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Malignant Nephrosclerosis

Fahr Volhard Disease

In general, the term nephrosclerosis describes a chronic vascular disorder that may eventually lead to renal failure. Benign and malignant nephrosclerosis differ in the rate of progressive hardening of renal arterioles.


Presentation

Patients suffering from malignant NS usually present with very high blood pressure or malignant hypertension. According to a retrospective study comprising 87 patients, mean systolic and diastolic blood pressures were 213 and 138 mm Hg, respectively [10]. Such high blood pressure may be accompanied by visual impairment, headaches, an altered mental status, nausea and vomiting. Chest pain and dyspnea may be very intense.

Some of the aforementioned symptoms may also be induced or exacerbated by uremia. Furthermore, this kind of intoxication is often associated with generalized pruritus. Some patients may experience seizures or show reduced awareness. They usually smell like urine (uremic fetor).

Dry Cough
  • ACE inhibitors may lead to chronic dry cough. What happens after treatment for the disease? A person who has malignant hypertension needs to continue taking the prescribed medications every day.[medicineonline.com]
Recurrent Abdominal Pain
  • He had a history of recurrent abdominal pain associated with periodic fevers above 38 degrees that resolved within three days.[ncbi.nlm.nih.gov]
Hematochezia
  • Haug Browse recently published Learning/CME Learning/CME View all learning/CME CME Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis Case 4-2019: An 18-Year-Old Man with Abdominal Pain and Hematochezia Bridging the Gap Challenge Yourself[nejm.org]
Cotton Wool Spots
  • An eye examination will reveal changes that indicate high blood pressure, including papilledema (swelling of the optic nerve), retinal bleeding, or infarction (cotton wool spots or soft exudate -- fluid with cellular debris) in the retina .[medical-dictionary-search-engines.com]
Kidney Failure
  • Malignant hypertension is usually accompanied by other organ damage like heart failure, kidney failure, and hypertensive encephalopathy.[medical-dictionary-search-engines.com]
  • Kidney failure may develop, which may be permanent and need dialysis (kidney machine). If treated right away, malignant hypertension can often be controlled without causing permanent problems.[kentuckyonehealth.org]
  • failure, as well as other complications, may develop.[stlukes-stl.com]
  • Kidney failure may develop, which may be permanent. If this happens, you may need dialysis (machine that removes waste products from blood). If treated right away, malignant hypertension can often be controlled without causing permanent problems.[medlineplus.gov]
Uremic Fetor
  • They usually smell like urine (uremic fetor). Assessment of renal function is based on laboratory analysis of blood and urine samples.[symptoma.com]

Workup

Assessment of renal function is based on laboratory analysis of blood and urine samples. In detail, hematocrit, total protein, serum creatinine and urea as well as electrolyte levels provide ample information about the condition of the kidneys. Further parameters should be evaluated to identify possible comorbidities that contribute to hypertension and cardiovascular disorders. These include a complete lipid profile and a blood glucose level. With regards to urine samples, proteinuria and increased albumin-to-creatinine ratio indicates renal damage. Urinary protein excretion often nears or exceeds 1 g/d [10]. Of note, these tests are also well-suited to evaluate disease progression and response to therapy during follow-up.

Confirmation of malignant NS requires histopathological analysis of a renal biopsy. Myo-intimal cell proliferation, intimal fibrosis and hyalinization are common, yet not specific findings in malignant NS. They may also be observed in case of chronic hypertension. In contrast, fibrinoid necrosis has been reported to be diagnostic in Blacks [11]. Severe alterations of vessel structure are readily detectable in afferent arterioles and also explain micro-hemorrhages that may be observed in those areas. The descriptive term onion-skin vessel is sometimes used to illustrate the appearance of renal vessels in NS patients.

Additional diagnostic measures, e.g., echocardiography and electrocardiography, may be carried out to further evaluate comorbidities.

Creatinine Increased
  • Damage to the kidneys may be demonstrated by: BUN increase Creatinine increase Arterial blood gas analysis showing metabolic acidosis Urinalysis showing high proteinlevels (especially with kidney impairment) or microscopic blood in the urine) A chest[medical-dictionary-search-engines.com]

Treatment

Although renal damage may be irreversible at the time of diagnosis, rigorous control of underlying diseases may considerably delay disease progression and thus improve outcome. This particularly applies to hypertension, but is not less important in case of hypercholesterolemia, hyperlipidemia, and diabetes mellitus.

With respect to antihypertensive therapy, calcium channel blockers, angiotensin-converting-enzyme inhibitors, diuretics, beta-blockers and angiotensin receptor blockers may be applied. It has been shown that blood pressure reduction by 20 to 30 mm Hg significantly favors resolution of pre-existing renal damage and delays disease progression to ESRD [2]. In most cases, two or more drug families are combined to reduce blood pressure. Calcium channel blockers and angiotensin-converting-enzyme inhibitors are most commonly prescribed. The former additionally cause dilatation of the afferent arterioles; the latter inhibit fibrotic remodeling processes.

In case of ESRD, dialysis is indicated until an organ transplant can be provided.

Prognosis

Patients suffering from malignant NS have a high risk of developing ESRD, with dialysis and organ transplantation being the only long-term options for survival. If concomitant hypertension is not adequately controlled, the risk of life-threatening cardiovascular and cerebral accidents increases and further diminishes life expectancy. In sum, 5- and 10-year survival rates of 85 and 70% have been reported [8] [9].

Etiology

In any case, hypertension is considered a major risk factor for NS - if not for the induction of the disease, then at least for its progress. The fact that large parts of the population suffer from hypertension for decades without developing renal lesions or ESRD prompted studies to assess whether the severity of hypertension or additional factors contributed to NS pathogenesis. According to current knowledge, both assumptions are true, but their relative importance in malignant NS is still a matter of debate.

Presumably, malignant hypertension; systemic hypertension surpassing a certain threshold, disables renal autoregulatory mechanisms that normally prevent vascular and glomerular lesions. This may be referred to as the critical blood pressure threshold [2], but there is no general consensus regarding the precise cut-off point.

On the other hand, elevated prevalence among Blacks supports the hypothesis of NS being a genetic vascular disorder followed by hypertension. Genotyping of affected individuals revealed a possible link between MYH9-APOL1 gene variants and NS. These are neighboring genes; the corresponding locus is situated on chromosomal position 22q12 and has also been related to several other forms of chronic kidney disease. Interestingly, the APOL1 variant predisposing for chronic kidney disease confers protection against a lethal form of African trypanosomiasis. Selective pressure for maintenance of this gene variant thus only exists in West Africa, which explains why it is preferentially found in Blacks [3].

Of note, MYH9 encodes for heavy chain 9 of non-muscle myosin IIA; APOL1 encodes for apolipoprotein L1, a minor component of high-density lipoproteins. It is not yet clear how any of those two proteins might contribute to renal damage.

Epidemiology

Hypertension is one of the most common causes of ESRD, with higher incidence rates only reported for diabetic nephropathy in Caucasians. Blacks are even more susceptible to hypertension and its sequelae [4].

Owing to the high prevalence of high blood pressure, it has been estimated that the majority of patients aged 60 years and older does present some degree of hypertension-induced renal damage. Fortunately, benign NS is much more common than malignant NS. It has been estimated that hypertension leads to ESRD in 1 out of 6,000 or 2,000 hypertensive patients in Europe and the United States, respectively [5]. Epidemiological data cannot be provided for African countries, but the higher risk of severe renal complications in the United States may result from a greater share of the Black population.

Besides the racial predilection described above, males seem to be more frequently affected than females [6]. Any pre-existing cardiovascular or renal disease increases the individual risk of malignant NS.

Sex distribution
Age distribution

Pathophysiology

Changes in blood pressure are largely physiologic and renal autoregulatory mechanisms strive to maintain the glomerular filtration rate (GFR) and blood pressure within a healthy range. However, if blood pressure exceeds a determined level or if the anatomic structures involved in those mechanisms are damaged, autoregulation is no longer helpful, and the results are detrimental.

Urinary sodium and chloride concentrations are constantly measured by cells of the macula densa, which, in turn, signal to adjacent renin-producing juxtaglomerular cells. Under physiological circumstances, enhanced sodium and chloride concentrations result from the inability to reabsorb these ions in the proximal convoluted tube and loop of Henle, and this happens if the GFR is increased. In order to reduce the glomerular filtration rate and to prevent excess loss of electrolytes and tubular overloads, afferent arterioles need to constrict and blood pressure has to be diminished. So as to achieve the latter, a reduction of renin release and thereby an inhibition of the renin-angiotensin-aldosterone system is mediated. Consequently, the GFR decreases and blood pressure normalizes to lower levels.

In contrast, if macula densa cells sense low sodium and chloride concentrations, pathways are activated that stimulate renin release and activate the renin-angiotensin-aldosterone system. Here, an increase in blood pressure shall provoke an enhanced GFR and improve kidney function.

Unfortunately, this last described mechanism is still effective if the GFR is reduced due to pathological alterations of renal blood flow, and these events lead to renal hypertension. In fact, renal hypertension is what causes disease progression in NS. Moreover, it seems plausible that patients suffering from malignant hypertension and systolic blood pressure that repeatedly exceeds 210 mm Hg sustain more severe and rapid renal damage.

However, the pathogenesis of renal hypertension in NS is not completely understood. NS may be the consequence of chronic hypertension, particularly in patients who are more sensitive to blood pressure alterations and who show a tendency to arteriolosclerosis. Alternatively, primary renovasculopathies may provoke a permanent reduction of blood flow through some glomeruli, what results in an overall reduced excretion of sodium and chloride, an increase in the gradient between urine and blood and thus sensation of "low sodium and chloride concentrations". According to the above described mechanisms, this may cause chronic hypertension and pathologic remodeling of the remaining nephrons. Both pathogenic mechanisms are not mutually exclusive and may simultaneously contribute to progressive hardening of afferent and glomerular vessels. Of note, the observation of focal segmental glomerulosclerosis does not necessarily indicate a primary renal disease [7].

Prevention

According to current knowledge, severe hypertension and genetic predisposition equally contribute to the onset of malignant NS. Preventive measures can only be taken with regards to the former and mainly consist of strict regulation of hypertension, or preferably, avoidance of pathological increases in blood pressure. Maintenance of a healthy balanced diet, together with prevention of overweight and obesity, are easily implemented measures to that purpose.

Summary

In blood vessels that are continuously exposed to high blood pressure, remodeling processes take place that include replacement of smooth muscle cells with connective tissue and hyalin, loss of elasticity, and progressive reduction of their lumen. Because arteries and, in decreasing order, arterioles and capillaries are more severely affected by systemic hypertension than venous vessels, the pathophysiological events mainly take place in arteries. If the kidneys are affected, the respective patient is diagnosed with nephrosclerosis (NS).

Hypertension plays a major role in NS pathogenesis and it is well known that hypertension contributes to renal damage and vice versa, thus leading into a vicious circle. However, considerable knowledge gaps remain concerning the starting point of that circle in case of NS. It is not clear whether NS results from systemic hypertension or provokes increases in blood pressure [1].

Two types of NS have been distinguished; benign and malignant nephrosclerosis. While similar processes occur in both diseases, the latter progresses much more rapidly than the former. Benign NS may cause end-stage renal disease (ESRD), particularly if the affected individual is genetically predisposed. Malignant NS does provoke ESRD and is much less dependent on a patient's genetic susceptibility [2].

Clinical presentation is generally marked by hypertension-induced symptoms and progressive renal failure. In this context, visual impairment, headaches, nausea, vomiting, altered mental state, reduced awareness, as well as further signs of uremia may be present. While preliminary data and the results of laboratory analyses of blood and urine samples may prompt a strong suspicion of malignant NS, a renal biopsy is required to confirm that diagnosis.

Treatment aims at normalizing blood pressure and impeding the progress of renal damage.

Patient Information

In general, the term nephrosclerosis (NS) refers to a chronic kidney disease that may eventually lead to renal failure. NS is usually associated with very high blood pressure and preferentially affects Blacks. The latter presumably results from genetic disposition of people pertaining to that race.

The precise causes of NS are not completely understood. In detail, it is not clear whether NS results from systemic hypertension or provokes increases in blood pressure. Presumably, both mechanisms contribute to renal damage. If renal arterioles, i.e., small vessels supplying blood to the kidneys that needs to be filtered, are continuously exposed to high blood pressure, remodeling processes take place in their walls, they harden, lose elasticity, and their lumens narrow. Reductions of blood flow cause the kidneys to stimulate the renin-angiotensin-aldosterone system, which ultimately causes a further increase in blood pressure.

Some people suffer from hypertension for decades without developing renal disorders and if their kidneys show nephrosclerotic lesions, they are generally mild. In a minor share of patients, the disease does progress rapidly. These patients are diagnosed with malignant nephrosclerosis.

In order to interrupt the above described vicious circle, hypertension needs to be strictly controlled. In fact, antihypertensive therapy is the mainstay of nephrosclerosis treatment, and should be initialized before irreversible renal damage occurs. If nephrosclerosis progresses to end-stage renal disease, dialysis and kidney transplantation are the only therapeutic options available.

References

Article

  1. Meyrier A. Nephrosclerosis: a term in quest of a disease. Nephron. 2015; 129(4):276-282.
  2. Griffin KA, Polichnowski A, Litbarg N, Picken M, Venkatachalam MA, Bidani AK. Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model. Hypertension. 2014; 64(4):801-807.
  3. Rosset S, Tzur S, Behar DM, Wasser WG, Skorecki K. The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus. Nat Rev Nephrol. 2011; 7(6):313-326.
  4. Hughson MD, Puelles VG, Hoy WE, Douglas-Denton RN, Mott SA, Bertram JF. Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race. Nephrol Dial Transplant. 2014; 29(7):1399-1409.
  5. Luke RG. Hypertensive nephrosclerosis: pathogenesis and prevalence. Essential hypertension is an important cause of end-stage renal disease. Nephrol Dial Transplant. 1999; 14(10):2271-2278.
  6. Ogeng'o JA, Gatonga P, Olabu BO, Ongera D. Pattern of hypertensive kidney disease in a black Kenyan population. Cardiology. 2011; 120(3):125-129.
  7. Kim JS, Han BG, Choi SO, Cha SK. Secondary Focal Segmental Glomerulosclerosis: From Podocyte Injury to Glomerulosclerosis. Biomed Res Int. 2016; 2016:1630365.
  8. González R, Morales E, Segura J, Ruilope LM, Praga M. Long-term renal survival in malignant hypertension. Nephrol Dial Transplant. 2010; 25(10):3266-3272.
  9. Amraoui F, Bos S, Vogt L, van den Born BJ. Long-term renal outcome in patients with malignant hypertension: a retrospective cohort study. BMC Nephrol. 2012; 13:71.
  10. Liang S, Le W, Liang D, et al. Clinico-pathological characteristics and outcomes of patients with biopsy-proven hypertensive nephrosclerosis: a retrospective cohort study. BMC Nephrol. 2016; 17:42.
  11. Isaacson C, Milne FJ, van Niekerk I, Kenyon MR, Mzamane DV. The renal histopathology of essential malignant hypertension in black South Africans. S Afr Med J. 1991; 80(4):173-176.

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Last updated: 2019-07-11 20:34