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Chronic Kidney Disease 383
Table 9.13 Classification of chronic kidney disease
Test Measurement method Definition
Impaired GFR Formulae based on SCr
Proteinuria
Early morning urine
sample
Haematuria
Dipstick urinalysis
eGFR <60 mL/min/1.73 m
ACR ≥30 mg/mmol or PCR
≥50 mg/mmol
>1 + and urological causes
excluded
ACR, albumin:creatinine ratio; (e)GFR, (estimated) glomerular filtration rate; PCR,
protein:creatinine ratio; SCr, serum creatinine.
Table 9.14 Causes of chronic kidney disease
Congenital and inherited disease
Polycystic kidney disease (adult and infantile forms)
Tuberous sclerosis
Congenital obstructive uropathy
Other rare causes
Glomerular disease
Primary glomerulonephritides
Secondary glomerular disease, e.g. diabetes mellitus, amyloidosis, SLE
Vascular disease
Hypertensive nephrosclerosis (common in black Africans)
Reno-vascular disease
Small and medium-sized vessel vasculitis
Tubulointerstitial disease
See page 367
Urinary tract obstruction
Any causes of chronic obstruction (p. 364)
SLE, systemic lupus erythematosus.
2
are the most common causes in European countries (Table 9.14). In parts of
the Middle East, schistosomiasis is a common cause due to a ureterovesical stricture causing urinary tract obstruction. Regardless of the underlying
cause, fibrosis of the remaining tubules, glomeruli and small blood vessels
results in progressive renal scarring and loss of renal function in some
individuals.
384 Renal disease
Clinical features and investigations
The early stages of renal failure are often asymptomatic. With a declining GFR
and an associated rise in serum urea and creatinine, there is an accumulation of symptoms and signs described below. The actual metabolites that
are involved in the genesis of many of these clinical features are not known
(Fig. 9.6). Investigations are similar to those in AKI (p. 380).
Anaemia. Anaemia is primarily due to reduced erythropoietin production
by the diseased kidney. Shortened red cell survival, increased blood
loss (from the gut, during haemodialysis and as a result of repeated
Anaemia
Pallor
Lethargy
Breathlessness on exercise
Platelet
abnormality
Epistaxis
Bruising
Skin
Pigmentation
Pruritus
GI tract
Anorexia
Nausea
Vomiting
Diarrhoea
Endocrine/gonads
Amenorrhoea
Erectile dysfunction
Infertility
Polyneuropathy
CNS
Confusion, coma, fits
(severe uraemia)
CVS
Uraemic pericarditis
Hypertension
Peripheral vascular
disease
Heart failure
Renal
Nocturia
Polyuria
Salt and water
retention
Oedema
Mineral and bone disorder
Osteoporosis
Osteomalacia
Hyperparathyroidism
Osteosclerosis
Adynamic bone disease
Fig. 9.6 Symptoms and signs of chronic kidney disease. Oedema may be due
to a combination of primary renal salt and water retention and heart failure.
CNS, central nervous system; CVS, cardiovascular system; GI, gastrointestinal.
Chronic Kidney Disease 385
Chronic kidney disease
Mechanism
Radiological
sampling) and dietary deficiency of haematinics (iron and folate) also
contribute.
Bone disease. The term ‘renal osteodystrophy’ embraces the various
forms of bone disease that develop in CKD, i.e. osteomalacia, osteoporosis,
secondary and tertiary hyperparathyroidism and osteosclerosis. Renal
phosphate retention and impaired production of 1,25-dihydroxyvitamin
D (the active hormonal form of vitamin D) lead to a fall in serum calcium
concentration and hence to a compensatory increase in parathyroid hormone
(PTH) secretion. A sustained excess of PTH results in skeletal decalcification
with the classic radiological features described in Fig. 9.7. Osteosclerosis
(hardening of bone) may be a result of hyperparathyroidism.
Low bone turnover
( remodelling
bone formation)
e.g. calcitriol
prescribed
for low Ca
± Ca
Ca
Normal ALP
PO
4
PTH PTH
Adynamic bone disease
Serum
Disease
1,25-(OH2)D
( conversion)
Bone
mineralization
2+
Ca
absorption
ALP, Ca,
PO
4
Osteomalacia
Secondary
hyperparathyroidism
Tertiary
hyperparathyroidism
(long term)
Osteosclerosis
3
Osteopenia
Pseudofractures
signs
Fig. 9.7 Renal osteodystrophy. Pathogenesis and radiological features of renal
bone disease. ALP, alkaline phosphatase; PTH, parathyroid hormone.
(Looser’s zones)
Subperiosteal erosions
Pepperpot skull
Rugger jersey spine
(Adenomas [brown tumours])
Iatrogenic,
e.g. steroids,
post-transplantation
High → low
bone turnover later
Osteoporosis
386 Renal disease
Neurological complications. Neurological complications occur in almost
all patients with severe CKD and are improved by dialysis. Polyneuropathy
manifests as peripheral paraesthesiae and weakness. Autonomic dysfunction
presents as postural hypotension and altered gastrointestinal motility. In
advanced uraemia (serum urea >50–60 mmol/L) there is depressed cerebral
function, myoclonic twitching and convulsions. Median nerve compression
in the carpal tunnel is common and is usually caused by β2-microglobulinrelated amyloidosis (a complication of dialysis).
Cardiovascular disease. The highest mortality in CKD is from
cardiovascular disease, particularly myocardial infarction, cardiac failure,
sudden cardiac death and stroke. This occurs due to an increased
frequency of hypertension, dyslipidaemia and vascular calcification. Renal
disease also results in a form of cardiomyopathy with both systolic and
diastolic dysfunction. Pericarditis and pericardial effusion occurs in severe
uraemia.
Other complications. These include an increased risk of peptic
ulceration, acute pancreatitis, hyperuricaemia, erectile dysfunction and an
increased incidence of malignancy.
Differentiating AKI from CKD
Distinction between AKI and CKD depends on the history, duration of
symptoms and previous urinalysis or measurement of serum creatinine.
A normochromic anaemia, small kidneys on ultrasonography and the presence of renal osteodystrophy favour a chronic process.
Management
The aims of treatment are:
• Specific therapy directed at the underlying cause, e.g. immunosuppressive
agents for vasculitis, tight metabolic control in diabetes
• Slow deterioration of kidney function (renoprotection)
• Reduce cardiovascular risk
• Treat any complications, e.g. anaemia
• Appropriate dose adjustment of prescribed drugs to take into account
renal impairment.
Renoprotection
The goal of treatment should be to maintain the blood pressure at less than
120/80 mmHg and to maintain a urinary protein concentration of less than
0.3 g/24 hours. Good blood pressure control may slow the decline in renal
function.
Patients with CKD and proteinuria >1 g/24 hours should receive:
• ACE inhibitor or angiotensin II antagonist, increasing to maximum
tolerated dose
• Diuretic to prevent hyperkalaemia and help to control blood pressure
Chronic Kidney Disease 387
• Calcium channel blocker (verapamil or diltiazem) if goals not
achieved.
Reduce cardiovascular risk
• Optimal control of blood pressure and reduction of proteinuria
(as above)
• Statins to lower cholesterol to <4.5 mmol/L
• Cessation of smoking
• Optimize diabetic control, glycosylated haemoglobin (HbA1c) ≤53 mmol/
mol (<7%)
• Normal protein diet (0.8–1 g/kg body weight/day).
Correction of complications
Hyperkalaemia. Hyperkalaemia often responds to dietary restriction of
potassium intake. Drugs which cause potassium retention should be stopped.
Occasionally it is necessary to prescribe ion-exchange resins to remove
potassium in the gastrointestinal tract. Emergency treatment of severe
hyperkalaemia is described on page 336.
Calcium and phosphate. The serum calcium should be maintained in
the normal range through the use of synthetic vitamin D analogues such
as 1α-cholecalciferol or the vitamin D metabolite 1,25-dihydroxyvitamin
D3 (1,25-(OH)2D3). Hyperphosphataemia is treated by dietary phosphate
restriction and administration of oral phosphate-binding agents such as
calcium carbonate (contraindicated with hypercalcaemia or hypercalciuria),
sevelamer or lanthanum carbonate.
Anaemia. Iron deficiency is common in patients with CKD. Recombinant
human erythropoietin is an effective but expensive treatment for the
anaemia of CKD. It is administered subcutaneously or intravenously three
times weekly. Target haemoglobin (Hb) is 11–12 g/dL and failure to respond
may be the result of haematinic deficiency, bleeding, malignancy or infection.
The disadvantages of treatment are that erythropoietin may accelerate
hypertension and, rarely, lead to encephalopathy with convulsions.
Acidosis. Systemic acidosis accompanies the decline in renal function
and may contribute to increased serum potassium levels as well as dyspnoea
and lethargy. Treatment with oral sodium bicarbonate (4.8 g or 57 mmol daily)
is often commenced.
Infections. Patients with CKD have an increased risk of infections
which may be fatal. Influenza and pneumococcal vaccination should be
administered.
Referral to a nephrologist
Most patients with CKD are managed in primary care and do not require
referral to a nephrologist at the outset. Indications for specialist referral are
based on the need for further investigation, complex treatment or because
there is a high likelihood of progression to dialysis (Table 9.15).
388 Renal disease
Table 9.15 Indications for referral of a patient with CKD to a
nephrologist
Patient group Assessment
Severe CKD
Rapidly deteriorating kidney
function
Higher levels of proteinuria ACR ≥70 mg/mmol or PCR ≥100 mg/mmol
Proteinuria and haematuria Proteinuria with ≥+1 blood on urine
Poorly controlled hypertension Despite use of four antihypertensive drugs
Suspected rare or genetic
cause of CKD
ACR, albumin:creatinine ratio; CKD, chronic kidney disease; (e)GFR, (estimated) glomerular
filtration rate; PCR, protein:creatinine ratio.
GFR <30 mL/min/1.73 m
Fall in eGFR >5 mL/min in 1 year or
>10 mL/min/year in 5 years
dipstick
2
RENAL REPLACEMENT THERAPY
Dialysis
‘Uraemic toxins’ are efficiently removed from the blood by the process of
diffusion across a semipermeable membrane towards the low concentrations present in dialysis fluid (Fig. 9.8). The gradient is maintained by
replacing used dialysis fluid with fresh solution. In haemodialysis, blood in
an extracorporeal circulation is exposed to dialysis fluid separated by an
artificial semipermeable membrane. In peritoneal dialysis, the peritoneum is
used as the semipermeable membrane and dialysis fluid is instilled into the
peritoneal cavity.
Haemodialysis
Adequate dialysis requires a blood flow of at least 200 mL/min and is most
reliably achieved by surgical construction of an arteriovenous fistula, usually
in the forearm. This provides a permanent and easily accessible site for the
insertion of needles. An adult of average size usually requires 4–5 hours of
haemodialysis three times a week, which may be performed in hospital or at
home. All patients are anticoagulated during treatment (usually with heparin)
because contact of blood with foreign surfaces activates the clotting cascade.
The most common acute complication of haemodialysis is hypotension,
caused in part by excessive removal of extracellular fluid.
Renal Replacement Therapy 389
[Na
H
[K
Urea 0 mmo
[Ca
[HC
Dialyser
membrane
BLOOD
DIALYSATE
+
] 140 mmol
O
2
+
] 1.0 mmol
2+
] 1.2 mmol
–
O
] 30 mmol
3
l
[Na+] 140 mmol
H
O
2
+
[K
] 6.0 mmol
Urea 40 mmol
2+
[Ca
] 1.2 mmol
–
[HCO
] 15 mmol
3
Fig. 9.8 The principle of haemodialysis.
Peritoneal dialysis
A permanent tube (Tenckhoff catheter) is placed into the peritoneal cavity via
a subcutaneous tunnel. The bags of dialysate are connected to the catheter
using a sterile, no-touch technique and the fluid run into the peritoneal cavity.
Urea, creatinine, phosphate and other uraemic toxins pass into the dialysate
down a concentration gradient and the dialysate is then collected. With
continuous ambulatory peritoneal dialysis (CAPD) 1.5–3 L of dialysate are
introduced and exchanged three to five times a day. Bacterial peritonitis, often
with Staphylococcus epidermidis, is the most common serious complication of
peritoneal dialysis. Appropriate antibiotics can be given intraperitoneally.
Haemofiltration
Haemofiltration involves the removal of plasma water and its dissolved constituents (e.g. Na+, K+, urea, phosphate) and replacing it with a solution of the
desired biochemical composition. The procedure employs a highly permeable
membrane, which allows large amounts of fluid and solute to be removed
from the patient (Fig. 9.9). It is used mostly in the intensive care setting in
the management of AKI.
Complications of all long-term dialysis
Cardiovascular disease (as a result of atheroma) and sepsis are the leading
causes of death in long-term dialysis patients. Causes of fatal sepsis include
peritonitis complicating peritoneal dialysis and Staphylococcus aureus
infection (including endocarditis) complicating the use of indwelling access
devices for haemodialysis.
200 mL/min
390 Renal disease
Blood
Blood
inflow
Haemofiltrate
1000 mL/h
Fig. 9.9 Principles of haemofiltration.
Amyloidosis is the result of the accumulation and polymerization of
β2-microglobulin. This molecule (a component of human leucocyte antigen
[HLA] proteins on most cell membranes) is normally excreted by the kidneys,
but is not removed by dialysis membranes. Deposition results in the carpal
tunnel syndrome and joint pains, particularly of the shoulders.
Semipermeable
membrane
return
Replacement
solution
1000 mL/h
Transplantation
Successful renal transplantation offers the potential for complete rehabilitation for most patients with end-stage renal failure. In specialist centres,
graft survival is approximately 80% at 10 years. Kidneys are obtained from
cadavers or, less frequently, a living donor, e.g. a close relative. The donor
must be ABO compatible, and good HLA matching increases the chances of
successful transplantation. The donor kidney is placed in the iliac fossa and
anastomosed to the iliac vessels of the recipient; the donor ureter is placed
into the recipient’s bladder.
Long-term immunosuppressive treatment is necessary (unless the
donor is an identical twin, i.e. genetically identical) to reduce the incidence
of graft rejection. This treatment comprises corticosteroids, azathioprine
or mycophenolate mofetil and ciclosporin or tacrolimus. Monoclonal and
polyclonal antibodies such as anti-lymphocyte and anti-thymocyte globulin
or basiliximab and daclizumab are potent immunosuppressives and are
used in selected patients. The complications of renal transplantation and
immunosuppression include opportunistic infection (e.g. with Pneumocystis
jiroveci), hypertension, development of tumours (skin malignancies and
lymphomas) and, occasionally, recurrence of the renal disease (e.g.
Goodpasture’s syndrome).
Cystic Renal Disease 391
CYSTIC RENAL DISEASE
Solitary and multiple renal cysts
Renal cysts are common, particularly with advancing age. They are usually
asymptomatic and discovered incidentally on ultrasonography performed for
some other reason. Occasionally they may cause pain and/or haematuria.
Autosomal-dominant polycystic kidney disease
Autosomal-dominant polycystic kidney disease (ADPKD) is a common
(1:1000) inherited condition in which multiple cysts develop throughout both
kidneys. Cysts increase in size with advancing age and lead to renal enlargement and the progressive destruction of normal kidney tissue, with gradual
loss of renal function. Most cases are due to a mutation in the PKD1 gene
situated on the short arm of chromosome 16. This gene encodes a protein
called polycystin 1 which is an integral membrane protein regulating tubular
and vascular development in kidneys and other organs. A second gene, PKD2,
on chromosome 4 accounts for the remaining cases.
Clinical features
ADPKD presents at any age after the second decade. Clinical features include:
• Acute loin pain due to cyst haemorrhage or infection, or urinary tract
stone formation (uric acid calculi occur more commonly)
• Abdominal discomfort caused by renal enlargement
• Complications of hypertension
• Progressive renal impairment; end-stage renal failure develops in about
50% of patients by 50–60 years of age.
• Complications of associated liver cysts (occur in approximately 50%);
rarely cysts occur in the pancreas, spleen, ovary and other organs
• Subarachnoid haemorrhage associated with berry aneurysm rupture
• Mitral valve prolapse in 20%.
Diagnosis
Clinical examination commonly reveals large irregular kidneys, hypertension and possibly hepatomegaly. A definitive diagnosis is established by
ultrasonography. In adults with a family history, criteria for diagnosis are at
least two renal cysts in patients aged <30 years, two cysts in each kidney
in patients aged 30–59 years and four cysts in each kidney in patients aged
>60 years.
Management
No treatment has definitively been shown to slow disease progression
or decrease cyst size. Blood pressure should be carefully controlled and
392 Renal disease
disease progression monitored by serial measurement of serum creatinine.
Many patients will eventually require renal replacement by dialysis and/or
transplantation. Children and siblings of patients with the disease should be
offered screening by renal ultrasonography in their 20s.
Medullary sponge kidney
Medullary sponge kidney is an uncommon condition characterized by dilatation of the collecting ducts in the papillae, sometimes with cystic change. In
severe cases the medullary area has a sponge-like appearance. Small calculi
form within the cysts and patients present with renal colic or haematuria.
In 20% of patients there is hypercalciuria or renal tubular acidosis (p. 342).
Renal function is usually well preserved. The diagnosis is made by excretion
urography.
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
Renal cell carcinoma
Renal cell carcinomas are the most common renal tumours in adults. The
average age at presentation is 55 years, with a male:female ratio of 2:1. They
arise from the proximal tubular epithelium and may be solitary, multiple and
occasionally bilateral.
Clinical features
Haematuria, loin pain and a mass in the flank are the most common presenting features. Other features include malaise, weight loss and fever.
Left-sided scrotal varicoceles occur if the renal tumour obstructs the gonadal
vein where it enters the renal vein. At presentation, 25% will already have
metastasized to bone, liver and lung. Anaemia or polycythaemia and hypercalcaemia are other findings.
Investigations
• Ultrasonography will distinguish a simple benign cyst from a more
complex cyst or solid tumour.
• CT scanning is more sensitive than ultrasound for detecting a renal mass
and will show involvement of the renal vein or inferior vena cava. MRI is
the preferred modality for tumour staging.
A presumptive diagnosis of renal carcinoma is made on imaging studies
in patients with isolated solid renal masses and they will usually go straight
to surgery (which provides tissue diagnosis and definitive treatment) without
further investigation.