Tick borne diseases for the nephrologist - Babesiosis

The following few posts are a summary of tick borne illnesses that can cause renal failure and/or electrolyte problems. 

Babesiosis

First identified on Nantucket Island in 1969 and was initially know as Nantucket fever.

Endemic areas.
CDC map. Reported cases in 2012

Cases have been reported in Europe (Croatia, France, Great Britain, Ireland, Portugal, Spain, Sweden, Switzerland)(Babesia divergens).

The tick.

Ixodes scapularis. The Blacklegged tick.

The pathogen.

Babesia microti and B. duncani (USA). B divergens (Europe). Protozoan parasites infecting red blood cells

Humans are not a natural host. Infection by blood transfusion has been reported.

Incubation period 1 – 9 weeks

Clinical features.

Fever, chills, sweats, Malaise, fatigue, Myalgia, arthralgia, headache, Gastrointestinal symptoms, such as anorexia and nausea (less common: abdominal pain, vomiting)

Dark urine

Less common: cough, sore throat, emotional lability, depression, photophobia, conjunctival injection

Mild splenomegaly, mild hepatomegaly, or jaundice may occur in some patients

Lab features

Haemolytic anemia, thrombocytopenia, renal failure, transaminitis.

Diagnosis - Light microscopy of blood cells, serology and PCR for B. microti or B. duncani

Treatment - Atovaquone plus azithromycin or quinine plus clindamycin orally for 7 to 10 days.

Atovaquone plus azithromycin is preferred as this combination is better tolerated.

The source for this review is mainly from the CDC website as well as various references cited in the posts. The tick pictures provided may differ from what might be found on a bitten human. Ticks become larger and engorged after feeding and will look different.

Bedside Urinalysis - Blood

All to often now doctors in well-resourced hospitals rely on high tech, expensive and sometimes invasive tests to make a diagnosis. One of the most basic and cheapest tools we have at our disposal is the bedside urine ‘dipstick’ test. What can we learn from such an easy to perform test? 

One urinalysis reagent strip or ‘dipstick’ costs about 14cents (Pinnacle 10SG Urinalysis).

Finnian wrote two excellent blog posts on urine specific gravity and osmolality and on urine albumin and protein measurements using the ‘dipstick’ test. Here’s what else this bedside test can help you with.

Urine dipstick ‘Blood’ test

Heme acts as a pseudoperoxidase and when exposed to the peroxide and a chromagen on the test pad a colour change takes place.

The urine dipstick is a highly sensitive test for the presence of heme in the urine and detects as few as 1 to 2 RBCs per high power field.

The presence of urinary ascorbic acid is one circumstance where false negative tests for hematuria occur. Some manufactures make test strips that can oxidize ascorbic acid to reduce false negative tests.

Semen in the urine can cause a false positive test.

Of course the ‘blood’ panel turns positive due to the heme in free urinary hemoglobin or myoglobin.

Thus the presence of RBCs in the urine needs to be confirmed by microscopic analysis of the urine.

What disorders can we assess with the ‘dipstick’ test for blood/heme?

           

Rhabdomyolysis

Myoglobin is released from damaged muscle along with CK. 

Myoglobin is not avidly bound to protein and is thus rapidly excreted in the urine and has a half-life of about 2 hours. It is also rapidly metabolized to bilirubin so serum levels return to normal within 8 hours.

Thus, a diagnosis of rhabdomyolysis is not ruled out by negative urinary myoglobin.

On must also be aware that there may also be heme or RBCs present in the urine for other reasons during rhabdomyolysis.

Myoglobin appears in the urine when serum levels are above 1.5mg/dl but visible changes in urine colour only occur when serum levels are above 100mg/dl. A clear urinary supernatant usually helps to distinguish myoglobinuria from hemoglobinuria (red supernatant) after centrifugation.

Myoglobin can be detected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL.

Mean peak serum Creatinine Kinase (CK) levels in a large study of rhabdomyolysis was 10,000 to 25,000. 46% of this cohort had AKI. In another study that included only patients with a CK over 5000 AKI was present in 51%.

A good history and physical exam helps makes the diagnosis.

Hemolysis

Again this diagnosis is easy with a good history and physical exam and some basic ‘hemolysis’ lab tests. What can you do while waiting for the lab results?

The urine dipstick will be positive for heme in the urine. In theory there will be no RBCs in the urine and the supernatant will be red without a red cell pellet. However, there are caveats to this, an old urine sample and rarely a very dilute urine sample (low specific gravity – see Finnians post) may cause red cells present in the urine to hemolyze. Urine microscopy should be done to look for presence or absence of RBCs.

Red urine supernatant but negative dipstick ‘blood/heme’?

Rifampin, phenytoin, food dyes, beets (beeturia), rhubarb, senna or Acute intermittent porphyria.

Renal or urological bleeding.

In either of these circumstances urine dipstick tests will be positive for blood.

Hematuria present with proteinuria is suggestive of a glomerular cause. Hematuria with proteinuria greater than 1+ is almost never due to extra glomerular bleeding even when gross hematuria is present. However, massive bleeding can cause proteinuria. Massive bleeding is more likely to occur due to extra glomerular bleeding and the presence of clots and very red or pink urine as opposed to Coca-Cola coloured urine indicates extra glomerular bleeding.

Hematuria: Deep on the DDx

Recently at our biopsy conference we had the case of a healthy middle aged man presented who had come to medical attention with episodes of painless gross hematuria. He had consistent rbcs on UAs, normal renal imaging, a serum creatinine of 1.1 mg/dl, 360 mg per day of proteinuria and unremarkable serologies. An extensive urologic evaluation had been unrevealing and a kidney biopsy was normal.


When the usual suspects of urologic and glomerular causes of relatively isolated hematuria (IgA nephropathy, Thin Basement Membrane Disease, Alport's Syndrome) are not around you sometimes have to go a bit deeper down the differential diagnostic list.


Along those lines RFN has had a couple of posts on some of the more unusual painful causes of hematuria including renal infarction, Loin Pain-Hematuria Syndrome and the Nutcracker Syndrome (also covered on PBF).


As mentioned, our patients hematuria was painless. He had no history of diabetes, NSAID use, infection or obstruction to implicate renal papillary necrosis. There was no travel history to suggest Schistosoma haematobium or Tuberculosis. His ethnicity made Sickle cell unlikely. He only exercised as much as the average first year renal fellow (ie not much) so exercise hematuria seemed out. The room was a little stumped.


A metabolic possibility that came up after conference was hypercalciuria and or hyperuricosuria in the absence of nephrolithiasis.


In a small series of patients without nephrolithiasis and with persistent microscopic hematuria in the setting of normal renal function, urinary protein excretion and renal imaging published in KI, hypercalciuria was defined as greater than 4 mg/kg/day and hyperuricosuria was defined as greater than 800 mg/day in men and greater than 750 mg/day in women.


37 patients were identified who fit the above description and had hypercalciuria, hyperuricosuria or both. 43% of them reported having episodes of gross hematuria in addition to their known microscopic hematuria. The authors went on to treat the entire group with HCTZ and or allopurinol with the goal of normalizing urinary calcium and uric acid excretion which was achieved in all patients. Hematuria completely resolved in 59.4% of cases.


In the discussion the authors speculated that perhaps microlithiasis was the cause of the hematuria in some of their cases. Of the patients who did not respond to lowering of urinary calcium and uric acid they all persisted with microscopic hematuria and at about a year followup a reasonable alternate cause (IgA nephropathy, Thin Basement Membrane Disease ect) was ultimately found or strongly suspected in all but four cases.


Another small case series of 12 similar patients in familial clusters was subsequently published in AJKD. Here again 30% had reported episodes of gross hematuria in addition to microscopic hematuria and all patients were able to normalize their urinary calcium and uric acid excretion through medication and dietary measures. All 12 patients were able to achieve resolution of their hematuria.

Isolated microscopic hematuria

We have had a rush of patients with isolated hematuria in my clinic recently. The question that occupies so much precious time of the nephrologist reared it's head....... 'what are the indications for a renal biopsy'.

Isolated persistent glomerular hematuria (with dysmorphia) without proteinuria, hypertension or reduced GFR is one of 4 things according to several studies [Caldas et al (1990) Lab Ix; 62:15A. Tiebosch et al (1989) NEJM;320:140]. IgA nephropathy, Alport's Syndrome, Thin Basement Membrane disease or mild glomerulonephritis. Approximately 5% have other diagnoses and a number have a normal biopsy.

Most of these patients have a long term benign course. However many patients with Alport's disease develop progressive renal disease, as do a number of patients with this form of IgA nephropathy. Although thin basement membrane disease is said to be benign, it is not exclusively so and many patient have mutations in Col4a3, Col4a4 genes, similar to Alport patients.

In a pediatric study of Physicians deciding whether to biopsy children for isolated hematuria, only 5% said they would. Further in Pediatric studies where biopsies were performed, only 1 in 39 biopsies for isolated hematuria resulted in a change in management.
It is not always possible from family history to make the diagnosis. However, TBMD is frequently inherited in an AD manner, while Alports syndrome is both autosomal recessive and X-linked (rarely AD). Fewer than 10% of IgA nephropathy patients have an inherited form.

The presence of sterile pyuria might also point to a nephrotoxic cause or a component of interstitial disease and might be taken as a sign of underlying disease activity.


So for patients with isolated persistent hematuria and no clear diagnosis one can either monitor the patients regularly for changes in renal presentation or perform a biopsy.

I would favor performing a renal biopsy only if:

• patient requests for certainty/inform family members/diagnostic curiosity
• Any suggestion from H & P that this might be the early stages of a non-benign disease
• Other atypical features including pyuria.