Sickle Cell Trait and Renal disease

Are there any association of sickle cell trait( SCT) and renal disease? Sickle cell disease and renal disease has been well established, but SCT and renal disease is an area understudied. A recent JAMA study showed association using a registry data.  Primary outcomes were CKD , incident CKD, albuminuria and decline in eGFR. The study concluded that among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers.

What type of diseases do we see with SCT in the kidney? In SCT, injection radiographs demonstrate renal medullary vascular disruption, though to a lesser extent than seen in sickle cell disease, suggesting that sickle hemoglobin may have a dose-dependent relationship with kidney injury.  Our finding that SCT was related to both CKD and albuminuria is consistent with these proposed mechanisms. SCT is 4-5 times more common than sickle cell disease.  Hematuria by far is the most common complication of SCT especially seen in African Americans.  Admission rate in one study with patients with SCT and hematuria was 4%.  

The most common renal involvement in SCT are:

1.    Papillary necrosis ( most common)

2.    Renal infarction

3.    Isosthenuria

4.    Increased risk of exercise induced rhabdomyolysis

5.    Renal medullary carcinoma( very rare)

6.    Earlier onset of ESRD if also have ADPKD

Clinical Case 72: Answer and Summary

A 62 year old male with sole microscopic hematuria is asked to seek renal consultation. He has had 3-4 urine samples in the last year with this finding. What would you do next?

Seroligcal workup           0%

Kidney biopsy                2%

Follow closely, nothing specific now        7%

ACEI or ARB therapy                            2%

Urological workup                               87%

This is a common situation faced by many. This can be seen mostly in primary care settings and usually in this age group, urological workup to rule out malignancy of the GU track is likely the first thing to do. But then again, the role of cystoscopy is uncertain in patients with unexplained persistent microscopic hematuria who have no risk factors for malignancy( smoking history, weight loss, B symptoms). The AUA recommendations on asymptomatic microscopic hematuria included the following risk factors for malignancy: ( coutesy AUA and uptodate.com)

• Age >35 years
• Smoking history in which the risk correlates with the extent of exposure
• Occupational exposure to chemicals or dyes (benzenes or aromatic amines)
• History of gross hematuria
• History of chronic cystitis or irritative voiding symptoms
• History of pelvic irradiation
• History of exposure to cytoxan
• History of a chronic indwelling foreign body
• History of analgesic abuse, which is also associated with an increased incidence of carcinoma of the kidney 

 Following that being negative, the choices can be variable. Most would likely follow closely and do nothing specific or potentially do a kidney biopsy. Usually the renal disease with just the above findings has a limited differential and usually benign. 

NEPHSAP review: Glomerular Disease: Hematuria Risk long term?

At Nephsap review, we discussed a question re asymptomatic isolated hematuria in an young adult and the discussion was regarding the long term risk to ESRD? Is it truly measurable risk?
Young adults often present with asymptomatic hematuria. This was elegantly studied by the researchers in Israel looking at close to a million sample size.  It was a retrospective cohort study using medical data from ages 16-25 (60% males and 40% females) who had been examined for fitness to the military.

Persistent asymptomatic isolated microscopic hematuria was diagnosed in 3690 of 1,203,626 eligible individuals (0.3%). After over 21 years, ESRD developed in 26( 0.7%) of the hematuria group and 529( 0.045%) without the hematuria group. This was a hazard ratio of 19.5.  A substantially increased risk for treated ESRD attributed to primary glomerular disease was found for individuals with persistent asymptomatic isolated microscopic hematuria compared with those without the condition. The authors concluded that the "presence of persistent asymptomatic isolated microscopic hematuria in persons aged 16 through 25 years was associated with significantly increased risk of treated ESRD for a period of 22 years, although the incidence and absolute risk remain quite low."

CONSULT ROUNDS: Hematuria and renal failure?

45 year old with IgA Nephropathy has gross macroscopic glomerular hematuria. Following that, an episode of AKI ensues.  Is this pigment nephropathy? How does AKI result from gross hematuria?

1. 25% of patients with gross hematuria associated AKI had adverse long term outcomes
2. Of all the glomerular diseases, IgA is the most common cause of gross hematuria associated AKI
3. Older age seems to be a risk factor for longer recovery time from AKI from the hematuria
4. Severe ATN was the cause on biopsy for cause of late recovery
5. No cases of Alport's Syndrome and AKI with hematuria in the literature and one case of thin basement  membrane disease with Aki with hematuria.
6. Oral anticoagulation related injury has been now described and cases of warfarin associated renal disease have been identified
7. Hemoglobinuria from entities such as paroxysmal nocturnal hemoglobinuria have been associated with AKI due to hemolysis, intra-tubular cast obstruction.
8. Overall, why does hematuria cause AKI and renal damage. Initially, it was thought to be from intra-tubular obstruction from RBCs or hemoglobin casts.
9. Recent data suggest that there is direct tubular toxicity of hemoglobin, heme, iron molecules released from RBCs.  There is decrease in nitric oxide leading to intra renal vasoconstriction and ischemia.

A recent CJASN article summarizes these studies.

TOPIC DISCUSSION: Pure Thin Basement Membrane vs " Hereditary Nephritis with Thin Basement like features"

Classically, Hereditary Nephritis or Alports Syndrome shows the basket weaving appearing or thin and think alternating basement membrane.  Early in the course in some males and almost all females, the only finding on kidney biopsy might be thin basement membrane. The pathologist needs to carefully look for any subtle changes in lamination and change in thickness in other areas as it makes it almost impossible in that stage to differentiate from pure Thin Basement Membrane disease.  When its not possible to differentiate its called " Hereditary Nephritis with thin basement membrane phenotype".  Those cases have to be clinically followed closely in case they develop renal insufficiency.

Ref:
ASN Nephsap July 2011, Pathology

Topic Discussion: Warfarin Related Nephropathy

A commonly used agent is warfarin for anticoagulation.  Recently there have been some published case reports of warfarin induced nephropathy(WRN). More recent, an original article on the incidence and prevalence of this entity in CKD has also been mentioned.

What is this entity? High INR was associated with a rise in crt in biopsy of patients showed glomerular hemorrahge and renal tubular obstruction with red blood cell casts.  A recent retrospective review of over 15000 patients who were on warfarin and had an INR >3 and creatinine at the same time were reviewed.  A presumptive diagnosis of warfarin induced toxicity in the kidney was made if crt increased by 0.3mg/dl in 1 week after INR was >3.  WRN occurred in 20.5%,and 33% of the patients with CKD.  The mortality was also higher with people with this entity.  Other diagnosis that could have cause an acute renal injury were considered in those 4006 patients and carefully ruled out by looking at the chart.

The study highlighted few important points:
1. This entity should be considered in the differential diagnosis with AKI on warfarin
2. The risk factors to make this risk higher were age, DM, HTN and CVD but most important risk factor that doubled the risk was CKD.
3. Average INR to show this entity was only 4
4. The higher risk of WRN in CKD patients maybe be more likely due to having a sub therapeutic INR
5. There is no correlation of WRN and level of INR
6. WRN has substantial decreased survival rate but unclear if this is purely from WRN or other co morbid conditions.
7. Glomerular hemorrhage leading to tubular cast obstruction leading to ATN is the most likely mechanism
RFN also blogged about this in 2010 at
http://renalfellow.blogspot.com/2010/08/warfarin-induced-aki.html
Read more at the following references:
http://www.ncbi.nlm.nih.gov/pubmed/21389969
http://www.ncbi.nlm.nih.gov/pubmed/20413993
http://www.ncbi.nlm.nih.gov/pubmed/19577348

TOPIC DISCUSSION: Urinary Snapshot of Lupus Nephritis does not equal what you see on the Kidney Biopsy

What degree of Class IV lupus nephritis presents with just hematuria?

What degree of Class I lupus nephritis presents with just hematuria?

Take a look at this data from a recent paper in 2009 by Seshan et al.

Of 541 patients studied for classification of lupus nephritis,

40% of Class I, 19% of Class II, 22% of Class III, 4% of Class IV and 6% of Class V presented with asymptomatic hematuria.

40% of Class I, 42% of Class II, 25% of Class III, 7% of Class IV and 13% of Class V present with asymptomatic proteinuria

20% of Class I, 15% of Class II, 17% of Class III, 40% class IV and 65% of Class V presented with Nephrotic Syndrome.

20% of Class II, 34% of Class III, 27% of Class IV and 7% of Class V presented with Nephritic Syndrome

4% of Class II, 2% of Class III, 18% of Class IV and 2% of Class V presented with Acute renal failure

4% of Class IV and 8% of Class V had presented with Chronic renal injury.

So in summary: Lupus can present on kidney biopsy much more differently than clinically.  Look at the wide spectrum of just hematuria and proteinuria.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/19195967

Hematuria Post Kidney Transplantation

An entity often not talked about and not much out there in the literature. a nice review below by Dr.Krish.

Hematuria post transplant

View more presentations from Nephrology, NSLIJ