Sickling Hemoglobinopathy and the Kidney #ExpBio

HbSS from Wikipedia

This year a number of abstracts about sickle cell and the kidney caught my attention, having just initiated dialysis on a patient with HbSS. Since the science forces of the universe seemed determined to focus my attention on this disorder, I gave into their wishes.

Hemoglobin (hb), the molecule that carries oxygen to tissues in our body, is composed of two alpha protein chains and two beta chains. In the HbS mutation, a single change in the beta chain changes the structure of the protein so that when oxygen levels drop, it becomes straighter instead of round, stretching red blood cells into a crescent or sickle shape. Abnormally shaped red blood cells are prone to damage (hemolysis) and may clog the smallest vessels in the body, resulting in organ damage and pain.

Actual Sickle

If a child gets one copy of the HbS gene, then they are a carrier; this condition is also called sickle cell trait and occurs in 1 in 13 African American babies. Most people with trait have no symptoms, although under conditions of low oxygen their disorder may be unmasked. For example, the central part of the kidney (the medulla) has much lower oxygen tension normally. Cells often sickle there and cause damage, so individuals with otherwise asymptomatic sickle trait may not be able to fully concentrate their urine.

If a child gets a copy of HbS from both parents, then they have HbSS, the full-blown sickle cell anemia disease. This happens to about 1 in 365 African American children. These individuals have anemia because the sickling cells don’t last as long as those with normal Hb (3 weeks vs 3 months). The abnormally shaped cells may also impair blood flow to organs cause acute pain episodes, what most people think about with sickle cell disease. In addition, other organs may be damaged by these events, including the brain, heart, lungs, and kidneys.

For more general information about sickle cell disease, including other associated hemoglobin disorders, the NIH has an excellent resource here.

Kasztan M, Fox BM, Speed JS, Townes TM, and Pollock DM:  KIM-1 as a new biomarker for glomerular hyperfiltration and chronic kidney disease in humanized sickle cell disease mice

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The first poster on my list dealt with KIM-1 (Kidney Injury Molecule 1) as a new biomarker for kidney damage in a humanized mouse model.They followed glomerular filtration rate (GFR) and urinary biomarkers in HbSS mice and genetic controls every 4 weeks for 24 weeks starting at 8 weeks of age. At that starting point, no differences in GFR or proteinuria were demonstrated. By 12 weeks, the HbSS mice had a significant rise in GFR and proteinuria. By 32 weeks of age, GFR was lower in HbSS than Hb AA mice, even as proteinuria climbed higher. Urine biomarkers demonstrated early KIM-1 as a potential predictor of loss of GFR later in the course. Not included in the abstract was a cohort of patients with HbSS, some of whom have developed elevated KIM-1 excretion. This has the potential to drive important translational studies in the future.

Taylor CM, Kasztan M, Yoder B, Pollock JS, and Pollock D:  Reduced Renal Primary Cilia Expression in Humanized Sickle Cell Mice

The next poster looked at renal cilia in this same mouse model. Ciliary disorders often result in cysts in the kidneys, and patients with HbSS have an increased risk of cyst formation. Kidneys from HbSS mice have reduced ciliary proteins in their kidneys, suggesting reduced numbers or size of cilia in this model. Additional studies applied hypoxic stress to the mice, a maneuver that increased expression of the proteins under study. These experiments are still preliminary, but I would never have guessed that cilia would be a problem in sickle cell kidneys.

Eshback ML, Kaur A, Rbaibi Y, Agarwal Y, Zhang Q, Nolin TD, Tejero J, and Weisz OA:  Hemoglobin Inhibits Uptake of Filtered Proteins by Proximal Tubule Cells: Implications for Sickle Cell Disease and Vitamin D Status

The final poster examined the role of Hb uptake in tubular cells in nickels cell disease. Much of this study occurred in vitro, examining what happened to tubular transport when free Hb gets filtered and the tubules reabsorb it. It competes for transport with a number of other proteins, such as albumin and the vitamin D binding protein. Patients with HbSS have reduced red blood cell lifespan and episodic hemolysis, so they do filter higher amounts of free Hb. They also seem to be much harder to make replete with Vitamin D. These basic science observations may help explain some interesting clinical observations, even though these phenomena would seem unrelated at first glance.

Sometimes an abstract just grabs me; this time, three of them jumped me and made me write about them. All were really good science with excellent presenters, and a lot more information than I’ve included here (click the links, people). Best of luck helping us understand this difficult consequence of a fairly common disorder.

Uncommon Rocks

Kidney stones seem to be as common as rocks. A variety of factors can contribute to their formation, but sometimes an interesting cause can be identified. Protein in the urine can be a tip-off that something unusual is happening.

Dent’s Disease

This X-linked recessive disorder causes problems in the function of the kidneys’ proximal tubules, leading to:

  • Hypercalciuria (high urine calcium)
  • Nephrocalcinosis (calcium deposits in the kidney tissue)
  • Kidney stones (calcium crystals in the collecting system of the urinary tact)
  • Proteinuria (urine protein)
  • Rickets (poor bone mineralization)
  • Chronic kidney disease with loss of function

Because the disorder links to the X-chromosome, most affected patients are male. Girls may show mild signs and symptoms, but chronic kidney disease is rare.

In 60% of cases, a gene called CLC-5 shows a mutation. Abnormalities of OCRL1 cause another 15% of cases. The genetic cause is unknown in about one-quarter of patients who otherwise fit the diagnosis.

Click to Enlarge
Nephron: Click to Enlarge

Proximal Tubule Function

The kidneys receive about 20% of each heartbeat’s blood for filtration and removal of wastes. Most of this blood flows through special clumps of blood vessels that allow watery material from the blood to pass into Bowman’s Space, the first portion of the nephron. From there this filtrate enters the proximal tubule, the workhorse of the kidney. This part of the kidney retains most of the fluid and chemicals filtered into the nephron.

When I want to clean up the mess in a room, I pick up the trash and dispose of it. The kidney takes a different approach, instead sweeping everything in the room into the trash and then removing what it wishes to keep. The proximal tubule retains 2/3 to 3/4 of this good stuff for the kidney.

Severe proximal tubule dysfunction results in Fanconi Syndrome. The kidney wastes everything that it should retain, including bicarbonate, potassium, phosphate, protein, glucose, and calcium. In Dent’s disease the dysfunction is less severe. While excess urine calcium and protein is necessary for the diagnosis, phosphaturia and glucosuria are variable. Dent’s disease is ruled-out by the presence of renal tubular acidosis due to bicarbonate losses.


Affected boys often develop chronic progressive kidney disease, with 30-80% developing permanent kidney failure over time. Girls are generally asymptomatic carriers; if they have signs or symptoms, they are usually mild and cause no long-term kidney damage.

Treatment currently focuses on reducing stone risk through treatment of hypercalciuria with sodium restriction and thiazide diuretics. Other general treatments for chronic kidney disease should also be employed as necessary.