Striker,. Director. KUHP NIDDK, Bethesda,. MD. S everal large clinical trials on the management/ prevention ofprogresslve renal disease have been published.
Report on a Workshop To Develop Management Recommendations for the Prevention of Progression Chronic Renal Disease Gary
S
Striker,
everal
Director
large
KUHP NIDDK,
clinical
Bethesda,
MD
on the management/ prevention ofprogresslve renal disease have been published within the last year (1-4). Three relate to diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) and a fourth relates to renal disease of diverse causes (excluding IDDM). Those studies show that the incidence of chronic renal disease can be decreased by approximately 50%, that the rate of
trials
progression of proteinuria can be decreased by a similar percentage, and that these favorable results also apply to those with advanced nephropathy. Thus, for the first time, It has been conclusively shown that chronic progressive renal disease Is amenable to both
prevention and treatment. There had not been a consensus as to the Implications ofthese studies for general patient care. For this reason, a conference was held on April 4-5, 1994, for the purpose of developing practical management recommendations. eral panels
The
conference
was
composed
of sev-
of nephrology experts drawn from around the world. The panels reviewed the extant literature, heard presentations on the published studies, and reviewed manuscripts in press from secondary analyses of the MDRD data. The panels developed initial recommendations and presented them to an audience ofover 150, who provided a critique of the recommendations. A draft final recommendation report was then read to the audience participants for final comments. The final recommendations were agreed on and are the subject of this report. A.
Recommendations gressive Nephropathy
for
the
Prevention with
in Patients
in
of ProDiabetes
Mellitus 1 To prevent and delay the progression of complications, including nephropathy, intensive control of blood sugar Is recommended in all patients with type I diabetes meffitus. The goal should be to maintain a blood sugar within, or close to, the normal range while minimizing hypoglycemic attacks. These goals frequently require three or more insulin injections per day or the use of an insulin pump, with monitoring of blood glucose concentrations up to four times per day.
at high risk for the development of other microvascular and macrovascular complications. Although a formal evaluation has not been cornpleted, in the interim, patients with IDDM for more than 5 to 10 years and/or a family history of renal disease or hypertension should be screened annually for microalbuminurla. 3. Irrespective of other forms of therapy, providing there are no contraindications (see below), angiotensin-converting enzyme inhibitor (CEI) therapy should be Initiated in patients with IDDM who have one or both of the following: persistent microalbuminurla (30 to 300 mg/day or 20 to 200 pg/mm) on at least two of three measurements, or overt alburninuria (>300 mg/ day). CE! therapy should be titrated to achieve a maximal effect on albuminuria measured every 1 to 3 months; also, CE! therapy should be used as part of a hypertensive regimen if patients have hypertension (blood pressure > 130/85 mm Hg). 4. Pregnancy or preexisting hyperkalernia are absolute contraindications to CEI therapy. There are also relative contraindications that must be considered (see manufacturers’ recommendations).
5. Shortly after starting CE! therapy, serum creatinine and serum potassium should be monitored to detect patients who develop hyperkalemia or an abrupt reduction in GFR. Significant changes in clinical status (such as dehydration and intercurrent illness) and changes in renal function or therapy call for the close monitoring of serum potassium and creatinine.
.
2. Microalbumlnuria marker of nephropathy
Journal of the American
Society
is the and
best available early designates patients
of Nephrology
6. For patients with non-insulin dependent diabetes (NIDDM) who are normotensive and have only microalbuminurla, there Is presently insufficlent data to determine whether CE! therapy has a specific role in preventing progression. However, CEI therapy (as outlined above) may be considered in patients with type II diabetes mellitus who have hypertension or albuminuria (>300 mg/day), pending further information. 7.
Although
there
young children and I diabetes mellitus,
is
limited
young CE!
information
adolescents therapy
with should
in
type be
1537
Special
Articles
considered with appropriate adjustin dose according to age and size If one or of the following are present: microalbuminui-ia (> 15 gig/kg per hour); overt proteinuria (>4 mg/kg per day); changes in renal function as indicated by a significant change of serum creatinine, a decrease in GFR (95th percentile for
mendations for children and adolescents. However, If dietary therapy Is to be undertaken, consideration may be given to starting dietary modification at an earlier stage in pediatric patients with forms of renal disease that are known to progress. Protein intake should be targeted to a minimal recommended daily allowance for the patient’s age, and a behavioral model similar to that developed in the MDRD study should be modified appropriately for children and their families.
strongly
ments more
age.
B.
Recommendations sive
Renal
for Insufficiency
Prevention
of
in nondlabetic
Progres-
Blood
Patients
pressure
management
1 Hypertension should be controlled in patients with chronic renal failure to the level suggested in Joint National Commission (JNC) V (equlvalent to 130/80 to 85 mm Hg). .
Nutritional Management 1. NutrItional status should be monitored regularly, regardless of the level of protein intake prescribed, to ensure that patients do not become malnourished. This can be guided by maintaining both body weight and the concentrations of serum albumin (>4 g/dL) and transferrin (>200 mg/dL). Patients who lose weight may require an increase in energy intake from 25 to 30 to 35 kcal/kg per day. Third-party payment for nutritional services (excluding parenteral nutrition) may be justified on the grounds that adequate attention to nutrition can avoid many of the ravages and costs of end-stage renal dis-
2. In and mean to 92 those blood ease)
3. Although current studies suggest that CE! may be the most effective antihypertensive drugs for reducing proteinuria, this conclusion awaits studies with other agents. CE! may be the best choice for slowing the progression ofrenal failure in patients with chronic renal disease and proteinuria of greater than 3 g/24 h.
ease.
2.
For
patients
with a moderate loss of renal 25 to 55 mL/mln per 1.73 m2), the evidence that the prescription of a low-protein diet slows the progression of renal failure is function
(GFR,
Inconclusive. Until available from further MDRD or data from protein intake should
definitive
Information
appropriate.
3.
For
patients
with more severe loss of renal 13 to 25 mL/mln per 1.73 m2) who adhere to a diet containing 0.6 g of protein/kg per day, the rate ofloss of renal function Is reduced and the time to reach end-stage renal disease is prolonged. Moreover, dietary protein restrIction delays the onset of the uremic synfunction
(GFR,
drome.
4. A behavioral management that used in the MDRD study to ensure optimal adherence diet. 5. Nephrologists the assessment trogen
6.
1538
should of protein
mode! similar to should be followed to the prescribed
become intake
famifiar from
with urea
iii-
appearance.
No data
are available
to make
specific
4. For children, the blood pressure goal should be a reduction to less than 90% of the average value for age. For children with proteinuria greater than 1 .7 g/ 1 .73 m2 per 24 h, blood pressure should be reduced further to the mean value for the age.
is
subgroup analyses of the other studies, a standard be prescribed (>0.8 g/kg per day). If there is evidence of progression of renal insufficiency or the development of uremic symptoms, an intake of 0.8 g/kg per day Is
recom-
patients with chronic renal insufficiency proteinuria of greater that 1 g/24 h, the blood pressure should be reduced further, mm Hg (equivalent to 125/75 mm Hg) for in whom contraindications to such a low pressure level (e.g., cerebrovascular disare absent.
C.
Recommendations Groups of Nondlabetic sufficiency.
for
Management Patients
with
of Special Renal In-
African-Americans 1 Because there Is an excess incidence of endstage renal disease due to hypertension in Air!can-Americans, a major effort should be made to control hypertension, especially in those with evidence of renal disease, reduced renal function, or proteinurla. .
2. Hypertension should be controlled in patients with chronic renal failure to the level recommended in JNC V (equivalent to 130/80 to 85 mm Hg). 3. Until additional Information able from the NIH study Study of Kidney Disease and target mean arterial pressures
Volume
becomes avail(African-American Hypertension), the should be re-
5
‘
Number
7
‘
1995
Striker
in blood fluence thereby changes patients
pressure, or dietary protein Intake Intubular creatinine secretion and creatinine clearance, Independent of In GFR. Therefore, clinical decisions In that are based on changes in plasma creatinine, the reciprocal of plasma creatinine, or creatinine clearance should be made with caution, especially in the context of recent changes in nutritional status or medications. Nevertheless, once the patient is stable, changes in renal function can be assessed reasonably accurately from serial changes in serum creatinine concentration.
duced to less than 92 mm Hg (equivalent to 125/75 mm Hg) in those with chronic renal failure and proteinurla greater than 1 g/24 h. At present, these recommendations appear to be safe and beneficial. 4. There Is at present no clear evidence that one class of antihypertensive agents Is superior. Therefore, recommendations should await further studies. 5. Adequate
concerning the optimal manand renal failure during childhood and adolescence are lacking at present. However, blood pressure should be controlled to less than 90% of the average value for age and size in patients with renal insufficiency and/or sustained hypertension. agement
data
ofhypertenslon
Dominant Polycystic Kidney Disease (ADPKD) 1 Because the prescription of a protein-restricted diet in the MDRD study did not modify the progression of renal disease in ADPKD patients with a GFR of less than 55 mL/mln per 1 .73 m2, they should be allowed their customary level ofprotein intake (average 1.3 g/kg per day), except as required to prevent or treat symptoms of uremia.
3. Ideally, major changes In serum creatinine concentration or creatinine clearance, especially at the time of a planned change in therapy, should be followed by a verifiable measurement of GFR. The GFR measurement is best conducted by a nephrologist with an appropriate understanding of kidney physiology.
Autosomal .
E.
3.
Other
measures the
that
management
include: avoiding trauma, or urinary the prompt treatment lipophific
D.
have been reported to of patients with ADPKD hypokalemla, abdominal tract instrumentation and of renal infections with
for
Measurement
of Renal
Function. 1 The evaluation trials ofprogresslve the measurement
of renal function In clinical renal disease should rely on of GFR with inulln or iothalamate. However, time to doubling of serum creatinine or time to renal failure was used in a study of !DDM patients with advanced nephropathy. .
2. Although measurements of creatinine clearance can be performed as part of an assessment of renal function, It consistently overestimates the GFR by an average of 30% in whites. Moreover, a variety of factors such as drugs, changes
Journal of the American
Society
of Nephrology
total and left intake to diet; and
.
ventricular
achieve
hypertrophy;
electrolyte
a low-sodium/high-potassium
nutritional
status.
2. Smoking should pecially in diabetics cular disease.
be strongly with
discouraged,
hypertension
F.
Follow-up
esor
3. Targeted professional community should be developed to Improve the tion and management of hypertension.
early
vas-
projects detec-
Conferences
Regular updates be developed. CHAIRS OveraW
of these
(Bethesda,
H. Jacobson
recommendations
will
TN), G. Eknoyan (Houston, TQ, W. Mitch (Atlanta, GA), C. Wilcox (Washington, DC); Committee: D. Auslello (Boston, MA), R Blantz (San Diego, CA); G. Eknoyan (Houston, TX; T. Ferris (Minneapolis, MN); R. Glassock (Lexington, KY); J. Grantham (Kansas City, KS); W. Keane (Minneapolis, MN); R. Luke (Cincinnati, OH); D. Salant (Boston, MA); R. Schrler (Denver, CO). Striker
antibiotics.
Recommendations
Points
1 Other risk factors to be controlled: high and high-density lipoprotein cholesterol, hemoglobin A1C1; obesity/underactivity;
2. Lowering the target mean arterial pressure to 92 mm Hg in the MDRD study did not alter the progression of renal disease in ADPKD patients with a GFR ofless than 55 mL/m!n per 1.73 m2. Therefore, mean arterial pressure should be controlled at the JNC V recommended level (equivalent to approximately 130/80 to 85 mm Hg) to prevent cardiovascular morbidity and mortality.
benefit
Other
MD);
(Nashvffle,
Section:
G.
COMMITTEE MEMBERS T. Andreoli (Little Rock, AR); G. D’Amlco (Milan, Italy); I. Griefer (New York, NY); J-P. Grunfeld (Paris, France); J. Herrera-Acosta (Dallas, TX;
(New
York,
Kurtzman
S. Massry
(Mexico City, Mexico); Kahn (Alexandria, VA);
A.
Hull
S. King NY); K. Kurokawa fl’okyo, Japan); N. (Lubbock, TX); L. LI (Nanjing, China); (Los Angeles, CA); C. Mogensen (AarR
1539
Special
Articles
hus, Ritz, CA);
don,
Copenhagen); M. Molitch (Chicago, (Heidelberg, Germany); J. Roberts P. Ronco (Paris, France); D. Williams England).
IL); E. (Chico, (Lon-
on the development and progression of long-term plications in Insulin-dependent diabetes mellitus. ,.I Med 1993:329:977-986. 3. Bojestlg M, Arnqvist LU, Hermansson Ludvigsson J: Declining incidence
insulln-dependent
REFERENCES 1. Lewis E, Hunsicker I,, Bain angiotensin-convertlng-enzyme nephropathy.
2. DCCT Research
1540
N Engl
J Med
Group:
R, Rohde
R: The
inhibition 1993;329:
on
effect
diabetic
1456-1462.
The effect of intensive
treatment
of
diabetes
cornN Engl
BE,
G, Karlberg
of nephropathy
mellitus.
N Engl
in
J Med
1994;
330:15-18. S, Levey A, Beck G, Cagglula A, Hunsicker 1,, J, Striker G, and the MDRD Study Group: The of dietary protein restriction and blood pressure on the progression of chronic renal disease. N Med l994;330:877-884.
4. Klahr Kusek effects control Engl J
Volume
5
.
Number
7
‘
1995
