Renal

Morning Report: Hepatorenal Syndrome

February 19, 2009

kidneybeans.jpgCommentary by Catherine Lucero MD, PGY-3

Faculty Peer Reviewed

The patient is a 69-year old woman from El Salvador with a chief complaint of worsening abdominal distension for nine months. Three months earlier, the patient was told she had liver problems and was started on diuretics. Prior to presentation, the patient states that she stopped taking her medication and noticed increasing lower extremity edema and abdominal girth, as well as an unintentional 15-pound weight loss. The patient denied any other medical problems, including fever, chills, or toxic habits. On presentation, the patient was afebrile, HR 60/min, BP 90/60 mmHg, RR 20/min, O2 sat 98% on room air. Physical exam was notable for decreased breath sounds at bases, shifting dullness, presence of fluid wave, palmar erythema and 2+ pitting lower extremity edema bilaterally. Laboratory data were notable for sodium of 128 mEq/L, potassium of 5.5 mEq/L, BUN of 60 mg/dl, creatinine of 5.5 mg/dl, platelets of 205K. Urinalysis was unremarkable; there was no evidence of proteinuria or pyuria, and the sediment was bland. Fractional excretion of sodium was calculated to be less than 0.7%. A renal consult was obtained, and the patient was started on albumin, leading to an improvement in her renal function. She underwent therapeutic paracentesis and diuresis, but several days into her hospitalization she developed worsening renal function.

Hepatorenal syndrome (HRS) is a diagnosis of exclusion. The major criteria include liver disease with advanced hepatic failure evidenced by portal hypertension, decreased GFR evidenced by Cr> 1.5 mg/dl or creatinine clearance <40 mL/min, absence of shock, bacterial infection, treatment with nephrotoxic drugs, or GI or renal fluid losses. Obstructive uropathy or parenchymal disease as visualized by ultrasound should be ruled out(1). It also is defined by lack of improvement in renal function following diuretic withdrawal and expansion of plasma volume with isotonic saline. Proteinuria <500 mg/dl is characteristic. There are two types of HRS. Type 1 is characterized by a rapid deterioration with a creatinine greater than 2.5 mg/dl over a two week period. Type II is characterized as a slower, more chronic progression of renal failure.

Albumin has some benefit in patients with spontaneous bacterial peritonitis(2). A study published in the New England Journal focused on prevention of renal failure and improvement in in-hospital mortality in cirrhotic patients diagnosed with spontaneous bacterial peritonitis (ascitic cell count of greater than 250 polymorphonuclear cells/cc without evidence of secondary peritonitis). One hundred twenty-six patients were blinded and randomized to receive cefotaxime with albumin versus antibiotics alone. After three months, 33% patients who received cefotaxime developed renal impairment versus 10% in the cefotaxime plus albumin group, p= 0.0002. There was decreased in-hospital mortality in patients who received albumin and antibiotics: 6 of 63 (10%) versus 18 of 63 (29%) in the group that received antibiotics alone (p=0.01).

There is limited literature in the use of albumin with regards to improvement in hepatorenal syndrome. One prospective study published in Gastroenterology studied 20 consecutive patients with hepatorenal syndrome. Varying amounts of albumin were given to maintain a CVP above 3 cm H20(3). Furosemide was given to support urine output. Eleven out of the 20 patients had shown statistically significant, if minimal, improvement in creatinine clearance:from 27 ± 7.0 mL/min to 30.4 ± 5.2 mL/min. There was benefit seen in the number of days of survival in the patients who responded to the albumin versus those who did not: 259 ± 113 days versus 14 ± 3 days, p < 0.0005. A limitation to this prospective study was its small sample size, but the significant increase in days of survival warrants larger studies to confirm this finding.

A recent study published in Gastroenterology (4) focused on improvement of renal function or survival in cirrhotic patients with hepatorenal syndrome treated with terlipressin, a vasopressin analog thought to improve renal perfusion by countering splanchnic vasodilation and increasing effective arteriolar volume. Forty-four patients were blinded and randomized to either receive terlipressin and albumin versus albumin alone for 15 days with follow-up at three months. Patients had similar baseline characteristics and after three months, improvement in renal function (reduction in serum creatinine below 1.5mg/dl or reduction in initial values by 50 percent) was seen in 10 of 23 patients (43.5%) who received both terlipressin and albumin versus 2 of 23 (8.7%) who only received albumin. There was no significant difference in survival at three months: 27% in the terlipressin and albumin group versus 19% in the albumin group. Small sample size and lack of double-blinding make this study less valid, but significant improvements in serum creatinine concentration suggest treatment consideration in this patient population.

There have been small studies evaluating possible benefit of transjugular intrahepatic portosystemic shunt (TIPS) in patients with hepatorenal syndrome, with the thought that decreasing portal pressures will improve subsequent renal failure. Thirty-one cirrhotic patients not deemed candidates for transplant who developed HRS received TIPS and were followed retrospectively for renal function and survival. There was an improvement in creatinine clearance from 18 to 48 ml/min and improvement in three-month survival to 81% when compared to similar patients who did not receive TIPS (10%). This study suggested that TIPS should be considered as an earlier intervention as several patients were taken off dialysis soon after the procedure.

Ultimately the treatment for HRS is liver transplantation, as it is the only modality to improve renal function. Factors such as patient demographics, limited organ donation, and coexisting comorbidities hinder this intervention from improving survival. Given lack of major trials in this particular field, prevention of progressive liver disease remains the ideal intervention.

References
1. Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164–176.

2. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-409.

3. Peron JM, Bureau C, Gonzalez L, et al. Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study. Am J Gastroenterol 2005;100(12):2702-7.

4. Martin-Llahi, M, Pepin, MN, Guevara, M, et al. Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134:1352-1359.

5. Brensing KA, Textor J, Perz J, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: A phase II study. Gut 2000;47: 288–95

Reviewed by David Goldfarb, MD, Professor of Medicine, NYU Medical Center, Chief Nephrology Section VA New York Harbor

Grand Rounds: “VEGF and Renal Thrombotic Microangiopathy”

January 21, 2009

Grand Rounds Image

Commentary by Ilana Bragin, MD, PGY-3

Please also see the clinical vignette presented before last week’s grand rounds.

Last week’s Medical Grand Rounds was given by guest speaker Dr. Sue Quaggin, Associate Professor of Medicine at the University of Toronto, who shared with the audience her knowledge and passion of the role of Vascular Endothelial Growth Factor (VEGF) in kidney function.  VEGF is a critical family of signaling proteins that is involved in vasculogenesis and angiogenesis. While the discovery of VEGF could be applied to many aspects of medicine, it has become especially relevant to the realm of cancer therapy. Tumors are often highly vascular entities and require VEGF to create their own vasculature. If a rapidly growing tumor cannot create its own blood supply, the tumor will be unable to propagate. Agents that target VEGF have proliferated, revolutionizing cancer care in general, and particularly impacting the treatment of solid tumors with treatments like bevacizumab (Avastin), ranibizumab (Lucentis), sunitinib (Sutent), and sorafenib (Nexavar), with several more in clinical trials.

However, like all medications, researchers and clinicians are learning that anti-VEGF agents can have some adverse effects on non-tumor tissue as well.  This is where Sue Quaggin’s research plays a tremendous role. Dr. Quaggin’s lab focuses on the effect of VEGF on the kidney. She noted that some of the most common adverse affects of bevacizumab, an anti-VEGF agent, include hypertension (3-36% of patients) and proteinuria (in 21-64% of patients). More serious side effects include several cases of kidney failure due to thrombotic microangiopathy. Dr. Quaggin set about to define the role of VEGF in the development and maintenance of the glomerulus, thus possibly explaining the disease processes that occur when VEGF is inhibited.

Using mouse models, Dr. Quaggin explored how VEGF works on the podocytes of the glomerulus. Podocytes require VEGF production in order to create the glomerular endothelium, as done in embryonic development, but they also require VEGF throughout life in order to maintain the health of the adjacent glomerular endothelium.

When VEGF production is disrupted, by medications such as bevacizumab, there is a characteristic pattern of renal damage—mesangiolysis, endothelial swelling, and effacement of the foot processes—all characteristic of thrombotic microangiopathy. She suggests that the reason VEGF inhibition in the glomerulus is particularly significant compared to the minimal known effect on other vasculature in the body, lies in the delicate nature of the glomerulus. She proposes that this is because glomerular endothelial cells contain fenestrations that are responsible for the unique permeability of the glomerulus, and VEGF is vital to the formation of these fenestrations. A loss of healthy glomerular endothelial cells, along with their fenestrations, leads to microvascular injury and thrombotic microangiopathy.

Although it has been argued that the kidney disease associated with VEGF inhibition may be secondary to the HTN also seen due to these medications, Dr. Quaggin postulates that the HTN is seen after glomerular changes, and may also somehow be linked to the lack of VEGF.

This research has particular clinical relevance, given the impressive therapeutic use of these medications in oncology and the expectation that their use will increase. Perhaps, for example, further studies will lead to a difference in the type of monitoring of kidney function in patients who are on anti-VEGF medications.
With more patients surviving their cancer, understanding the side affects of the medication regimens involved in treatment is becoming more and more important.

Class Act: The Role of Angiotensin II in Renal Fibrosis and Diabetic Kidney Disease

December 9, 2008

zestril.jpgCommentary by Daniel Fine MD

Faculty Peer Reviewed

Diabetic nephropathy is the most frequent cause of end-stage kidney disease in the United States, Europe and Japan. Large scale randomized controlled trials have shown that both ACE inhibitors and angiotensin II receptor antagonists reduce microalbuminuria, slow rate of decline of GFR and delay end stage kidney disease.

The renin-angiotensin system plays a significant role in the human inflammatory process in addition to its well known effects on blood pressure and sodium homeostasis. The role of angiotensin II as a pro-inflammatory cytokine may be important in understanding the role of the renin/angiotensin/aldosterone axis in diabetic kidney disease.

The effect of angiotensin II on the physiology of the heart, blood vessels and kidneys begins when low renal perfusion pressure in the juxtaglomerular apparatus triggers renin release from the renal cortex, catalyzing the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II via the action of angiotensin converting enzyme (ACE). Angiotensin II then serves to increase sympathetic activity, reabsorb sodium and cause peripheral vascular constriction. Disorders of this system are now known to play an important role in the pathophysiology of hypertension, congestive heart failure, and renal disease. I will explore some new concepts regarding the role angiotensin II plays in diabetic kidney disease and why preventing its action results in delay of progression of diabetic nephropathy to end stage kidney disease.

Vascular tone is generally mediated by vasodilators such as nitric oxide (NO) and vasoconstrictors such as angiotensin II. The balance between NO and reactive oxygen species play an important role in normal endothelial function. Besides promoting vasodilatation, NO also is an inhibitor of vascular smooth muscle cell growth and migration, and expression of NF-kappaB and other pro-inflammatory molecules.

In addition to its well-known physiologic actions, angiotensin II is also itself a major mediator of oxidative stress and an antagonist of NO. Angiotensin II induces reactive oxygen species such as superoxide and hydrogen peroxide. It stimulates cytokines such as interleukin-6, tumor necrosis factor-alpha, VCAM and NF-KappaB. Inflammatory cells such as granulocytes, monocytes and macrophages have themselves been found to be potent producers of ACE, the enzyme which further induces angiotensin II production. This induction creates a positive feedback loop for local tissue inflammation.

Given the above ways that angiotensin may cause pathological states, blockage of the angiotensin converting enzyme makes a logical therapeutic target. Since ACE degrades kinin, its blockade by ACE inhibitors not only down regulates angiotensin II and all of its pro-inflammatory properties, but also serves to increase bradykinin levels. In turn, through NO and prostacyclin induction, bradykinin lowers blood pressure and exerts an overall anti-inflammatory effect.

Renal fibrosis is the abnormal accumulation of extracelluar matrix in normal kidney structures, which is the result of failed wound healing of kidney tissue following chronic sustained injury. In diabetics, glomerular lesions and renal vascular arteriosclerosis induce this chronic injury. TGF-beta secretion, stimulated by angiotensin II, is initiated by these events and ultimately leads to, vasoconstriction and extracellular matrix deposition. Angiotensin II is thus an important component in the progression of renal fibrosis.

Boffa et al studied the exaggerated gene and protein expression of TGF-beta, collagen I and collagen IV within the renal vasculature of mice with renal failure. The angiotensin II receptor antagonist losartan was administered, and after one week there were decreased collagen I, collagen IV, and TGF-beta gene expression. At four weeks the investigators reported regression of glomerulosclerosis, partial restoration in renal function, normalization of histological parameters and a decrease in mortality. This study suggested that in mice, through angiotensin II receptor blockade, collagen synthesis and renal fibrosis can be mitigated.

Humans are different than mice and the effects of ACE inhibitors and angiotensin receptor blockers are not as dramatic in human subjects. There is still reason to suggest that similar pathways exist in the progression of human renal fibrosis. Regardless of the mechanism, blocking the action of angiotensin II has the ability to slow the progression of end stage kidney disease in our patients. Older concepts regarding the effects of ACE inhibitors and ARBs to dilate the efferent arteriole and lower glomerular capillary pressure may still be operating in the drugs’ effects, but their effects on inflammation and fibrosis may be more important. The future of therapy for diabetic nephropathy likely lies in finding new mechanisms to dampen the inflammatory responses of the kidney.

Reference:
1. Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, and the AIPRI Study Group: Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med334 : 939-945,1996.

2. Dzau VJ. Theodore Cooper Lecture. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001; 37: 1047–1052.

3. Kranzhöfer R, Schmidt J, Pfeiffer CAH, Hagl S, Libby P, Kubler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999;19:1623–1629.

4. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–68.

5. Remuzzi, Giuseppe, Schieppati, Arrigo, Ruggenenti, Piero Nephropathy in Patients with Type 2 Diabetes N Engl J Med 2002 346: 1145-1151.

6. Gerstein HC, Yusuf S, Mann JF, Hoogwerf B, Zinman B, Held C, et al. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355(9200):253-9.

7. Chatziantoniou: Curr Opin Nephrol Hypertens, Volume 17(1).January 2008.76–81.

8. Boffa JJ, Ying L, Placier S, Stefanski A, Dussaule JC, and Chatziantoniou C. Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and metalloproteinases. J Am Soc Nephrol 14: 1132–1144, 2003.

Reviewed by David Goldfarb, M.D. Professor of Medicine, NYU Medical Center, Chief Nephrology Section VA New York Harbor

Diseases 2.0: Uric acid stones linked to diabetes

July 3, 2008

uric_acid_apatite_stone.jpgDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Commentary By David Goldfarb, M.D. Professor of Medicine, NYU Medical Center, Chief Nephrology Section VA New York Harbor

At the recent meeting of the National Kidney Foundation in Dallas, Dr. Orson Moe reviewed the links between diabetes and uric acid stones . Uric acid stones are most often caused by low urine pH. With a low urine pH, even relatively little uric acid can precipate, as it forms the protonated form, which is poorly soluble. At higher pH values, uric acid dissociates to the urate anion and the proton is titrated by the base. This dissociated form is quite soluble. With urine pH values of 6.5, even high amounts of urinary uric acid will not be associated with stones. Hyperuricosuria is a less important risk factor. So while patients with hyperuricosuria may have stones, urinary alkalinization is usually a preferred treatment as compared with allopurinol. If uric acid excretion is reduced by this xanthine oxidase inhibitor but urine pH is not raised, uric acid stones may still form. Allopurinol is best indicated in patients who have trouble alkalinizing the urine or continue to have stones despite alkalinization. Hyperuricosuria is seen with some myeloproliferative disorders such as polycythemia vera, high animal protein intake (equivalent to high purine intake). Low pH is seen in states of chronic diarrhea (ileostomy, colitis, Crohns) and diabetes.

The links between diabetes and low pH are being studied. Higher body mass intake is associated with lower urine pH, and this might be explained by higher BMI being associated with insulin resistance. In fact, the more features of metabolic syndrome become evident in an individual patient, the lower the urine pH. Insulin is important in ammoniagenesis, and recent data from U. Texas Southwestern indicate that insulin resistance is associated with impaired ammoniagenesis. In this case, there is less urine ammonia available to accept protons and with less urine buffer, and pH is lower. Some studies suggest that patients with uric acid stones also have increased net acid excretion, suggesting a dietary component of greater acid ingestion. Although research suggests that insulin directly impairs ammoniagenesis, new data from Southwestern are exploring the possibility that the effect is mediated by renal fat. In this hypothesis, increased BMI is associated with deposition of fat in the kidney. MR spectroscopy techniques developed at UT Southwestern are measuring renal fat deposition and attempting to correlate the imaging studies with fat stained in kidney biopsies. This lipotoxicity in the kidney may correlate with impaired insulin effect and impaired ammoniagenesis.

The treatment of recurrent uric acid stones is alkalinization of the urine. This is best accomplished with potassium citrate. Sodium citrate (e.g. Shohls solution or Bicitra) should be reserved for patients with hyperkalemia or GI intolerance as the sodium load, though often tolerated, may increase urine calcium excretion. Potassium citrate (20-30 meq) can be given with liquids or food to minimize GI intolerance. It is usually given 2-3 times per day to achieve round-the-clock alkalinization for patients with stones in place. It can be given once a day (at night) or even every other day for prevention in patients who do not currently have stones.

1: Bobulescu IA, Dubree M, Zhang J, McLeroy P, Moe OW. Effect of renal lipid accumulation on proximal tubule Na+/H+ exchange andammonium secretion.Am J Physiol Renal Physiol. 2008 Apr 16; [Epub ahead of print]PMID: 18417539

2: Sakhaee K, Maalouf NM. Metabolic syndrome and uric Acid nephrolithiasis.Semin Nephrol. 2008 Mar;28(2):174-80.PMID: 18359398

3: Maalouf NM, Cameron MA, Moe OW, Adams-Huet B, Sakhaee K. Low urine pH: a novel feature of the metabolic syndrome.Clin J Am Soc Nephrol. 2007 Sep;2(5):883-8. Epub 2007 Aug 16.PMID: 17702734

4: Cameron MA, Baker LA, Maalouf NM, Moe OW, Sakhaee K. Circadian variation in urine pH and uric acid nephrolithiasis risk.Nephrol Dial Transplant. 2007 Aug;22(8):2375-8. Epub 2007 May 3. No abstractavailable.PMID: 17478488

5: Cameron MA, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K. Urine composition in type 2 diabetes: predisposition to uric acidnephrolithiasis.J Am Soc Nephrol. 2006 May;17(5):1422-8. Epub 2006 Apr 5.PMID: 16597681

Grand Rounds: “Nephrogenic systemic fibrosis”

June 5, 2008

Bellevue Amphitheater

Commentary by Jatin Roper MD, PGY-3

Medical Grand Rounds today was presented last week by Dr. Shawn Cowper, Assistant Professor of Dermatology and Pathology at Yale University School of Medicine. Grand Rounds began with the presentation of a case from Tisch Hospital:

A 46 year old female with a history of end-stage renal disease secondary to diffuse-proliferative glomerulonephritis on hemodialysis, systemic lupus erythematosis, antiphospholipid antibody syndrome, and IVC thrombosis presents to a dermatology consultant for progressive hardness, tightness, and tenderness of skin of the legs and forearms for 3-4 months. Physical examination reveals brawny, indurated, cutaneous plaques on the legs and forearms. The differential diagnosis included morphea, scleromyxedema, and nephrogenic systemic fibrosis. Based on this differential further history is obtained which reveals a history of five gadolinium-containing MRI studies in the past two years, with two in the last month. Skin biopsy (read by Dr. Shawn Cowper) demonstrates diffuse proliferation of thin spindle cells, minimal inflammation, abundant collagen, and CD34+ spindle cells.

Final diagnosis: Nephrogenic systemic fibrosis due to gadolinium administration in the setting of end-stage renal disease.

So what is nephrogenic systemic fibrosis (NSF), and why should we care about it?

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Grand Rounds: “Hyponatremia: Something Old, Something New”

January 30, 2008

Bellevue Amphitheater

Commentary by Elizabeth Haskins MD, PGY-3

This week’s Grand Rounds was delivered by Dr. Tomas Berl, Chief of the Nephrology Division at the University of Colorado Health Sciences Center in Denver. Dr. Berl’s current research focuses on osmoregulated proteins of the inner medulla.

Hyponatremia, defined as a serum sodium concentration less than 136 mEq/L, is one of the most common electrolyte abnormalities in the hospitalized patient. In one Colorado hospital, the daily incidence of hyponatremia was 1% and the prevalence was 2.5%. The rate of hyponatremia increases with age and time spent in the hospital.

Serum sodium concentration is a function of free water intake and vasopressin release. Vasopressin, which is released from the posterior pituitary gland in response to both increased plasma osmolality and decreased intravascular volume, binds to V2 receptors in the collecting ducts resulting in increased water reabsorption. Thus hyponatremia occurs when vasopressin is released appropriately (as in hypovolemic states or when effective blood volume is low) or inappropriately, as in SIADH (syndrome of inappropriate anti-diuretic hormone).

Symptoms of hyponatremia are caused primarily from cellular water shifts resulting in cerebral edema. In acute (< 48 hours) hyponatremia, seizure, coma, and respiratory arrest can occur, sometimes without warning. Chronic (> 48 hours) hyponatremia tends to be less severe since there is time for adaptation to occur. The most prevalent symptoms are muscle cramps and ataxia, with seizures occurring with only very low serum sodium levels.

The rate of sodium correction is dependent on the acuity of the hyponatremia. Acute symptomatic hyponatremia can usually be corrected rapidly without permanent sequelae, although a rate of 2 mEq/L/hr is recommended. Hypertonic saline at 1-2 ml/kg/hr (or mannitol 0.25-1 gm/kg if hypertonic saline is unavailable), should be administered until cerebral symptoms subside. Lasix should be administered to increase free water excretion.

In chronic hyponatremia, however, rapid correction can result in osmotic demyelination syndrome (ODS) which is a delayed, gradual neurologic deterioration appearing one to several days after rapid correction. The goal is to increase serum sodium by 10% and not exceed 1.5 mEq/L/hr and 12 mEq in 24 hrs. Reversal of over correction with DDAVP or free water is recommended to relower the serum Na concentration and reduce the risk of ODS.

Vasopressin receptor antagonist (“aquaretics”) have recently emerged as a new treatment option for hyponatremia in euvolemic (SIADH) or hypervolemic (cirrhosis, CHF) states. These aquaretics stimulate the excretion of free water into urine with very little or no loss of sodium. Selective nonpeptide V2, receptor antagonists are in various stages of evaluation, including tolvaptan (PO), lixivaptan (PO), satavaptan (PO/), and Conivaptan (IV), a V1/V2 antagonists which is FDA approved for IV use in euvolemic and hypervolemic hyponatremia.

In 2003, Wong et al conducted a small randomized, placebo-controlled study of lixivaptan on 44 hyponatremic hospitalized patients with, cirrhosis, or SIADH. The results showed a significant, dose-related increase in free water clearance as well as serum sodium increase over 1 week. The randomized placebo-controlled clinical trials, SALT I and SALT II (Schrier et al.) demonstrated significant sodium concentration increase during a 30 day period with tolvaptan in 448 patients with euvolemic or hypovolemic hyponatremic, and improvement from baseline in the Mental Component of the Medical Outcomes Health Survey Short Form (SF-12).

Potential complications of aquaretics include ODS and hypotension secondary to the inappropriate use in hypovolemic hyponatremia, as well as unknown affects of blood-brain barrier penetration and CNS side effects. Questions still remain, including the long-term response rate, the role of water restriction, as well as the effects on cognitive function, functional state, overall quality of life, and survival.

Tumor Lysis Syndrome and the Role of Urinary Alkalinization

September 13, 2007

fluid1.jpgCommentary by Bani Chander MD, PGY-2, and Sergio Obligado MD, Attending Physician, Nephrology

Tumor lysis syndrome (TLS) is characterized by a group of metabolic abnormalities including hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia, following the initiation of cytotoxic therapy. Although there is no well established definition for this syndrome, the Cairo-Bishop definition [1] is a commonly used classification system that stratifies the degree of severity by utilizing specific laboratory data and clinical features. The constellation of abnormalities that occurs in TLS is due to a rapid release of potassium, purine nucleic acids, and phosphorus when tumor cells abruptly lyse their contents into the extracellular space. These abnormalities can subsequently lead to acute renal failure and may result in multiple organ failure and/or death. It is therefore important to identify those patients who are at risk for this syndrome in order to initiate early preventative treatments [2], most often including a combination of allopurinol, IV hydration, and/or urinary alkalinization.

TLS is most often seen in acute lymphoblastic leukemia and high grade non hodgkins lymphoma, most commonly in Burkitt’s lymphoma [3]. Other common malignancies associated with TLS include CLL, AML, multiple myeloma, small cell lung cancer, breast and ovarian cancer, medulloblastomas, and sarcomas. The kidney is the primary organ involved in the clearance of potassium, phosphorous, and uric acid. Uric acid can precipitate in an acidic environment or if there is decreased tubular flow rate within the renal tubules. When uric acid crystals form, they can precipitate within the collecting ducts and ureters and can cause obstructive uric acid nephropathy. Calcium phosphate deposition in the renal collecting ducts, vessels, and ureters may also contribute to acute renal function in this setting.

Standard of care in patients who are to receive chemotherapy or radiation in a cancer with high cell turnover is at least 2 days of allopurinol prior to initiation of therapy. IV fluid hydration should also be used in order to maintain urine output at a minimum of 2.5 liters/day. More recently, rasburicase has been introduced and used to prevent uric acid nephropathy in patients who are at increased risk for tumor lysis syndrome. High risk features are characterized by increased uric acid levels, LDH levels greater than two times normal or WBC >50,000microL (both indicative of high tumor burden), certain tumors including Burkitt’s lymphoma, lymphoblastic lymphoma, ALL, AML, decreased intravascular volume status, and the presence of tumor infiltration in the kidney.

Early recognition of a fall in glomerular filtration or diuresis in patients with tumor lysis is critical, as prompt initiation of dialysis in this group can prevent both further renal deterioration as well as dangerous metabolic derangements. In contrast to most causes of acute kidney injury in which dialysis is initiated to treat the sequelae of decreased GFR (i.e. hyperkalemia, uremia, volume overload), dialysis can actually reverse the kidney injury, as both uric acid and phosphate are efficiently cleared by the dialysis membrane.

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X-Ray Visions: Update on Nephrogenic Systemic Fibrosis and Gadolinium Contrast MRI

July 24, 2007

Commentary by Andrew Hardie MD, Body MRI Fellow, NYU Dept of Radiology

The recent discovery of a link between Nephrogenic Systemic Fibrosis (NSF) and the administration of gadolinium contrast for MRI examinations has sent the imaging world scrambling. NSF is a debilitating fibrosing reaction primarily involving the skin and, to a variable degree, internal organs. While longitudinal studies currently do not exist to help determine which patients can be safely administered gadolinium, it is clear that severe renal dysfunction, including those patients on dialysis, are at risk. (CJASN 2007;2:264) An additional factor which may increase the risk of NSF is the total dose of gadolinium. Unfortunately, MRI has previously been the imaging method of choice in patients with poor renal function to avoid the use of nephrotoxic iodinated contrast agents used in CT. Although well ingrained in the medical consciousness, this practice has been forced to change.

Radiologic examinations most affected by this change in practice are the evaluation of solid tumors (liver and kidney in particular) and MR angiograms (MRA). At the current time, although MR sequences can visualize solid tumors without gadolinium, the sensitivity and particularly the specificity of the exam is reduced. Further, gadolinium is essential for high quality MRA. The hope is that continued technical advancements in the field will made gadolinium less essential in the future. For now, the risks of NSF vs. contrast nephrotoxity from CT contrast must be weighed for each individual patient.

As no standardized national guidelines for the administration of gadolinium are in place, individual radiology departments have adopted individual guidelines based on the available information. The guidelines in the MRI department at NYU categorize patients based on calculated glomerular filtration rate (GFR) using serum creatinine, age, and weight. Patients with a normal GFR can receive any gadolinium contrast agent. Nevertheless, gadolinium dose is minimized when possible. Patients with a moderately reduced GFR (30-60) should be considered for alternative imaging but can still receive gadolinium. These patients are specifically consented for the risk of NSF and doses are minimized. Patients with a severely reduced GFR (< 30) should only be administered gadolinium under extreme medical necessity. When it is necessary, consent is obtained from the patient and ordering physician. Also, a gadolinium chelate which can be administered in a reduced dose with minimal reduction in image quality, gadobenate dimeglumin (Multihance), may be used.

Because serial dialysis even immediately following gadolinium administration has been shown not to reduce the risk of NSF, patients with end stage renal disease on dialysis should not receive gadolinium. Peritoneal dialysis is an absolute contraindication. In most cases, dialysis patients should undergo CT since nephrotoxicity is no longer an issue. However, non-contrast MR may also be appropriate in some patients.

The medical understanding of NSF is rapidly changing. Clinicians and imagers must continue to closely monitor the progress of ongoing studies and the implications on patient care.

Image courtesy of Wikimedia Commons

Hyperparathyroidism in Chronic Kidney Disease

June 13, 2007

Commentary by Sarah Berry MD, PGY-3 and Joseph Weisstuch, MD Clinical Assistant Professor of Medicine, Divsion of Nephrology

Case: Mr. K is a 59 year old gentleman with a past medical history of hypertension, non-insulin dependent diabetes mellitus, dyslipidemia and worsening chronic kidney disease (CKD) over the last six years, despite compliance with his medications and optimized glucose and blood pressure control. His current medication regimen includes metoprolol, hydrochlorothiazide, aspirin, simvastatin, glyburide, and monopril. Mr. K’s most recent lab work indicates that his serum creatinine is 1.7mg/dl, potassium 4.6mmol/l, sodium 141mmol/l, magnesium 1.7mg/dl, calcium 9.4mg/dl, phosphate 3.5mg/dl, HgA1c 7.1%. His calculated GFR (via the Cockroft Gault formula) is 50ml/min, meeting the definition of Stage 3 CKD.

At a glance, Mr. K’s electrolytes look fine, with no apparent metabolic effects due to his chronic kidney disease as of yet. Are there any interventions to be made today?

The answer is yes. Abnormal phosphate retention is known to begin as early as Stage 2 (GFR 60-90ml/min). A compensatory elevation in serum intact parathyroid hormone (iPTH) initially prevents hyperphosphatemia by decreasing proximal tubule phosphate reabsorption. However, this physiologic compensation over time causes hyperplasia and hypertrophy of the parathyroid gland, setting the stage for secondary hyperparathyroidism and the wide array of metabolic, vascular, rheumatologic, and cardiac complications that accompany its onset.

Therefore, in patients with early stage CKD, measurement of serum iPTH is a better benchmark for action by physicians. This fact is emphasized in the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease published in 2003. These guidelines specifically delineate goal iPTH values, varying by the severity of the CKD. In patients with Stage 3 CKD, such as Mr. K, goal iPTH is 35-70pg/ml. For patients with Stages 4 and 5 CKD, goal iPTH is 70-110pg/ml and 150-300pg/ml, respectively. [1]

On measurement, Mr. K’s iPTH level is 95pg/ml, significantly above the K/DOQI recommended value and an indication that he is progressing towards hyperparathyroidism. The K/DOQI guidelines also outline strict goals for serum phosphorus values: 2.7-4.6 for patients with stage 3 and 4 disease, and 3.5-5.5 for patients with Stage 5 CKD. How important is normalization of serum phosphorus? The evidence is mixed. In 2005, the data from 840 patients in the Modification of Diet in Renal Disease study showed that neither serum phosphate nor calcium-phosphate product were significantly associated with increased mortality in non-dialysis dependent patients. [2] However, a recent VA study of nearly 3490 veterans refuted those findings, showing that serum phosphate >3.5mg/dL in non-dialysis dependent patients was an independent marker for increased mortality at 2 years. Additionally, mortality increased linearly with each 0.5mg/dL increase in serum phosphate. [3]

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Recent Developments in the Treatment of Renal Cell Carcinoma

May 31, 2007

Commentary by Michael Seidman MD, Chief Oncology Fellow

New treatment options for both early and advanced Renal Cell Cancer have recently been published. Traditionally, treatment for early stage disease was partial or radical nephrectomy. In the metastatic setting, treatment options were limited to toxic cytokine therapy with IFN or IL-2.

Some recent literature has suggested that small, incidentally found renal tumors can safely be watched without the need for invasive surgery. Remzi et al [1] retrospectively reviewed 287 tumor bearing kidneys 4cm or less detected by imaging and surgically removed. High grade (poorer prognostic) tumors were seen in 4.2%, 5%, and 25.5% of tumors measuring 2 cm or less, 2.1-3.0 cm, and 3.1 to 4.0 cm respectively. Distant metastases were seen in 2.4% of tumors 3.0 cm or less compared to 10.8% of tumors 3.1-4.0 cm.

Schlomer et al [2] examined 349 renal masses form 331 patients. Malignant tumors were seen in 72.1% of tumors less than 2 cm compared to 93.7% of tumors greater than 7cm. The mean size of tumors in patients with symptoms at the time of diagnosis was 6.2cm compared to 3.7cm for tumors discovered incidentally. High grade histology was more common in larger tumors, occurring in 52 % of tumors >4cm compared to 7% and 29% in tumors measuring <2.0 cm and 2-4cm respectively.

These recent reports support the notion that most small renal tumors, especially those <3.0 cm are indolent in nature. In older patients, and those with multiple comorbidities, watchful waiting is an option. Newer technologies, specifically cryoablation and radiofrequency ablation, can provide good disease control with a less invasive procedure than nephrectomy. Matin et al [3] reported on 616 patients who underwent RFA and cryoablation. 10% of the patients had residual or recurrent disease after primary therapy. After salvage ablative therapy, failure was seen in only 4.2% of patients treated. 2 yr overall survival in patients with recurrent or residual disease was 82.5% with a 97.4% 2-year metastasis-free survival.

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How should you approach a pregnant patient with chronic kidney disease?

May 25, 2007

A 31 year old female with hypertension and proteinuria secondary to IgA nephropathy, currently treated with an ARB, presents to clinic stating that she would like to become pregnant.

What is the risk of fetal morbidity in the setting of ARBs/ACE-inhibitors? What antihypertensive medications are used during pregnancy? At what point would you switch a patient’s medications if she is trying to become pregnant? What is the natural course of IgA nephropathy during pregnancy?

-Minisha Sood MD, PGY-3

Pregnancy and Chronic Kidney Disease
Commentary by Sergio Obligado MD, Renal Fellow

Chronic kidney disease (CKD) carries significant risks to the mother and fetus in pregnancy. Diseases such as IgA nephropathy (which frequently occurs in the second and third decades of life) and diabetic glomerulosclerosis, are sufficiently common that reproductive-age women with these diseases present to their primary care doctors. The overall incidence of pregnancy and CKD has been estimated to be in the range of .03 to .12% in different populations. 1

During the first trimester, the physiology of normal pregnancy is characterized by decreased blood pressure, increased glomerular filtration rate and renal plasma flow, and sodium and water retention.1 Although normal pregnant woman will achieve this increased GFR without an increase in glomerular capillary pressure, women with renal disease tend to have increases in proteinuria, even during early stages of pregnancy. During the second and third trimesters, when blood pressure starts to rise and GFR falls in normal women, women with kidney disease can manifest dangerous elevations in blood pressure and dramatic increases in proteinuria.2

Although systemic diseases can significantly influence the maternal and fetal outcomes (i.e. diabetes, SLE), there isn’t any strong evidence that the type of glomerular disease independently effects pregnancy outcomes.3, 4 However, most retrospective and observational studies written on pregnancy and CKD clearly document that the risks are inversely related to GFR at onset of pregnancy. Women with creatinine < 1.3 seem to do quite well, with relatively insignificant changes in GFR and proteinuria.1 A study in the NEJM in 1996 followed 86 pregnancies in women with moderate to severe non-diabetic renal disease (creatinine > 1.4).5 They found that the mean creatinine rise was 1.9 to 2.6, and 20% of women had worsening hypertension and severe proteinuria by the third trimester. 8 of the women required dialysis by 1 year post-partum. The vast majority of the maternal morbidity occurred in the women who had a creatinine > 1.9 at initiation of pregnancy. The remaining small studies show similar outcomes; a third of women with creatinine > 1.5 have irreversible renal decline. Certainly, complications of pregnancy are more frequent as well. Preeclampsia has been reported to occur in up to 40% of women with CKD; although the definition of preeclampsia in a woman who begins a pregnancy with hypertension and proteinuria, in my opinion, is somewhat arbitrary.

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FDA Black Box Warning on Gadolinium

May 24, 2007

Back in December we reported on the FDA cautioning practioners about the use of gadolinium (an mri contrast agent) in patients with chronic kidney disease.  The FDA is now requesting a black box warning  stating “that patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing a debilitating, and a potentially fatal disease known as nephrogenic systemic fibrosis (NSF). In addition, it would state that patients just before or just after liver transplantation, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity.” 

Prior 12/06 post discussing NSF

FDA Request