CHRONIC RENAL FAILURE

•	Causes.
•	Symptoms and signs.
•	Complications.
•	Approach.
•	Investigations.
•	Management

Causes

1.	Unequal, irregular kidneys

a.	Chronic atrophic pyelonephritis.

b.	Bilateral segmental hypoplasia.

2.	Equal kidneys

a.	Focal segmental glomerular sclerosis.

b.	Cystinosis.

c.	Tubular interstitial nephritis.

d.	Juvenile nephrolithiasis.

e.	Bilateral renal hypoplasia.

3.	Large kidneys

a.	Obstructive uropathy.

b.	Infantile polycystic kidney.

c.	Renal dysplasia.

Symptoms and signs

1.	Anaemia:

a.	Pallor.

b.	Lethargy.

c.	Breathlessness on exercise.

2.	Platelet abnormality:

a.	Epitaxis.

b.	Bruising.

3.	Skin:

a.	Pigmentation.

b.	Pruritus.

4.	GI tract:

a.	Anorexia.

b.	Nausea and vomiting.

c.	Diarrhoea.

5.	Endocrine / gonads:

a.	Amenorrhoea.

b.	Erectile dysfunction.

c.	Infertility.

6.	CNS:

a.	Confusion.

b.	Fits.

c.	Coma.

7.	CVS:

a.	Uraemic pericarditis.

b.	Hypertension.

c.	Peripheral vascular disease.

d.	Herat failure.

8.	Renal:

a.	Nocturia.

b.	Polyuria.

c.	Salt and water retention.

d.	Edema.

9.	Renal osteodystrophy:

a.	Osteomalacia.

b.	Muscle weakness.

c.	Bone pain.

d.	Hyperparathyroidism.

e.	Osteosclerosis.

Complications

1.	Anaemia

a.	Anaemia is present in the great majority of patients with chronic renal failure.

b.	Causes:

i.	erythropoietin deficiency.

ii.	bone marrow toxins retained in renal failure.

iii.	bone marrow fibrosis secondary to hyperparathyroidism.

iv.	increased blood loss: occult GI bleeding, blood sampling, blood loss during haemodialysis or due to platelet dysfunction.

c.	Red cell survival is reduced in renal failure owing to the hostile biochemical environment in which red cells circulate.

d.	Increased red cell destruction may occur during haemodialysis owing to mechanical, oxidant and thermal damage.

2.	Renal osteodystrophy

a.	Components:

i.	hyperparathyroidism: osteitis fibrosa cystica.

ii.	rickets.

iii.	osteopenia.

iv.	osteosclerosis: rugger-jersey spine + calcified column.

b.	Pathogenesis:

i.	decreased renal production of 1-hydroxylase enzyme results in decreased conversion of 25-(OH)2D3 to the more metabolically active 1,25-(OH)2D3.

ii.	1,25-dihydroxycholecalciferol deficiency results in gut calcium malabsorption.

iii.	phosphorous retention due to reduced excretion by the kidneys results in an increase in PTH secretion and release.

iv.	PTH promotes absorption of calcium from bone and increased proximal renal tubular absorption of calcium.

3.	Skin disease

a.	Pruritus is common in severe renal failure and is caused by retention of nitrogenous waste products of protein catabolism.

b.	Other causes:

i.	hypercalcaemia.

ii.	hyperphosphataemia.

iii.	hyperparathyroidism.

iv.	iron deficiency.

c.	Chronic renal failure may also cause pseudoporphyria, a blistering photosensitive skin rash resulting from suppression of hepatic uroporphyrin D-carboxylase combined with a decreased clearance of porphyrins in the urine or by dialysis.

4.	Gastrointestinal complications:

a.	Decreased gastric emptying and increased risk of reflux esophagitis.

b.	Increased risk of peptic ulceration.

c.	Increased risk of acute pancreatitis.

d.	Constipation.

5.	Metabolic abnormalities:

a.	Urate retention leading to gout.

b.	Decreased clearance of insulin.

c.	Lipid metabolism: hypercholesterolaemia.

6.	Endocrine abnormalities:

a.	Hyperprolactinaemia: may present with galactorrhoea in men and women.

b.	Increased LH levels in both sexes and abnormal pulsatility of LH release.

c.	Decreased serum testosterone levels; impotence and decreased spermatogenesis are common.

d.	Absence of normal cyclical changes in female sex hormones, resulting in oligomenorrhoea or amenorrhoea.

e.	Complex abnormalities of growth hormone secretion and action, resulting in impaired growth in uraemic children.

f.	Abnormal thyroid hormone levels, partly due to altered protein binding.

7.	CNS abnormalities:

a.	Severe uraemia can lead to depressed cerebral function and decreased seizure threshold.

b.	‘Dialysis dementia’: a syndrome of progressive intellectual deterioration, speech disturbance, myoclonus and fits due to aluminium intoxication.

c.	Autonomic dysfunction:

i.	increasing circulating catecholamine levels associated with down-regulation of alpha receptors.

ii.	impaired baroreceptor sensitivity.

iii.	impaired efferent vagal function.

d.	Peripheral nervous system:

i.	median nerve compression in the carpal tunnel due to 2-microglobulin-related amyloidosis.

ii.	Polyneuropathy in patients who are inadequately dialysed.

8.	CVS disease

a.	Increased incidence of:

i.	myocardial infarction.

ii.	cardiac failure.

iii.	sudden cardiac death.

iv.	stroke.

b.	Systolic dysfunction due to:

i.	myocardial fibrosis.

ii.	abnormal myocyte function due to uraemia.

iii.	calcium overload and hyperparathyroidism.

c.	Uraemic pericarditis: a feature of severe, preterminal uraemia or underdialysis.

History

1.	Presenting complaint: reason for current admission.

2.	Current symptoms:

a.	General health: tiredness, coping at school, sports, poor growth, weakness, decreased exercise tolerance.

b.	Urinary: polyuria, nocturia, anuria.

c.	Gastrointestinal: anorexia, nausea, vomiting, abdominal pain, diarrhoea.

d.	Neurological: headache, paraesthesiae, seizures, confusion.

e.	CVS: hypertension, cardiac failure symptoms such as dyspnoea, edema.

f.	Skin: itching, bruising.

g.	Skeletal: bone pain, cramps.

3.	Past history:

a.	Initial diagnosis: when, where, presenting symptoms, initial investigations, etiology.

b.	Number of hospitalizations.

c.	Sequence of development of complications and their management.

4.	Family history: other members of immediate family affected.

5.	Management:

a.	Current diet.

b.	Medications.

c.	Dialysis routine.

d.	Management problems.

e.	Present treatment in hospital.

f.	Sequence of prior treatment changes.

g.	Use of growth hormone, erythropoietin, drug side effects, compliance, future treatment plans.

6.	Social history:

a.	Disease impact on child: amount of school missed, limitations on lifestyle, body image, self-esteem, peer reactions.

b.	Impact on family: financial considerations such as cost of drugs, frequent hospitalizations, special feeds, pumps and disposables.

c.	Impact on siblings.

d.	Benefits received, social supports.

e.	Understanding of disease. 

Clinical Examination

1.	General observations

a.	Sick or well.

b.	Growth parameters:

i.	height: short with CRF.

ii.	weight: thin with CRF, obese with steroids.

c.	Tanner staging: delay with CRF.

d.	Nutrition:

i.	muscle bulk: poor in CRF.

ii.	subcutaneous fat: poor in CRF.

e.	Skin:

i.	sallow: CRF.

ii.	pallor: CRF, HUS.

iii.	jaundice: hepatorenal syndrome.

iv.	bruising, petechiae: CRF.

v.	scratch marks: CRF.

f.	vagus deformity of knee: CRF.

g.	tachypnoea: with acidosis in CRF.

h.	Interventions:

i.	peritoneal dialysis catheter, bag.

ii.	arteriovenous fistula.

iii.	nasogastric tube.

iv.	gastrostomy.

2.	Upper limb

a.	Pulse: tachycardia (dehydration, cardiac failure with CRF).

b.	Hands:

i.	nails: brown lines in CRF.

ii.	palms: crease pallor in CRF, HUS.

iii.	wrists: shunt in CRF.

iv.	asterixis in CRF.

v.	blood pressure.

vi.	arms: proximal myopathy in CRF, steroids use.

3.	CVS examination: assess for complications of CCF.

4.	Respiratory examination: check lung fields for pleural effusion and pulmonary edema.

5.	Abdomen

a.	Intervention: CAPD.

b.	Scars.

c.	Swelling.

d.	Tanner stage.

e.	Percuss bladder for urine retention.

6.	Lower limbs and gait

a.	Inspection.

b.	Palpation.

c.	Gait examination.

d.	Reflexes.

7.	Assessment of complications

a.	Uraemia:

i.	sallow complexion: due to subcutaneous deposition of urea salts.

ii.	signs of severe uraemia: nausea, lethargy, reduced consciousness level.

b.	Anaemia:

i.	pallor in nail beds, conjunctiva, palmar creases.

ii.	signs of severe anaemia: tachypnoea, tachycardia, eyeball bruit, hemic murmur, heart failure.

c.	Infection:

i.	fever, toxicity.

ii.	if present, attempt to localize site of infection, examine chest, pharynx, etc.

d.	Bleeding: purpura and ecchymoses.

e.	Growth retardation:

i.	measure height and compare with percentiles.

ii.	ask for average heights of family members.

f.	Renal osteodystrophy:

i.	enlarged epiphyses: thickened wrist and ankle bones.

ii.	long bone deformities: tibia and fibula, humerus, radius and ulnar.

iii.	chest deformities: Harrison’s sulcus, Ricketty rosary.

iv.	spinal deformities: scoliosis, lordosis, kyphosis.

v.	pathological fractures.

g.	Fluid overload:

i.	peripheral or generalized edema.

ii.	raised JVP.

iii.	signs of heart failure: cardiomegaly, gallop rhythm, edema, hepatomegaly.

h.	Hypertension:

i.	raised BP.

ii.	chronic hypertensive retinopathy.

iii.	hypertensive encephalopathy.

I.	Pericarditis: pericardial rub.

8.	Request for:

a.	Urinalysis:

i.	blood.

ii.	protein.

iii.	nitrites.

iv.	pH.

v.	glucose.

b.	Temperature chart.

9.	Summary

a.	General features: anaemia, uraemia, infection, bleeding.

b.	Growth and musculoskeletal: growth retardation, renal osteodystrophy.

c.	CVS: fluid overload, hypertension, pericarditis.

Investigations

1.	FBC

a.	Hb: anaemia.

b.	WBC: underlying infection.

c.	Fragmented red cells / thrombocytopenia: intravascular haemolysis due to accelerated hypertension or haemolytic uraemic syndrome.

2.	Urea and electrolytes

a.	24-hour creatinine clearance: useful in assessing the severity of renal failure.

b.	Electrolytes abnormalities: not very useful in CRF.

c.	Urine osmolality: measure of concentrating ability; a low urine osmolality may be indicative of renal failure.

3.	Urinalysis

a.	Haematuria: may indicate glomerulonephritis.

b.	Proteinuria: strongly suggestive of glomerular disease.

c.	Glycosuria: with normal blood glucose is common in CRF.

4.	Infection screen:

a.	CXR.

b.	Urine culture.

5.	Immunology

a.	Complement components: may be low in active renal disease due to SLE, mesangiocapillary GN, post-streptococcal GN.

b.	Autoantibody screening is useful in detection of SLE, scleroderma.

6.	Assessment of renal osteodystrophy

a.	X-ray of wrist, knee and joints.

b.	Serum calcium and phosphate levels.

c.	Serum alkaline phosphatase.

d.	Serum PTH.

7.	Radiological:

a.	Ultrasound: for renal size and to exclude hydronephrosis.

b.	KUB: to exclude low-density renal stones or nephrocalcinosis.

c.	Intravenous urography: seldom diagnostic in advanced renal disease.

d.	CT: diagnosis of retroperitoneal fibrosis.

8.	Renal biopsy: should be considered in every patient with unexplained renal failure and normal-sized kidneys. 

8.	Summary

a.	Confirm renal failure:

i.	GFR is used as an indicator of renal insufficiency:

GFR (mL / min / 1.73m2)	Measure	
> 25	Monitor	
7 – 25	Medical manipulation	
< 7	Renal replacement	
 
ii.	Calculation of GFR:

GFR = 40 x height (in cm) / serum creatinine (in mol/L).

b.	Assessment of rate of evolution of renal failure:

i.	a graph was plotted of the reciprocal of serum creatinine against time for 1 year; at least five measurements over that time were needed, and the patient had to be stable.

ii.	this gives the rate of decline of renal function and the stage at which a given child will develop ESRF could be determined by extrapolating the graph to where it intersected the time axis.

c.	Assess etiology: UFEME, US, biopsy.

d.	Assess complications: FBC, UE, infection screen, investigations of renal osteodystrophy, etc.

Management

1.	Aims:

a.	Improve or maintain renal function and homeostasis: identify and treat acute exacerbating factors.

b.	Permit growth, as much as possible by adequate nutrition and dietary control.

c.	Prevent renal osteodystrophy.

d.	Permit the child to continue to lead an active life.

e.	Delay the use of dialysis and transplant.

2.	Identify and treat acute exacerbating factors

a.	Dehydration: give IV saline.

b.	Electrolyte imbalance: replace accordingly.

c.	Infection, e.g. UTI, chest infection.

d.	Hypertension: use of diuretics.

e.	CCF: use of diuretics and inotropes.

f.	Hypotension due to haemorrhage.

g.	Obstructive uropathy: surgery.

h.	Nephrotoxic drugs, e.g. NSAIDS.

3.	Dietary Control

a.	Aims:

i.	maintain adequate protein and calories for growth.

ii.	delay accumulation of catabolic toxins like urea.

iii.	minimizing electrolyte and acid-base disturbances.

b.	Fluid intake:

i.	generally no need for restriction.

ii.	restriction only if patient has features of fluid overload.

iii.	two main groups to consider: those who require fluid restriction, low-salt diet, diuretics and dialysis for fluid overload and those who waste salt and water, requiring a high fluid intake.

iv.	the former group commonly have a glomerular cause for CRF while the latter has a structural cause.

c.	Protein intake:

i.	protein restriction: 1.5 – 2g / kg / day relieves symptoms and prevents deterioration.

ii.	use high biological value proteins such as egg whites, milk to prevent malnutrition due to protein restriction.

d.	Caloric intake:

i.	adequate calories to maintain ideal body weight and protein-sparing effect.

ii.	distribution: 75% CHO, 20% fat, 5% protein.

e.	Sodium intake: restriction to 2g/day to prevent fluid overload.

f.	Potassium intake:

i.	2g / day to prevent hyperkalaemia, usually not a problem as when protein intake is restricted, potassium is restricted as well.

ii.	patients on diuretics may require potassium supplement.

4.	Prevention of Renal Osteodystrophy

a.	Actively exclude osteodystrophy once GFR < 35 – 40 ml / min / 1.73m3

b.	Control serum phosphate:

i.	this is very important, as hyperphosphataemia can also lead to more rapid decline in renal function.

ii.	it is best to correct the hyperphosphataemia before trying to raise the serum calcium level.

iii.	calcium carbonate can be given as a phosphate binder with food to be effective.

c.	Calcium supplementation:

i.	calcium carbonate is given in between meals.

ii.	the serum calcium is not restored to normal until the hyperphosphataemia is under control.

d.	Vitamin D supplementation:

i.	vitamin D therapy is indicated if calcium levels is still now with normal phosphate levels.

ii.	phosphate levels must be controlled before vitamin D can be given because vitamin D increase both calcium and phosphate.

iii.	PTH is a good way of monitoring response to therapy – the aim is for PTH to be 2 – 3 times normal.

e.	X-ray bones annually for bone age, hips, knees and ankles.

5.	Complications of Uraemia

a.	Issues:

i.	major: poor growth and nutrition.

ii.	minor: anaemia, congestive cardiac failure, infection, neurotoxicity and gastric ulceration.

b.	Factors impairing growth in CRF:

i.	disease onset: CRF from infancy leads to an attained height of – 3 height standard deviation score at 3 years of age.

ii.	disease type: nephrotic syndrome rquiring high-dose steroid use.

iii.	growth hormone resistance.

iv.	deficient calorie intake.

v.	poor protein synthesis and low protein turnover.

vi.	renal osteodystrophy.

vii.	glucose intolerance (on steroid).

viii.	salt wasting.

ix.	infection.

c.	Measures to improve growth:

i.	optimum nutrition.

ii.	monitoring of bone disease.

iii.	correction of acidosis and anaemia.

iv.	avoidance of high-dose steroids.

v.	provision of adequate salt.

vi.	use of rhGH in children with CRF.

d.	Nutrition:

i.	restrict milk intake due to high phosphate content.

ii.	infant formulae for renal patients: high calorie, low phosphate, high salt content.

e.	Recombinant human erythropoietin:

i.	erythropoietin increases the terminal differentiation of erythroid progenitor cells, increases cellular haemoglobin synthesis and increases reticulocyte release from bone marrow.

ii.	symptoms of uraemia improved by erythropoietin: fatigue, poor exercise tolerance, anorexia, pruritis, sleep disturbance, cold intolrance and cognitive dysfunction.

iii.	side effects: hypertension, hyperkalaemia, iron deficiency, vascular access thrombosis.

6.	Monitoring and follow-up

a.	Routine check of growth, BP, edema.

b.	Electrolytes, bicarbonate, creatinine, urea, serum calcium, phosphate, serum alkaline phosphatase.

c.	Haemoglobin, white cell count, platelet count.

d.	Cholesterol, triglycerides, uric acid.

e.	Bone X-rays – hips, knees, ankles, hands.

f.	Chest X-ray.

g.	Calculated GFR.

h.	Follow up by dietician, social worker and occupational therapist. 

Dialysis

1.	Indications

a.	Complications of CRF can no longer be managed by medical therapy alone.

b.	When GFR is below 5 – 10 mL/min/1.73m2.

c.	Awaiting renal transplant.

2.	Haemodialysis

a.	Basic principles:

i.	in haemodialysis, blood from the patient is pumped through an array of semi-permeable membranes which bring the blood into close contact with dialysate, flowing countercurrent to the blood.

ii.	the dialysis machine comprises a series of blood pumps, with pressure monitors and bubble detectors and a proportionating unit, also with pressure monitors and blood leak detectors.

iii.	blood flow during dialysis is usually 200 – 300 mL per minute and the dialysate flow usually 500 mL per minute.

iv.	dialysate is prepared by a proportionating unit which mixes specially purified water with concentrate.

b.	Access for haemodialysis:

i.	adequate dialysis requires a blood flow of at least 200 mL per minute.

ii.	the most reliable long-term way of achieving this is surgical construction of an arteriovenous fistula, using the radial or brachial artery and the cephalic vein.

iv.	this results in distension of the vein and thickening of its wall, so that after 6 – 8 weeks large-bore needles may be inserted to take blood to and from the dialysis machine.

v.	arteriovenous shunts are large-bore plastic cannulae surgically tied into a superficial artery and adjacent vein allowing direct flow of arterial blood into the dialyser.

vi.	disadvantages: high rate of infection, thrombosis and potential for disconnection resulting in exsanguination.

c.	Dialysis prescription:

i.	dry weight: weight at which a patient is neither fluid overloaded or depleted; patients are weighed at start of each dialysis and the transmembrane pressure adjusted to achieve fluid removal equal to the amount by which they exceed their dry weight.

ii.	dialysate buffer: usually acetate or bicarbonate; the sodium and calcium concentrations of the dialysate buffer are carefully monitored.

iii.	frequency and duration: adjusted to achieve adequate removal of uraemic metabolites and to avoid excessive fluid overload between dialysis sessions; an adult of average size usually receives 4 – 5 hours’ treatment 3 times a week.

d.	Complications:

i.	hypotension during dialysis due to excessive removal of extracellular fluid.

ii.	anaphylactic reactions to ethylene oxide used to sterilize most dialysers.

iii.	haemolytic reactions.

iv.	air embolism.

e.	Adequacy of Dialysis:

i.	underdialysis: insomnia, itching, fatigue, restless legs and a peripheral sensory neuropathy.

ii.	overdialysis: nausea and vomiting, restlessnes, headache, hypertension, myoclonic jerking, seizures and coma due to rapid osmolality changes leading to cerebral edema. 

3.	Haemofiltration

a.	This involves removal of plasma water and its dissolved constituents by convective flow across a high-flux semi-permeable membrane, and replacing it with a solution of the desired biochemical composition.

b.	Used for both acute and chronic renal failure.

c.	Typically a 22L exchange 3 times a week for maintenance treatment and 1L per hour in acute renal failure.

4.	Peritoneal Dialysis

a.	Principles:

i.	utilize the peritoneal membrane as a semi-permeable membrane, avoiding the need for extracorporeal circulation of blood.

ii.	a tube is placed into the peritoneal cavity through the anterior abdominal wall.

iii.	dialysate is run into the peritoneal cavity, usually under gravity.

iv.	urea, creatinine, phosphate, and other uraemic toxins pass into the dialysate down their concentration gradients.

v.	water is attracted into the peritoneal cavity by osmosis.

b.	Chronic peritoneal dialysis requires insertion of a soft catheter, with its tip in the pelvis, exiting the peritoneal cavity in the midline and lying in a skin tunnel with an exit site in the lateral abdominal wall.

c.	The volume of dialysis fluid instilled into the peritoneal cavity on each occasion is usually between 40 and 60 mL/kg.

d.	Continuous Ambulatory Peritoneal Dialysis (CAPD):

i.	uses gravity to instill prefilled bags of dialysate into the peritoneal cavity 3 – 4 times a day.

ii.	each exchange takes 20 – 40 minutes.

iii.	advantages: no pain and continuous dialysis.

iv.	disadvantages: no ‘days off’, the requirement for repeated connections and disconnections, and the attendant risk of peritonitis.

v.	CAPD is associated with the best growth, best control of anaemia and best patient tolerance.

e.	Continuous Cycler-assisted Peritoneal Dialysis (CCPD):

i.	involves use of an automated cycler for overnight instillation and drainage of dialysate fluid.

ii.	advantages: only one connection and disconnection between the cycler and the peritoneal cavity per day, hence less risk of infection and less time demand on the family. 

f.	Bacterial peritonitis:

i.	bacterial peritonitis and catheter blockage: abdominal pain and a cloudy peritoneal effluent.

ii.	measures to counter peritonitis: 3 times every 2 years, standard IP antibiotics such as cephalothin and gentamicin are added once daily to fluid that dwells in the abdomen all day. 

iii.	if the child develops abdominal pain and the fluid becomes cloudy, treatment with intravenous and intraperitoneal flucloxacillin and gentamicin is effective.

g.	Other complications:

i.	constipation.

ii.	failure of peritoneal membrane function resulting in worsening biochemical exchange and decrease ultrafiltration with hypertonic dialysate.

iii.	sclerosing peritonitis: progressive thickening of peritoneal membrane with adhesions and strictures.

h.	Contraindications:

i.	presence of a stoma.

ii.	active intra-abdominal sepsis.

iii.	abdominal hernia.

iv.	visual impairment. 

I.	Complications of long-term dialysis:

i.	cardiovascular disease and sepsis are main causes of death.

ii.	accumulation of amyloid protein causing pathological bone cysts and fractures, pseudotumors and GI bleeding. 

Transplantation

1.	Benefits

a.	Treatment of choice for end-stage renal failure.

b.	Particularly beneficial in terms of growth.

c.	Living related donor are preferable to cadaveric grafts, as they have a better rate of patient survival at 5 years and graft survival at 5 years. 

2.	Work-up

a.	Blood grouping and tissue typing is done on all family members. 

b.	HLA-matching.

c.	Assessing the bladder for vesicoureteric reflux and outlet obstruction.

d.	Minimal weight of 6kg. 

3.	Major problem: need for long-term immunosuppressive therapy, with associated risk of opportunistic infection and increased risk of malignancy later in life.

4.	Drugs used in immunosuppression

a.	Prednisolone.

b.	Azathioprine: bone marrow suppression, GI upset.

c.	Cyclosporin A: nephrotoxicity, hypertension, anaemia.

d.	Antibodies: 

i.	OKT3: pulmonary edema, bronchospasm, chills, aseptic meningitis.

ii.	polyclonal antilymphocyte agents: allergic reactions, serum sickness, neutropenia, thrombocytopenia.

iii.	CD 25 monoclonal antibodies: basiliximab.

5.	Post-transplantation

a.	After transplantation, children usually remain in hospital for a fortnight or less, after which they are reviewed regularly.

b.	Often patients will have one or more episodes of rejection, with clinical findings of tenderness over graft and fever, laboratory findings of a rising serum creatinine level, and leukocytosis.

c.	High-dose intravenous steroids or OKT3 are usually effective.

d.	Gancyclovir is given IV and then orally for 3 months, when a CMV-negative recipient receives a CMV-positive kidney.

e.	At each outpatient visit, check growth, blood pressure, look for signs of opportunistic infection, side-effects of drugs.

f.	Rising serum creatinine may be due to rejection, infection, obstructed blood supply to graft, obstructed ureter or nephrotoxicity.