Category Archives: Renal

Cobalamin related metabolic disorders

Amino acid homocysteine is converted to methionine (“remethylated”) – cobalamin is involved in some of these processes, folate metabolism also important.

Various disorders.

Variety of presentations, at different ages:

  • Neurological (central and peripheral)
    • Feeding difficulties, apnoea in babies
    • Seizures
    • Subacute combined degeneration of spinal cord (peripheral neuropathy, ataxia, incontinence)
    • Acute and/or chronic encephalopathy – hypotonia, regression
    • Neuropsychiatric problems
  • vascular problems (stroke/embolism)
  • bone marrow (megaloblastic anaemia, cytopenia) – folate related
  • Atypical HUS
  • Glomerulopathy

Investigations

  • High homocysteine, usually
  • Vitamin B12 and folate, for differential
  • Methylmalonic acid (in urine)
  • Acylcarnitine
  • Methionine (usually goes low)

Treatment

Start intramuscular B12 (hydroxocobalamin) as soon as samples collected, to prevent end organ damage.

Betaine should be started if high homocysteine with low methionine found, helps push conversion to methionine.

Homocystinuria

Autosomal recessive condition of high homocysteine in blood and urine, causing similar neurological problems, thrombosis, Marfanoid appearance, downward subluxing lenses.

Needs low methionine diet. Betaine supplements help.

Fractional excretion

Used to work out whether biochemical abnormalities are due to renal dysfunction. There is not really a “normal range” for sodium and potassium in the urine, because it depends whether the body is trying to retain or excrete at any given time. So urinary sodium can be undetectable in dehydration, for instance.

Since creatinine is filtered passively, you can compare how much sodium/potassium is being excreted with what you would expect, by calculating:

Sodium excretion (Urinary Na/Plasma Na), divided by creatinine clearance (urinary creatinine/Plasma creatinine). Multiply by 100 to get a percentage.

Note that creatinine in plasma is usually measured in micromoles, and in urine in millimoles. Online calculator here:
https://www.thecalculator.co/health/FENa-Calculator-309.html

If sodium low, you expect the kidneys to retain, so fractional excretion should be less than 1%. For low potassium, fractional excretion should be less than 10%. The opposite is true for high values.

Even where plasma sodium normal, fractional excretion can give you a clue to kidney disease – 1-4% suggests intrinsic renal pathology, over 4% post-renal.

Renal causes of low sodium/potassium include renal tubular acidosis (various forms), Bartter’s syndrome. Non-renal causes include GI losses (eg pyloric stenosis), Pseudo-Bartter’s syndrome (eg CF).

An alternative, possibly simpler method is transtubular potassium gradient (TTKG) :

TTKG = urine potassium/(plasma osmolality/urine osmolality)/serum potassium

For this formula to be accurate urine osmolality should be higher than plasma osmolality and urine sodium should be greater than 25 mEq/L.

Individuals with hyperkalemia should have a TTKG above 10. Values below 7 are consistent with mineralcorticoid deficiency, especially if accompanied by hyponatremia and high urine sodium concentration.

Individuals with hypokalemia should have TTKG values below 2.

Autosomal dominant polycystic kidney disease

ADPKD – previously Adult PCKD but now recognized as having manifestations in childhood.  Cf Autosomal recessive disease, severe, renal failure in infancy.

1 in 400 to 1,000 live births, making it the most common monogenic cause of renal failure. The typical age of onset is in middle life, but the range is from infancy to 80 years.  Associated with liver cysts (asymptomatic) and intracranial aneurysms. 10-25% do not have family history (de novo mutations, missing records or mosaicism).

Possible presenting symptoms of renal disease in children with ADPKD are frequency, nocturia and/or, hematuria, urinary tract infection(s) and back, flank or abdominal pain. Often, the earliest symptoms are polyuria and polydipsia, from decreased urinary concentrating ability.

Extrarenal manifestations seen esp hypertension (renin angiotensin system, sodium retention, endothelial dysfunction), also liver cysts (asymptomatic), intracranial cysts and valvular defects but these are only seen in adults. 25% of children are hypertensive by the time they reach adolescence.  (GFR stays stable until around 40yrs, then rapid decline, about 50% have ESRF by 60yrs).

Importantly, children who were diagnosed in utero or within their first 18 months of life, the so-called VEO group, represent a particularly high-risk group of ADPKD patients and should be managed accordingly.  Diagnostic imaging criteria not validated under 15yrs, genetic testing also challenging.

Recommendation from Kidney Disease Improving Global Outcomes (KDIGO) Consortium against screening children for APCKD.  [Also highlight variety of different cystic disorders in children, so recommend thorough clinical assessment for extrarenal manifestations in case syndrome eg Von Hippel Lindau, USS of parents and/or grandparents if negative family history, and USS to look for dysplastic kidneys, glomerulocystic disease, and tuberous sclerosis complex].[Kidney international 2015]

Increasing evidence that hypertension, left ventricular hypertrophy (even between 75th and 95th centile for BP) and increased kidney volume predates symptoms in affected children.  A study of early use of ACE inhibitor halted progression of LVH and fall in renal function.  Adding pravastatin reduced progression of structural kidney disease.  Disease modifying drugs in development.  [BMJ 2016;353:i2957 Editorial, GOS, Birmingham, Evelina].  “We propose an urgent national debate on an improved inclusive approach involving patients and their families and a range of clinicians, ethicists, and commissioners. A few pounds spent now on screening and early intervention could save many thousands later by delaying hypertensive complications and chronic kidney disease.”

Potential for pre-implantation genetic diagnosis.  See Ethics.

Only one drug known to have moderate effect on disease progression in adult ADPKD patients, vasopressin V2 receptor antagonist tolvaptan (recent Cochrane review).  But timing of use unclear.

Psychological impact of having genetic disease that can be passed on to children very common in adult patients.  But a benefit of diagnosis is potential to target modifiable risk factors  – children with normal BP have slower cyst growth.  And knowledge can give sense of control over life decisions, esp reproductive decisions.

Posterior urethral valves

1 in 5000 births.  Mostly failure of Wolffian duct development, rarely failure of urethral canalisation.

2/3 detected antenatally, with distended bladder. If missed, then present with urinary tract infection, abnormal voiding (dribble rather than fountain!) else incontinence (if toilet trained, of course).

Later detrusor failure, tubular dysfunction, renal failure.

Renal investigations

Ultrasound

Renal uss image anotated

Incomplete bladder emptying cannot be diagnosed on a single post-void residual urine on ultrasound, due to significant intra-individual variability. Two post-void residual urine tests are recommended; larger volumes are seen if the bladder has been over distended (eg initial volume greater than 115% of expected), and in younger children. Greater than 20 ml is more specific than 10% bladder capacity. [J urology 2009 (182):1933]

Bladder capacity is = (Age +1) x 30 (ml) max 390ml.

 

Haematuria

In a study of 342 kids with asymptomatic microscopic haematuria, no cause was found in the large majority of patients. The most common cause discovered was hypercalciuria (16% of patients) followed by post–streptococcal glomerulonephritis (1%). No evidence for value of early detection of hypercalciuria (may be at long-term risk for nephrolithiasis and bone demineralization).  The children with asymptomatic post–streptococcal glomerulonephritis all improved spontaneously and without complication.  None had evidence of urinary tract infection! Clinically insignificant abnormalities in the upper urinary tracts of 5 children and grade 3 reflux in 1  [Arch Pediatr Adolesc Med. 2005;159(4):353-355. doi:10.1001/archpedi.159.4.353]

Asympt recurrent can be monitored for 5yr!

Beware:

  • frank blood,
  • protein,
  • hypertension,
  • other features (joints, rash, wt loss)

Haematuria defined as persistent dipstick positive on at least 3 occasions for at least 3 months. Else as >2rbc per HPF (not same as flow cytometry). Then consider:

  • Red cells or not?
    • myoglobinuria = haemolysis
    • beetroot!
    • Porphyrins, other unusual pigments
  • Proteinuria or not?

If spot urine abnormal, repeat on early morning urine and then proceed to 12-14hr collection. Urine calcium/creatinine has age specific normals, high at birth (up to 1.5 in toddlers) falling to adult max of 0.7 at age 7. High levels especially significant in the presence of a normal plasma calcium

Investigations – only do bloods if macroscopic or nephritis suspected:

  • Do urine culture and microscopy.
  • Do PCR if proteinuria.
  • If macroscopic, do FBC, U&Es, LFTs, Coag.
  • Renal USS
  • Screen family members with urinalysis
  • Spot urine calcium/creatinine
  • If acute nephritis, do C3/4, ASOT, immunoglobulins, ANCA, anti GBM as below.
  • If stones suspected, do 2 sets of spot urine Ca/creat, Oxalate/creat, Urate, amino & organic acids, pH, KUB.

Differential is:

  • Tumour – bladder (colour changes during voiding, dysuria with sterile culture) or kidney
  • IgA nephropathy – persistent, progressive in 30%, diagnosis on biopsy
  • Alports – usually X dominant, deafness in minority, cataracts in 10%
  • Sickle cell – 1% macroscopic, 16% microscopic. Papillary necrosis, usually painless, episodic. May progress to sickle nephropathy.
  • Venous thrombosis – esp neonates, nephrotics.
  • Vascular – AVM, Nutcracker syndrome (compression of the left renal vein between the abdominal aorta and SMA)
  • Nail-patella syndrome (BM disorder, like Alports)
  • Polycystic Kidney Disease

Biopsy if persistent high grade microscopic, or microscopic with proteinuria (>150 mg/24 hr)/hypertension/impaired renal function, or 2 episodes of gross haematuria. Cystoscopy for bladder problem.

Atypical HUS

Most Haemolytic Uraemic Syndrome is associated with a diarrhoeal illness (D+ HUS), esp E coli O157.

Atypical HUS is a bad name for HUS that develops in certain individuals due to a genetic, complement disorder.  Disease is typically triggered by infection, esp respiratory tract, else diarrheal illness in 80% of pediatric forms.

Consider in young infants (less than 5% of D+HUS cases occur before the age of 6 mo), severe cases, non-colitis.

The penetrance of the disease among carriers of mutations in CFH, CFI and MCP genes is approximately 50%-60%.

Low C3 levels are a clue (seen with mutations in CFH, CFI and MCP).  In almost all cases of aHUS C4 levels are normal. Normal C3 levels do not however exclude a mutation.  Check factor H and factor I too.

Diagnosis

Measure CFH, CFI and MCP levels using radio-immune-diffusion assay (RIDA) or FACS. This however fails to detect low protein levels in 25%-75% of mutations, so genetic analysis also needed.

Check ADAMTS13 activity (as seen in thrombotic thrombocytopaenic Purpura, TTP) as part of differential.

Make sure you have enough blood samples before plasma exchange!

In neonates, screen for defective cobalamin metabolism (excess homocystine and methylmalonate in urine ).  These babies have high mortality from multiorgan failure, a prompt diagnosis and B12 supplementation is their only hope.

Haemolytic Uraemic Syndrome

Or HUS for short.  Mainly caused by VTEC (Verocytotoxin producing E coli), esp serotype O157.  But note also:

  • Occasionally Pneumococcal
  • Atypical HUS – not infective, but a genetic complement disorder
  • D- HUS is the shorthand for HUS which manifests in absence of diarrhoeal illness.  Still worth looking for E coli O157, but need to look at other possibilities.

Clinically

What it says on the tin!

  • Haemolysis
  • Uraemia

Mechanism is Thrombotic Microangiopathy, with microthrombi circulating that affect not just kidneys (producing uraemia) but also:

  • Thrombocytopenia,
  • MI/stroke/infarction
  • Encephalopathy

Differential

  • Acute dysentery eg campylobacter, shigella
  • Intussusception
  • Atypical HUS
  • Acute colitis (Ulcerative Colitis)

Although atypical HUS has a genetic cause, it is typically triggered by infection, esp respiratory tract, else diarrheal illness in 80% of kids, so may be difficult to exclude.  Consider in young infants, severe cases, non-colitis. Low C3 levels are a clue.

Acute colitis will usually have more extensive history or other clues.  The emphasis on managing these cases is on identifying toxic megacolon, and surgical intervention if necessary.  Antibiotics are recommended if high risk of infection (eg signs of sepsis) and/or immediately pre-surgery.

Diagnosis

Features of established disease are:

  • Microangiopathic haemolysis
    • Falling Hb, Plts – clinically pallor, petechiae and bruising
    • Fragmented rbc’s on film
    • High LDH
    • Blood/protein on urinalysis (if there’s any urine being produced to collect)
  • Rising Urea/Creatinine

But ideally you get the diagnosis early, before too much damage has been done.  Clues are:

  • Rising LDH
  • Falling Plts
  • Oliguria
  • Blood/protein on urinalysis

Stool results, to confirm E coli O157, take 24-48hrs (culture and toxin test). Discuss with microbiology if stool culture negative, consider gene PCR, serology.

[Pediatr Int. 2009 Apr;51(2):216-9 PMID 19405919]

Progression

But not everyone who gets E coli O157 gets HUS. Some people get diarrhoea without progressing to colitis (prob the majority), some get colitis without progressing to HUS (only a minority).  Predictors of progression to HUS are:

  • Fever (usually not at presentation, but in history – not very specific)
  • WCC >11
    • Normal WBC provides reliable reassurance against progression to HUS in 9/10
    • WCC>11 predicts progression to HUS in 70–90% of children
  • Raised CRP

[Ikeda, Epid infection 2000; 124:343.  Archimedes, Arch Dis Child 2007]

Ikeda proposes scoring system of 2+ features of fever, high CRP and WCC – 32% sens cf 98% spec.

Public Health

Preventing further cases is as important as managing your case.  About 20% of cases in outbreaks are secondary, but this increases to over 50% of cases in under 6yrs.  Interestingly, secondary cases are usually other children in the nursery (but rarely adults) if pre-school, but family members if primary/secondary school age!  [BMC Infect Dis. 2009 Aug 28;9:144. doi: 10.1186/1471-2334-9-144] Notify Health Protection team on suspicion of E. coli O157 syndrome.

Antibiotics?

Controversial.  Would be considered for other infective dysenteries viz Clarithro for campylobacter, Cipro/cef for salmonella, Azithro for shigella.

But do they precipitate HUS in E coli O157? “Exposure to antibiotics (aOR 3.62; 95% CI, 1.23–10.6) in 1st week independently associated with development of HUS” [Wong 2012].  Current 2011 UK guidance states “The use of antibiotics should, therefore, be governed by good paediatric practice as indicated by needs other than the suspicion of enteric VTEC infection”.

Fluids etc

Loperamide has traditionally been associated with toxic megacolon in acute dysentery so is not advised.

Pain – can be significant with colitis.  Opiates, NSAIDs contraindicated given potential for megacolon or nephropathy.

IV fluid volume and sodium during E coli O157:H7 infections, esp in first 4 days of illness, associated with oligoanuric HUS:

  • 1.6x more likely to become oligoanuric if no IV fluids were given during the first 4 pre-HUS days

[Christina Hickey (St Louis) and Jim Beattie, prospective study Arch Pediatr Adolesc Med. 2011;165(10):884-889. doi:10.1001/archpediatrics.2011.152]

Hence, seems reasonable to:

  • Give 20ml/kg at presentation
  • Rehydrate aggressively eg correct over 6-8hrs
  • Repeat boluses if urine output reduces

Monitoring

Since onset of HUS is from 5 to a maximum of 13 days into diarrhoea illness, there is a need to monitor those with suspected or proven E coli O157 without HUS viz repeat bloods at 5-7 days or earlier if symptoms worsen.  Consider admission if significant infection control issues eg young children/siblings.

Advanced Measures

  • Renal replacement therapy
  • Plasmapheresis (not done in Glasgow)
  • Eculizumab – drug of choice for aHUS, recommended for children in whom plasma exchange is technically difficult
  • Monoclonal antibodies vs STX1/2

Eculizumab = Recombinant monoclonal anti-C5 antibody. Orphan drug.  No good evidence from Germany, but they had good results from plasma exchange anyway.  Evidence from severe TTP that it is effective in cases resistant to immunosuppression and plasma exchange.

 

E. coli O157

Notorious STEC/VTEC producing strain of E coli. STEC is shigella toxigenic E coli, VTEC is verocytotoxin toxigenic E coli (same thing).

Cause of potentially fatal Haemolytic uraemic syndrome. But other strains also recognised.

1996 Lanarkshire outbreak, traced back to meat pies from John Barr’s butcher’s in Wishaw.  21 deaths, 512 cases, esp Wishaw Parish Church Hall luncheon and a local pub birthday party.  Emerged in late 80s, rates in Scotland have always been highest in UK until Northern Ireland outbreak with 140 cases in 2012.

Scotland is said to have 2nd highest incidence globally, although not great data from many places, high regional variability, under-reporting…  Canada and Iran worse?

At the same time as the Lanarkshire outbreak, there was an outbreak in Sakai city, Japan – 12 000 cases of infection, mostly primary school kids.  121 developed HUS, 3 died.  Traced to white radish sprouts.

Since then, another major outbreak in 2011, Northern Germany. O104 strain however, enteroaggregative plus toxin. 800 cases HUS (90% adults), 53 deaths.  Traced to organic fenugreek sprouts, although Spanish cucumbers blamed initially, exports dropped £120 million per week until consumer confidence returned.

Ratio of unreported human VTEC O157 infection to reports to national surveillance is estimated at 7.4 to 1.

Cows

E coli O157 is now commonly found in cattle, but causes no clinical effect, therefore no incentive for farmers to control. Supershedders are recognized, with one such cow able to contaminate a huge proportion of other animals’ hides.   Current FSA research project underway.  A vaccine has been developed.

Sheep have also been found to carry it…  Likely cause of outbreaks related to “Tough Mudder” events.

Pathology

Lots of acronyms!

  • EHEC = Enterohaemorrhagic E coli
  • O157:H7 = serotype
  • STEC = Shiga toxin producing E coli, same as VTEC (verocytotoxin)
  • STX1/2 genes (same as VTX) code for this toxin.
  • D+/- = Diarrhoeal illness associated (or not)
  • HUS – Haemolytic uraemic syndrome

More than 400 O:H serotypes – 6 account for most HUS.

Other genes are also relevant for virulence eg Intimin (an adherence factor, coded for by eae gene).

Diagnosis

  • Stool culture – should be collected and processed urgently.  State if bloody diarrhoea present and/or suspicion of STEC infection. Routinely tested for the presence of E. coli O157 at local laboratory, which takes 24-48 hours from sample receipt, but will miss non-O157 types. If positive, isolates are referred to SERL for confirmation of identity and typing.
  • PCR stool testing – if stool culture negative, and clearly bloody (or clinical info suggests likely STEC), then Scottish (SNERL) guidance is to send stool for PCR at the Scottish E. coli O157/ STEC Reference Laboratory (SERL), which detects both E. coli O157 and non-O157 STEC.
  • Serum serology – is used for suspected cases where culture/PCR negative.
  • Rectal swabs – may be submitted directly to SERL from cases of HUS who are unable to produce a stool sample.

Do not delay appropriate clinical and public health management while awaiting reference laboratory results.

Regarding laboratory processes:

  • Rapid referral of samples from diagnostic laboratories to SERL is important to improve the probability of culture confirmation.
  • Positive PCR results will be telephoned immediately to the referring diagnostic laboratory and culture results will follow.
  • The local diagnostic laboratory will inform the clinical team and the local public health team of positive PCR and culture results.
  • PCR (stool) may become available to local diagnostic laboratory, removing need for samples to be referred to SERL . However, if a patient presenting with HUS or acute bloody diarrhoea tests negative by local PCR and is causing clinical concern, please discuss referral of stools for further testing with SERL.

Post streptococcal acute glomerulonephritis

PSAGN for short.  Develops 7-14 days post streptococcal pharyngitis, longer if pyoderma.

Classic presentation is with acute nephritis viz

  • Oliguria
  • Hypertension
  • Haematuria

which leads to fluid overload.  But can be milder eg microscopic haematuria without oliguria.

Microscopic haematuria may persist 1yr+. Acute severe hypertension can present with symptoms of visual impairment, headache, encephalopathy.  Treat with labetolol or nitroprusside infusion.

Insensible losses = 400ml/m2/d.

Less than 2% have long term haematuria or hypertension.