Overview
Dipstick urinalysis is a simple, noninvasive
test for the detection of proteinuria, often a marker of unsuspected chronic
renal disease. (Other analyses available on multiple dipstick urine tests
are not considered in this review.) There is a strong correlation between
urinary protein excretion and progression of renal failure. Ironically,
patients with chronic renal failure and persistent proteinuria may remain
minimally symptomatic until renal function is severely impaired, with the
eventual need for endstage renal disease (ESRD) management (dialysis or
transplantation). ESRD programs have a significant socioeconomic impact
on our health care system. Unfortunately, effective, nontoxic therapy to
arrest or slow disease progression is not available for most renal disorders,
the exception being insulin dependent diabetes mellitus (IDDM) patients
with proteinuria. Detection of microalbuminuria may be useful in patients
with IDDM but this technique is not readily available in most primary care
settings.
Although the cost of screening the general adult population would be equivalent to the cost of caring for 15 hemodialysis patients for one year, effective nontoxic therapy is not available for most renal diseases detected by dipstick urine testing. Thus, screening is not advocated except in those patients with IDDM.
Burden of Suffering
Over 13,000 patients are on ESRD programs (dialysis
and transplantation) in Canada. An additional 2,000 patients enter dialysis
programs every year, an annual increase of 7%.
The cost of health care incurred through dialysis and transplantation is enormous. The average cost of peritoneal or hemodialysis is $50-58,000 per patient year with lower figures for long-term successful renal allografts. By comparison, the cost of a urine dipstick analysis is approximately 30 cents per test which translates to $7 million if all adults were to be screened in Canada. These fiscal calculations, however, do not take into consideration the diminished quality of life associated with long-term dialysis.
Maneuver
Most commercial dipstick urine tests for protein
use a pH-dependent tetrabromphenol-blue indicator system. Sensitivity and
specificity for proteinuria is between 95 and 99%, the latter reported
in the laboratory setting.
False positives may occur in the presence of gross blood, very alkaline or decomposed urine. False negatives can occur with very dilute, acidic urine or with non-albumin proteinuria (e.g. tubular or light chain proteinuria). False negatives will mislabel patients as being normal with consequent failure to detect the renal disease and loss of the opportunity to treat comorbid disease that may accelerate progression to ESRD.
Eleven studies of both general and specialised adult populations were reviewed.<1-11> In all of these studies, not all patients who were found to have persistent proteinuria underwent the gold standard test (usually a renal biopsy). Thus, the positive predictive values (0-68%) likely represent an underestimate of the true prevalence of renal disease.
All patients who had persistent non-orthostatic proteinuria were designated as having "possibly significant renal disease" for the purpose of this review in order to give an overestimate of those with underlying renal disease at risk for developing ESRD. This gave an overall positive predictive value of 30% with a range of 6 to 70% depending upon the population under study.
A suggested algorithmic workup for those found to have dipstick positive proteinuria (³0.3 g/L) is presented in Figure 1. It should be noted that proteinuria itself may not actually represent a primary renal disorder. Proteinuria can be detected in patients with underlying cardiovascular diseases (e.g. chronic congestive heart failure) in the absence of an underlying primary renal disorder. Proteinuria in these clinical settings is likely not benign – a re-analysis of data from the Framingham study has demonstrated that dipstick positive proteinuria was associated with a higher mortality risk from cardiovascular disease. Although urine dipstick screening in the general adult population could provide another window of opportunity to screen for and modify cardiovascular risk factors in the general population, no study has yet addressed this issue.
Effectiveness of Prevention and
Treatment
Those who are found to have significant disease
are offered interventions to either arrest (in some cases, reverse) the
disease process (designated forthwith as "specific" renal therapy) or slow
the progression of the disease to ESRD ("nonspecific" renal therapy). Most
studies to date have focused on nonspecific therapy to retard progression
to ESRD. The paucity of specific therapy is largely due to the lack of
understanding of the mechanisms for the initiation and progression of most
renal diseases.
Specific therapy may be efficacious in the following disorders which can present with proteinuria (listed with their relative percentage contribution to ESRD in Canada): renovascular disease (6%); vasculitis and other treatable forms of glomerulonephritis (18%); tubulointerstitial disorders, including reflux nephropathy (8%); specific long-term infections of the urinary tract (tuberculosis, schistosomiasis) (<1%); and urinary tract tumors (<1%). Controlled clinical trials demonstrating the efficacy of treatment have been reported only for reflux nephropathy,<12> chronic urinary tract infections<13> and some forms of chronic glomerulopathies.<14,15> Consultation with a nephrologist or urologist is advised in specific cases as therapeutic measures vary depending upon disease severity and the presence of comorbid conditions.
Diabetes accounts for approximately one quarter of the ESRD population in Canada. Specific therapy is not available to reverse established diabetic renal disease associated with persistent proteinuria. Antihypertensive agents, most notably angiotensin-converting enzyme inhibitors, have been shown to slow the progression to ESRD in patients with IDDM associated with proteinuria.<16-19> The recent Collaborative Study Group trial demonstrated that patient and renal mortality were significantly lower in those treated with captopril as compared to placebo over a 3.5 year follow-up period.<16> It should be noted that proteinuria can be detected earlier in the disease course (microalbuminuric stage) by more sensitive methods of protein excretion.<20> Early studies have shown benefit to treating IDDM patients at this stage with angiotensin-converting enzyme inhibitors.<21,22> Lack of wide availability of the detection method for microalbuminuria and lack of large long-term studies showing benefit of treatment makes this technique impractical for screening purposes.
A recent case-control study has suggested a benefit to the use of angiotensin-converting enzyme inhibitors in non-insulin dependant diabetes mellitus (NIDDM).<23> This has yet to be shown in a prospective blinded, controlled trial.
Small prospective trials have also shown a benefit of angiotensin-converting enzyme inhibitors in retarding progression to ESRD in various proteinuric disorders of non-diabetic etiology.<24,25> These studies have used surrogate outcome measures (rate of decline in kidney function). Moderate increases in serum potassium have been noted in some patients treated with the use of these agents.<24> They cannot be widely recommended for treatment at this time.
Systemic hypertension is prevalent among patients with chronic renal failure and has been suggested to accelerate the rate of progression to ESRD. Although several uncontrolled trials<26-28> suggest a benefit to blood pressure control in patients with mild to moderate hypertension associated with chronic renal failure, this has not been definitively demonstrated in a prospective controlled trial.<29> Data from large hypertension trials<30-38> looking at cardiovascular mortality as the primary outcome of interest, have suggested either no benefit or worse outcome for renal mortality in those with better blood pressure control. ESRD however, was not the outcome of interest. Although accelerated or malignant hypertension associated with renal failure has been shown to benefit from aggressive blood pressure control, this comprises a very small proportion of the hypertensive population in North America.<39>
Present nonspecific treatment in all forms of renal diseases to prevent progression to ESRD focuses on dietary protein restriction. There is good evidence to suggest that moderate protein restriction retards the rate of progression to ESRD<40> but its safety and long-term compliance have not been demonstrated (this question is the subject of the recently completed Modification of Diet in Renal Disease trial). Most trials have studied patients with moderate to advanced renal failure (glomerular filtration rate of 15-50 cc/minute) but a trend toward benefit has been observed in studies that included patients with mild renal failure.<41>
Recommendations of Others
A recommendation not to screen the general population
is in keeping with previous Task Force recommendations, as well as those
of Frame and Carlson<42> and the U.S. Preventive Services Task Force.<43>
Conclusions and Recommendations
A successful screening program is predicated
on the principle that efficacious, nonharmful treatment is available early
in the disease course. We thus do not recommend dipstick screening for
proteinuria in the general adult population for the prevention of endstage
renal disease (D Recommendation). Exceptions to this recommendation are
IDDM patients as good recent evidence shows a benefit of therapy in early
asymptomatic disease associated with proteinuria. (A Recommendation)
Unanswered Questions (Research
Agenda)
Large clinical trials are needed to investigate
the safety and effectiveness of angiotensin-converting enzyme inhibitors
and other antihypertensive agents in non-diabetic progressive renal disease.
Further basic science research is needed to elucidate mechanisms of initiation
and progression of renal disease in order for new therapies to be developed.
Evidence
The literature was identified with a MEDLINE
search for the years 1966 to December, 1992 using the following key words:
evaluation studies, proteinuria, population studies, prospective studies,
screening, protein restriction, hypertension, kidney disease, antihypertensive
agents, diabetes mellitus and diabetic nephropathy.
This review was initiated in January, 1993 and the recommendations finalized by the Task Force in June, 1993. A draft technical report (1993) with a full reference list is available upon request.
Acknowledgements
Assistance was provided by Drs. David Churchill,
FACP, ABIM (Nephrol), FRCPC, Professor, McMaster University, Hamilton,
Ontario; and Stanley SA Fenton, MD, MB, BCh, BAO, FRCP(Ire), Associate
Professor of Medicine, University of Toronto, Toronto, Ontario, in providing
cost analyses of dialysis in Canada. The authors thank Lorraine Rosendall
for the preparation of the manuscript and Patrick S. Parfrey, MD, FRCPC,
FACP, Professor of Medicine, Memorial University of Newfoundland, St. John’s,
Newfoundland for reviewing the draft report.
Full Citation
Nagai R, Wang EEL and Feldman W. Dipstick proteinuria
screening of asymptomatic adults to prevent progressive renal disease.
In: Canadian Task Force on the Periodic Health Examination. Canadian
Guide to Clinical Preventive Health Care. Ottawa: Health Canada,
1994; 436-45.