Tag: CKD

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PBFluids has been a little quiet recently

In the past few weeks I have been working on two presentations. The first was to Genzyme’s scientists and the second was grand rounds at Providence. I have been spending way too much time working on those two talks. Thankfully the bones of both talks were the same. I spoke on the problem of chronic kidney disease on the elderly, specifically whether CKD was over diagnosed (yes it is) in this population and can it be safely ignored (no it can’t).

I’m not completely through the gauntlet yet. I still have to provide a chapter on lifestyle modification for the control of blood pressure.

But I can’t describe the awesome feeling of relief from delivering the grand rounds this morning.

For those of you with iWork and Keynote here is the presentation:

The Two Faces of Geriatric CKD

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Nephrology myths: drink a lot of water

I am on the twitter and I came across this tweet:


The tweet reads, “It annoys us at The Kidney Group when so-called experts claim being well-hydrated is overrated and without much merit. Completely untrue.”

The fact is this is total bullshit. Outside of patients with kidney stones or pre-renal azotemia, I am aware of no human data showing improved kidney function from increased fluid intake. In fact in the MDRD study they found an association with high fluid intake and faster progression to dialysis. Having a 24-hour urine volume of 2.4 liters was associated with a loss of kidney function of 1 ml/min/year faster than patients with a urine output of 1.4 liters.

In a comprehensive study on the risk factors for the development of ESRD (PDF) (27+ years of follow-up of 177,570 patients) having nocturia (HR 1.36) was about as important a risk factor as anemia (HR 1.33) or family history of kidney disease (HR 1.40) on multivariate analysis.

The authors take on the significance of nocturia:

It is interesting that nocturia (defined herein as self-report of “always having to interrupt sleep to urinate”) emerged as an independent risk factor for ESRD because it is a widely held clinical belief that nocturnal polyuria is an early sign of chronic kidney disease due to decreased urinary concentrating ability, although some data suggest that increased salt, not water excretion, is more important. Therefore, nocturia may reflect subtle early renal disease not captured by serum creatinine level or urine dipstick analysis. We also cannot exclude the possibility that nocturia reflects undiagnosed DM. An alternative hypothesis is that nocturia reflects a high volume of ingested fluid that is detrimental (especially among patients with existing kidney disease), as high urine volume increases intratubular volume and pressure and these stretch forces induce fibrosis. Practically speaking, our data lend no support to the notion that a high volume of water intake should be recommended in clinical practice as being beneficial to kidney function.

For a summary of the myth of water intake and kidney health look at this excellent review by Wenzel et al in CJASN (PDF).

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eGFR: the problem of false positives

Last week I saw a 58 year old African American woman who was referred to me for an eGFR (i.e. MDRD equation) of 58. Her insurance company notified her primary care doctor about this decreased GFR. I saw the letter that Blue Cross sent and it did not give the physician any guidance on what to do with this information. The insurance company just wanted to make sure the physician was aware that the patient was flagged as having CKD. The primary care doctor sent her to me for further evaluation.

The patient, however, was completely freaked out. She went on the internet and started to learn about kidney disease and to her horror found (correctly) that her lisinopril and simvastatin could cause kidney disease. Since both of these medications had been started in the last few years she suspected (wrongly) that they were the cause of her kidney disease and stoppd both of them.

Her GFRs for three years before referral had been: 65, 63, 65 and 58. When I repeated her GFR it was 62.

This is a classic case of what Dr. Harold Feldman was writing about in the Feburary CJASN (PDF). Here is a patient who stopped the two most important drugs for her future health (statin, ACEi) because of a false positive eGFR.

This article uses a Markov chain Monte Carlo method to simulate use of serum Cr or serum Cr plus eGFR for CKD screening. The model they used is illustrated below:

In the model patients gets screened once a year (a cycle) from age 60 to 78. There are 6 states patients must be assigned to:

  1. No kidney disease (CKD stage 0)
  2. No kidney disease but false positive screening test (my patient)
  3. CKD, diagnosed
  4. CKD undiagnosed (false negative screening test)
  5. ESRD
  6. Death

In each cycle every patient must be assigned to a state. Dead patients must remain dead, ESRD patients can remain ESRD or die. Patients must develop CKD (state 3 or 4) at least one cycle prior to progressing to ESRD. Patients in any living state can die. Patients with CKD (state 3 or 4) can not tranition to no CKD (state 1 or 2). And according to the text but not the figure, patients without kidney disease but false positive screening (state 2) would go back to state 1 for the next cycle.

Some assumptions in the calculation:

  • Incidence of CKD 0.7% until age 65 then 2.3%
  • Mortality without CKD 0.97% from age 60 to 70, then 2.4% after age 70
  • Mortality with CKD 0.050% (why this would be half the rate of non-CKD makes no sense)
  • Mortality with ESRD age 62-67: 15%; 67-75: 19%; and 75+: 26%
  • Annual rate of progressing from CKD to ESRD 0.076%
  • Treatment of CKD had no effect on mortality
  • Treatment of CKD reduced the annual rate of progression to ESRD by 21% (from 0.076% to 0.055%)
The Baysean test characteristics for eGFR and sCr:
  • Sensitivity of eGFR: 0.924
  • Specificity of eGFR: 0.835
  • Sensitivity of serum Cr: 0.559
  • Specificity of serum Cr: 0.950

The model used the following evaluation of CKD

  • Two clinic visits with a nephrologist
  • Limited renal ultrasound
  • Renal function panel
  • U/A, urine protein, urine creatinine

The costs for the different states are outlined in the table below:


In the initial analysis eGFR was more accurate and more cost-effective than the serum Cr. Use of eGFR kept patients off dialysis (29 patients) and reduced deaths (13 patients) at the expence of an ocean of false positives:


But when you assigned a false positive CKD a slightly lower quality of life than a true negative, 0.98 versus 1.0, the serum creatinine came out more cost effective per quality adjusted life year (QALY).

Summary: the better test (as measured by the area under the curve of a receiver operator characteristics curve) loses to the worse test because of the decreased quality of life that results from a false positive reading. The false positives were so much more prevelant that they overwelmed the benefit from the decrease in death and ESRD found with the more accurate eGFR test.

This study has received tremendous publicity, likely because noone had looked at eGFR in this way before and it had a contrarian view. While the whole nephrology community has been pushing for routine eGFR reporting along with creatinine, Feldman comes and publishes a scathing indictment. Additionally, it makes good copy to say that nephrologists developed a new way to measure renal function that dramatically increases the demand for nephrology services.

My primary concearn with this study is two fold:

  1. The eGFR equation is used as a screening test in this study and in real- life. Screening tests need to be as sensitive as possible even at the expense of specificity. The thought is that the increased false positives will be picked up with secondary testing. But a screening test never wants to give patients a clean bill of health when in actuality they have smoldering unrecognized disease. In Feldman’s analysis the eGFR works perfectly as a screening test by picking up nearly all of the patients with CKD but the decreased specificity results in numerous false positives. It is interesting that it is not the cost of evaluating the false positives that results in the cost ineffectiveness of eGFR but it is the decreased quality of life that results from the anxiety associated with the initially positive diagnosis of CKD. In my mind this means we need to do a better job educating patients and providers to the nature of the eGFR test.
  2. The other problem with the study is it threatens to throw out the baby with the bath water. Even if the study does show that eGFR is not cost effective, part of the problem is that the only utility given to the eGFR is in the early diagnosis of CKD to prevent ESRD. However, I more often use the eGFR to dose adjust medications, to estimate the risk of contrast nephropathy, guide the use of loop versus thiazide diuretics. All of these uses of the eGFR cannot be replaced by a serum creatinine because the serum creatinine does not account for age, gender and race.

False positive diagnosis of CKD by the eGFR are real problems and Dr. Feldman has done the nephrology community a favor by bringing this issue to light. It would be interesting for Feldman to re-run his Monte Carlo simulation with various definitions of CKD, does an eGFR of 50 ml/min reduce the false positives enough to reduce the cost below the benefits? What about 45 ml/min (sometimes called CKD 3b)? It is important for a dialog to be initiated among primary care doctors, nephrologists and payers to come up with better definitions of CKD that don’t freak our patients unnecessarily while providing the best care we can.

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Lead time bias

As I go through the literature on early nephrology referral, I am troubled by the possibility of lead time bias. This was a large issue in the debate surrounding the optimal time to initiate dialysis. The problem comes from measuring survival from the initiation of dialysis.

Patients with good nephrologic care regularly get started on dialysis earlier than their counterparts with poor or non-existent CKD care. This is evidenced by the lower creatinines at the time of initiation of dialysis in patients with early referral seen in multiple studies.

This is consistent with my practice where I tell my patients that we “…want to delay dialysis as long as possible, but not longer than possible…” because if they have profound malnutrition or advanced heart disease due to the delay of dialysis they will do poorly once they transition to dialysis.

Because of this skew in the initiation of dialysis it is important to account for that in any analysis of survival on dialysis. I hope this short slide show makes this clear.

Note: I do not know if lead time bias is responsible for the prolonged survival with early referral to nephrology I just know that it needs to be accounted for and most literature ignores this potential source of error.

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CJSAN Article on CKD care and 1st year survival on dialysis

The Nephrology Blog has an interesting post on early nephrology referral of CKD patients and outcome on dialysis. I pulled all the references from that paper which have looked at the subject. I’ll be adding my thouhts on these references over next few pages so that this post becomes a quasi review article or annotated reference list.

Hasegawa et al. Greater First-Year Survival on Hemodialysis in Facilities in Which Patients Are Provided Earlier and More Frequent Pre-nephrology Visits. Clin J Am Soc Nephrol (2009) 4 595-602. (PDF)

  • DOPPS I and II databases
  • 8500 new starts to dialysis
  • Pre-ESRD Nephrology contact defined as at least one visit prior to HD
  • PNV associated with adjusted odds ratio of 0.57! (half the risk of death for one visit! what a bargain!) p<0.001
  • adjusted for age, sex, race, primary cause of ESRD, 14 summary comorbidities (CAD, CHF, other cardiac disease, htn, dm, cerebroVD, PAD, cancer, HIV/AIDS, lung disease, neurologic disorders, GI bleeding, recurrent cellulitis/gangrene)
  • Facility level data is consistent with the individual patient data. DOPPS always tries to show this because it controls for some of the biases inherent in a retrospective study. From the ESRD NephSap:

  • When we choose to examine facility practice using statistical models, patients are assigned not to the individual treatment received but to the facility’s practice (e.g., percentage of patients receiving vitamin D or having phosphorus within guideline range). Patient- or facility-level outcomes can be used. The rationale for this method is fundamental to the DOPPS and merits additional emphasis here. In standard observational analyses, the true effect of a treatment of interest may be distorted analytically by the effect of the indication to receive that treatment (treatment-by-indication bias). This bias is a fundamental challenge to inferring the causal effect of a treatment from observational data. The DOPPS facility practice-based analytic approach is conceptually similar to instrumental variable analysis, a method embraced for decades in econometrics and now used more commonly in clinical studies to address treatment-by-indication bias (9,10). The approach seeks to identify natural experiments in which patients are nearly “randomly” assigned to a particular facility practice by factors independent of clinical characteristics, such as proximity to the patient’s residence. Ideally, this mimics randomized treatment assignment in a clinical trial. Recent publications discussed theoretical considerations and provided examples in clinical medicine outside nephrology (9 –17).

  • They found a dose effect of frequency of seeing a nephrologist. seeing a nephro doc 5 times had 28% lower mortality than if they saw one once or less.
  • The people with nephrology care were more likely to be diabetic and hypertensive but were less likely to have CHF, lung disease or cancer
  • Nephrology care was also linked to marriage, employment and college educated
  • The creatinine at initiation of dialysis was lower with CKD care 7.2 versus 7.6. [Of note: with creatinines that high, a change of 0.4 only represents a difference of 1 mL/min (9 mL/min with predialysis care, 8 mL/min without)]

Innes et al. Early deaths on renal replacement therapy: the need for early nephrological referral. Nephrol Dial Transplant (1992) vol. 7 (6) pp. 467-71.

Forty-four patients who commenced renal replacement therapy between January 1983 and January 1988 died within 1 year of starting treatment. To examine the factors influencing early mortality of patients on renal replacement therapy these patients (group A) were compared with a group of 44 age- and sex-matched subjects who started dialysis over the same period and who survived more than 1 year (group B). The interval between first presentation and dialysis was significantly shorter in group A (median 36 days) than group B (median 30 months) patients. Plasma urea and creatinine were significantly greater in group A than group B at the time of first presentation to a nephrologist but not at first dialysis. Patients in group A were more often treated first by hemodialysis. Systemic disease as the cause of renal failure did not appear to influence early death. Early death on renal replacement therapy appears to be associated with late referral to a nephrologist. Early referral may be beneficial because it allows for planning of dialysis and treatment of the complications of progressive uremia.

  • 44 patients who died in the first year of dialysis (group A)
  • Compared to 44 patients (age and sex matched) who survived the first year of dialysis (group B)
  • Association found with early death and late referral to a nephrologist. Average time between first visit to nephrologist and initiation of dialysis 36 days in group A and 30 months in group B.
  • no difference in BUN or Cr at initiation of dialysis

Sesso et al. Late diagnosis of chronic renal failure. Braz J Med Biol Res (1996) vol. 29 (11) pp. 1473-8.

BACKGROUND: Recent observations in our country have shown that late diagnosis of chronic renal failure (CRF) is an important cause of late referral and late commencement of maintenance dialysis. We prospectively investigated the influence of late diagnosis of CRF on patient mortality during dialysis therapy. METHODS: Among 184 consecutive patients with nondiabetic end-stage renal disease starting chronic dialysis at the Federal University Hospital in the city of São Paulo, 106 had a late diagnosis of CRF (less than 1 month before starting dialysis) and 78 had an early diagnosis. During the first 6 months of dialysis treatment, patient survival was compared in the two groups, using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Six-month patient survival rate was lower in the late than in the early diagnosis group (69% versus 87%, P less than 0.01). In the late diagnosis group, the hazard ratio of mortality was 2.77 (95% CI, 1.36-5.66) times that of the early diagnosis group. In a multivariate analysis, after adjusting for age, comorbid illness, and serum biochemical measurements, time of diagnosis did not remain significantly associated with mortality risk. In this analysis, age, pulmonary infection, and low serum albumin were significant predictors of mortality. CONCLUSIONS: Patients with a late diagnosis have a higher mortality risk during the first 6 months of maintenance dialysis. This increased risk is related to comorbid conditions, some of which could be prevented by predialysis care. Interventions to promote early diagnosis of CRF and adequate predialysis follow-up need to be evaluated if the survival of patients with chronic renal failure is to improve.

  • 184 new dialysis patients
  • Lack of pre-ESRD CKD care defined as initiation of dialysis within 1 month of the first visit to the nephrologist
  • 6-month rather than 1 year analysis
  • raw mortality was 31% for late dx and 13% for early diagnosis
  • HR for death in the first 6 months of dialysis with late diagnosis was 2.77
  • Despite a very high hazard ratio with late diagnosis, this was not an independent association such that after controlling for age, comorbid illness and biochemical measurments the time of diagnosis was not significant.

Jungers et al. Longer duration of predialysis nephrological care is associated with improved long-term survival of dialysis patients. Nephrol Dial Transplant (2001) vol. 16 (12) pp. 2357-64. (PDF)

  • 1057 consecutive patients
  • pre-dialysis nephrology care less than 6 months in 258 patients (193 of them initiated within a month of the first nephro encounter.)
  • 6-35 months in 267 patients
  • 36-71 months in 227 patients
  • over 71 months in 307 patients
  • mean age 54
  • only 13% diabetics (French study), little hypertension
  • half of the late presentation group had been referred earlier but had neglected or refused nephrological care
  • DM, PVD, HTN, CVD all were more prevelant with late referral
  • Cr was higher in late referral [We need to worry about systemic lead time bias]
  • Dramatic changes in the rates of catheter use and the length of hospital stay associate dwith the initiation of dialysis. Importantly the authors excluded 60 patients who had either AKI or RPGN which precluded prolonged pre-dialysis care.
  • one-year mortality was 13.6% for less than 6 months pre-dialysis nephrocare and 7.4% (6-35 mo), 7.2% (36-71 mo) and 2.5% (over 71 mo) for longer care
  • With multivariate analysis only the longest duration of care (over 71 mo) was significantly and independantly associated with survival with a RR of death of 0.56 p=0.002.
  • The two shorter periods barely missed signifigance: 6-35 mo RR=0.73, p=0.058 and 36-71 mo RR=0.71, p=0.066.
  • Age, DM and prior CVD were each significant with multivariate analysis

Kinchen et al. The timing of specialist evaluation in chronic kidney disease and mortality. Annals of Internal Medicine (2002) vol. 137 (6) pp. 479-86. (PDF)

  • 828 new on-set ESRD from 81 centers
  • time from first visit to initiation of dialysis
  • Late: less than 4 months
  • Intermediate: 4-12 months
  • Early: over 12 months
  • 213 patients were eliminated because of a lack of definitive medical records
  • Significantly associated with late referral was Black ethnicity, not attending college, not having insurance, PD, not having DM, less urine output, lower renal function, less exercise, more anemia, lower albumin, less ESA, less vascular access.
  • Late referral was associated with death
  • Notice how quickly the Late and Early curves digress. By 10 months it looks like the association is maximal and the curves are roughly parallel after that.
  • The association with timing of referral and mortality was robust and remained significant when examined with 5 recipes for controlling different factors:

  • An interesting finding was that late referral was worse for patients with diabetes and hypertension, growing segments of the ESRD population
  • Sicker patients were referred later begging the question does the sickness prevent the consultation or does lack of nephrologic care cause other co-morbid diseases to become more severe (i.e. better use of diuretics in a heart failure patient, sometimes the nephrologist is the only one still willing to use ACEi with a GFR of 18)

Roderick et al. Late referral for end-stage renal disease: a region-wide survey in the south west of England. Nephrol Dial Transplant (2002) vol. 17 (7) pp. 1252-9. (PDF)

  • 361 of 411 in England
  • Late within 4 months
  • Late’ within 1 month
  • 35% within 4 months
  • 23% within 1 month
  • Again late referrals were older, sicker, had less accesses
  • 33% Six-month mortality with less than 1 month versus 16% for longer than a month
  • A late referral occured in 60% of patients with an established diagnosis of CKD for more than year (preventing the physcian or patinet from excusing themselves by stating “I didn’t know.”)
  • Again the cr was higher at initiation (10.7 versus 9.4 mg/dl) for late referrals.
  • Time of referral was not an independent predictor of survival at 6 months in regression analysis (p=0.293)
  • The only interesting figure comes from the discussion where the authors graph the rates of Late referrals in the medical literature and make a case that it is getting better.

Kessler et al. Impact of nephrology referral on early and midterm outcomes in ESRD: EPidémiologie de l’Insuffisance REnale chronique terminale en Lorraine (EPIREL): results of a 2-year, prospective, community-based study. Am J Kidney Dis (2003) vol. 42 (3) pp. 474-85 (PDF)

Stack. Impact of timing of nephrology referral and pre-ESRD care on mortality risk among new ESRD patients in the United States. Am J Kidney Dis (2003) vol. 41 (2) pp. 310-8. (PDF)

Winkelmayer et al. A propensity analysis of late versus early nephrologist referral and mortality on dialysis. J Am Soc Nephrol (2003) vol. 14 (2) pp. 486-92. (PDF)

Kazmi et al. Late nephrology referral and mortality among patients with end-stage renal disease: a propensity score analysis. Nephrol Dial Transplant (2004) vol. 19 (7) pp. 1808-14. (PDF)

Khan et al. Does predialysis nephrology care influence patient survival after initiation of dialysis?. Kidney Int (2005) vol. 67 (3) pp. 1038-46.

BACKGROUND: Early nephrology referral of patients with chronic kidney disease (CKD) has been suggested to reduce mortality after initiation of dialysis. This retrospective cohort study of incident dialysis patients between 1995 and 1998 was performed to address the association between frequency of nephrology care during the 24 months before initiation of dialysis and first-year mortality after initiation of dialysis. METHODS: Patient data were obtained from the Centers for Medicare & Medicaid Services. Patients who started dialysis between 1995 and 1998, and were Medicare-eligible for at least 24 months before initiation of dialysis, were included. One or more nephrology visits during a month was considered a month of nephrology care (MNC). RESULTS: Of the total 109,321 patients, only 50% had received nephrology care during the 24 months before initiation of dialysis. Overall, first-year mortality after initiation of dialysis was 36%. Cardiac disease was the major cause of mortality (46%). After adjusting for comorbidity, higher mortality was associated with increasing age (HR, 1.04 per year increase; 95% CI, 1.03 to 1.04) and more frequent visits to generalists (HR, 1.009 per visit increase; 95% CI, 1.003 to 1.014) and specialists (HR, 1.012 per visit increase; 95% CI, 1.011 to 1.013). Compared to patients with >/=3 MNC in the six months before initiation of dialysis, higher mortality was observed among those with no MNC during the 24 months before initiation of dialysis (HR, 1.51; 95% CI, 1.45 to 1.58), no MNC during the six months before initiation of dialysis (HR, 1.28; 95% CI, 1.20 to 1.36), and one or two MNC during the six months before initiation of dialysis (HR, 1.23; 95% CI, 1.18 to 1.29). CONCLUSION: Nephrology care before dialysis is important, and consistency of care in the immediate six months before dialysis is a predictor of mortality. Consistent nephrology care may be more important than previously thought, particularly because the frequency and severity of CKD complications increase as patients approach dialysis.

Schwenger et al. Late referral–a major cause of poor outcome in the very elderly dialysis patient. Nephrol Dial Transplant (2006) vol. 21 (4) pp. 962-7. (PDF)

Schmidt et al. Early referral and its impact on emergent first dialyses, health care costs, and outcome. Am J Kidney Dis (1998) vol. 32 (2) pp. 278-83. [negative trial] (PDF)

Roubicek et al. Timing of nephrology referral: influence on mortality and morbidity. Am J Kidney Dis (2000) vol. 36 (1) pp. 35-41. [negative trial] (PDF)

Avorn. ( )

Zhao et al. Physician access and early nephrology care in elderly patients with end-stage renal disease. Kidney Int (2008) vol. 74 (12) pp. 1596-602 (PDF)

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Comment on the latest MDRD article and the state of clinical nephro research

Last Thursday in journal club we reviewed the latest data on protein restriction and progression of CKD.

The best summery of the results are provided at the end of the paper:

…a very low-protein diet increased the risk of death in long-term follow-up of the MDRD Study, but had no impact on delaying the progression to kidney failure…

Imagine that the primary results had been different. Imagine for a moment that the MDRD study, rather than being one of the first of the large, NIH-sponsored, negative clinical trials in nephrology, was instead a great success. Imagine that the very-low-protein diets resulted in a delay of dialysis of 20% compared to a low protein diet and that a low-protein diet resulted in a 25% delay in progression compared to a normal-protein diet. Imagine a universe where protein restriction is the ACE inhibitors of our universe.

Now imagine if this most recent analysis came out in that universe. The above quote in this imagined universe would read something like:

…a very low-protein diet increased the risk of death in long-term follow-up of the MDRD Study, despite successfully delaying the progression to kidney failure…

How would we as a nephrology community come to terms with the fact that our primary intervention that we were advocating in a thousand CKD clinics across the land, was actually killing our patients after they start dialysis. Imagine the hand wringing as we start to realize that we were able to delay dialysis from 12 months to 18 months but at the cost of a doubling of their first year mortality from 22% to 40%.

I would be horrified and stop advocating it in my clinic but lots of my patients would adopt the low protein strategy, essentially play the lottery that this radical change in diet would allow them to escape their fate.

We as the nephrology community need to demand better research. This study stands alone (nearly? or completely?) by looking at a pre-dialysis intervention but measuring the outcome in dialysis. This study goes over the wall separating chronic kidney disease research from dialysis research. We need a name for this x-ray vision of looking through the artificial barrier between CKD and dialysis. I propose transitional research.

We need to demand that our CKD research does this. This distinction is less important when looking at CKD 3 where only 1% go on to dialysis; but when looking at CKD4 patients we need to know how that intervention affects dialysis survival. In CKD 4, 18% of patients will end up on dialysis in 5 years. (D. Keith’s data, PDF)

Which of today’s avant garde treatment of CKD results in a doubling of dialysis mortality?

  • Use of active vitamin D to treat secondary hyperparathyroidism
  • Treatment of anemia with ESAs
  • Use of phos binders, calcium based or otherwise
  • Bariatric surgery
  • Aggressive control of blood sugar

None of these “standard” therapies has been examined with an eye on total mortality before and after initiation of dialysis. We need the definitive studies so at some time in the future we don’t have to tell a patient’s family that the pills we have been prescribing may actually have caused the stroke or heart attack or cancer or…

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Journal Club: low protein diet

Effect of a very low protein diet on outcome: long-term follow-up.

This is the long-term follow-up of the B group from the original MDRD study.
Enrollment criteria:
  • Age: 18-70
  • Abnormal Cr 1.2-7 women 1.4-7 in men.
  • MAP of 125 or less (160/100)
  • Proteinuria less than 10g per day
  • No diabetics
GFR 13-24 mL/min for the B study (low protein versus very low protein diet). Higher GFR were enrolled in the A study (normal protein versus low protein diet).
Protein was restricted for 3 years.
9 months after the study every nutritional parameter was the same between the two groups.

The primary end-point was a composite of death or dialysis and just about every patient in both groups (95.7%) reached this end-point preventing a separation between the groups (p=0.5). Likewise there was no separation with regards to time to dialysis (p=0.4).

The surprising finding occurs when they looked at death after the initiation of dialysis. There were 34 deaths in the very low-protein group and 19 deaths in the low-protein group (p=0.01).

The separation begins around 15 months and grows over time. This difference was statistically significant and grew to a 2-fold increased risk of death after 6 years.

My take is this fits well with what I tell my patients when they ask me about protein restriction. I have always counseled patients against protein restriction. The two largest RCT were both negative trials (The Modification of Diet in Renal Disease and the Northern Italian Cooperative Study Group). Additionally my patients do not have the benefit of dedicated and repeated nutritional couseling that the patients in these trials receive. My fear is that with little therapeutic upside there is signifigent risk of malnutrition from overzealous protein restriction.

This study probably does not apply to my worry as I doubt patients would adhere to a very low-protein diet.

My other concearn regarding low-protein diets is patients need to get calories from somewhere. Calories can only come from protein, carbohydrates or fat. Considering that the vast majority of CKD patients are destined to die before dialysis I worry that my advice for protein restriction will result in increased carbohydrates (bad for diabetes and possibly CV disease, see Richard Johnson’s fructose hypertension research) and/or increased fats (bad for CV disease) and enhance the risk of death from the more likely outcome.

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Kidney Stones and Chronic Kidney Disease

One of the biggest stories coming out of Renal Week 2008 was this abstract which linked kidney stones to the development of CKD. This is an important study but I filed it under “no duh.” Patients with kidney stones tend to be heavier, have more hypertension, get episodes of acute renal failure and have repeated instrumentation on the kidneys. They also have gout, and associated hyperuricemia, an increasingly important progression factor for CKD and hypertension.

The most important aspect of this is the question that was left unanswered: do kidney stones cause CKD. The association makes sence but causality would be much more important because we have good tools to prevent kidney stones and it would be wonderful if by preventing kidney stones we could also be preventing future kidney failure.

Hopefully this question will be answered in the near future.

[F-FC202] Kidney Stones Are Associated with an Increased Risk of Developing Chronic Kidney Disease

Andrew Rule, Eric Bergstralh, L. Joseph Melton, Xujian Li, Amy Weaver, John Lieske Nephrology, Mayo Clinic; Health Sciences Research, Mayo Clinic

Background: Kidney stones lead to chronic kidney disease (CKD) in patients with rare genetic diseases (e.g., primary hyperoxaluria), but it is less clear if kidney stones are an important risk factor for CKD in the general population.

Methods: A cohort of all Olmsted County, MN residents with incident kidney stones in the years 1984-2003 were matched 3:1 to controls in the general population based on index date (first stone diagnosis for stone formers and any clinic visit for controls), age, and sex. Diagnostic codes (yrs: 1935-2007) and serum creatinine levels (yrs: 1983-2006) were captured with the linkage infrastructure of the Rochester Epidemiology Project. Risk of incident chronic kidney disease was assessed using clinical diagnostic codes, end-stage renal disease (dialysis, transplant or death with CKD), sustained (>90 days) elevated serum creatinine (>1.3 mg/dl in men, >1.1 mg/dl in women), and sustained estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Proportional hazards models adjusted for age, sex, and baseline and time-dependent co-morbidities (diabetes, obesity, gout, hypertension, hyperlipidemia, alcohol, tobacco, coronary artery disease, heart failure, cerebral infarct, and peripheral vascular disease).

Results: After excluding persons with prevalent CKD, 4424 stone formers and 10995 controls were identified with a mean follow-up of 8.4 and 8.8 years, respectively. Stone formers had an increased risk of developing a clinical diagnosis of CKD [hazard ratio (HR)=1.6, 95% CI: 1.4-1.8, see figure], end-stage renal disease (HR=1.4, 95% CI: 0.9-2.2), a sustained elevated serum creatinine (HR = 1.4, 95% CI: 1.2-1.7), and a sustained reduced eGFR (HR = 1.4, 95% CI: 1.2-1.6).

Conclusions: These data argue kidney stones to be an important risk factor for chronic kidney disease.

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Over collection or just a big guy


A patient came to my office with a creatinine of 2.2 indicating a GFR of 33mL/min by the MDRD formula. 

His primary care doctor ordered a 24 hour urine for creatinine and protein as part of her work-up for CKD:
  • 24-hour urine creatinine was 3,232 mg 
  • 24-hour urine protein was below the level of detection (<183>
To calculate the CrCl multiply the urine cr (total mass, not the concentration) by 100 then divide the product by 1440 (the number of minutes in 24-hours) and then by the serum creatinine (in mg/dl).
  • His CrCl is 102 mL/min
This is a huge discrepancy: 
  • Advanced Stage 3b CKD by MDRD
  • Normal kidney function by 24-hour urine collection
The first thing you should do is determine if the 24-hour urine was an adequate sample. Usually I worry about under-collections of urine due to a missed void or spillage. In this case I worried that an over-collection was masking renal failure.  (i.e. Did he collect his urine for more than 24-hours? Did his wife join in and contribute to the collection?) The average man produces 23 mg/kg of creatinine. The average woman produces 18 mg/kg. I am unaware of the proper figures for children.
His body weight is 123 kg and the 24-hour creatinine collection was 3,232 mg. This yields 23 mg/kg, right on the money for an average adult male.
This is just a big guy and this is where the MDRD can fail us.
Supporting the diagnosis of CKD stage zero was a normal renal ultrasound, a lock of proteinuria and a normal U/A and microscopic exam.

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Patient information: Contrast nephropathy

I am writing some patient information articles to go on our SCSP’s website, scsp.net.

I am including them here as I fine tune them. I have been in contact with Dr. Shah, a nephrologist who has produced some gorgeous patient information booklets that we will be posting online also.

I have heard that getting a dye for a cardiac catheterization or CAT scan can damage my kidneys. Is that true?

Yes. X-ray dye is usually made with iodine and is sometimes called iodinated contrast. The dye allows doctors to see the blood vessels and used when using x-rays to diagnose a number of medical problems. The dye that can damage the kidneys is always given intravenously. Another type of dye is given as a oral liquid. This oral contrast is not harmful to the kidneys.

If you have healthy kidneys the IV dye is almost never harmful; however if you have weak kidneys (chronic kidney disease stage 3, 4 or 5) and especially if you also have diabetes or are also over the age of 65 you are at risk of kidney damage from the contrast.

The kidney damage is called radiocontrast nephropathy. The damage is usually temporary (7-10 days) but sometimes it can cause permanent renal failure requiring dialysis.

There are ways to reduce the risk of developing radiocontrast nephropathy, though even in expert haqnds the risk cannot be eliminated. Protective strategies include:
1. Stopping diuretics
2. Hydrating the patient with saline solution
3. Taking an anti-oxidant called N-acetyl cysteine
4. Reducing the dose of contrast
5. Using a contrast agent with less toxicity

It is important, that if you are at risk of radiocontrast nephropathy and are going to get IV contrast that you notify your nephrologist beforehand so she can coordinate the protective strategy to spare your kidneys.