Vit C Deficiency in MHD

NDT Advance Access originally published online on November 14, 2006
Nephrology Dialysis Transplantation 2007 22(2):328-331; doi:10.1093/ndt/gfl534

Vitamin C deficiency in dialysis patients—are we perceiving the tip of an iceberg?

Garry J. Handelman

University of Massachusetts, Lowell, MA 01854 and Renal Research Institute, New York, NY 10128, USA

Correspondence and offprint requests to: Garry J. Handelman, 3 Solomont Way, University of Massachusetts, Lowell, MA, 01854, USA. Email: garry_handelman@uml.edu

The occurrence of vitamin C deficiency has complicated the management of dialysis patients since the beginning of renal replacement therapy .
The major portion of dietary vitamin C is provided by potassium-rich foods such as orange juice, strawberries and broccoli, but these foods are restricted for haemodialysis (HD) patients .

Under these circumstances, low dietary vitamin C intake can readily occur.

Since vitamin C is partly metabolized to oxalate, which can accumulate in renal failure patients, many clinicians only recommend a dose of 60–100 mg/day, which may not be optimal.
The problem is made more severe by vitamin C losses during dialysis, which may remove several hundred mg of vitamin C in a single dialysis treatment .

Plasma vitamin C in dialysis patients is frequently <10> population. Normal plasma vitamin C levels in the non-dialysis population are 30–60 µM

Very high levels of vitamin C can also occur in dialysis patients, the effect of dialysis on vitamin C is highly variable. For patients who take large vitamin C supplements, the lack of the normal renal clearance mechanism can result in very high plasma levels (>200 µM)

Vitamin C deficiency can interfere with iron absorption and utilization, as well as leading to various abnormalities that are part of the syndrome of scurvy.

There is a situation where a large portion (10–25%) of dialysis patients have plasma vitamin C levels <10> plasma vitamin C <2> Epidemiological data suggest that these low plasma vitamin C levels are associated with increased mortality .

Although a 60–100 mg daily vitamin C supplement is generally recommended, prescriptions are provided only to 10–70% of patients, depending on nationality . Lack of compliance may lead to even lower levels of actual vitamin C usage.

The instability of vitamin C leads to problems in laboratory analysis , and vitamin C is not routinely measured in dialysis practice.

Concerns about oxalosis need to be vigorously addressed, but if vitamin C is demonstrated to be safe, its more active use could lead to reduction of iron burden, more efficient erythropoiesis and alleviation of some of the scorbutic symptoms seen in HD patients.

Mild renal failure as a marker for cardiovascular mortality

Eur Heart J. 2007 Feb;28(4):478-83. Epub 2007 Jan 12.

The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years.

• Van Biesen W,
• De Bacquer D,
• Verbeke F,
• Delanghe J,
• Lameire N,
• Vanholder R.

Department of Internal Medicine, Renal Division, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.

AIMS: Moderate-to-severe chronic renal failure is an established risk factor for cardiovascular disease and mortality.

However, most studies have been performed in selected populations and the impact of very small decrements of renal function on long-term cardiac morbidity and mortality has not yet been established.

Also, the cut-off level of glomerular filtration rate (GFR) from which cardiovascular risk increases has not exactly been established. This study wants to address these questions.

METHODS AND RESULTS: Ten year follow-up of a representative population-based cohort comprised 8913 randomly selected, apparently healthy participants. Participants were randomly drawn from Belgian voting lists. Cardiovascular risk factors were noted.

Serum creatinine values were corrected to isotope dilution mass spectrometry standard, and GFR was calculated using the recently modified 'modification of diet in renal disease' equation.

Participants were followed for 10 years, and cause-specific death was registered by analysis of death certificates.

The probability to die from all causes or from cardiovascular causes during the 10 year follow-up period increased in each quartile of GFR, even after correction for different other comorbid conditions.

CONCLUSION: Even mild renal failure is an independent risk factor for cardiovascular mortality within 10 years in an apparently healthy unselected population.

This detrimental effect starts already at a relatively high GFR of 90 mL/min/1.73 m(2) and remains present after correction for other established cardiovascular risk factors.

----------------------------
A similar study published earlier
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Kidney Int. 2002 Oct;62(4):1402-7.

Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study.

• Henry RM,
• Kostense PJ,
• Bos G,
• Dekker JM,
• Nijpels G,
• Heine RJ,
• Bouter LM,
• Stehouwer CD.

Institute for Research in Extramural Medicine, Department of Clinical Epidemiology and Biostatistics, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

BACKGROUND: Cardiovascular mortality is extremely high in end-stage renal disease. Cardiovascular mortality risk also is increased in selected (high-risk) individuals with mild to moderate impairment of renal function.

It is not clear whether a similar association exists in the general population and, if so, through what mechanisms. We investigated the association of renal function with all-cause and cardiovascular mortality in a population-based cohort and explored potential mechanisms underlying any such relationship.

METHODS: An age-, sex-, and glucose-tolerance-stratified sample (N = 631) of a population-based cohort aged 50 to 75 years was followed prospectively. After up to 10.2 years of follow-up, 117 subjects had died (50 of cardiovascular causes).

At baseline, renal function was estimated by the serum creatinine level, the Cockcroft-Gault formula and Levey's equation.

RESULTS: At baseline, the mean age was 64 +/- 7 years, 48% were men, 55% had hypertension, and 27% (by design) had type 2 diabetes.

• Serum creatinine was 91.7 +/- 19.0 micromol/L;
  
• creatinine clearance as estimated by the Cockroft-Gault formula was 72.5 +/- 13.7 mL/min/1.73 m(2),
  
• glomerular filtration rate (GFR) estimated by Levey's equation was 67.8 +/- 12.1 mL/min/1.73 m(2).
  

Renal function was inversely associated with all-cause and with cardiovascular mortality.

Relative risks (95% confidence intervals) were

• 1.08 (1.04 to 1.13) and 1.11 (1.07 to 1.16) per 5 micromol/L increase of serum creatinine;
• 1.07 (0.98 to 1.17) and 1.15 (1.01 to 1.31) for each decrease of 5 mL/min/1.73 m(2) creatinine clearance;
  
• 1.15 (1.05 to 1.26) and 1.26 (1.12 to 1.42) for each decrease of 5 mL/min/1.73 m(2) of GFR.
  

These associations remained after adjusting for age, sex, glucose tolerance status, hypertension, prior cardiovascular disease, low-density lipoprotein cholesterol, homocysteine, (micro)albuminuria, von Willebrand factor, soluble vascular adhesion molecule-1 and C-reactive protein.
Analyses in diabetic and hypertensive subjects gave similar results.

CONCLUSION: Mild to moderate loss of renal function is strongly associated with an increased risk of cardiovascular mortality.
The mechanism behind this association is unclear but does not appear to involve common risk factors such as hypertension, diabetes or hyperhomocysteinemia.

Estimation of renal function by relatively simple methods therefore may be a valuable tool for cardiovascular risk assessment over and above that provided by conventional risk factors.

Our results were obtained in a general middle-aged to elderly population, and thus have broad applicability.

Hypertension biomarkers

Hypertension. 2007 Mar;49(3):432-8. Epub 2007 Jan 22.

Multiple biomarkers and the risk of incident hypertension.

• Wang TJ,
• Gona P,
• Larson MG,
• Levy D,
• Benjamin EJ,
• Tofler GH,
• Jacques PF,
• Meigs JB,
• Rifai N,
• Selhub J,
• Robins SJ,
• Newton-Cheh C,
• Vasan RS.

Framingham Heart Study, Framingham, Mass, USA. tjwang@partners.org

An understanding of mechanisms underlying the development of essential hypertension is critical for designing prevention and treatment strategies. Selected biomarkers may be elevated before the onset of hypertension, but previous studies are limited by cross-sectional designs or a focus on single biomarkers.

We prospectively studied 1456 nonhypertensive individuals who had baseline measurement of 9 biomarkers:

1. C-reactive protein (inflammation);
   
2. fibrinogen (inflammation and thrombosis);
   
3. plasminogen activator inhibitor-1 (fibrinolytic potential);
   
4. aldosterone, renin, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide (neurohormonal activity);
   
5. homocysteine (renal function and oxidant stress);
   
6. urinary albumin/creatinine ratio (glomerular endothelial function).
   

Incident hypertension, defined as blood pressure > or =140/90 mm Hg or antihypertensive therapy, developed in 232 participants over a mean follow-up of 3 years.

After adjustment for clinical risk factors, the biomarker panel was significantly associated with incident hypertension (P=0.002).

Three (of 9) biomarkers were significantly related to incident hypertension on backward elimination (multivariable-adjusted odds ratios, per SD increment in biomarker):

1. C-reactive protein (1.26; 95% CI: 1.05 to 1.51),
   
2. plasminogen activator inhibitor-1 (1.28; 95% CI: 1.05 to 1.57),
   
3. urinary albumin/creatinine ratio (1.21; 95% CI: 1.02 to 1.43).
   

The incidence of hypertension was 4.5, 6.4, and 9.9 per 100 person years for participants with 0, 1, and > or=2 elevated biomarkers, respectively (elevation defined as > or =1 SD above the mean).

The threshold of > or =2 elevated biomarkers for predicting hypertension was associated with high specificity (0.92) but low sensitivity (0.15).

Biomarkers of inflammation, reduced fibrinolytic potential, and low-grade albuminuria are jointly associated with the incidence of hypertension.
These data support the premise that abnormalities in multiple biological pathways antedate the onset of overt hypertension.

No more heplock??? its citlock now.

Nephrol Dial Transplant. 2007 Feb;22(2):477-83. Epub 2006 Oct 2.

Trisodium citrate 4%--an alternative to heparin capping of haemodialysis catheters.

* Lok CE,
* Appleton D,
* Bhola C,
* Khoo B,
* Richardson RM.

Department of Medicine, Division of Nephrology, The Toronto General Hospital, 11 EN-216, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. charmaine.lok@uhn.on.ca.

BACKGROUND: Central venous catheters (CVCs) continue to be used at a high rate for dialysis access and are frequently complicated by thrombus-related malfunction. Prophylactic locking with an anticoagulant, such as heparin, has become standard practice despite its associated risks. Trisodium citrate (citrate) 4% is an alternative catheter locking anticoagulant.

METHODS: The objective was to prospectively study the clinical effectiveness, safety and cost of citrate 4% vs heparin locking by comparing rates of CVC exchanges, thrombolytic use (TPA) and access-associated hospitalizations during two study periods: heparin period (HP) (1 June 2003-15 February 2004) and Citrate Period (CP) 15 March-15 November 2004. Incident catheters evaluated did not overlap the two periods.

RESULTS: There were 176 CVC in 121 patients (HP) and 177 CVC in 129 patients (CP).
The event rates in incident CVC were:

1. CVC exchange 2.98/1000 days (HP) vs 1.65/1000 days (CP) (P = 0.01);
   
2. TPA use 5.49/1000 (HP) vs 3.3/1000 days (CP) (P = 0.002);
   
3. hospitalizations 0.59/1000 days (HP) vs 0.28/1000 days (CP) (P = 0.49).
   
4. longer time from catheter insertion to requiring CVC exchange (P = 0.04) and TPA (P = 0.006) in the citrate compared with the heparin lock group.
   

Citrate locking costs less than heparin locking but a formal economic analysis including indirect costs was not done.

CONCLUSION:

• Citrate 4% has equivalent or better outcomes with regards to catheter exchange, TPA use and access-related hospitalizations compared with heparin locking.
  
• It is a safe and less expensive alternative.
  

Randomized trials comparing these anticoagulants with a control group would definitively determine the optimal haemodialysis catheter locking solution.

Vasopressin in ESRD - Maintainance HD patients.

Kidney Int. 2007 Feb;71(4):318-24. Epub 2006 Sep 27.

Vasopressin administration facilitates fluid removal during hemodialysis.

• van der Zee S,
• Thompson A,
• Zimmerman R,
• Lin J,
• Huan Y,
• Braskett M,
• Sciacca RR,
• Landry DW,
• Oliver JA.

1Department of Medicine, Columbia University, New York, New York, USA.

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal.

To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase.

We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed.

Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription.

We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024).

Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01).

Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid.

Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.

MMF Rocks!!

Am J Transplant. 2007 Feb;7(2):366-76.

Mycophenolate mofetil is associated with altered expression of chronic renal transplant histology.

* Nankivell BJ,
* Wavamunno MD,
* Borrows RJ,
* Vitalone M,
* Fung CL,
* Allen RD,
* Chapman JR,
* O'Connell PJ.

Department of Renal Medicine, University of Sydney, Westmead Hospital, Westmead 2145, Sydney, NSW, Australia. Brian_Nankivell@wsahs.nsw.gov.au

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking.

We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry.

MMF reduced
acute rejection and OKT3 use (p < 0.05) compared with AZA.
MMF therapy was associated with
limited chronic interstitial fibrosis,
striped fibrosis and periglomerular fibrosis (p < 0.05-0.001),
mesangial matrix accumulation (p < 0.01),
chronic glomerulopathy scores (p < 0.05)
glomerulosclerosis (p < 0.05).
MMF was associated with
delayed expression of CSA nephrotoxicity,
reduced arteriolar hyalinosis,
striped fibrosis and
tubular microcalcification (p < 0.05-0.001).
The beneficial effects of MMF remained in recipients without acute rejection.

MMF therapy was associated with
substantially reduced fibrosis in the glomerular,
microvascular and interstitial compartments,
delayed expression of CSA nephrotoxicity.

These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.

Calciphylaxis

Dr Lobo asked this on the rounds to day so I read it up.
Source emedicine.com


Calciphylaxis is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia.

Pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic renal failure, hypercalcemia,
hyperphosphatemia, an elevated calcium-phosphate product, and secondary hyperparathyroidism. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare.

Selye defined calciphylaxis as a condition of hypersensitivity induced by a set of "sensitizing" agents, in which calcinosis occurred only in those subsequently subjected to a group of "challengers" and only after a critical lag time.

1-4% of the population with ESRD. A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran.

Mortality rate of calciphylaxis is reported to be as high as 60-80%. The leading cause of death is sepsis from infected, necrotic skin lesions. Mortality rate is higher in patients with proximal disease than in those with only distal or acral disease. A 2-fold increase in mortality is seen in those with ulcerative disease.

female-to-male ratio of approximately 3:1.

History :
long-standing history of chronic renal failure and renal replacement therapy.
renal allograft transplantation.
Lesions of calciphylaxis typically develop suddenly and progress rapidly. Lesions may be singular or numerous, and they generally occur on the lower extremities,however, lesions also may develop on the hands and torso.
Intense pain is a constant finding.

Triggers include the following:
o Long-term obesity
o Recent and sudden weight loss
o Infusion of medications such as iron dextran
o Remote and/or recent use of immunosuppressive agents, especially corticosteroids
o Concurrent use of warfarin anticoagulation: Current data suggest that warfarin therapy may lower protein C concentrations, leading to a procoagulant condition in the calcified vessel.

Clincial
* Early lesions of calciphylaxis manifest as nonspecific violaceous mottling; as livedo reticularis; or as erythematous papules, plaques, or nodules.
* More developed lesions have a stellate purpuric configuration with central cutaneous necrosis.
* Lesions are excruciatingly tender and extremely firm.
* The distribution of the lesions may be characterized as proximal or distal.
o Ninety percent of lesions of calciphylaxis occur on the lower extremities.
o Distal lesions are those that occur below the knee; proximal lesions occur on the thighs or the trunk.
* An intact peripheral pulse helps to distinguish acral calciphylaxis from atherosclerotic peripheral vascular disease.

Causes:
* The cause of calciphylaxis remains obscure. Most cases occur in the setting of chronic renal failure, abnormal calcium-phosphate homeostasis, and hyperparathyroidism.
o Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.
o Disorders associated with the development of calciphylaxis include the following:
+ Common – Chronic renal failure, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, vascular calcification
+ Speculative – Aluminum toxicity, coagulation abnormalities, iron dextran infusion
+ Suggested from clinical observation – Renal transplantation, immunosuppressive agents, corticosteroid use, obesity

o Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, 2 pathologic roles may be attributed to this vascular calcification: (1) Calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability.
(2) Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion. These mechanisms remain hypothetical and have not yet been proven in cases of calciphylaxis.

Imaging Studies:

* Plain films uniformly demonstrate an arborization of vascular calcification within the dermis and the subcutaneous tissue. However, this is common in ESRD and not specific for calciphylaxis.
* Bone scintigraphy may be used as a noninvasive diagnostic tool because the bone matrix protein osteopontin has recently been demonstrated in calciphylaxis lesions. Serial bone scans can also possibly be used to monitor progression or regression of disease.

Procedures:
* An incisional cutaneous biopsy is usually diagnostic.

Histologic Findings:
* Biopsy specimens typically demonstrate calcification within the media of small- and medium-sized arterioles with extensive intimal hyperplasia and fibrosis. A mixed inflammatory infiltrate frequently occurs. Subcutaneous calcium deposits with panniculitis and fat necrosis may sometimes be found. Vascular microthrombi are frequently evident.

Medical Care:
Medical care is mainly supportive. Aggravating conditions should be addressed, and trigger factors should be eliminated. This may mean the discontinuation of parenteral iron therapy, calcium, supplementation, and vitamin D supplementation. Although implicated as a trigger in the past, recent studies suggest that some patients may benefit early on from systemic glucocorticoids, unless ulcerated lesions are present.
* Serum calcium and phosphate concentrations must be brought to low-normal levels as quickly and safely as possible.
o Conservative therapy should be tried first, with dietary alteration; use of noncalcium, nonaluminum phosphate binders; and low-calcium bath dialysis. Some benefit may be achieved with increasing the frequency of dialysis sessions.
o If calcium and phosphate levels remain high, especially in the setting of hyperparathyroidism, intravenous use of a vitamin D analog may be beneficial.
o Although only speculative, calcimimetics such as cinacalcet hydrochloride may be beneficial in cases of hyperparathyroidism.
o Parathyroidectomy should be considered if conservative management fails and hyperparathyroidism is present.
* Marked improvement of calciphylaxis has now been reported with the use of intravenous sodium thiosulfate. Sodium thiosulfate increases the solubility of calcium deposits.
* Judicious use of antibiotics may be advantageous.
* In some cases, hyperbaric oxygen may be beneficial.
* Conditions of hypercoagulability should be sought and addressed.

Complications:
* Complications of calciphylaxis range from moderate interference with activity to death.
* Lesions of calciphylaxis frequently result in nonhealing ulcers and cutaneous gangrene. Acral lesions may fail to heal with conservative therapy and require amputation.
* Sepsis may result from the nonhealing wounds.
* Patients with internal involvement may develop gastrointestinal hemorrhage, infarction, or organ failure.
* Patients treated with calcimimetics, sodium thiosulfate, and parathyroidectomy must be monitored for hypocalcemia.

Prognosis:

* The prognosis is generally not good, with a mortality rate as high as 60-80% in patients with ulcerative disease. Patients who do not die of sepsis or organ failure frequently undergo amputation of an involved limb. Vascular calcification is theoretically reversible with aggressive management, but many patients have numerous comorbid diseases.

Currently, the 1- and 5-year survival rates are estimated to be 45% and 35%, respectively.

Lupus Nephritis - Classification update

Kidney International advance online publication 31 January 2007; doi: 10.1038/sj.ki.5002118

The ISN/RPS 2003 classification of lupus nephritis: An assessment at 3 years

G S Markowitz¹ and V D D'Agati¹

Abstract

The 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Classification of lupus nephritis (LN) was designed to eliminate ambiguities and standardize definitions.

Major changes from the 1982 Modified WHO Classification include the elimination of the normal biopsy category and the subcategories of membranous Class V, the introduction of sharper distinctions between the classes, and the addition of subcategories within diffuse LN (class IV) for predominantly segmental (LN IV-S) and global (LN IV-G) lesions.It stipulates that sclerotic glomeruli owing to scarred LN should be taken into account when assessing the percentage of glomeruli affected by LN.

Since its publication, the ISN/RPS classification has been used successfully in a number of clinical-pathologic studies. Several studies addressing the relationship between LN IV-S and LN IV-G have failed to identify a significantly worse outcome in IV-S than IV-G, although there were some differences in presenting clinical and pathologic features.

Importantly, the ISN/RPS classification has achieved its goal of improved interobserver reproducibility. Its use has increased the percentage of LN biopsies meeting criteria for class IV. As it gains widespread acceptance, the ISN/RPS classification is already providing a standardized approach to renal biopsy interpretation needed to compare outcome data across centers.

Lanthanum does not make a terrific difference?

Kidney International (2007) 71, 252–259. doi:10.1038/sj.ki.5001932; published online 11 October 2006

Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: No adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy

P Altmann¹, M E Barnett^2,3 and W F Finn⁴ on Behalf of the SPD405-307 Lanthanum Carbonate Study Group

Abstract

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials.

Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy.

A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter – Numeric Working Memory – showed a statistically significant between-group difference in favor of lanthanum carbonate (P=0.02).

Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful.

This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy.

Very low protein diet is anti hypertensive

Kidney International (2007) 71, 245–251. doi:10.1038/sj.ki.5001955; published online 11 October 2006

Very low protein diet supplemented with ketoanalogs improves blood pressure control in chronic kidney disease

V Bellizzi¹, B R Di Iorio¹, L De Nicola², R Minutolo², P Zamboli², P Trucillo², F Catapano², C Cristofano³, L Scalfi⁴ and G Conte² on behalf of the ERIKA Study-group

Abstract

Blood pressure (BP) is hardly controlled in chronic kidney disease (CKD).

We compared the effect of very low protein diet (VLPD) supplemented with ketoanalogs of essential amino acids (0.35 g/kg/day), low protein diet (LPD, 0.60 g/kg/day), and free diet (FD) on BP in patients with CKD stages 4 and 5.

Vegetable proteins were higher in VLPD (66%) than in LPD (48%). LPD was prescribed to 110 consecutive patients; after run-in, they were invited to start VLPD. Thirty subjects accepted; 57 decided to continue LPD; 23 refused either diet (FD group). At baseline, protein intake (g/kg/day) was 0.790.09 in VLPD, 0.780.11 in LPD, and 1.110.18 in FD (P<0.0001).>

After 6 months, protein intake was lower in VLPD than LPD and FD (0.540.11, 0.780.10, and 1.040.21 g/kg/day, respectively; P<0.0001). src="http://www.nature.com/__chars/plus/special/plusmn/black/med/base/glyph.gif" style="border: 0pt none ; vertical-align: baseline;" alt="plusminus">19/8410 to 12816/787 mm Hg (P<0.0001), src="http://www.nature.com/__chars/plus/special/plusmn/black/med/base/glyph.gif" style="border: 0pt none ; vertical-align: baseline;" alt="plusminus">1.1 to 1.81.2; P<0.001). src="http://www.nature.com/__chars/plus/special/plusmn/black/med/base/glyph.gif" style="border: 0pt none ; vertical-align: baseline;" alt="plusminus">32 to 13136 mEq/day; P<0.001).>

At multiple regression analysis (R²=0.270, P<0.0001),>P=0.023) and VLPD prescription (P=0.003), but not to the level of protein intake.

Thus, in moderate to advanced CKD, VLPD has an antihypertensive effect likely due to reduction of salt intake, type of proteins, and ketoanalogs supplementation, independent of actual protein intake.

Cystatic - C and relation to bio-inflammatory markers

Kidney International (2007) 71, 239–244. doi:10.1038/sj.ki.5002042; published online 20 December 2006

Kidney function and markers of inflammation in elderly persons without chronic kidney disease: The health, aging, and body composition study

C R Keller^1,2, M C Odden², L F Fried³, A B Newman⁴, S Angleman⁵, C A Green⁶, S R Cummings^1,7, T B Harris⁵ and M G Shlipak^1,2,8

Abstract

Inflammatory markers are elevated in persons with estimated glomerular filtration rates less than 60 ml/min/1.73 m². As cystatin C may detect small changes in kidney function not detected by estimated glomerular filtration rate, we evaluated the association between cystatin C and serum markers of inflammation in older adults with estimated glomerular filtration rate 60. This is an analysis using measures from the Health, Aging, and Body Composition Study, a cohort of well-functioning adults aged 70–79 years.

Cystatin C correlated with all five inflammatory biomarkers: C-reactive protein (r=0.08), interleukin-6 (r=0.19), tumor necrosis factor (TNF-) (r=0.41), soluble TNF receptor 1 (STNF-R1) (r=0.61), and soluble TNF receptor 2 (STNF-R2) (r=0.54); P<0.0005>

Participants with a cystatin C1.0 mg/l had significantly higher levels of all five biomarkers compared to those with a cystatin C<1.0>P<0.05).>

Cystatin C has a linear association with inflammatory biomarkers in an ambulatory elderly cohort with estimated glomerular filtration rates 60; associations are particularly strong with TNF- and the STNF-R.

Chronic acidosis and poor osteoblast function

Kidney International (2007) 71, 201–209. doi:10.1038/sj.ki.5002035; published online 20 December 2006

Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells

S Disthabanchong¹, P Radinahamed¹, W Stitchantrakul², S Hongeng³ and R Rajatanavin⁴

Abstract

Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.

Insula in cigarette smoking

Science 26 January 2007: Vol. 315. no. 5811, pp. 531 - 534 DOI: 10.1126/science.1135926

Reports

Damage to the Insula Disrupts Addiction to Cigarette Smoking

Nasir H. Naqvi,¹ David Rudrauf,^1,2 Hanna Damasio,^3,4 Antoine Bechara^1,3,4*

A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.

¹ Division of Cognitive Neuroscience, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
² Laboratory of Computational Neuroimaging, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
³ Dornsife Cognitive Neuroscience Imaging Center, SGM 501, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Brain and Creativity Institute, HNB B26, University of Southern California, Los Angeles, CA 90089, USA.

Polypill - Mirage or Miracle

BMJ 2007;334:172 (27 January), doi:10.1136/bmj.39101.539352.DB

News

NEJM sees promise in polypill for low and middle income countries

Janice Hopkins Tanne

¹ New York

A "perspectives" commentary in the New England Journal of Medicine by a leading Indian cardiologist says that a "polypill" to combat heart disease "would be quite cost-effective in reducing the burden of cardiovascular disease even in low-income and middle-income countries" (New England Journal of Medicine 2007;356:3).

The polypill, a combination of a statin, aspirin, drugs to lower blood pressure, and folic acid, was first proposed by Nicholas Wald and M R Law of the Wolfson Institute of Preventive Medicine, Barts, and Queen Mary's School of Medicine and Dentistry at the University of London in the BMJ (2003;326:1419).

In the commentary, Srinath Reddy, president of the Public Health Foundation of India and professor of cardiology at the All India Institute of Medical Sciences in New Delhi, says that drugs for primary or secondary prevention of cardiovascular disease have not been widely used even in developed countries.

"Poor adherence to multidrug regimens is a common barrier to effective therapy. In low and middle-income countries, the unaffordable cost of such regimens represents another obstacle," he writes.

The polypill might prove useful, but Dr Reddy noted that other experts have proposed different combinations of four or five drugs.

"The availability of most of these drugs in a generic form may help to reduce the cost of a polypill, especially in countries such as India, with its active generic drug industry," Dr Reddy writes.

The World Heart Federation recently announced that it would support the development of a polypill containing aspirin, an angiotensin converting enzyme inhibitor, and a statin. Two Indian drug manufacturers have developed a combination pill that also includes a blocker and will soon begin clinical trials, he writes. However, trials are needed to show "whether the polypill is a miracle or a mirage."

Steroid free induction and maintainence protocols in kidney transplant

Excellent Kidney-Transplant Outcomes Seen After Early Steroid Withdrawal

Marlene Busko

January 18, 2007 — Primary kidney-transplant recipients maintained on sirolimus (Rapamune, Wyeth) and cyclosporine (Neoral, Novartis) immunosuppression after a 5-day induction with antithymocyte globulin (Thymoglobulin, Genzyme Transplant) and prednisone (Solu-Medrol, Pfizer) had excellent 1-year graft and patient survival, similar to that of a comparator group receiving steroids. In this single-center study, the steroid-free group also had a lower incidence of biopsy-proven acute rejection than the comparator group (4.9% vs 9.4%; P < .01).

"We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of Neoral and sirolimus," the group, led by Amer Rajab, MD, from Ohio State University in Columbus, write.

The article is published in the December 2006 issue of Clinical Transplantation.
The immunosuppressive regimens of the 2 groups were:

• Steroid-free-maintenance group (n=301) — Induction therapy with Thymoglobulin and prednisone over 5 and 4 days, respectively, followed by maintenance therapy with sirolimus and Neoral.
• Steroid-based-maintenance group (n = 502) — Induction therapy with basiliximab (Simulect, Novartis), followed by maintenance therapy with prednisone, mycophenolate mofetil (MMF, Cellcept, Roche), and Neoral.

The low rate of acute rejection is a "remarkable" contrast with studies from the early 1990s that suggested that early steroid withdrawal was associated with high rates of acute rejection, said Dr. Hricik. He added that the only logical explanation is that the combination of sirolimus and Neoral is more potent than earlier immunosuppressants, which is discussed in a recent review article about steroid sparing that he coauthored (Clin J Am Soc Nephrol. 2006;1:1080-1089). In the current study, therapy with sirolimus and Neoral produced no significant adverse effects.

He noted that 1 weakness of this study is that there were more cadaveric donors and fewer living donors in the comparator group than in the steroid-free group, possibly accounting for the different rejection rates. Also, it is also not clear whether the results can be extrapolated to high-risk patients such as non-primary-kidney-transplant recipients or African Americans.

Clin Transplant. 2006;20:537-546.

CKD patients have increased peripheral arterial disease risk

Individuals With Chronic Kidney Disease Have Increased PAD Risk CME

News Author: Marlene Busko
CME Author: Charles Vega, MD, FAAFP

January 17, 2007 — An analysis from the Atherosclerosis Risk in Communities (ARIC) study confirms that patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). Because early PAD detection is critical to prevent leg revascularization and amputation, further studies are needed to see whether PAD screening strategies in CKD patients are effective, researchers conclude.

"The findings of our study call for an increased awareness and early detection of PAD in the CKD population," the group, with lead author Keattiyoat Wattanakit, MD, from the University of Minnesota in Minneapolis, writes. They add that "Recognition of an increased risk for PAD in this population, particularly in individuals with no typical ischemic symptoms, potentially could avert adverse limb as well as cardiovascular disease (CVD) events if modification of risk factors were intensified."

The article is published in the January 10 JASN Express issue of the Journal of the American Society of Nephrology.

The ARIC study cohort comprised 15,792 participants, aged 45 to 64 years at baseline in 1987 to 1989, who were recruited in 4 communities in the United States. The current study included 14,280 participants who had no PAD, defined as an ankle-brachial index of 0.9 or higher, or intermittent claudication at baseline.

Study Highlights

• Participants were between the ages of 45 and 64 years and were of white or black race. No subject had PAD, defined by an ankle-brachial index of 0.9 or higher, at baseline.
• GFR was estimated by applying serum creatinine levels to the Modification of Diet in Renal Disease formula. Subjects were divided into 3 groups, according to GFR: more than 90 mL/minute per 1.73 m² (normal kidney function), 60 to 89 mL/minute per 1.73 m² (mildly decreased kidney function), and 15 to 59 mL/minute per 1.73 m² (chronic kidney disease).
• The main study outcome was the relationship between kidney function and the risk for PAD, which was diagnosed by a finding of ankle-brachial index less than 0.9; new intermittent claudication symptoms; or a hospital discharge diagnosis of PAD, leg amputation, or leg revascularization procedure. Only a random subgroup of participants had ankle-brachial measurements performed during the course of the study. The main study result was adjusted for the presence of existing cardiovascular risk factors, as well as glucose and lipid levels.
• 14,280 individuals comprised the study cohort. Mean age of the subjects was 54 years, and 55% of the cohort was women.
• The mean follow-up time was 13.1 years. During this period, 1016 subjects developed PAD. Nearly half of cases were found because of a low ankle-brachial index. Patients with PAD were more likely to be older and have diabetes and other cardiovascular risk factors.
• After adjustment for age, sex, race, and study center, the rates of incident PAD were 4.7, 4.9, and 8.6 per 1000 person-years among subjects with normal kidney function, mildly decreased kidney function, and CKD, respectively. The adjusted risk for PAD began to increase in linear fashion after eGFR fell below 75 mL/minute per 1.73 m².
• Compared with normal kidney function, mildly decreased kidney function did not significantly and independently increase the risk for PAD.
• Conversely, compared with normal kidney function, CKD was associated with a multivariate-adjusted relative risk of 1.56 for PAD.
• Examining subgroups of patients based on age and chronic disease failed to significantly alter the study's main findings. Reduced GFR was a particularly strong risk factor for PAD among men vs women.
• In a separate analysis, kidney disease was not related to the risk for asymptomatic PAD diagnosed by reduced ankle-brachial index scores alone. CKD remained a significant risk factor for symptomatic PAD.

Pearls for Practice

• Previous research has demonstrated that reduced renal function is an independent risk factor for cardiovascular disease, although the precise mechanisms of this association are unclear. Reduced renal function might also increase the risk for PAD among postmenopausal women.
• The current study found that an eGFR between 15 and 59 mL/minute per 1.73 m² (chronic kidney disease) is an independent risk factor for incident PAD, but that an eGFR between 60 and 89 mL/minute per 1.73 m² (mildly decreased kidney function) was not a risk factor for PAD.

Calcineurin Inhibitors and Transplant immunosuppression

From American Journal of Health-System Pharmacy

Effects of Genetic Polymorphisms on the Pharmacokinetics of Calcineurin Inhibitors

Posted 01/12/2007

Kyle N. Utecht; Jon J. Hiles; Jill Kolesar

Abstract

Purpose. The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined.
Summary. The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial.
Conclusion. For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25–45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.

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Is anyone actually involved in the study of pharmacogenomics amongst us??
How soon can we actually tailor not just our immunosuppression doses but mundane things as anti hypertensive drugs, on the basis of the genetic picture of the patient. Is it really looking too far in the future or it may happen soon?? Only time will tell.
Any comments??
EK

GRADE system of grading new clinical guidelines for nephrology

From Kidney International

Grading Evidence and Recommendations for Clinical Practice Guidelines in Nephrology. A Position Statement From Kidney Disease: Improving Global Outcomes (KDIGO)

Posted 01/12/2007

K Uhlig; A MacLeod; J Craig; J Lau;, A S Levey; A Levin; L Moist; E Steinberg; R Walker; C Wanner; N Lameire; G Eknoyan

Abstract

Considerable variation in grading systems used to rate the strength of guideline recommendations and the quality of the supporting evidence in Nephrology highlights the need for a uniform, internationally accepted, rigorous system. In 2004, Kidney Disease: Improving Global Outcomes (KDIGO) commissioned a methods expert group to recommend an approach for grading in future nephrology guidelines.

This position statement by KDIGO recommends adopting the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach for the grading of evidence and guidelines on interventions. The GRADE approach appraises systematic reviews of the benefits and harms of an intervention to determine its net health benefit.

The system considers the design, quality, and quantity of studies as well as the consistency and directness of findings when grading the quality of evidence. The strength of the recommendation builds on the quality of the evidence and additional considerations including costs.

The recommendations made by the ERG were then reviewed and adopted by the KDIGO Board of Directors as a position statement on guideline development. The position statement has also been reviewed by representatives for Caring for Australasians with Renal Impairment, United Kingdom Renal Association, European Best Practice Guidelines, Canadian Society of Nephrology, and Kidney Disease Outcomes Quality Initiative.
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The above mentioned guidelines can be viewed in a table form at the following link -
http://www.medscape.com/viewarticle/550140_Tables#T1
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The GRADE system assigns separate grades for the quality of evidence and for the strength of recommendations.
It is suitable for questions that address the efficacy of clinical interventions and incorporates summary effect estimates from meta-analyses.
The quality of the evidence is defined as the extent to which 'one can be confident that an estimate of effect or association can be correct'. This is based on the likelihood that further targeted research would not change confidence in the estimate. The strength of recommendation indicates 'the extent of the grader's confidence that adherence to the recommendation will do more good than harm'.
Table 3 shows the sequential process recommended by GRADE for guideline development. Steps 1-3 describe the process that is followed for conducting the systematic reviews and for tabulating data in evidence profiles. Evidence profiles provide a summary of the effects for each important outcome and record the decision making for each step of grading and synthesis.
Steps 4-7 describe how to grade the quality of the evidence and to assess the net health benefit. Steps 8 and 9 describe how to determine whether to issue a recommendation and of what strength.