria, hypertension and oliguria suggest glomerulonephritis. IgA nephropathy is more common in white populations and in certain parts of Asia than in bl ack populations. \200 The incidence and aggressiveness of systemic lupus ery- thematosus is higher in oriental, hispanic and black popu- lations than in Caucasians. Auscultation Abdominal auscultation is essential in patients with hyper- tension, as the pr esence of a bruit may suggest renal artery stenosis. Amyloidosis as a complication of familial Mediterranean fever occurs more often in Arabs, T urks and Sephardic Jews from the Mediterranean area compared to Sephardic Jews from other r egions, Ashkenazi Jews and Armenians. General examination Every patient with renal disease has to be examined com- pletely to det ect any abnormality that might be of diagnos- tic value. The risk of developing tuberculosis during immunosup- pressive therapy, e.g. after transpla ntation, is higher in Table 1.1.4 Classi \201 cation of the most important inherited kidney diseases 1. Polycystic kidney disease 2. Alport \200\231s syndrome and variants (e.g. \200\230benig n \200\231 familial hematuria) 3. Inherited metabolic diseases with renal involvement without glomerular involvement - with glomerular involvement Cystinosis, hyperoxaluria, inherited urate nephropathy Fabry \200\231s disease, lecithin-ch olesterol acyltransferase de \201 ciency 4. Other inherited diseases with glomerular or nonglomerular involvement with glomerular involvement - with nonglomerular involvement nephronophthisis - with cystic kidney disease congenital nephrotic syndrome renal angiomyolipoma in tuberous sclerosis renal cell carcinoma in von Hippel \200\223Linda u \200\231s disease 5. Familial IgA nephropathy or focal segmental glomerulosclerosis 6. Inherited tubular diso rders cystinuria - various other inherited tubular defects 7. Renal diseases with variable polygenetic in \202 uence diabetic nephropathy - re \202 ux nephropathy - calcium nephrolithiasis 8. Unclassi \201 ed cases J. FLOEGE AND J. KANNMACHER 6 Facial appearance An abnormal facial appearance may suggest underlying dis- ease. In patien ts with systemic sclerosis a typical facies with thickening and rigidity of the skin is vis ible. A loss of the buccal pad accompanied by fat loss from the upper part of the body (par tial lipodystrophy) is associated with mesangiocapillary glomerulonephritis (MCGN) type 2. In Wegener \200\231s granulomatosis a characteristic facies may appear due to loss of the n asal cartilaginous septum. Patients receiving steroids frequently develop typical mooning o f the face. Skin The skin should always be examined thoroughly, as there is a wide variety of cutaneous alterations associated with renal disease. \200 Skin turgor is an important sign to dete ct \202 uid imbalances. \200 Patients with uremia frequently have a dry and \202 aky skin of yellowish-brown color. Depigmented scratch marks or reddish-brown papules may indic ate pruritus. Pallor is common in patients with chronic renal failure as a consequence of r enal anemia, but there may also be diffuse hyperpigmentation of sun-exposed areas. Due to i mpaired coagulation and fragile small vessels there may be a tendency to hematoma formation (Figure 1.1.1). Fig. 1.1.2 Allergic rash in a patient. Nails Patients with CKD may have variable nail abnormalities. The most common anomalies are absence of the lunula and half-and-half nails characterized by a proximal white band and a distal red brown band. Transverse ridges (Beau \200\231s lines) may be a result of serious preceding illness. Patients with vasculitis or endocarditis may have splinter hemorrhages. Dystrophic nail alterations accompanied by absent or hypoplastic patella are seen in patie nts with the nail \200\223patella syndrome, which is associated with renal failure. Subcutaneous nodules may appear due to the deposi- tion of calcium salts within the skin (c alcinosis cutis) in patients with secondary hyperparathyroidism. Palpable purpura, particularly on the lower limbs and the buttocks, is a common sign of Hen och \200\223Sch nlein purpura. Eyes Examination of the eyes may show peri-limbal calci \201 cation following longstanding uremia, subconjunctival hemor- rhages in patients with vasculitis, or lenticonus in Alport \200\231s syndrome. Fundoscopy may reveal typical alterations in patients with diabetes me llitus, hypertension, vasculitis, or MCGN type 2. Heart During cardiac auscultation particular attention should be paid to murmurs, which may be due to renal anemia, and a pericardial rub which indicates pericarditis in terminal ure mia. Chest When examining the chest of patients with renal disease one should consider the possi bility of pleural effusions and listen for crepitations and pleural rubs. Increased breathi ng with an open mouth may indicate compensation of meta- bolic acidosis (Kussmaul \200\231s respiration). Fig. 1.1.1 Typical skin alterations in a patient with chronic renal failure. Note the diffu se hyperpigmentation, the local deposition of hematin and the depigmented scratch marks. Allergic exanthema accompanied by renal failure may Abdomen Important findings on abdominal examination include organomegaly or hernias, especi ally in patients who might subsequently require continuous ambulatory peritoneal dialysis. suggest interstitial nephritis (Figure 1.1.2). The appearance of vasculitis may be variable (Figure 1.1.3). \200 Patients receiving long -term immunosuppression may develop hyperkeratotic lesions, which can transform into malign ant lesions. Limbs Attention should be paid to edema, which is mostly obvi- ous in the lower limbs, but may also appear in the face and the arms or even occur as anasarca. In bedridden patients e dema usually occurs in the calves, the sacrum and the loins. In children, edema is predomin antly visible in the face. The vascular tree should be examined by taking the pulse on all limbs and looking for trophic disorders. In longstanding In patients with Fabry \200\231s disease small reddish-purple papules (angiokeratoma) appea r on the skin with pre- dominance on the lower abdomen and the groin area. \200 Uremic fr ost is a manifestation of terminal renal failure which is now rarely seen. It is due to the crystallization of urea and other nitrogenous waste products in sweat presenting as a whit e crystalline material on the skin, particularly on the face. CHAPTER 1.1 History and clinical examination of patients with renal disease 7 Fig. 1.1.3 Different manifestations of vasculitis. Note the wide range of appearances from an allergic-like exanthema to the presence of necrosis and hemorrhages. Further reading Dyachenko P, Monselise A, Shustak A, Ziv M, Rozenman DJ. Nail disorders in patients with chronic renal failure and undergoing haemodialysis treatment: a case \200\223 control study. Eur Acad Dermatol Venereol 2007;21:340 \200\223344. renal failure atherosclerosis is very common and may cause problems for subsequent dialysis access. A neurological examination is essential to exclude polyneu- ropathy, which may be secondary to uremia or diabetes mellitus. Polyneuropathy due to renal disease is symmetric with predominance of the lower limbs. It may cause sen- sory loss, paresthesias, dysesthesi as, itch and muscular cramps. Feehally J. Ethnicity and renal disease: questions and challenges Clin Med 2003;3:578 \200\223582. Nuyts GD, Van Vlem E, Thys J, De Leernijder D, D \200\231Haese PC, Elseviers MM, De Broe ME . New occupational risk factors for chronic renal failure. Lancet 1995;346:7 \200\22311. Measurement of blood pressure Taking the blood pressure in both arms is an essential part o f the clinical examination of renal patients. The measure- ment conditions should be as sta ndardized. Overestimation of systolic blood pressure may occur due to hard, calci \201 ed vessels. This can be detected by a positive Osler \200\231s sign, in which the radial arter y is palpable in spite of the cuff in \202 ated above systolic blood pressure. Pic MR, Lugo-Somolinos A, S nchez JL, Burgos-Calder n R. Cutaneous alterations in patie nts with chronic renal failure. Int J Dermatol 1992;31:860 \200\223863. See also Urinalysis and microscopy p. 8 Clinical assessment of renal function p. 12 J. FLOEGE AND J. KANNMACHER 8 Urinalysis and microscopy Urine examination is one of the basic diagnostic evaluations in patients with disease of th e kidneys or the urinary tract. Normally urine is transparent. An increased concentration of particles may cause turbidity. The underlying condi- tions are diverse, but the most common causes are urinary tract infe ctions, hematuria and contamination from genital secretions. Collection of urine samples The method of obtaining and handling urine specimens has a grea t effect on the result. It is therefore essential to standardize these procedures as far as possible. \200 The patient should not perform arduous physical exer- cise for 72 h befor e collecting the urine, otherwise pro- teinuria, hematuria or cylindruria might be induced. Odor In urinary tract infections with bacteria producing ammo- nia a pungent smell can ofte n be noted. A sweet, fruity odor may be due to ketonuria. In some rare metabolic dis- eases characteristic odors of urine are described: \200 phenylketonuria (distinctive musty or \200\230mousy \200\231 odor); \200 maple syrup urine disease (maple syrup odor); \200 isovaleric acidemia (sweaty feet odor); \200 hypermethioninaemia ( \201 shy or rancid bu tter odor). Relative density Relative density provides a measure of the urine concen- trati on and can provide information about the \202 uid balance of a patient. It can also sugge st whether the patient has a normal ability to adjust the urine concentration in states of dehydration or \202 uid overload. There are different methods to measure relative density : \200 Speci \201 c gravity (SG) depends on the number and weight of the solute particle s. It is determined with a weighted \202 oat called a urinometer and normal SG ranges fro m 1003 to 1035 g/L. Urinalysis should not be performed in females during menstruation because of possible blood contamination. \200 The first or second morning urine is preferred for analysis. To prevent contamination, females should spread the labia, males withdraw the foreskin and the genitalia should have been washed. The \201 rst few milliliters of urine are discarde d. Urine collection through bladder catheters may be asso- ciated with hematuria, bacteriuria or leukocyturia. In small children urine bags are commonly used, but they increase the probability of contamination. Written instructions for the patient contribute to the optimization of urine collection. Physical characteristics of urine Color and turbidity Depending on the urochrome concentrat ion, the normal color of urine ranges from pale yellow to amber. An abnor- mal coloration m ay be caused by several pathologic condi- tions and the intake of certain drugs or foods (T able 1.2.1). It is important to remember that red urine is not always due to hematuria. Osmolality is de \201 ned as the number of particles per kg. Urine osmolality is determine d by measuring the freez- ing point and physiologically it ranges from 50 to 1200 mosmol/kg . Refractometry is a method based on the measurement of the refractive index which correlates with osmolality. \200 The most common means to determine relative density is dipstick te sting based on dry chemistry with cations in the urine causing the color change of an indic ator substance. This method is not very accurate but is ade- quate for everyday use. As dip stick use is widespread, it is important to pay attention to conditions that may confound t he results (Table 1.2.2). Table 1.2.1 Causes of abnormal color changes in urine Underlying condition Possible urine coloration Pink, red, brown or black Hematuria, hemoglobinuria, myoglobinuria Chemical characteristics of urine pH Urine pH is useful in evaluating acid \200\223base dis orders and for the interpretation of certain dipstick tests and microscopic \201 ndings. The commonly used dipsticks can measure pH values from 5.0 to 9.0. \200 Urine pH normally ranges from 4.8 to 7.6. \200 Acidic urine may be due to high meat intake or acidosis. \200 Alkaline urine may be due to vegetarianism, infections of the urinary tract with ammo nia-producing bacteria (e.g. Proteus spp.), prolonged storage of the specimen or alkalosis. Dark yellow to brown Jaundice White and milky Chyluria Pink Massive uric acid crystalluria Red (possibly darkening upon standing or \202 uorescence in UV light) Porphyrinuria Brown to black Alkaptonuria Drugs Rifampicin Phenytoin Chloroquine Triamterene Methylene blue Metronidazole, imipenem/ cilastatin, methyldopa Orange to red Red Brown Green Blue Darkening upon standing Hemoglobin The detection of hemoglobin by dipsticks utilizes the pseu- doperoxidase activit y of the heme moiety to produce a colored product. In the presence of intact erythrocytes g reen spots become visible, whereas a homogeneous color change may occur following hemolysis due to longer stor- age of the specimen, alkaline urine or low relative urine density. Wit h a high erythrocyte concentration there may also be a diffuse color change. Foods Beetroot Rhubarb, senna Carotene Red Yellowish-brown or red Brown CHAPTER 1.2 Urinalysis and microscopy 9 and therefore the latter a used routinely in everyday clini- cal practice to quantify prote inuria. To analyze proteinuria qualitatively, electrophoretic protein separation can be don e on the basis of molecular weight. Thus information can be obtained about the origin of th e excreted proteins and help to inform possible underlying disorders. Alternatively, speci \201 c marker proteins can indi- cate tubular damage (see below). Prerenal (overload) prot einuria. An increased serum con- centration of a protein results in urinary excretion witho ut a glomerular or tubular defect. Examples are Bence \200\223Jones proteinuria in monoclon al gammopathy, myoglobinuria following rhabdomyolysis or hemoglob inuria due to hemolytic c risis. In the case of Bence \200\223Jones proteinuria, immuno \201 xation of serum should be performed. Glomerular proteinuria. Increased permeability of the glomer- ular filtration membrane causes pathologic proteinuria. Further differentiation is made based on the patte rn of protein excretion. \200 Selective glomerular proteinuria means that predomi- nantly albumin and transferrin are detected, which sug- gests the presence of a moderate glomerul ar disorder (e.g. minimal change nephritis). Table 1.2.2 Main causes for false dipstick results Measurement False-negative False-positive results results Underestimation in glucosuria, pH >6.5 Overestimation in proteinuria >7 g/L, ketoaciduria Speci \201 c gravity Reduced values in presence of formaldehyde pH Myoglobinuria, bacterial peroxidases, intravascular hemolysis, hydrochloric acid Ascorbic acid, standing before examination, high relative density, formaldehyde Hemoglobin Ascorbic acid, bacteria Hydrochloric acid, Glucose oxidizing agents pH >9, quaternary ammonium detergents Light chains, tubular proteins, hydrochloric acid Albumin Oxidizing detergents High relative density, vitamin C, proteinuria >5 g/L, glucosuria >20 g/L, cephalosporins Leukocyte esterase Nonselective glomerular proteinuria implies that higher molecular weight proteins (e.g. IgG ) appear in the urine, which indicates severe glomerular damage. No vegetable intake, vitamin C, bacteria that do not reduce nitrates Nitrites The selectivity can be assessed by determining the ratio of IgG clearance to transferrin cl earance. Values <0.1 re \202 ect selective proteinuria, whereas values >0.2 indi- cate non selective proteinuria. Drugs containing free sulfhydryl groups Ketones This dipstick method has low sensitivity but high speci \201 city. False-positive results may be seen in patients with intravas- cular hemolysis, myoglobinuria or infection with bac teria showing pseudoperoxidase activity (Enterobacteriaceae, staphylococci and streptococci ). Therefore phase-contrast microscopy of a fresh specimen of urine may be useful to con \201 rm positive cases or those where the result is unclear. Microalbuminuria implies an albumin excretion of 30 \200\223300 mg/day or 20 \200\223200 mg /L (ACR of 2.5 \200\22330 mg/mmol in men, or 3.5 \200\22330 mg/mmol in women). It is a typi cal early albeit nonspecific feature of diabetic or hypertensive nephropathy. Tubular prote inuria. This is characterized by the presence of low molecular weight proteins, which are n ormally \201 l- tered in the glomeruli and reabsorbed in the tubules, such as 1-microgl obulin or B2-microglobulin. Their increased concentration in the urine indicates tubular da mage. Glucose Dipstick testing is also commonly used for the detection of glucosuria. By using th is method glucose concentrations of 0.5 \200\22320 g/L can be measured. Usually glucosuria is a conse- quence of hyperglycemia due to diabetes mellitus, but renal glucosuria may occu r as a result of certain tubular disorders. See Table 1.2.2 for causes of false-positive or -negative results. Leukocyte esterase Dipstick testing for leukocyturia as a marker for urinary tract infectio n is based on the activity of leukocyte este- rase released from lysed macrophages and neut rophil granulocytes. High glucose or protein concentrations may cause false-negative result s (see Table 1.2.2). Protein Normally, daily urinary protein excretion does not exceed 150 mg (140 mg/m2 for chi ldren), as most of the \201 ltered protein is reabsorbed in the proximal tubules. A dipst ick can provide a rough quanti \201 cation of pro teinuria. This method has a high sensiti vity to albumin, but only low sensitivity to other proteins, e.g. immunoglobulin light chai ns. For more detailed assessment other laboratory techniques are necessary. The most reliab le results are obtained by 24 h urine collection. The results should be denoted as g/L or g /24 h. Alternatively spot or better timed urine collections can be assessed for albumin or protein concentration and this is then normalized for urinary dilution by dividing it by th e urinary creatinine concentration (albumin:creatinine ratio (ACR) or protein:creatinine ra tio (PCR)). There is a good correlation between carefully performed 24 h urine collec- tion for protein estimation and ACR/PCR on spot urine Nitrites Most Gram-negative uropathogenic bacteria are capable of reducing nitrates to nitr ites. Pseudomonas spp., Staphylococcus albus and Enterococcus spp. lack this ability. Thus dipstick testing for nitrite can help to characterize the causative agent of urinary tract infection. The test is depend- ent on an adequate nitrate intake (e.g. from vegetables). Ketones Acetoacetate and acetone are detected using dipsticks. They may occur in the urine due to diabetic ketoacidosis, fasting, vomiting or arduous exercise.